Adverse Effects of Early Dexamethasone Treatment in Extremely-Low-Birth-Weight Infants
Ann R. Stark, M.D., Waldemar A. Carlo, M.D., Jon E. Tyson, M.D., M.P.H., Lu-Ann Papile, M.D., Linda L. Wright, M.D., Seetha Shankaran, M.D., Edward F. Donovan, M.D., M.P.H., William Oh, M.D., Charles R. Bauer, M.D., Shampa Saha, Ph.D., W. Kenneth Poole, Ph.D., Barbara J. Stoll, M.D., for The National Institute of Child Health Human Development Neonatal Research Network
Background Early administration of high doses of dexamethasonemay reduce the risk of chronic lung disease in premature infantsbut can cause complications. Whether moderate doses would beas effective but safer is not known.
Methods We randomly assigned 220 infants with a birth weightof 501 to 1000 g who were treated with mechanical ventilationwithin 12 hours after birth to receive dexamethasone or placebowith either routine ventilatory support or permissive hypercapnia.The dexamethasone was administered within 24 hours after birthat a dose of 0.15 mg per kilogram of body weight per day forthree days, followed by a tapering of the dose over a periodof seven days. The primary outcome was death or chronic lungdisease at 36 weeks' postmenstrual age.
Results The relative risk of death or chronic lung disease inthe dexamethasone-treated infants, as compared with those whoreceived placebo, was 0.9 (95 percent confidence interval, 0.8to 1.1). Since the effect of dexamethasone treatment did notvary according to the ventilatory approach, the two dexamethasonegroups and the two placebo groups were combined. The infantsin the dexamethasone group were less likely than those in theplacebo group to be receiving oxygen supplementation 28 daysafter birth (P=0.004) or open-label dexamethasone (P=0.01),were more likely to have hypertension (P<0.001), and weremore likely to be receiving insulin treatment for hyperglycemia(P=0.02). During the first 14 days, spontaneous gastrointestinalperforation occurred in a larger proportion of infants in thedexamethasone group (13 percent, vs. 4 percent in the placebogroup; P=0.02). The dexamethasone-treated infants had a lowerweight (P=0.02) and a smaller head circumference (P=0.04) at36 weeks' postmenstrual age.
Conclusions In preterm infants, early administration of dexamethasoneat a moderate dose has no effect on death or chronic lung diseaseand is associated with gastrointestinal perforation and decreasedgrowth.
Chronic lung disease develops in approximately 30 percent ofinfants with a birth weight of less than 1 kg who survive theinitial hospitalization.1 Lung inflammation resulting from mechanicalinjury, a high oxygen concentration, or infection contributesto the development of this condition.2,3 Low base-line serumcortisol concentrations and poor responses to physiologic dosesof corticotropin have been associated with an increased riskof chronic lung disease among infants with very low weight atbirth,4,5 suggesting that the inflammatory response to lunginjury may be exaggerated.
Data from some, though not all, clinical trials suggest thatthe early administration of dexamethasone (with the first dosegiven within 24 to 48 hours after delivery) may reduce the riskof chronic lung disease.6,7,8,9,10,11 In these studies, theinitial dose of dexamethasone was high (0.5 mg per kilogramof body weight per day), and many infants had adverse effects,such as hypertension or hyperglycemia. We performed a studyto determine whether treatment with a moderate dose of dexamethasonewould reduce the risk of chronic lung disease and have minimaladverse effects.
Methods
Infants
Inclusion criteria were a birth weight of 501 to 1000 g, treatmentwith mechanical ventilation within 12 hours after birth, andthe presence of an indwelling vascular catheter. For infantswhose birth weight was 751 to 1000 g, additional inclusion criteriawere ventilation at a fraction of inspired oxygen of 0.3 ormore and the administration of at least one dose of surfactant.We excluded infants with major congenital anomalies, congenitalnonbacterial infection, findings indicating a very low likelihoodof recovery (pH <6.8 or hypoxemia with bradycardia for morethan two hours), or prior postnatal treatment with a glucocorticoid.The study was conducted at 13 participating centers betweenFebruary 1998 and February 1999. The protocol was approved bythe institutional review board at each center, and written informedconsent was obtained from a parent of each infant.
