PEDIATRICS Vol. 115 No. 5 May 2005, pp. 1446-1447 (doi:10.1542/10.1542/peds.2004-2673)
Weighing Statistical Certainty Against Ethical, Clinical, and Biologic Expediency: The Contributions of the Watterberg Trial Tip the Scales in the Right Direction
Phillip V. Gordon, MD, PhDDepartment of Pediatrics
University of Virginia Children's Hospital
Charlottesville, VA
To the Editor.—
The study by Watterberg et al,1 published in the December 2004 issue of Pediatrics, does much to forward the debates surrounding prophylactic steroid use in extremely low birth weight infants. The long-term effect of dexamethasone on neurodevelopment has moved most neonatologists away from the belief that, if a little potency is good, a lot must be better. For some of us, that same concern exists for intestinal perforations. However, many of us had hoped that physiologic replacement of cortisol would prove to be a more biologically appropriate strategy to reduce the incidence of chronic lung disease while avoiding neurodevelopmental and intestinal complications. Others have suggested that the problem is not one of biology but of chemistry and that we have yet to test all the proper synthetic variants of glucocorticoids, one of which might avoid adversity. With regard to perforations, this now seems an unlikely prospect, because those in the Watterberg study who had perforations were found to have significantly higher endogenous cortisol levels when compared with those who did not have them.
In a recent editorial exchange with Alan Jobe, I argued that one of the flaws in the current methodologies of dexamethasone study was that we were performing trials in which we examined 1 drug but in fact had 2 other drugs in the climate that were capable of harmful synergism (indomethacin and antenatal betamethasone).2 Now, for the second time,3 we have found that the combination of steroids and indomethacin was significantly associated with intestinal perforation. Although the incidence of antenatal steroid exposure was also high (77–81%), there was unfortunately no analysis of dosage timing to determine if those supraphysiologic cortisol levels might have been secondary to late administration of betamethasone. Nonetheless, findings such as these make it clear that the harmful-synergism hypothesis is one that cannot be rejected in this patient population simply because a drug has proven to be safe or beneficial as a single agent.
The biological basis for perforations is being actively investigated. As alluded to in the Watterberg article, we now know that glucocorticoids cause a skewing of ileal growth such that the mucosa undergoes proliferative hypertrophy, whereas the bowel wall atrophies and the submucosa thins over the course of just a few days.4,5 In newborn mice, dexamethasone administration dramatically rearranges growth factors and alters metabolism to accomplish this. Indomethacin also alters ileal metabolism, and some facets are synergistic; in particular, the combination of the 2 drugs diminishes all 3 isoforms of nitric oxide synthase,6 reduces S-nitrosylation within smooth muscle nuclei (unpublished data) and halts production of transforming growth factor 
.7 These last findings are particularly compelling because the muscularis is found to have focal necrosis in infants with perforations.8 Another accomplishment of this clinical study was to knit together the basic science and the clinical data by measuring cortisol levels in all enrolled patients, allowing us to recognize that adrenal replete infants seem to be more abundant than previously anticipated.
What then is this study's failing? According to Roberts' recent Pediatrics commentary,9 it is that the world missed the opportunity to "settle the issue" of whether early steroids are advisable to prevent bronchopulmonary dysplasia because the trial was stopped early. No doubt that his assertion will resonate with statistical purists, but it must sound terribly hollow to the parents of children who acquired perforations. Roberts' priorities are wrong. The answer is not to keep lumping our extremely low birth weight infants into endless cohorts, ignoring an unacceptably morbid complication to grab at the Holy Grail of hypotheses. We can do better than that. Watterberg and her colleagues have masterfully shown us that the answer lies in better defining our cohorts into subpopulations, according to their capacity to respond to the intervention. This "arch skeptic" (Roberts' term for those of us who would halt additional trials of "one-size-fits-all" steroid prophylaxis) was thrilled to find that hypoadrenal infants exposed to chorioamnionitis had a significant reduction in bronchopulmonary dysplasia with hydrocortisone treatment, whereas those infants with supraphysiologic levels acquired intestinal perforations. This is real progress in the right direction, even if some will be reluctant to recognize it as such.
REFERENCES
- Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.
Pediatrics. 2004;114
:1649
–1657
[Abstract/Free Full Text] - Gordon PV. Postnatal dexamethasone for lung disease of prematurity.
N Engl J Med. 2004;350
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[Free Full Text] - Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.
N Engl J Med. 2001;344
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–101
[Abstract/Free Full Text] - Gordon PV, Price WA, Stiles AD. Dexamethasone administration to newborn mice alters mucosal and muscular morphology in the ileum and modulates IGF-I localization. Pediatr Res. 2001;49 :93 –100[Web of Science][Medline]
- Herman AC, Carlisle EM, Paxton JB, Gordon PV. Insulin-like growth factor-I governs submucosal growth and thickness in the newborn mouse ileum. Pediatr Res. 2004;55 :507 –513[Medline]
- Herman AC, Paxton JB, Gaston BM, Gordon PV. Pharmacologic doses of indomethacin and dexamethasone synergistically reduce nitric oxide synthase abundance in newborn mouse ileum [abstract]. Pediatr Res. 2004;55 :485a
- Gordon PV, Price WA, Stiles AD, Rutledge JC. Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants. Pediatr Dev Pathol. 2001;4 :532 –537[CrossRef][Web of Science][Medline]
- Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol. 1999;19 :573 –577[CrossRef][Medline]
- Roberts R. Early closure of the Watterberg trial [commentary].
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[Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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- Weighing Statistical Certainty Against Ethical, Clinical, and Biologic Expediency: The Contributions of the Watterberg Trial Tip the Scales in the Right Direction: In Reply
- Kristi Watterberg and for the PROPHET Study Group
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