Background We studied the outcomes at school age in childrenwho had participated in a double-blind, placebo-controlled trialof early postnatal dexamethasone therapy (initiated within 12hours after birth) for the prevention of chronic lung diseaseof prematurity.
Methods Of the 262 children included in the initial study, 159lived to school age. Of these children, 146 (72 in the dexamethasonegroup and 74 in the control group) were included in our study.All the infants had had severe respiratory distress syndromerequiring mechanical ventilation shortly after birth. In thedexamethasone group, 0.25 mg of dexamethasone per kilogram ofbody weight was given intravenously every 12 hours for one week,and then the dose was tapered. We evaluated the children's growth,neurologic and motor function, cognition, and school performance.
Results Children in the dexamethasone group were significantlyshorter than the controls (P=0.03 for boys, P=0.01 for girls,and P=0.03 for all children) and had a significantly smallerhead circumference (P=0.04). Children in the dexamethasone grouphad significantly poorer motor skills (P<0.001), motor coordination(P<0.001), and visual–motor integration (P=0.02). Ascompared with the controls, children in the dexamethasone groupalso had significantly lower full IQ scores (mean [±SD],78.2±15.0 vs. 84.4±12.6; P=0.008), verbal IQ scores(84.1±13.2 vs. 88.4±11.8, P=0.04), and performanceIQ scores (76.5±14.6 vs. 84.5±12.7, P=0.001).The frequency of clinically significant disabilities was higheramong children in the dexamethasone group than among controls(28 of 72 [39 percent] vs. 16 of 74 [22 percent], P=0.04).
Conclusions Early postnatal dexamethasone therapy should notbe recommended for the routine prevention or treatment of chroniclung disease, because it leads to substantial adverse effectson neuromotor and cognitive function at school age.
Postnatal dexamethasone therapy has been used to treat or preventchronic lung disease of prematurity1,2,3,4,5,6,7,8; however,the long-term effects of dexamethasone on development are notknown. We previously reported results from our two-year follow-upstudy of dexamethasone treatment9 and from other studies conductedin young children.10,11,12,13,14,15,16,17,18,19,20,21 Thesestudies indicated that early postnatal dexamethasone therapymight affect somatic growth and neurodevelopmental outcome.Since the results of two-year follow-up cannot always predictfuture morbidity, there is a compelling need for long-term follow-up.In the current study, we analyzed the outcomes in the same cohortof children at school age.
Methods
Initial Study
All infants born between October 1992 and April 1995 in sixparticipating hospitals who had a birth weight between 500 and1999 g and had severe respiratory distress syndrome requiringmechanical ventilation within six hours after birth were includedin the initial double-blind, placebo-controlled clinical trial.In the dexamethasone group, dexamethasone sodium phosphate wasadministered intravenously every 12 hours, at a dose of 0.25mg per kilogram of body weight from day 1 through day 7, 0.12mg per kilogram from day 8 through day 14, 0.05 mg per kilogramfrom day 15 through day 21, and 0.02 mg per kilogram from day22 through day 28. The first dose was given within 12 hoursafter birth. The study was approved by the scientific and humanexperimentation committee of each hospital. Written informedconsent was obtained from the parents in each case.
A total of 262 infants were included in the initial study; 130received saline placebo, and 132 received dexamethasone. Duringthe study, none of the physicians or caretakers were aware ofthe treatment assignments. The results of the study have beenreported previously.1 In summary, early dexamethasone therapysignificantly reduced the incidence of chronic lung diseasediagnosed either at 28 days after birth (21 of 132 in the dexamethasonegroup [16 percent] vs. 40 of 130 in the control group [31 percent],P=0.004) or at 36 weeks after conception (20 of 132 [15 percent]vs. 37 of 130 [28 percent], P=0.009). The mortality rate wassimilar in the two groups (44 of 132 [33 percent] vs. 39 of130 [30 percent], P=0.56).
Clinical suspicion of sepsis was slightly, but not significantly,more common in the dexamethasone group than in the control group(30 of 132 [23 percent] vs. 19 of 130 [15 percent], P=0.09).Bacteremia was identified in 13 infants in the dexamethasonegroup (10 percent) and 8 infants in the control group (6 percent).The total number of infants with bacteremia, clinical sepsis,or both was significantly higher in the dexamethasone groupthan in the control group (43 of 132 [33 percent] vs. 27 of130 [21 percent], P=0.03). Meningitis occurred in four infantsin each group. Fungus cultures were available in three participatinghospitals. Four infants in the control group and four in thedexamethasone group had fungemia (Candida albicans). Transienthyperglycemia, hypertension, cardiac hypertrophy, hyperparathyroidism,and a transient delay in weight gain were associated with dexamethasonetherapy. An initial follow-up study at two years of age showedthat the dexamethasone-treated children had poorer somatic growthand neuromuscular function than the children in the controlgroup.9
Follow-up Study
Of the 262 children included in the initial study, 159 livedto school age. Of these children, 146 (92 percent) were includedin the current study (72 in the dexamethasone group and 74 inthe control group). Figure 1 indicates what happened to thechildren in each group up to the time of the current study.
