Original Article
Outcomes at 2 Years of Age after Repeat Doses of Antenatal Corticosteroids
N Engl J Med 2007; 357:1179-1189September 20, 2007
- Abstract
Background
We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment.
Methods
Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age.
Results
Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04).
Conclusions
Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428.)
Media in This Article
Figure 1
Randomization, Treatment, and 2-Year Follow-up of Participants.Table 1
Characteristics of the Women and Their Infants.Article Activity
- Article
Preterm birth is a major risk factor for neurosensory impairments and disabilities, including cerebral palsy.1,2 A single course of antenatal corticosteroids given to women at risk for preterm delivery substantially reduces the risk of neonatal mortality and morbidity and reduces the risk of long-term neurologic sequelae.3 However, in comparison with unexposed infants, infants born more than 7 days after exposure to a single course of antenatal corticosteroids have lower birth weight3 and increased perinatal mortality.4 It therefore became common clinical practice to repeat the dose of antenatal corticosteroids after 7 or more days, despite a lack of evidence to support this practice.5 However, current guidelines do not support the use of repeat doses of antenatal corticosteroids outside of clinical trials.6
Lambs exposed to repeat doses of antenatal corticosteroids have higher blood pressure,7 reduced skeletal growth,7 delayed neuronal myelination,8 and lower brain weight in later life9 than lambs exposed to a single dose. In observational studies in humans, exposure to repeat courses of corticosteroids has been associated with poorer infant growth,10 abnormal childhood behavior,11 and delayed psychomotor development12 as compared with exposure to a single course. However, not all observational studies have shown an increased incidence of neurosensory disability in childhood after repeat doses of corticosteroids,10,13 and one study suggested a reduction in the incidence of cerebral palsy.11
We previously reported short-term results of the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS), in which babies of women randomly assigned to repeat doses of corticosteroids as compared with babies of women assigned to a single course, were much less likely to have respiratory distress syndrome (33% vs. 41%, P=0.01), severe neonatal lung disease (12% vs. 20%, P<0.001), and serious neonatal morbidity (20% vs. 26%, P=0.02).14 However, z scores for weight and head circumference were lower at birth in the repeat-dose group, although there were no significant differences by the time of hospital discharge.
A meta-analysis of the currently available evidence from randomized, controlled trials of women given repeat doses of antenatal corticosteroids similarly showed a reduction in the risk of neonatal respiratory distress syndrome as compared with those given a single course (26% vs. 32%; relative risk, 0.82; 95% confidence interval [CI], 0.72 to 0.93; four trials, 2155 women).15 We are unaware of any reports from randomized clinical trials on developmental and health outcomes in later childhood after exposure to repeat doses of antenatal corticosteroids.
We assessed outcomes at 2 years of corrected age of surviving children whose mothers took part in the ACTORDS trial. We aimed to determine whether exposure to repeat doses of antenatal corticosteroids affected the rate of survival free of major neurosensory disability (caused by impairments such as cerebral palsy, blindness, deafness, or developmental delay); body size; general health, including respiratory health; blood pressure; or behavior.
Methods
Design and Study Population
Eligible children were born to women recruited into the ACTORDS trial and were discharged home alive. As previously reported,14 women were eligible for the trial if they were considered by their obstetricians to be at risk for preterm delivery at less than 32 weeks of gestation with a single, twin, or triplet pregnancy and had received an initial course of a corticosteroid 7 or more days earlier. The research and ethics committees at the 23 collaborating hospitals approved the protocol.
Intervention
Women who gave written informed consent that included follow-up of their children through 2 years of corrected age were randomly assigned to the repeat-corticosteroid group or the placebo group and given an intramuscular injection of either betamethasone (11.4 mg of Celestone Chronodose, Schering-Plough) or saline placebo; the dose was repeated weekly if the woman remained at risk for preterm delivery before 32 weeks of gestation. Randomization was performed by a central telephone randomization service with stratification according to center, gestational age, and number of fetuses.14
Two-Year Follow-up
Contact with mothers of infants discharged home alive was maintained at 6, 12, and 18 months after birth. Surviving children were assessed at 2 years of corrected age by a developmental pediatrician and a psychologist, with staff and families unaware of treatment-group assignment. The pediatric assessment included measurement of weight, height, head circumference, and blood pressure; assessment of vision and hearing; and a neurologic examination. Body-size measurements were converted to z scores (standard-deviation scores) specific for age and sex.16 Blood pressure was measured according to local practice, and measurements were converted to z scores specific for age, height, and sex, with hypertension defined as systolic or diastolic blood pressure above the 95th percentile.17 Children were considered blind if vision in both eyes was worse than 6/60. Children were considered deaf if they required hearing aids. The criteria for cerebral palsy included abnormalities of muscle tone as well as loss of motor function.18
The psychological assessment included the Psychomotor Developmental Index and the Mental Developmental Index of the Bayley Scales of Infant Development19 or an equivalent psychological test. Both indexes of the Bayley Scales have a mean (±SD) score of 100±15, and higher scores indicate better performance. Children unable to complete the Psychomotor Developmental Index or the Mental Developmental Index because of severe psychomotor or developmental delay were assigned scores of 49.
Severe neurosensory disability was defined as severe cerebral palsy (the child was considered permanently nonambulant), severe developmental delay (Mental Developmental Index score, >3 SD below the mean), or blindness. Moderate disability was defined as moderate cerebral palsy (the child was nonambulant at 2 years of age but was likely to walk), moderate developmental delay (Mental Developmental Index score, >2 SD to 3 SD below the mean), or deafness. Mild disability was defined as either mild cerebral palsy (the child was able to walk by 2 years of age) or mild developmental delay (Mental Developmental Index score, >1 SD to 2 SD below the mean).