Randomization
In a two-by-two factorial design, we tested both dexamethasonetreatment and a strategy of minimal ventilatory support (permissivehypercapnia). Infants were randomly assigned to one of fourgroups according to the study medication (dexamethasone or placebo)and ventilatory treatment (routine treatment with the goal ofmaintaining the partial pressure of carbon dioxide at a levelbelow 48 mm Hg or minimal ventilatory support with the goalof maintaining the partial pressure of carbon dioxide at a levelabove 52 mm Hg)12 with the use of a random, permuted-block algorithm.The treatment assignments were stratified according to the centerand the infant's birth weight (501 to 750 g or 751 to 1000 g).All staff members except the pharmacist were unaware of thedrug-group assignments, but the ventilatory-group assignmentswere not masked.
Study Protocol
Treatment with the study medication was initiated within 24hours after birth. The dexamethasone-treated infants receiveda 10-day tapered course (0.15 mg of dexamethasone per kilogramper day for three days, followed by 0.10 mg per kilogram forthree days, 0.05 mg per kilogram for two days, and 0.02 mg perkilogram for two days), with the daily dose divided in halfand given at 12-hour intervals intravenously or orally, if anintravenous catheter was no longer in place. The initial dosewas approximately equivalent to five times the estimated cortisol-replacementdose.13 The infants in the placebo groups received equal volumesof saline. During the 10-day treatment period, we discouragedthe prescription of open-label glucocorticoids by the attendingneonatologist, and we recorded any use of glucocorticoid therapyduring hospitalization.
Outcomes
The primary outcome was the combination of death by 36 weeks'postmenstrual age or chronic lung disease (defined by a needfor supplemental oxygen at least 12 hours per day) at 36 weeks'postmenstrual age. Secondary outcomes included chronic lungdisease, death by 36 weeks' postmenstrual age, a need for supplementaloxygen 28 days after birth, open-label glucocorticoid treatment,the level of respiratory support (mechanical ventilation, continuouspositive airway pressure, or supplemental oxygen alone) at 28days after birth and at 36 weeks' postmenstrual age, and theduration of oxygen therapy, ventilatory support, and the hospitalstay.
During the 10-day intervention period, we recorded hypertension(systolic pressure, >80 mm Hg), drug treatment for hypertension,hyperglycemia (blood glucose concentration, >180 mg per deciliter[10 mmol per liter]), insulin treatment for hyperglycemia, andevidence of upper gastrointestinal bleeding (a heme-positivegastric aspirate or emesis). We also recorded nosocomial infection,necrotizing enterocolitis, spontaneous gastrointestinal perforation,pulmonary interstitial emphysema, pneumothorax, pulmonary hemorrhage,patent ductus arteriosus, intracranial hemorrhage, periventricularleukomalacia, retinopathy of prematurity, and growth at thetime of discharge or death or at 120 days of age, if the infantremained hospitalized. Research nurses collected all study dataaccording to defined criteria and transmitted the data to acentral coordinating center.
Statistical Analysis
Using the Neonatal Research Network data base, we calculatedthat to determine whether treatment with dexamethasone wouldreduce the primary outcome from 55 percent to 44 percent (i.e.,reduce the relative risk of the outcome by 20 percent), we wouldneed a sample of 532 infants in each group. To ensure an adequatenumber of infants to evaluate the neurodevelopmental outcome,which we expected to do at 18 months' corrected age, we plannedto enroll 600 infants in each group.
We performed an intention-to-treat analysis. Base-line datafor infants enrolled in the study and for eligible infants whowere not enrolled were compared by t-tests for continuous variablesand by chi-square tests for categorical data. Logistic regressionwas used to analyze differences in outcomes and complicationsbetween the treatment groups. Multiple logistic-regression analysiswas used for categorical variables with more than two values(e.g., respiratory support). Initially, the analyses includeddexamethasone treatment, ventilatory treatment, and an interactionterm for dexamethasone and ventilatory treatment as factors.Because none of the interactions were significant, the analyseswere repeated without the interaction term, and we report theresulting P values for the main effects.
