Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Does antepartum steroid therapy cause fetal brain injury?
- Ralph L Cavalieri (7 February 2006)
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Betamethasone: safety and efficacy
- David J R Hutchon (12 March 2006)
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Cochrane Collaboration RE meta analysis
- David JR Hutchon (25 March 2006)
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Prenatal steroids
- James P Neilson (11 April 2006)
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Prenatal steroids -response
- David JR Hutchon (12 April 2006)
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Ralph L Cavalieri, Attending, OB/GYN Department of OB/GYN, Jamaica Hospital Medical Center,89-06 135th Street, Jamaica, NY 11418
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Editor-- Use of antepartum steroid therapy to prevent respiratory distress syndrome(RDS) in infants born prematurely is widespread, but relatively little has been done to prove long-term safety of this practice. Animal and human data indicate possible fetal brain injury caused by maternal administration of betamethasone or dexamethasone (1). The recent paper of SR Dalziel et al.(2) is the largest study to date addressing the question of long-term safety of antenatal steroid therapy, but issues of selection bias seriously taint their conclusions. Only 17% of the initial 1142 cases in the trial were included. Crucial effects may therefore have been overlooked in the 83% of patients who were not analyzed. Patients that were less educated and in lower socioeconomic classes were excluded, albeit inadvertently, as noted by the authors. These are the very patients who would be most likely to exhibit uncompensated adverse effects of antenatal steroid therapy. There was no breakdown by whether the mother had been given a high or low dose of betamethasone. There was no delineation according to gestational age at the time of administration of maternal steroid or any analysis of the clinical course of the infants such as reduction in incidence of respiratory distress syndrome or decrease in perinatal mortality. The range of treated gestations was very broad, 24-36 weeks. Development in earlier gestations would be more likely to be adversely affected. These authors have neither proven safety nor provided evidence to recommend further promotion of antenatal steroid therapy. The fact that their study showed no harm could be a consequence of limitations in study design. Thousands of pregnant mothers with minimal likelihood of preterm birth are treated every year with the aim of preventing respiratory distress syndrome. As many as 50 normal infants are exposed to steroids to prevent one case of RDS(3). Steroid-related hippocampal and other brain damage may rob an individual of sophisticated thought capabilities, linguistic, spatial, and expressive functions. Our zeal to reap the benefits of steroids could result in an epidemic of subtle brain disorders that will be extraordinarily difficult to diagnose over the next 30 to 40 years. Their use should not be undisciplined. We should not use this medicine unless the risk benefit analysis is clear and shows that permanent lung disability, intraventricular hemorrhage and death prevented outweighs potential iatrogenic brain damage in the large number of treated fetuses. 1. Cavalieri RL, Cohen WR. Antenatal steroid therapy: have we undervalued the risks? J Matern Fetal Neonatal Med, accepted for publication. 2. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, Harding, JE. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomized controlled trial. BMJ,doi:10.1136/bmj .38576.494363.EO 3. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress syndrome: discussion. Am J Obstet Gynecol 1995; 173:335-44. Competing interests: None declared |
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David J R Hutchon, Consultant Obstetrician and Gynaecologist Memorial Hospital, Darlington, Co Durham, England
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Long term follow-up after antenatal exposure to betamethasone is very important especially when one considers the frequency that it is now being used in pregnancy. Betamethasone has recently been recommended prior to elective Caesarean Section at term. (1) I have studied this article and the references in detail but I am having difficulty in equating the figures in this paper and its references with the conclusions given. In the electronic version of this paper (2) there is a flow diagram showing the randomisation and outcome for the 1142 mothers. There were 601 babies exposed to betamethasone and 617 in the placebo arm. There were 108 neonatal deaths in the betamethasone arm and 122 in the placebo arm. There were 21 subsequent deaths in each arm, therefore presumed survival in the betamethasone arm was 472 and 474 in the placebo group. Analysis shows a 6.2% relative reduction for death in the treatment arm, with an odds ratio of 1.1 (95% confidence interval 0.8 