Courses Of Antenatal Corticosteroids Research Articles

Long-term cognitive benefits of antenatal corticosteroids for prematurely born children with cranial ultrasound abnormalities

Objective: Previous studies have examined possible long-term effects of antenatal corticosteroids, but not by the presence of neonatal brain lesions. This study of long-term neurodevelopmental outcomes of antenatal corticosteroid exposure among preterm, very-low-birth-weight infants investigated whether the effects are differential by the presence of neonatal brain injury. Study design: Prospective cohort study of cognition, behavior, and cerebral palsy in 251 children (ages 6-8 years) born at ≤32 weeks of gestation. This sample included 91 children with abnormal neonatal cranial ultrasound findings and 106 children who had been exposed to antenatal corticosteroids. Results: In children with abnormal cranial ultrasound findings, a complete course of antenatal corticosteroids was associated with an 8.7-point advantage in IQ (95% CI, 1.8, 15.6; P = .016), controlling for confounding factors. Both verbal and nonverbal cognitive scores were increased in a dose-response manner. The advantage was greater for infants born at ≤28 weeks of gestation and in those with ventriculomegaly. In children with normal cranial ultrasound scans, cognitive function was not related to antenatal corticosteroid exposure. No statistically significant associations were observed between antenatal corticosteroid exposure and either childhood behavioral scores or cerebral palsy. Conclusion: Antenatal corticosteroids appear to confer substantial long-term benefits on cognition of very-low-birth-weight infants with cranial ultrasound abnormalities. (Am J Obstet Gynecol 2002;186:818-25.)

Single Versus Multiple Courses of Antenatal Corticosteroids

Single Versus Multiple Courses of Antenatal Corticosteroids

Single vs Weekly Courses of Antenatal Corticosteroids for Women at Risk of Preterm Delivery: A Randomized Controlled Trial

This randomized, double-blind, placebo-controlled trial compared single with weekly courses of antenatal corticosteroids in 502 women at 24 to 32 completed weeks' gestation, seen at 13 academic centers in the United States. They were viewed as being at high risk of preterm delivery because of preterm labor with intact membranes; premature membrane rupture; maternal medical illness such as preeclampsia, diabetes, or hypertension: or suspected fetal jeopardy (intrauterine growth restriction, oligohydramnios, abnormal fetal test findings, a progressive fetal anomaly consistent with life, or twin-twin transfusion syndrome). All women received a complete course of antenatal steroids (12 mg of betamethasone intramuscularly, repeated once in 24 hours, or 6 mg of dexamethasone intramuscularly, repeated at 12-hour intervals for four doses). Those who did not deliver within 1 week then were randomly assigned to receive either betamethasone in the same dose every week up to 34 weeks' gestation or delivery, whichever came first, or placebo on the same schedule. Apgar scores were comparable in all groups. Composite neonatal morbidity rates (which took account of severe respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, proved sepsis, and death before discharge from the nursery) were 22.5% in the weekly-course group and 28.0% in the single-course group. The unadjusted relative risk was 0.80 (95% confidence interval, 0.59-1.10). Neither group assignment nor the number of treatment courses could be related to reduced composite morbidity. The difference in morbidity rates was statistically significant only in neonates delivered before 28 weeks' gestation. A reduction in severe respiratory distress syndrome accounted for this difference. Severe intraventricular hemorrhage was more frequent with the weekly treatment course, although not significantly so. No patient exhibited clinical changes of Cushing syndrome. The investigators believe that these findings do not warrant routine weekly antenatal steroid treatment for women at risk of delivering before term.

Multiple courses of antenatal corticosteroids are associated with early severe lung disease in preterm neonates.

Determine whether the increased neonatal mortality following repeated courses of antenatal corticosteroids (ANCS), observed in the Thyrotropin-Releasing Hormone (TRH) Trial, was related to confounding maternal risk factors or specific preterm morbidities. A post hoc analysis of 595 TRH trial neonates, 26 to 32 weeks' gestation, studied the association between > or =3 courses ANCS and mortality. Potential confounding maternal factors and preterm morbidities were evaluated using logistic regression and log likelihood modeling. Mortality was 9.2% after > or =3 courses (13/141) vs. 4.8% after 1 or 2 courses (22/454). This association was not explained by maternal factors, or other common preterm morbidities. However, 15/141 infants receiving > or =3 courses (10.6%) had early severe lung disease (ESLD) with 10 deaths, compared to 16/454 of the 1- to 2-course infants (3.5%) with 7 deaths (odds ratio 3.5, p<0.001). ESLD, but not maternal risk factors, was associated with increased mortality in preterm infants after > or =3 courses ANCS.