Results
The trial was monitored by an independent data and safety monitoringcommittee. The committee's initial evaluation, performed becauseof a high rate of unanticipated adverse events, identified frequentgastrointestinal perforations among the infants treated withdexamethasone. Because of the uncertainty involved in weighingthe relative importance of potential benefits and adverse outcomes,the committee recommended continuation of the trial with a modificationof the consent form to include this complication. However, thesteering committee voted to terminate the trial.
Infants
During the study period, 340 infants were eligible for enrollment,and 220 were enrolled. The other 120 eligible infants were notenrolled because of a parent's refusal (55 percent), the unavailabilityof a parent to provide consent or failure to seek consent (41percent), the physician's refusal (2 percent), or other, unknownreasons (2 percent). The infants who were not enrolled weresimilar to the enrolled infants with regard to birth weight(mean, 743 g in the group of unenrolled infants and 735 g inthe enrolled group), gestational age (mean, 25.7 and 25.6 weeks,respectively), male sex (51 percent and 52 percent, respectively),vaginal delivery (42 percent in both groups), and antenatalglucocorticoid therapy (77 percent and 75 percent, respectively),but they differed in racial distribution (26 percent white vs.41 percent, 52 percent black vs. 47 percent, and 20 percentHispanic vs. 10 percent, respectively).
Because the effect of dexamethasone treatment did not vary accordingto the type of ventilatory treatment, the ventilatory-treatmentgroups were combined for the purpose of analysis. The base-linecharacteristics of the infants in the dexamethasone and placebogroups were similar (Table 1).
Table 1. Base-Line Characteristics of the Infants According to the Treatment Assignment.
Outcomes
The relative risk of death or chronic lung disease at 36 weeks'postmenstrual age in the dexamethasone group was 0.9 (95 percentconfidence interval, 0.8 to 1.1) (Table 2). The relative riskdid not differ significantly between the two birth-weight groups.Mortality at 36 weeks' postmenstrual age and the rate of chroniclung disease among the infants who survived also did not differsignificantly between the dexamethasone and placebo groups.
Table 2. Relative Risks of Chronic Lung Disease or Death at 36 Weeks' Postmenstrual Age and of Oxygen Supplementation or Death 28 Days after Birth.
Twenty-eight days after birth, the infants in the dexamethasonegroup were less likely to be receiving supplemental oxygen orto have died than those in the placebo group (relative risk,0.8) (Table 2). Although mortality at 28 days was similar inthe two groups, a smaller proportion of infants in the dexamethasonegroup were receiving oxygen supplementation at 28 days.
The mean (±SD) proportion of doses of the study drugthat were actually given was lower in the dexamethasone group(93±16 percent) than in the placebo group (98±12percent, P=0.01), reflecting in part doses withheld becauseof complications potentially attributable to the study drug.Infants in the dexamethasone group were less likely than thosein the placebo group to receive open-label glucocorticoid treatmentduring hospitalization (34 percent vs. 51 percent, P=0.01).Only one infant in the dexamethasone group received open-labelglucocorticoid treatment during the 10-day intervention period,as compared with eight infants in the placebo group. Among theinfants who received supplemental treatment with open-labeldexamethasone, the mean duration of treatment was 25±33days in the dexamethasone group and 27±35 days in theplacebo group (P=0.82). The proportion of infants who requiredmechanical ventilation, continuous positive airway pressure,or supplemental oxygen alone 28 days after birth or at 36 weeks'postmenstrual age did not differ significantly between the twostudy groups. Similarly, there were no significant differencesbetween the groups in the duration of oxygen therapy or mechanicalventilation or in the median hospital stay among either infantswho survived or those who did not.