to 1.5). The number needed to treat (NNT) to benefit one individual is 67 and the 95% confidence interval lies between an NNT(benefit) of 16 through infinity to an NNT(harm) of 29. As has already been pointed out by Ralph Cavalieri, the number of individuals who could be contacted or agreed to follow-up at age 30 years was only 17% of the initial 1142 cases in the trial. Purely on the basis of the figures in this publication it is quite wrong to conclude that a single course of betamethosone does not affect psychological functioning. Equally there is no evidence that the use of betamethasone has any benefit in long term survival, and the number needed to treat (NNT benefit) is alarmingly high. The authors need to address these issues in a written response. References 1. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, Harding, JE. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomized controlled trial. BMJ,doi:10.1136/bmj .38576.494363.EO 2. Giving steroids before elective caesarean section: Authors respond to editorial P R Stutchfield and R Whitaker BMJ 2005 331: 1475. Competing interests: I believe in careful analysis of all published opapers in my field of interest |
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David JR Hutchon, Consultant Obstetrician and Gynaecologist Memorial Hospital, Darlington, DL3 6HX
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Since I have not had any response from the authors, I can assume that the figures provided on the electronic version of this paper were not a misprint. In other words there were 108 neonatal deaths in the treatment group of 601 and 122 neonatal deaths in the control group of 617. If these figures are inserted into the Cochrane Collaboration meta-analysis replacing the Auckland 1972 figures provided, it results in important changes. For the Auckland study the Peto Odds Ratio becomes 0.89 with 95% CI 0.667 to 1.185 which is a statistically insignificant difference. For the meta-analysis the Peto odds ratio becomes 0.73 with 95% CI 0.6 to 0.88 The confidence interval is very close to making this an insignificant difference and emphasizes the need to be extremely cautious with the use of corticosteroids for the prevention of RDS in preterm infants. It also emphasizes the need to explore other physiological approaches to the problem until we are able to prevent preterm delivery altogether. Anyone who wishes to see the calculations in detail is welcome to contact me. Competing interests: A slight correction to the figures in the previous rapid response |
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James P Neilson, Co-ordinating Editor, Cochrane Pregnancy and Childbirth Group School of Reproductive & Developmental Medicine, University of Liverpool
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The important Cochrane review on the use of prenatal steroids before anticipated preterm birth has been updated and radically revised by Devender Roberts and Stuart Dalziel. It will be published in the next issue of the Cochrane Library. I don't think it is helpful, in the meantime, to draw conclusions by altering the results of a single, albeit important, trial in a systematic review that contains many studies. Competing interests: None declared |
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David JR Hutchon, Consultant Obstetrician Darlington Memorial Hospital, DL3 8QZ
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I await the publication of the updated and radically revised review with anticipation. I presume that Professor Neilson is party to the results as he uses the word “radical”. Does this mean there is a reversal of the conclusion?
I did not try to draw any conclusion, nor was I aware that a Cochrane update was almost ready for publication, but I do not see this as a reason for not raising awareness of possible weaknesses of the current review. Looking carefully at the current review I have been able to identify other inconsistencies that readers may wish to check themselves. The original metanalysis appeared in “Effective care in Pregnancy” Page 754 table 45.12 contains 12 studies used to assess the effect of corticosteroids on early neonatal deaths. Some of these are in the latest Cochrane review analysis 01.02 which compares corticosteroids versus placebo for outcome neonatal death. However for the Auckland, Block, Gamsu, and Morales studies the figures remain unchanged between the two reports. Does this mean there were no deaths 7 –28 days? We now know this is not true for the Auckland study. There is also something peculiar about the randomisation in the Schmidt study. In the treatment group there were 15 more cases and no deaths, but no more cases and one less death in the controls. (resurrection?) Professor Neilson does not feel it is helpful at this time to reanalyse the figures even when this involves the major study of the metanlaysis. He does not however appear to dispute the figures. Competing interests: None declared |
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