Each child's parent or caregiver completed a questionnaire on the child's history of illness, including respiratory illness, and the use of health services since the primary hospitalization. Each parent or caregiver also completed the Child Behavior Checklist, a rating scale that screens for behavioral and emotional problems.20
Outcome Variables
Primary Outcomes
The primary prespecified outcome was survival at the corrected age of 2 years free of major neurosensory disability, defined as survival free of moderate or severe disability. The other primary outcome was body size (weight, height, and head circumference).
Secondary Outcomes
The secondary outcomes were general health, including the use of health services since primary discharge; hospital readmission; respiratory morbidity, defined as the need for hospital admission for respiratory illness and the rate of asthma (determined on the basis of parental report of recurrent cough and wheeze requiring treatment with a bronchodilator); blood-pressure z scores and proportions in the hypertensive range; child behavior assessed by the Child Behavior Checklist20; incidence of neurosensory impairments and disabilities; total number of deaths by 2 years of corrected age, including stillbirths, neonatal deaths, and deaths after hospital discharge; and the combined adverse outcome of death or any neurosensory disability at 2 years of corrected age.
Statistical Analysis
We originally estimated that 918 children who were alive at 2 years of corrected age would be available for assessment. A trial with 524 babies in the repeat-corticosteroid group and 536 babies in the placebo group, on the assumption of a design effect of 1.2 to account for the clustering effect due to multiple gestations, has an 80% power to detect a significant difference at an alpha level of 0.05 (two-tailed) if survival free of major disability changed from 81% up to 88% or down to 73%. For measures of body size, this sample size would detect a change in z score of 0.2 SD with 80% power.
Statistical analyses were performed on an intention-to-treat basis with SAS software, version 9.1. All analyses were adjusted for gestational age at trial entry, antepartum hemorrhage, and preterm prelabor rupture of the membranes.14 Binary outcomes are presented as relative risks with 95% confidence intervals. Relative risks were calculated with the use of log binomial regression.21 Continuous variables, if normally distributed, were analyzed by analysis of variance, with transformation of skewed data to normality before analysis. Robust variance estimation was used to account for clustering effects due to multiple gestations. A P value of less than 0.05 was considered to indicate statistical significance. All P values were two-sided.
Results
Of the 982 women enrolled, 489 were assigned to the repeat-corticosteroid group and 493 to the placebo group (Figure 1Figure 1
Randomization, Treatment, and 2-Year Follow-up of Participants.). Clinical outcomes up to the time of discharge after the primary hospitalization have been reported previously for all 982 women who underwent randomization and their 1146 fetuses who were alive at randomization.14 Of the 1090 infants discharged home alive, 5 had died by 2 years of corrected age (2 in the repeat-corticosteroid group and 3 in the placebo group). Of the 1085 survivors, 1047 (96%) were assessed at 2 years of corrected age and 38 had no pediatric assessment (18 in the repeat-corticosteroid group and 20 in the placebo group) (Figure 1). The maternal characteristics and the reasons for the risk of preterm delivery were similar in the two treatment groups (Table 1Table 1
Characteristics of the Women and Their Infants.).Primary Outcomes
The rates of survival free of major disability did not differ significantly between the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04; 95% CI, 0.98 to 1.10; adjusted P=0.20) (Table 2Table 2
Primary Outcomes, Assessed at 2 Years of Corrected Age.). There were also no significant differences between the groups in measurements or z scores for weight, height, or head circumference (Table 2). In a prespecified analysis according to the number of repeat trial treatments given (one, two or three, or four or more treatments), there were no significant interactions with the treatment effect for survival free of major disability or for measures of body size (unadjusted and adjusted P>0.25).Secondary Outcomes
There were no significant differences between the groups in the use of health service resources. The overall rates of readmission to the hospital were similar, as were the rates of asthma and admission to the hospital with a respiratory illness. There were no significant differences between the groups in mean systolic or diastolic blood pressures or in the proportions of children with blood pressure in the hypertensive range (Table 3Table 3
Secondary Outcomes, Assessed at 2 Years of Corrected Age.). Children exposed to one or more repeat doses of antenatal corticosteroids were not more likely to be small for their age in weight, height, or head circumference than children not exposed (Table 3).There were 61 deaths (5.3%): 29 (5.1%) in the repeat-corticosteroid group and 32 (5.5%) in the placebo group (Table 3). There were no significant differences between the treatment groups in the distribution of the severity of neurosensory disability, in any of the individual neurosensory impairments (cerebral palsy, blindness, deafness, and developmental delay), or in the combined outcome of death or any neurosensory disability (Table 3). The mean Psychomotor Developmental and Mental Developmental Index scores did not significantly differ between treatment groups (Table 3).
For the Child Behavior Checklist, there were no significant differences between the groups in the total or individual mean scores for internalizing, externalizing, emotional reactivity, anxiety or depression, somatic complaints, withdrawal, sleep problems, attention problems, or aggressive behavior (Table 4Table 4
Child Behavior Checklist Scores at 2 Years of Corrected Age.). Similarly, there were no significant differences in the proportions of children with scores within the clinical range (the top 2.5th percentile, indicating further assessment is warranted)20 in any of these behavioral domains, with the exception of attention problems, for which there were more children in the clinical range in the repeat-corticosteroid than in the placebo group (6.0% vs. 3.2%; adjusted relative risk, 1.87; 95% CI, 1.03 to 3.42; P=0.04) (Table 4). In post hoc analyses, there were no significant interactions between sex and treatment effect on child behavior (unadjusted and adjusted P>0.18).Discussion
In this follow-up study of offspring of women at risk for preterm delivery who were assigned to repeat doses of betamethasone or placebo, exposure to repeat doses of corticosteroids had no significant effects on survival free of major neurosensory disability or on childhood growth to 2 years of corrected age. The study used central randomization, the outcome assessors were unaware of treatment-group assignment, the follow-up rate achieved was very high, and the sample size was sufficiently large to detect important but small differences between treatment groups.