Pulmonary interstitial emphysema was diagnosed less frequentlyin the dexamethasone group than in the placebo group (relativerisk, 0.4), although the frequencies of pneumothorax, pulmonaryhemorrhage, and patent ductus arteriosus did not differ significantlybetween the two groups (Table 3). The rates of other outcomesascertained at death or discharge or at 120 days among hospitalizedinfants did not differ significantly between the dexamethasoneand placebo groups (Table 3).
A higher proportion of infants in the dexamethasone group thanin the placebo group had hypertension or received antihypertensivedrugs (Table 4). Although the frequency of hyperglycemia wassimilar in the two groups, a larger proportion of infants inthe dexamethasone group were treated with insulin. Upper gastrointestinalbleeding was uncommon, and the proportion of infants with thiscomplication did not differ significantly between the two groups.
Table 4. Complications Attributable to the Study Drug.
When an early increase in spontaneous intestinal perforationswas noted in the dexamethasone group, additional data were obtainedby reviewing medical records. During the first 14 days afterbirth, 14 infants in the dexamethasone group (13 percent) and4 in the placebo group (4 percent) had spontaneous intestinalperforations without evidence of necrotizing enterocolitis (P=0.02).Three additional infants in each group had necrotizing enterocolitiswith perforation. All but one of the infants with spontaneousperforation underwent laparotomy or peritoneal drain placement.The site of perforation was the small bowel in 13 infants andthe stomach in 1; the site was unknown in 4 infants. Duringthe remainder of the study period, four additional infants inthe placebo group and one in the dexamethasone group had spontaneousperforations (Table 3).
Perforation appeared to be associated with indomethacin treatmentwithin the first 24 hours (P= 0.02), and the effect of dexamethasoneon the perforation rate also appeared to be greater in the presenceof indomethacin than in its absence (Table 5). Perforation occurredin 19 percent of infants treated with both dexamethasone andindomethacin, in 2 percent of those treated with dexamethasonealone, in 5 percent of those who received placebo and indomethacin,and in none of the infants who received only placebo (Table 5).Although indomethacin treatment was not randomly assigned,the difference in the rates of perforation between the infantswho received indomethacin and those who did not was significantin both the dexamethasone group and the placebo group (P=0.05).
Table 5. Gastrointestinal Perforation within 14 Days after Birth, According to Whether Indomethacin Was Administered with or without Dexamethasone.
Weight, length, and head circumference were similar in the twostudy groups at birth (Table 6). The infants in the dexamethasonegroup weighed less than those in the placebo group 10 days afterbirth (P= 0.001) and at 36 weeks' postmenstrual age (P=0.02)and had a smaller head circumference (P=0.04) and tended tobe shorter at 36 weeks' postmenstrual age.
Unlike some previous investigators,6,7,8,9 we found no significantdifference in the relative risks of chronic lung disease at36 weeks' postmenstrual age, death, or the combined outcomein extremely-low-birth-weight infants treated with dexamethasoneor placebo. However, since a criterion for enrollment in ourstudy was a birth weight of 501 to 1000 g, our infants wererelatively immature and at high risk for a poor respiratoryoutcome.
Infants in the dexamethasone group were less likely than thosein the placebo group to require oxygen 28 days after birth,a finding that may be related to an antiinflammatory effectof dexamethasone treatment.14,15 Furthermore, infants in theplacebo group were more likely than those in the dexamethasonegroup to be treated with open-label dexamethasone. Since thedecision to administer open-label dexamethasone was made bythe attending neonatologist, these infants may have had a poorerclinical status than those who received early treatment withdexamethasone. An increased use of subsequent glucocorticoidtreatment in the placebo group has been noted in other trialsof early systemic9,10 or inhaled16 glucocorticoid treatment,and such use may minimize differences in the respiratory outcomebetween the glucocorticoid and placebo groups.