Multiple courses of antenatal corticosteroids: A systematic review and meta-analysis

Objective: To assess the effects of multiple courses of antenatal corticosteroids on perinatal and neonatal death and neonatal, infant, and maternal disease. Methods: MEDLINE and Embase were searched for human studies published in English. Studies that compared multiple courses of antenatal corticosteroids versus a single course were included if they were published in full and were controlled for gestational age at birth. Meta-analyses (odds ratio and 95% confidence interval) were undertaken when possible. Results: Eight observational studies were included. Selection bias was present in all studies. Multiple courses of antenatal corticosteroids were associated with a decreased risk of respiratory distress syndrome (odds ratio, 0.79; 95% confidence interval, 0.64 to 0.98) and patent ductus arteriosus (odds ratio, 0.56; 95% confidence interval, 0.35 to 0.90) and were associated with an increased risk of endometritis (odds ratio, 3.42; 95% confidence interval, 1.92 to 6.11). There was no significant effect on other neonatal and maternal outcomes. Conclusion: It is not possible to establish the true effects of multiple courses of antenatal corticosteroids by a review of the results of observational studies because of the effect of confounding variables. Randomized controlled trials are needed to address this important issue. (Am J Obstet Gynecol 2001;185:1073-80.)

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.

Weekly courses of antenatal corticosteroids: no added benefit

Weekly courses of antenatal corticosteroids: no added benefit

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.

Relationship between birthweight and repeated courses of antenatal corticosteroids.

A retrospective study was conducted in a university teaching hospital to review the association between birthweight and the number of courses of antenatal corticosteroids received in 236 singleton pregnancies. Those pregnancies complicated with pregnancy-induced hypertension, preeclampsia, diabetes mellitus and intrauterine growth restriction were excluded. The results showed that the birthweight ratio (calculated as the baby's birthweight divided by the median birthweight for that gestational age) was negatively correlated with the number of courses of corticosteroids received. Further, exposure to four or more courses of antenatal corticosteroids was associated with a significant reduction in birthweight ratio and a three-fold increase in the risk of being small-for-dates compared to those exposed to one to three courses.

Multiple courses of antenatal betamethasone and cognitive development of mice offspring.

To measure the effect of multiple courses of antenatal betamethasone, used for lung maturation, on long-term cognition of mice offspring. Forty gravid CD-1 mice were randomly assigned to receive one of four treatments (n = 10 per group): 0.1 mg betamethasone or saline placebo, given subcutaneously either once daily on gestational days 13-16 or twice daily on days 14 and 15. This dose of betamethasone given on gestational day 14 causes fetal lung maturation in mice. Three offspring per gender in each litter underwent standard cognitive tasks as juveniles and as adults. Analysis of variance or Kruskal-Wallis testing was used to compare data. Learning acquisition and memory were indistinguishable between the betamethasone-exposed and the corresponding placebo-exposed offspring when performing the following tasks: juvenile runway with adult memory, adult water runway and Morris spatial maze. This lack of difference in task performance between treatment groups persisted after controlling for gender and for each multiple-course regimen. Multiple courses of antenatal corticosteroids did not impact the mouse offsprings' long-term learning and memory.

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.

Effect of antenatal corticosteroids on postmortem brain weight of preterm babies.

To investigate the effects of single and repeated courses of antenatal corticosteroids on brain growth in very preterm babies. Retrospective study of 110 very preterm babies delivered at a single University Teaching Hospital between 1992 and 1999 who had a full necropsy including detailed examination of the brain. Mean brain weight did not differ significantly between babies who received corticosteroids and those who did not 160 vs. 157 g, (p=0.82), nor was there a difference between mean brain weight of stillborn or liveborn babies in relation to steroid use 164 vs. 159 g, (p=0.84) and 156 vs. 152g (p=0.81). There was no apparent dose-response relationship between the total number of doses of corticosteroids or timing since the first dose of corticosteroids and brain weight, p=0.95 and p=0.87. Single and multiple courses of antenatal corticosteroids had no significant effect on brain growth in babies delivered preterm who died but long-term follow-up studies are required to evaluate the functional neurological outcome of surviving children.