These results may be viewed as reassuring, given previous reports of adverse effects of repeat doses of corticosteroids on neuronal myelination8 and brain weight in sheep,9 as well as the increased rate of neurosensory disability in childhood reported in some observational studies of children whose mothers received repeat corticosteroid doses.12 The differences between the findings in sheep and humans may be related to the much greater effects of repeat corticosteroids on fetal growth in sheep,7 perhaps due to the higher doses used, as well as differences in the timing of brain growth and myelination in the two species.22 Our results are robust, in that they show a similar distribution of developmental outcomes in the corticosteroid and placebo groups across a range of different measures of neurosensory disability. However, since neurosensory abilities at 2 years of age are of limited predictive value, particularly for more subtle problems, follow-up of these children is warranted later in childhood, when other important cognitive outcomes, such as executive function, can be determined more completely.
We also found no differences between treatment groups in body-size measurements at 2 years. This is consistent with our earlier finding that there were no differences between the groups in body size at initial discharge from the hospital. The mean size at birth also did not differ significantly between the groups, although the z scores for weight and head circumference at birth were slightly lower in infants who were exposed to repeat doses of corticosteroids.14 Together these findings suggest that any effects of repeat doses of corticosteroids on growth before birth are unlikely to have any clinically important effect on size in later life. The reason for the difference between our findings and those of many studies in animals showing long-term impairment of growth after antenatal corticosteroids is not clear, but it may in part be related to the longer period of administration and larger doses of corticosteroids used in the studies in animals.7
Almost one third of the children in our study had blood pressures above the 95th percentile. Preterm birth is itself associated with increased blood pressure in adulthood23,24 and with a doubling of the risk of hypertension by 30 years of age.25 However, we found no apparent effect of exposure to repeat corticosteroids on blood pressure at 2 years of age. This is consistent with the findings of previous randomized trials that exposure to a single course of antenatal corticosteroids has no effect on blood pressure in later childhood26 and early adulthood,27,28 but not with findings of observational studies23,29 and studies in animals suggesting that antenatal corticosteroid exposure increases blood pressure in both fetal30 and postnatal7,31 life. These differences may be related in part to the lack of effects on growth in our study, since in rats, exposure to antenatal corticosteroids does not alter blood pressure unless growth is also affected.32 The differences may also be related to the timing of corticosteroid exposure, since fetuses exposed to repeat doses of corticosteroids, as was the case in our study, often are exposed to their first dose earlier in gestation than those exposed to a single dose.33
Some studies in animals have suggested that the effects of antenatal corticosteroid exposure on blood pressure may increase with increasing postnatal age.34 Therefore, long-term follow-up of this and similar randomized trials will be important to determine whether repeat doses of antenatal corticosteroids have adverse effects on later cardiovascular health beyond those associated with preterm birth.
Overall child behavior was similar between the treatment groups. We did not find an increase in aggressive behavior in children who had been exposed to repeat doses of corticosteroids, as was reported in an earlier observational study.11 The higher proportion of children exposed to repeat doses of corticosteroids who reached the clinical range of scores for attention problems may have been a chance finding, since it represents a difference in the sum of 5 items in a 100-item standardized test. However, further follow-up is warranted, given the reported changes in neurotransmitter systems and associated increases in hyperactivity and anxiety-like behavior in animals after antenatal exposure to repeat doses of corticosteroids.35,36
Our results should not be generalized to other treatment regimens or inclusion criteria. A trial using a single rescue or booster dose of corticosteroid when preterm birth was imminent (within 48 hours) did not show benefit in the neonatal period.37 The 2-to-3-year follow-up of children in the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network trial38 reported in this issue of the Journal 39 showed no significant differences in physical or neurocognitive measures between children who had been exposed to repeat courses of antenatal corticosteroids and those who had been exposed to single courses. Another trial of repeat antenatal corticosteroids has completed recruitment, and the results are awaited.40
Exposure to one or more repeat doses of antenatal betamethasone has previously been shown to reduce the risk of respiratory distress syndrome and overall serious neonatal morbidity.14,15 The current report shows that this treatment does not change survival free of major neurosensory disability or growth to 2 years of age. On the basis of this evidence, clinicians may wish to consider the use of a single injection of Celestone Chronodose, or equivalent, repeated weekly if the woman remains at risk for very preterm delivery, 7 or more days after an initial course of antenatal corticosteroids.
Supported by two project grants from the National Health and Medical Research Council Australia (ID 157915 and 349459), a grant from the Channel 7 Research Foundation, South Australia, and a grant from the Women's and Children's Hospital Research Foundation, Adelaide; and by the Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide — all in Australia.
No potential conflict of interest relevant to this article was reported.
We thank all the women and their children who participated in this study.
Source Information
From the Disciplines of Obstetrics and Gynaecology (C.A.C., J.S.R.) and Public Health (J.E. Hiller), University of Adelaide, Adelaide; the Department of Obstetrics and Gynaecology and Paediatrics, University of Melbourne, Melbourne (L.W.D.); and the Department of Neonatal Medicine, Women's and Children's Hospital, Adelaide (R.R.H.) — all in Australia; and the Liggens Institute, University of Auckland, Auckland, New Zealand (J.E. Harding).