Although the risk of necrotizing enterocolitis did not differbetween the two study groups, the rate of spontaneous gastrointestinalperforation within the first two weeks in the dexamethasonegroup was more than three times that in the placebo group, andthis complication appeared to be associated with the administrationof indomethacin. Because indomethacin treatment was not assignedrandomly, the infants who received indomethacin may have beenmore susceptible to perforation. Nevertheless, the high perforationrate in the dexamethasone group was unanticipated and resultedin termination of the trial.
Spontaneous perforation has been reported in very-low-birth-weightinfants17,18 and has also been associated with dexamethasonetreatment for chronic lung disease19 and indomethacin treatmentfor patent ductus arteriosus.20,21,22 The small numbers of extremely-low-birth-weightinfants enrolled in previous trials of dexamethasone may havelimited the ability to detect this adverse event. In a recentlarge trial of a short course of dexamethasone given soon afterbirth, perforation during the first week occurred in 8 percentof the dexamethasone-treated infants and in 1 percent of theinfants who received placebo, although there was no significantdifference between the groups in the overall rate of perforation.9Similarly, in a large trial of a 12-day course of dexamethasoneor placebo, perforation occurred more often in the dexamethasonegroup, although the difference was not statistically significant.10
The mechanism of perforation may be related to the role of prostaglandinsin maintaining gastrointestinal mucosal integrity.23 Glucocorticoidsand indomethacin inhibit prostaglandin production at two pointsin the synthetic pathway,24,25 perhaps explaining the associationwith perforation.
Hypertension and hyperglycemia are recognized complicationsof dexamethasone therapy.7,9,10,26,27 In our study, hypertensionand insulin treatment were more frequent in the dexamethasonegroup than in the placebo group, although the rates of hypertensionand insulin treatment were lower in our dexamethasone-treatedinfants than in similar infants given a higher dose of dexamethasoneand a longer course of treatment.10 Use of other glucocorticoidsor physiologic replacement28 rather than therapeutic doses mayfurther reduce complications.
Dexamethasone treatment has been reported to have both transientand sustained negative effects on growth.7,10,29 In our study,the dexamethasone-treated infants weighed less than the placebo-treatedinfants at the end of the intervention period. In addition,the infants who received dexamethasone weighed less and hada smaller head circumference at 36 weeks' postmenstrual age,even though a larger proportion of infants in the placebo groupwere subsequently treated with open-label dexamethasone. Extremely-low-birth-weightinfants may be especially susceptible to the catabolic effectsof glucocorticoid treatment30 during the early postnatal period,when they are likely to receive too few calories, and this susceptibilitymay affect their subsequent growth.31
In summary, we found that a 10-day tapered course of dexamethasonegiven at a moderate dose had no discernible effect on chroniclung disease or mortality in extremely-low-birth-weight infants.The dose we used, although substantially lower than the initialdoses used in other trials or in clinical practice, was associatedwith an increased risk of spontaneous gastrointestinal perforation,as well as with known complications of glucocorticoid therapy.The risk of perforation appears to be associated with concomitantindomethacin treatment. Given these serious complications andthe lack of a discernible benefit, we believe that early treatmentwith dexamethasone to prevent chronic lung disease in extremely-low-birth-weightinfants is not indicated.
Supported by cooperative agreements with the National Instituteof Child Health and Human Development (U10 HD34167, U10 HD34216,U10 HD21373, U10 HD27881, U10 HD21385, U10 HD27853, U10 HD27904,U01 HD21397, U01 HD36790, U10 HD27851, U10 HD21364, U10 HD27871,and U10 HD21415) and by grants from the General Clinical ResearchCenters Program (M01 RR 02635, M01 RR 02172, M01 RR 00997, M01RR 08084, M01 RR 06022, M01 RR 08084, and M01 RR 00070).
We are indebted to Drs. Gordon Avery, Mary D'Alton, John Fletcher,Christine Gleason, Maureen Maguire, Carol Redmond, and RobinRoberts for their contributions as members of the data and safetymonitoring committee; to Drs. John Sinclair and Mark Klebanofffor their helpful review of the manuscript; and to our medicaland nursing colleagues and the infants and their parents whoparticipated in the study.