Children who were exposed to antenatal corticosteroids and had birth weights ⩽1500 g did not have adverse growth, cognitive, or lung function outcomes at age 14 years

Doyle LW, Ford GW, Rickards AL, et al. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams. Pediatrics2000 Jul; 106 :...

REPEATED COURSES OF ANTENATAL CORTICOSTEROIDS

In Brief A single course of corticosteroids given to women before an anticipated preterm birth reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, and neonatal death. For women who do not deliver within 1 week, repeated courses of corticosteroids have become common obstetric practice, despite little evidence of efficacy. Emerging data suggest little benefit and potential harm from that practice, so corticosteroids to improve perinatal outcomes should be restricted to a single course unless future randomized trial data prove additional courses to be beneficial. More than one course of antenatal corticosteroids might harm fetuses.

Repeated courses of antenatal corticosteroids

A single course of corticosteroids given to women before an anticipated preterm birth reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, and neonatal death. For women who do not deliver within 1 week, repeated courses of corticosteroids have become common obstetric practice, despite little evidence of efficacy. Emerging data suggest little benefit and potential harm from that practice, so corticosteroids to improve perinatal outcomes should be restricted to a single course unless future randomized trial data prove additional courses to be beneficial.

Timing of antenatal corticosteroids and neonatal pulmonary mechanics

Objective: We sought to compare lung mechanics in infants treated with multiple courses of antenatal corticosteroids with those in matched control infants delivered >7 days from dosing and those of matched untreated infants. Study Design: Eighteen infants who received multiple courses of corticosteroids and were delivered within 7 days of dosing were matched with 18 infants who received 1 course of corticosteroids >7 days before delivery (remote) and 18 untreated infants. Respiratory compliance and functional residual capacity were measured within 36 hours. Differences were compared by analysis of variance. Results: Infant demographics were similar. Respiratory compliance was higher in the multiple-course group than in the remote or untreated group ( P < .02). Functional residual capacity was higher in the multiple-course group than in the untreated group ( P < .05) but similar to that found in the remote group. Conclusion: Babies delivered after multiple courses of corticosteroids and within 7 days of dosing demonstrated improved respiratory compliance compared with untreated and remotely treated infants. This suggests that the enzyme system responsible for surfactant production can be repetitively induced despite prior treatment with corticosteroids. The increased functional residual capacity in remotely treated infants may reflect a maturation of lung architecture independent of surfactant production. (Am J Obstet Gynecol 2000;183:895-9.)

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.

Antenatal corticosteroids: is more better?

Ever since the landmark observations by Liggins that corticosteroids given to pregnant sheep were associated with accelerated lung maturation in the fetus, 1 Liggins GC Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol. 1969; 45: 515-523 Crossref PubMed Scopus (627) Google Scholar several studies have shown the beneficial effects, on the fetus, of an antenatal course of corticosteroids for women undergoing premature labour. A Cochrane systemic review 2 Crowley P Prophylactic corticosteroids for preterm delivery (Cochrane Review). The Cochrane Library, Issue 4. Update Software, Oxford1999 Google Scholar indicates that a single antenatal course of corticosteroids reduces the occurrence of respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH), and neonatal mortality in babies born prematurely. However, until the US National Institutes of Health Consensus Conference in 1994, physicians were slow to adopt this treatment for women at increased risk of premature delivery. The importance of corticosteroids given antenatally has led to several detailed clinical surveys, which have all identified the spread of the practice of prescribing multiple antenatal courses of corticosteroids when the risk of preterm delivery is judged to persist. For example, a recent survey of obstetric units in the UK 3 Brocklehurst P Gates S McKenzie-McHarg K Alfirevic Z Chamberlain G Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK. Br J Obstet Gynaecol. 1999; 106: 977-979 Crossref PubMed Scopus (121) Google Scholar showed that 98% of such units are prescribing repeated courses. This trend is worrying because there is no good evidence to support an advantage of multiple over single courses, 2 Crowley P Prophylactic corticosteroids for preterm delivery (Cochrane Review). The Cochrane Library, Issue 4. Update Software, Oxford1999 Google Scholar whereas there is an increasing body of evidence suggesting that fetal exposure to corticosteroids may have long-term adverse consequences for childhood and adult development.