Address reprint requests to Dr. Crowther at the Discipline of Obstetrics and Gynaecology, University of Adelaide, Women's and Children's Hospital, 72 King William Rd., North Adelaide SA 5006, Australia, or at caroline.crowther@adelaide.edu.au.
The members of the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group are listed in the Appendix.
Appendix
The following persons and institutions participated in the ACTORDS Study Group: Steering group — C.A. Crowther, R.R Haslam, J.E. Hiller, L.W. Doyle, J.S. Robinson; Coordinating team — C.A. Crowther, P. Ashwood, J. Paynter, C. Holst, K. Robinson; Statistical support — K. Willson; Data monitoring committee — J. Lumley (chair), J. Carlin, E. Carse; Writing group — C.A. Crowther, L.W. Doyle, R.R. Haslam, J.E. Hiller, J.E. Harding, J.S. Robinson. The collaborating hospitals where children were assessed and the participating investigators were as follows (the total number of women recruited at each hospital is given in parentheses; staff at other institutions assessed a few children; asterisks indicate associate investigators named on the National Health and Medical Research Council project grants): Caboolture Hospital, Queensland, Australia (3) — M. Ratnapala, A. Hanafy; Christchurch Women's Hospital, New Zealand (34) — R. Reid, N. Austin, B. Darlow,* J. Hunter, H. Liley, N. Mogridge, D. Poad; Dunedin Hospital, New Zealand (16) — R. Broadbent,* K. Gillies, F. Patel, S. Tout, D. Wilson; Hervey Bay Hospital, Queensland, Australia (8) — D. Ludwig,* G. Carman, K. Ende, J. Heininger, F. Tan, J. Van der Westhuyzen; John Hunter Hospital, New South Wales, Australia (10) — W. Giles, A. Gill,* L. Miljkovic, A. Nicoll, S. O'Callaghan, A. Vimpani; Mater Mothers' Hospital, Brisbane, Queensland, Australia (86) — F. Chan (deceased), V. Flenady, R. Cincotta, P. Gray, J. Hegarty, S. Jenkins-Manning, L. Lewis, H. Liley, L. Poulsen, Y. Rogers, J. Toohill, D. Tudehope,* P. Woodgate; Middlemore Hospital, New Zealand (26) — L. Mildenhall,* I. Brown, L. Hayward, D.W. Smith, A. Thesing, S. Wadsworth; Monash Medical Centre, Victoria, Australia (30) — R. Burrows, E. Carse, M. Charlton, M. Hayes, N. Taylor, V. Yu*; National Women's Hospital, New Zealand (156) — L. McCowan, R. Taylor, J. Harding,* C. Bevan, S. Aftimos, J. Alsweiler, D. Armstrong, M. Battin, J.A. Dezoete, M. Light, P. Stone, A. Thesing, N. Webster, C. West, C. Kuschel; Palmerston North Hospital, New Zealand (1) — K. Gillies, G. Bates, D. Baillie, L. Hastings, A. Jory, P. Mercer, R. Pullen, G. Scott; Royal Hobart Hospital, Tasmania, Australia (13) — G. Bury, S. Bacic, K. Butterley, H. Giannaros, S. Jarrell, G. Standen; Royal Hospital for Women, New South Wales, Australia (8) — C. Fisher, D. Challis, K. Asgill, R. Buist, D. Cameron, K. Dyer, K. Lui, S. Milner, L. Sutton, L. Woodhart; Royal North Shore Hospital, New South Wales, Australia (28) — J. Morris, J. Bowen, V. Gallimore, F. Gibson, G. Leslie, C. Maher; Royal Prince Alfred Women's & Babies Hospital, New South Wales, Australia (7) — A. Child, D. Henderson-Smart, H. Jeffery, R. Ogle, D. Osborn, B. Peat, H. Phipps, J. Polverino, I. Rieger, J. Vaughan, C. Wocadlo; Royal Brisbane and Women's Hospital, Queensland, Australia (104) — P. Colditz,* R. Allen, T. de Dassel, T. Fitzsimmons, J. Horn, W. Katterns, M. Pritchard, V. Smith-Orr, T. Somville, J. Wilson, M. Wilson; Canberra Hospital, Australian Capital Territory, Australia (46) — G. Reynolds,* P. Downes, D. Ellwood, P. Hand, E. Jacob, J. Lindgren, J. Nugent, M. Peek, C. Ringland, C. Rollason; Mercy Hospital for Women, Victoria, Australia (56) — A. Watkins; S. Fraser,* P. Wein, J. Higgins, E. Kelly, J. Keng, E. McCarthy, A. Turner, S. Walker, H. Woods; Royal Women's Hospital, Victoria, Australia (80) — L. Doyle,* S. Brennecke, C. Callanan, N. Davis, G. Ford, K. Howard, E. Kelly, L. Kornman, M. Lim, G. McGrath, D. Rushford; Townsville Hospital, Queensland, Australia (37) — D. Watson,* A. Blair; S. Campbell, A. Dederer, E. Green, A. Lawrence, G. Roberts, K. Roberts, J. Whitehall; Toowoomba Base Hospital, Queensland, Australia (2) — M. Ratnapala, Y. Chadha, E.D. Gibson, B. Morris; Waikato Hospital, New Zealand (33) — D. Bourchier,* A. Haslam, C. Holmes, R. McLaughlin, N. Meher-Homji, J. Reetz, P. Weston; Wellington Women's Hospital, New Zealand (24) — M. Sangalli, N. Bedford, S. Calvert, C. Coles, G. Corbett, D. Elder, U. Preston, V. Richardson; Women's and Children's Hospital, South Australia, Australia (174) — C. Crowther, P. Ashwood, C. Barnett, V. Bhatia, V. Coppinger, A. Deussen, J. Dodd, J. Fitzgerald, S. Gibbons, E. Griffith, K. Harris, R. Haslam,* B. Headley, J. Hiller, C. Holst, T.Y. Khong, E. Lioulios, K. McLaughlin, A. McPhee, M. O'Grady, B. Paine, J. Paynter, J. Ramsay, J. Robinson,* K. Robinson, S. Russell, M. Santich, R. Vigneswaren (deceased), L. Zhang.