* Other members of the National Institute of Child Health andHuman Development Neonatal Research Network are listed in theAppendix.
Source Information
From Brigham and Women's Hospital, Boston (A.R.S.); the University of Alabama at Birmingham, Birmingham (W.A.C.); the University of Texas at Houston, Houston (J.E.T.); the University of New Mexico, Albuquerque (L.-A.P.); the National Institute of Child Health and Human Development, Bethesda, Md. (L.L.W.); Wayne State University, Detroit (S. Shankaran); the University of Cincinnati, Cincinnati (E.F.D.); Women and Infant's Hospital, Providence, R.I. (W.O.); the University of Miami, Miami (C.R.B.); Research Triangle Institute, Research Triangle Park, N.C. (S. Saha, W.K.P.); and Emory University, Atlanta (B.J.S.). Other authors were Avroy A. Fanaroff, M.B., B.Ch., Case Western Reserve University, Cleveland; Richard A. Ehrenkranz, M.D., Yale University, New Haven, Conn.; Sheldon B. Korones, M.D., University of Tennessee at Memphis, Memphis; and David K. Stevenson, M.D., Stanford University, Stanford, Calif.
Address reprint requests to Dr. Stark at Newborn Medicine, CWN-6, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at astark{at}uptodate.com.
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Appendix
Other members of the National Institute of Child Health andHuman Development Neonatal Research Network who participatedin the study were as follows: University of Alabama at Birmingham— M.V. Collins; Brigham and Women's Hospital — K.A.Fournier; Case Western Reserve University — M. Hack, N.Newman; University of Cincinnati — A. Jobe (chair of steeringcommittee), M. Mersmann; Emory University — E. Hale; Universityof Miami — S. Duara, A.M. Worth; National Institute ofChild Health and Human Development — S.J. Yaffe, E.M.McClure; University of New Mexico — C. Backstrom; ResearchTriangle Institute — B. Hastings; Stanford University— M.B. Ball; University of Tennessee at Memphis —H. Bada, T. Hudson; University of Texas Southwestern MedicalCenter — A. Laptook, S. Madison; Wayne State University— G. Konduri, G. Muran; Women and Infants' Hospital —B. Stonestreet, A. Hensman; Yale University — P. Gettner.
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Doyle, L. W., Davis, P. G., Morley, C. J., McPhee, A., Carlin, J. B.
(2006). Reopening the Debate on Corticosteroids: In Reply. Pediatrics
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Manzar, S.
(2006). High-Dose Indomethacin for Patent Ductus Arteriosus Closure: How Strong Is the Evidence?. Pediatrics
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Walsh, M. C., Szefler, S., Davis, J., Allen, M., Van Marter, L., Abman, S., Blackmon, L., Jobe, A.
(2006). Summary proceedings from the bronchopulmonary dysplasia group.. Pediatrics
117: S52-S56
[Abstract][Full Text]
Ng, P. C., Lee, C. H., Bnur, F. L., Chan, I. H.S., Lee, A. W.Y., Wong, E., Chan, H. B., Lam, C. W.K., Lee, B. S.C., Fok, T. F.
(2006). A Double-Blind, Randomized, Controlled Study of a "Stress Dose" of Hydrocortisone for Rescue Treatment of Refractory Hypotension in Preterm Infants. Pediatrics
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Doyle, L. W., Davis, P. G., Morley, C. J., McPhee, A., Carlin, J. B., and the DART Study Investigators,
(2006). Low-Dose Dexamethasone Facilitates Extubation Among Chronically Ventilator-Dependent Infants: A Multicenter, International, Randomized, Controlled Trial. Pediatrics
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Shashikant, B. N., Miller, T. L., Welch, R. W., Pilon, A. L., Shaffer, T. H., Wolfson, M. R.
(2005). Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles. J. Appl. Physiol.
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Ehrenkranz, R. A., Walsh, M. C., Vohr, B. R., Jobe, A. H., Wright, L. L., Fanaroff, A. A., Wrage, L. A., Poole, K., for the National Institutes of Child Health and Hu,
(2005). Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia. Pediatrics
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Hack, M., Taylor, H. G., Drotar, D., Schluchter, M., Cartar, L., Wilson-Costello, D., Klein, N., Friedman, H., Mercuri-Minich, N., Morrow, M.
(2005). Poor Predictive Validity of the Bayley Scales of Infant Development for Cognitive Function of Extremely Low Birth Weight Children at School Age. Pediatrics
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Lodygensky, G. A., Rademaker, K., Zimine, S., Gex-Fabry, M., Lieftink, A. F., Lazeyras, F., Groenendaal, F., de Vries, L. S., Huppi, P. S.
(2005). Structural and Functional Brain Development After Hydrocortisone Treatment for Neonatal Chronic Lung Disease. Pediatrics
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Gordon, P V, Paxton, J B, Fox, N S
(2005). The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells. J Endocrinol
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Gordon, P. V.
(2005). Weighing Statistical Certainty Against Ethical, Clinical, and Biologic Expediency: The Contributions of the Watterberg Trial Tip the Scales in the Right Direction. Pediatrics
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Christou, H., Brodsky, D.
(2005). Lung Injury and Bronchopulmonary Dysplasia in Newborn Infants. J Intensive Care Med
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Doyle, L. W., Halliday, H. L., Ehrenkranz, R. A., Davis, P. G., Sinclair, J. C.
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Wood, N S, Costeloe, K, Gibson, A T, Hennessy, E M, Marlow, N, Wilkinson, A R, for the EPICure Study Group,
(2005). The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch. Dis. Child. Fetal Neonatal Ed.
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Stark, A. R.
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Nanthakumar, N. N., Young, C., Ko, J. S., Meng, D., Chen, J., Buie, T., Walker, W. A.
(2005). Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol.
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Watterberg, K. L., Gerdes, J. S., Cole, C. H., Aucott, S. W., Thilo, E. H., Mammel, M. C., Couser, R. J., Garland, J. S., Rozycki, H. J., Leach, C. L., Backstrom, C., Shaffer, M. L.
(2004). Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial. Pediatrics
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Roberts, R. S.
(2004). Early Closure of the Watterberg Trial. Pediatrics
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Thebaud, B., Michelakis, E. D., Wu, X.-C., Moudgil, R., Kuzyk, M., Dyck, J. R.B., Harry, G., Hashimoto, K., Haromy, A., Rebeyka, I., Archer, S. L.
(2004). Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus: Implications for Infants With Patent Ductus Arteriosus. Circulation
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Lommatzsch, M., Klotz, J., Virchow, J. C. Jr., Watchko, J. F., Brozanski, B. S., Gordon, P. V., Yeh, T. F., Lin, H. C., Huang, C. C., Jobe, A. H.
(2004). Postnatal Dexamethasone for Lung Disease of Prematurity. NEJM
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Yeh, T. F., Lin, Y. J., Lin, H. C., Huang, C. C., Hsieh, W. S., Lin, C. H., Tsai, C. H.
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Jobe, A. H.
(2004). Postnatal Corticosteroids for Preterm Infants -- Do What We Say, Not What We Do. NEJM
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Parikh, N. A., Locke, R. G., Chidekel, A., Leef, K. H., Emberger, J., Paul, D. A., Stefano, J. L.
(2004). Effect of Inhaled Corticosteroids on Markers of Pulmonary Inflammation and Lung Maturation in Preterm Infants With Evolving Chronic Lung Disease. JAOA: Journal of the American Osteopathic Association
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Baud, O
(2004). Postnatal steroid treatment and brain development. Arch. Dis. Child. Fetal Neonatal Ed.
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Shek, C. C., Ng, P. C., Fung, G. P. G., Cheng, F. W. T., Chan, P. K. S., Peiris, M. J. S., Lee, K. H., Wong, S. F., Cheung, H. M., Li, A. M., Hon, E. K. L., Yeung, C. K., Chow, C. B., Tam, J. S., Chiu, M. C., Fok, T. F.