- References
References
1
The Victorian Infant Collaborative Study Group
CrossRef | Web of Science | Medline2
Lorenz JM ,Wooliever DE ,Jetton JR ,Paneth N . A quantitative review of mortality and developmental disability in extremely premature newborns. Arch Pediatr Adolesc Med 1998;152:425-435
Web of Science | Medline3
Roberts D ,Dalziel S . Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454-CD004454
Medline4
McLaughlin KJ ,Crowther CA ,Walker N ,Harding JE . Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol 2003;43:101-106
CrossRef | Web of Science | Medline5
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 | Medline6
National Institutes of Health Consensus Development Panel
CrossRef | Web of Science | Medline7
Moss TJ ,Harding R ,Newnham JP . Lung function, arterial pressure and growth in sheep during early postnatal life following single and repeated prenatal corticosteroid treatments. Early Hum Dev 2002;66:11-24
CrossRef | Web of Science | Medline8
Dunlop SA ,Archer MA ,Quinlivan JA ,Beazley LD ,Newnham JP . Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med 1997;6:309-313
CrossRef | Medline9
Huang WL ,Beazley LD ,Quinlivan JA ,Evans SE ,Newnham JP ,Dunlop SA . Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213-218
CrossRef | Web of Science | Medline10
French NP ,Hagan R ,Evans SF ,Godfrey M ,Newnham JP . Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114-121
CrossRef | Web of Science | Medline11
French NP ,Hagan R ,Evans SF ,Mullan A ,Newnham JP . Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behaviour. Am J Obstet Gynecol 2004;190:588-595
CrossRef | Web of Science | Medline12
Spinillo A ,Viazzo E ,Colleoni R ,Chiara A ,Maria Cerbo R ,Fazzi E . Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 2004;191:217-224
CrossRef | Web of Science | Medline13
Hasbargen U ,Reber D ,Versmold H ,Schulze A . Growth and development of children to 4 years of age after repeated antenatal steroid administration. Eur J Pediatr 2001;160:552-555
CrossRef | Web of Science | Medline14
Crowther CA ,Haslam RR ,Hiller JE ,Doyle LW ,Robinson JS . Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367:1913-1919
CrossRef | Web of Science | Medline15
Crowther C ,Harding J . Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 2007;3:CD003935-CD003935
Medline16
Freeman JV ,Cole TJ ,Chinn S ,Jones PR ,White EM ,Preece MA . Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17-24
CrossRef | Web of Science | Medline17
Rosner B ,Prineas RJ ,Loggie JM ,Daniels SR . Blood pressure nomograms for children and adolescents, by height, sex, and age, in the United States. J Pediatr 1993;123:871-876
CrossRef | Web of Science | Medline18
Kitchen WH ,Doyle LW ,Ford GW ,Rickards AL ,Lissenden JV ,Ryan MM . Cerebral palsy in very low birth weight infants surviving to 2 years with modern perinatal intensive care. Am J Perinatol 1987;4:29-35
CrossRef | Web of Science | Medline19
Bayley N. Bayley scales of infant development. 2nd ed. San Antonio, TX: Psychological Corporation, 1993.
20
Achenbach TM, Rescorla LA. Manual for the ASEBA preschool forms and profiles. Burlington: University of Vermont, 2000.
21
McCullagh P, Nelder JA. Generalized linear models. 2nd ed. London: Chapman & Hall, 1989.
22
Dobbing J. The later development of the brain and its vulnerability. In: Davis JA, Dobbing J, eds. Scientific foundations of paediatrics. London: Heinemann, 1974: 565-77.
23
Doyle LW ,Ford GW ,Davis NM ,Callanan C . Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci (Lond) 2000;98:137-142
CrossRef | Web of Science | Medline24
Leon DA ,Johansson M ,Rasmussen F . Gestational age and growth rate of fetal mass are inversely associated with systolic blood pressure in young adults: an epidemiologic study of 165,136 Swedish men aged 18 years. Am J Epidemiol 2000;152:597-604
CrossRef | Web of Science | Medline25
Dalziel SR, Parag V, Rodgers A, Harding JE. Cardiovascular risk factors at age 30 following pre-term birth. Int J Epidemiol (in press).