(2003). Infants Born to Mothers With Severe Acute Respiratory Syndrome. Pediatrics
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(2003). Statement on the Care of the Child with Chronic Lung Disease of Infancy and Childhood. Am. J. Respir. Crit. Care Med.
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Counsell, S J, Rutherford, M A, Cowan, F M, Edwards, A D
(2003). Magnetic resonance imaging of preterm brain injury. Arch. Dis. Child. Fetal Neonatal Ed.
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Clark, R. H., Thomas, P., Peabody, J.
(2003). Extrauterine Growth Restriction Remains a Serious Problem in Prematurely Born Neonates. Pediatrics
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Kallapur, S. G., Kramer, B. W., Moss, T. J. M., Newnham, J. P., Jobe, A. H., Ikegami, M., Bachurski, C. J.
(2003). Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am. J. Physiol. Lung Cell. Mol. Physiol.
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Davis, J. M., Parad, R. B., Michele, T., Allred, E., Price, A., Rosenfeld, W.
(2003). Pulmonary Outcome at 1 Year Corrected Age in Premature Infants Treated at Birth With Recombinant Human CuZn Superoxide Dismutase. Pediatrics
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Lassus, P., Nupponen, I., Kari, A., Pohjavuori, M., Andersson, S.
(2002). Early Postnatal Dexamethasone Decreases Hepatocyte Growth Factor in Tracheal Aspirate Fluid From Premature Infants. Pediatrics
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Vaucher, Y. E.
(2002). Bronchopulmonary Dysplasia: An Enduring Challenge. Pediatr. Rev.
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Jacobs, H. C., Chapman, R. L., Gross, I., Barrington, K. J., Stark, A. R.
(2002). Premature Conclusions on Postnatal Steroid Effects. Pediatrics
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Romagnoli, C, Zecca, E, Luciano, R, Torrioli, G, Tortorolo, G
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87: F55-58
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Moritz, K., Butkus, A., Hantzis, V., Peers, A., Wintour, E. M., Dodic, M.
(2002). Prolonged Low-Dose Dexamethasone, in Early Gestation, Has No Long-Term Deleterious Effect on Normal Ovine Fetuses. Endocrinology
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Kritsch, K. R., Murali, S., Adamo, M. L., Ney, D. M.
(2002). Dexamethasone decreases serum and liver IGF-I and maintains liver IGF-I mRNA in parenterally fed rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.
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Banks, B. A.
(2002). Postnatal Dexamethasone for Bronchopulmonary Dysplasia: A Systematic Review and Meta-analysis of 20 Years of Clinical Trials. NeoReviews
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Wright, L. L.
(2001). The Role of Follow-up in Randomized Controlled Trials. NeoReviews
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(2001). Other Articles Noted. Evid. Based Nurs.
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Auten, R. L., Richardson, R. M., White, J. R., Mason, S. N., Vozzelli, M. A., Whorton, M. H.
(2001). Nonpeptide CXCR2 Antagonist Prevents Neutrophil Accumulation in Hyperoxia-Exposed Newborn Rats. J. Pharmacol. Exp. Ther.
299: 90-95
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Barrington, K. J.
(2001). Hazards of systemic steroids for ventilator-dependent preterm infants: What would a parent want?. CMAJ
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Barrington, K. J.
(2001). Postnatal Steroids and Neurodevelopmental Outcomes: A Problem In the Making. Pediatrics
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New;, M. I., Frias, J., Levine, L. S., Oberfield, S. E., Pang, S., Silverstein, J.
(2001). Prenatal Treatment of Congenital Adrenal Hyperplasia: Author Differs With Technical Report. Pediatrics
107: 804-804
[Full Text]
0.5 mg per kilogram of body weight per day), and many infants had adverse effects, such as hypertension or hyperglycemia. We performed a study to determine whether treatment with a moderate dose of dexamethasone would reduce the risk of chronic lung disease and have minimal adverse effects. 
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