26
Dalziel SR ,Liang A ,Parag V ,Rodgers A ,Harding JE . Blood pressure at 6 years of age after prenatal exposure to betamethasone: follow-up results of a randomized, controlled trial. Pediatrics 2004;114:e373-e377
CrossRef | Web of Science | Medline27
Dalziel SR ,Walker NK ,Parag V , et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005;365:1856-1862
CrossRef | Web of Science | Medline28
Dessens AB ,Haas HS ,Koppe JG . Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000;105:E77-E77
CrossRef | Web of Science | Medline29
Mildenhall LF ,Battin MR ,Morton SM ,Bevan C ,Kuschel CA ,Harding JE . Exposure to repeat doses of antenatal glucocorticoids is associated with altered cardiovascular status after birth. Arch Dis Child Fetal Neonatal Ed 2006;91:F56-F60
CrossRef | Web of Science | Medline30
Jensen EC ,Gallaher BW ,Breier BH ,Harding JE . The effects of a chronic maternal cortisol infusion on the late-gestation fetal sheep. J Endocrinol 2002;174:27-36
CrossRef | Web of Science | Medline31
O'Regan D ,Kenyon CJ ,Seckl JR ,Holmes MC . Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab 2004;287:E863-E870
CrossRef | Web of Science | Medline32
Woods LL . Maternal glucocorticoids and prenatal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 2006;291:R1069-R1075
CrossRef | Web of Science | Medline33
McLaughlin KJ ,Crowther CA ,Vigneswaran P ,Hancock E ,Willson K . Who remains undelivered more than seven days after a single course of prenatal corticosteroids and gives birth at less than 34 weeks? Aust N Z J Obstet Gynaecol 2002;42:353-357
CrossRef | Web of Science | Medline34
Dodic M ,Baird R ,Hantzis V , et al. Organs/systems potentially involved in one model of programmed hypertension in sheep. Clin Exp Pharmacol Physiol 2001;28:952-956
CrossRef | Web of Science | Medline35
Seckl JR ,Meaney MJ . Glucocorticoid “programming” and PTSD risk. Ann N Y Acad Sci 2006;1071:351-378
CrossRef | Web of Science | Medline36
Owen D ,Matthew SG . Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs. J Physiol 2007;578:249-257
CrossRef | Web of Science | Medline37
Peltoniemi OM ,Kari MA ,Tammela O , et al. Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics 2007;119:290-298
CrossRef | Web of Science | Medline38
Wapner RJ ,Sorokin Y ,Thom EA , et al. Single versus weekly courses of antenatal cortiocosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 2006;195:633-642
CrossRef | Web of Science | Medline39
Wapner RJ ,Sorokin Y ,Mele L , et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1190-1198
Full Text | Web of Science | Medline40
Maternal, Infant and Reproductive Health Research Unit (MIRU). Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS). Toronto: University of Toronto, 2006. (Accessed August 24, 2007, at http://www.utoronto.ca/miru/macs/.)
- Citing Articles (56)
Citing Articles
1
Thomas J. Garite, C. Andrew Combs. (2012) Obstetric Interventions Beneficial to Prematurely Delivering Newborn Babies: Antenatal Corticostetroids, Progesterone, Magnesium Sulfate. Clinics in Perinatology
CrossRef2
Ariana Murata, Patrick M. Ling. (2011) Asthma Diagnosis and Management. Emergency Medicine Clinics of North America
CrossRef3
Sara K. Damsted, A.P. Born, Olaf B. Paulson, Peter Uldall. (2011) Exogenous glucocorticoids and adverse cerebral effects in children. European Journal of Paediatric Neurology 15:6, 465-477
CrossRef4
Cheryl A. Riley, Kathileen Boozer, Tekoa L. King. (2011) Antenatal Corticosteroids at the Beginning of the 21st Century. Journal of Midwifery & Women's Health 56:6, 591-597
CrossRef5
Yoon-Soo Cindy Bae, Abby S. Van Voorhees, Sylvia Hsu, Neil J. Korman, Mark G. Lebwohl, Melody Young, Bruce Bebo, Alexa Boer Kimball. (2011) Review of treatment options for psoriasis in pregnant or lactating women: From the Medical Board of the National Psoriasis Foundation. Journal of the American Academy of Dermatology
CrossRef6
Élisabeth Autret-Leca, Hawaré Cissoko, Annie Pierre Jonville-Béra. (2011) Risque néonatal des médicaments pris à la fin de la grossesse. Thérapie 66:5, 431-436
CrossRef7
M.W. Church, B.R. Adams, J.I. Anumba, D.A. Jackson, M.L. Kruger, K.-L.C. Jen. (2011) Repeated antenatal corticosteroid treatments adversely affect neural transmission time and auditory thresholds in laboratory rats. Neurotoxicology and Teratology
CrossRef8
Wessel Ganzevoort, Baha M. Sibai. (2011) Temporising versus interventionist management (preterm and at term). Best Practice & Research Clinical Obstetrics & Gynaecology 25:4, 463-476
CrossRef9
Christopher J.D. McKinlay, Caroline A. Crowther, Philippa Middleton, Jane E. Harding. (2011) Repeat antenatal glucocorticoids for women at risk of preterm birth: a Cochrane Systematic Review. American Journal of Obstetrics and Gynecology
CrossRef10
OUTI M. PELTONIEMI, M. ANNELI KARI, MIKKO HALLMAN. (2011) Repeated antenatal corticosteroid treatment: a systematic review and meta-analysis. Acta Obstetricia et Gynecologica Scandinavica 90:7, 719-727
CrossRef11
Caroline A Crowther, Christopher JD McKinlay, Philippa Middleton, Jane E Harding, Caroline A Crowther. 2011. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. .
CrossRef12
Christopher P Barnett, David Chitayat, Timothy J Bradley, Yanting Wang, Aleksander Hinek. (2011) Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys–Dietz syndrome fibroblasts: a possible treatment?. European Journal of Human Genetics 19:6, 624-633
CrossRef13
Libor Velíšek. (2011) Prenatal corticosteroid exposure alters early developmental seizures and behavior. Epilepsy Research 95:1-2, 9-19
CrossRef14
R. Coutant. (2011) Hormones et comportement Les traitements hormonaux, quels effets sur le comportement ?. Archives de Pédiatrie 18:5, H49-H50
CrossRef15
LI-TUNG HUANG. (2011) The Link Between Perinatal Glucocorticoids Exposure and Psychiatric Disorders. Pediatric Research 69:5 Part 2, 19R-25R
CrossRef16
Hanna Norberg, Jannica Stålnacke, Rochellys Diaz Heijtz, Ann-Charlotte Smedler, Margareta Nyman, Hans Forssberg, Mikael Norman. (2011) Antenatal corticosteroids for preterm birth: dose-dependent reduction in birthweight, length and head circumference. Acta Paediatrica 100:3, 364-369
CrossRef17
2011. Part Introduction. , 33-280.
CrossRef18
Frédéric Amant, Sarah Deckers, Kristel Van Calsteren, Sibylle Loibl, Michael Halaska, Lieselot Brepoels, Jos Beijnen, Fatima Cardoso, Oreste Gentilini, Lieven Lagae, Olivier Mir, Patrick Neven, Nelleke Ottevanger, Steven Pans, Fedro Peccatori, Roman Rouzier, Hans-Jörg Senn, Henk Struikmans, Marie-Rose Christiaens, David Cameron, Andreas Du Bois. (2010) Breast cancer in pregnancy: Recommendations of an international consensus meeting. European Journal of Cancer 46:18, 3158-3168
CrossRef19
Michael W. Church, Ronald J. Wapner, Lisa M. Mele, Francee Johnson, Donald J. Dudley, Catherine Y. Spong, Alan M. Peaceman, Atef H. Moawad, Mary J. O'Sullivan, Menachem Miodovnik. (2010) Repeated courses of antenatal corticosteroids: Are there effects on the infant's auditory brainstem responses?. Neurotoxicology and Teratology 32:6, 605-610
CrossRef20
Rebecca M. Reynolds. (2010) Corticosteroid-mediated programming and the pathogenesis of obesity and diabetes. The Journal of Steroid Biochemistry and Molecular Biology 122:1-3, 3-9
CrossRef21
Michael Peek, George J. Mangos, Mark A. Brown. 2010. Approach to Fetal Assessment, Optimization of Neonatal Outcome, Mode of Delivery and Timing for Nonobstetric Readers. , 749-753.
CrossRef22
Cindy McEvoy, Diane Schilling, Dawn Peters, Carrie Tillotson, Patricia Spitale, Linda Wallen, Sally Segel, Susan Bowling, Michael Gravett, Manuel Durand. (2010) Respiratory compliance in preterm infants after a single rescue course of antenatal steroids: a randomized controlled trial. American Journal of Obstetrics and Gynecology 202:6, 544.e1-544.e9
CrossRef23
S. M. Breathnach, C. H. Smith, R. J. G. Chalmers, R. J. Hay. 2010. Systemic Therapy. , 1-53.
CrossRef24
A. A. McKendry, H. K. Palliser, D. M. Yates, D. W. Walker, J. J. Hirst. (2010) The Effect of Betamethasone Treatment on Neuroactive Steroid Synthesis in a Foetal Guinea Pig Model of Growth Restriction. Journal of Neuroendocrinology 22:3, 166-174
CrossRef25
S. M. Breathnach. 2010. , 1.
CrossRef26
Johan Verhaeghe, Rita van Bree, Erik Van Herck. (2009) Oxidative stress after antenatal betamethasone: Acute downregulation of glutathione peroxidase-3. Early Human Development 85:12, 767-771
CrossRef27
Rosalie Grivell, Jodie Dodd, Jeffrey Robinson. (2009) The prevention and treatment of intrauterine growth restriction. Best Practice & Research Clinical Obstetrics & Gynaecology 23:6, 795-807
CrossRef28
Máximo Vento, Marta Aguar, Javier Escobar, Alessandro Arduini, Raquel Escrig, María Brugada, Isabel Izquierdo, Miguel Angel Asensi, Juan Sastre, Pilar Saenz, Ana Gimeno. (2009) Antenatal Steroids and Antioxidant Enzyme Activity in Preterm Infants: Influence of Gender and Timing. Antioxidants & Redox Signaling 11:12, 2945-2955
CrossRef29
Olli M. Pitkänen. (2009) Lung liquid transport components in human perinatal respiratory distress. Acta Paediatrica 98:11, 1709-1711
CrossRef30
GV Nair, SA Omar. (2009) Blood pressure support in extremely premature infants is affected by different courses of antenatal steroids. Acta Paediatrica 98:9, 1437-1443
CrossRef31
R. Morley, R. Saffery, D. F. Hacking, J. M. Craig. (2009) Epigenetics and Neonatology: The Birth of a New Era. NeoReviews 10:8, e387-e395
CrossRef32
E.S. Shinwell, S. Eventov-Friedman. (2009) Impact of perinatal corticosteroids on neuromotor development and outcome: Review of the literature and new meta-analysis. Seminars in Fetal and Neonatal Medicine 14:3, 164-170
CrossRef33
Lex W Doyle. (2009) Antenatal progesterone to prevent preterm birth. The Lancet 373:9680, 2000-2002
CrossRef34
John P. Newnham, Alan H. Jobe. (2009) Should we be prescribing repeated courses of antenatal corticosteroids?. Seminars in Fetal and Neonatal Medicine 14:3, 157-163
CrossRef35
Ana Raquel Mesquita, Yvonne Wegerich, Alexandre V. Patchev, Mario Oliveira, Pedro Leão, Nuno Sousa, Osborne F.X. Almeida. (2009) Glucocorticoids and neuro- and behavioural development. Seminars in Fetal and Neonatal Medicine 14:3, 130-135
CrossRef36
Sharon R Sheehan, Deirdre J Murphy. (2009) Can repeated courses of antenatal corticosteroids for threatened preterm birth be justified?. Expert Review of Obstetrics & Gynecology 4:3, 223-226
CrossRef37
Frédéric Amant, Kristel Van Calsteren, Michael J. Halaska, Jos Beijnen, Lieven Lagae, Myriam Hanssens, Liesbeth Heyns, Lore Lannoo, Nelleke P. Ottevanger, Walter Vanden Bogaert, Laszlo Ungar, Ignace Vergote, Andreas du Bois. (2009) Gynecologic Cancers in Pregnancy. International Journal of Gynecological Cancer 19:Suppl 1, S1-S12
CrossRef38
Clarissa Bonanno, Ronald J. Wapner. (2009) Antenatal corticosteroid treatment: what's happened since Drs Liggins and Howie?. American Journal of Obstetrics and Gynecology 200:4, 448-457
CrossRef39
Diana E Schendel. (2009) Cerebral palsy and preterm birth: how far have we come?. Pediatric Health 3:2, 111-113
CrossRef40
Thomas J. Garite, James Kurtzman, Kimberly Maurel, Reese Clark. (2009) Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. American Journal of Obstetrics and Gynecology 200:3, 248.e1-248.e9
CrossRef41
Clarissa Bonanno, Ronald J. Wapner. (2009) To rescue or not to rescue: that is the question. American Journal of Obstetrics and Gynecology 200:3, 217-218
CrossRef42
Alberto Gulino, Enrico De Smaele, Elisabetta Ferretti. (2009) Glucocorticoids and neonatal brain injury: the hedgehog connection. Journal of Clinical Investigation
CrossRef43
Vivi M. Heine, David H. Rowitch. (2009) Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism. Journal of Clinical Investigation
CrossRef44
Shadi N. Malaeb, Virginia Hovanesian, Matthew D. Sarasin, Silvia M. Hartmann, Grazyna B. Sadowska, Barbara S. Stonestreet. (2009) Effects of maternal antenatal glucocorticoid treatment on apoptosis in the ovine fetal cerebral cortex. Journal of Neuroscience Research 87:1, 179-189
CrossRef45
Kellie E Murphy, Mary E Hannah, Andrew R Willan, Sheila A Hewson, Arne Ohlsson, Edmond N Kelly, Stephen G Matthews, Saroj Saigal, Elizabeth Asztalos, Susan Ross, Marie-France Delisle, Kofi Amankwah, Patricia Guselle, Amiram Gafni, Shoo K Lee, B Anthony Armson. (2008) Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. The Lancet 372:9656, 2143-2151
CrossRef46
S Eventov-Friedman, ES Shinwell. (2008) Current controversies in perinatal steroid therapy. Acta Paediatrica 97:11, 1492-1501
CrossRef47
Petra Aden, Ingeborg Goverud, Knut Liestøl, Else Marit Løberg, Ragnhild E. Paulsen, Jan Mæhlen, Jon Lømo. (2008) Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum. Brain Research 1236, 39-48
CrossRef48
Monique Robinson, Wendy H. Oddy, Jianghong Li, Garth E. Kendall, Nicholas H. de Klerk, Sven R. Silburn, Stephen R. Zubrick, John P. Newnham, Fiona J. Stanley, Eugen Mattes. (2008) Pre- and postnatal influences on preschool mental health: a large-scale cohort study. Journal of Child Psychology and Psychiatry 49:10, 1118-1128
CrossRef49
Joseph Lam, Janine E. Polifka, Magdalene A. Dohil. (2008) Safety of dermatologic drugs used in pregnant patients with psoriasis and other inflammatory skin diseases. Journal of the American Academy of Dermatology 59:2, 295-315
CrossRef50
Robert De Matteo, Victoria Stacy, Megan E Probyn, Nadine Brew, Natasha Blasch, Richard Harding. (2008) DOES MODERATE PRETERM BIRTH LEAD TO ALTERED ARTERIAL PRESSURE? STUDIES IN SHEEP. Clinical and Experimental Pharmacology and Physiology???-???
CrossRef51
TAK YEUNG LEUNG, DALJIT SINGH SAHOTA. (2008) REPEAT ANTENATAL CORTICOSTEROIDS: SHOULD IT BE PRESCRIBED AND IF SO WHEN AND HOW?. Fetal and Maternal Medicine Review 19:02,
CrossRef52
Malcolm R. Battin, Coila Bevan, Jane E. Harding. (2008) Reply. American Journal of Obstetrics and Gynecology 198:5, 606-607
CrossRef53
Xavier Miracle, Gian Carlo Di Renzo, Ann Stark, Avroy Fanaroff, Xavier Carbonell-Estrany, Erich Saling (Coordinators of WAPM Premat. (2008) Guideline for the use of antenatal corticosteroids for fetal maturation. Journal of Perinatal Medicine 36:3, 191-196
CrossRef54
(2008) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 17:3, i-xii
CrossRef55
Wapner, Ronald J., Sorokin, Yoram, Mele, Lisa, Johnson, Francee, Dudley, Donald J., Spong, Catherine Y., Peaceman, Alan M., Leveno, Kenneth J., Malone, Fergal, Caritis, Steve N., Mercer, Brian, Harper, Margaret, Rouse, Dwight J., Thorp, John M., Ramin, Susan, Carpenter, Marshall W., Gabbe, Steven G., . (2007) Long-Term Outcomes after Repeat Doses of Antenatal Corticosteroids. New England Journal of Medicine 357:12, 1190-1198
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Stiles, Alan D., . (2007) Prenatal Corticosteroids — Early Gain, Long-Term Questions. New England Journal of Medicine 357:12, 1248-1250
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