Figure 1. Disposition of the Study Subjects According to Treatment Assignment at Birth.
Most of the children who died after the initial study period but before school age died of chronic lung disease at one year of age or earlier.
A follow-up evaluation team was formed. None of the team memberswere aware of the study design or the clinical courses of thechildren. At the visit, an interim medical history was obtainedand a physical examination was performed. The head circumferencewas measured, with the use of a tape measure, from the superiorborders of the eyebrows anteriorly to the occipital protuberanceposteriorly. The weight and height were measured with the useof an electronic scale.
Neurologic examination was performed by a pediatric neurologist.A standard motor test, the Movement Assessment Battery for Childrendesigned by Henderson and Sugden,22 was administered by a physicaltherapist. The test includes eight tasks, grouped under threeheadings: manual dexterity (which includes placing pegs, threadinglace, and following a flower trail with a pencil on paper),ball skills (which include one-hand bounce and catch and throwinga beanbag into a box), and static and dynamic balance (whichincludes "stork balance" on one foot, jumping in squares, andheel-to-toe walking). For each task the child was given a score,ranging from 0 to 5, depending on his or her age and performance;lower scores indicated better performance. The total impairmentscore was the sum of the scores on the eight tasks and rangedfrom 0 to 40.
Motor coordination, visual perception, and visual–motorintegration were assessed by means of the Beery–Buktenicadevelopmental test, fourth edition.23 This test evaluated thesuccess or failure of the drawing, the identification, or boththe drawing and identification of a total of 27 geometric figures;the total score ranges from 0 to 27, with higher scores indicatingbetter performance. The performance score for each child wasadjusted for age.
Cognitive function was assessed by means of the Wechsler IntelligenceScale for Children, third edition (WISC-III), with scales forfull IQ, verbal IQ, and performance IQ. In addition, other compositecognitive outcomes measured by subscales of the WISC-III wereassessed. All these tests have Chinese-language versions thathave been verified by the Chinese Behavioral Science Association.
Hearing was measured with pure-tone audiometric screening. Hearingimpairment was defined as a hearing loss of more than 20 dBin at least one ear. Visual acuity was tested with a Snellenchart. Visual impairment was defined as visual acuity of lessthan 20/60 in at least one eye.
Each child's academic performance was assessed by a teacherwho had 20 years of experience in a special school for handicappedchildren. Arithmetic,24 language,25 and adaptive behavior26were evaluated. A parent, usually the mother, was interviewedwith the use of questionnaires in order to characterize thechild's adaptive behavior and performance in school. These questionnaires,which were modified from Kaufman and Kaufman27 and Luckassonet al.,28 assessed the personal and social proficiency of thechild by measuring four domains: communication, daily living,socialization, and motor function.
The definition of clinically significant disability in thisstudy was modified from the criteria of Robertson et al.29 Anyone of the following was defined as a clinically significantdisability: a clinical diagnosis of cerebral palsy, visual acuityof less than 20/60, cognitive delay (a full IQ below the 5thpercentile for age), and hearing impairment severe enough torequire a hearing aid.
Statistical Analysis
Data were analyzed with the use of SAS software (SAS Institute).Analysis of variance and, when appropriate, t-tests were usedto compare the groups in terms of continuous variables. Categoricalvariables were compared by means of the chi-square test. Thecorrelation of two continuous variables was evaluated by meansof simple two-variable regression analysis. Multiple correlationswere performed to evaluate the outcomes at school age in relationto perinatal and neonatal factors. Results are expressed asmeans ±SD.
Results
Perinatal Data and Socioeconomic Background
Perinatal and neonatal data and information about maternal educationand socioeconomic background are summarized in Table 1. Therewere no significant differences between the groups in termsof these characteristics. The mean postnatal age at the timeof the administration of the first dose of dexamethasone was8.4±3.0 hours. The majority of the study population camefrom middle-class families, and most mothers were high-schoolgraduates (having 12 years of education).
Table 1. Perinatal Data and Socioeconomic Background.
Neonatal Course
Of the children included in the long-term follow-up study, 15in the dexamethasone group (21 percent) and 26 in the controlgroup (35 percent) had chronic lung disease at the beginningof the study (P=0.08 for the comparison between groups). Childrenin the dexamethasone group required high-concentration oxygentherapy (concentration, >40 percent) for a shorter lengthof time than did controls (8.0±4.1 vs. 9.4±3.9days, P=0.04). The two groups were similar in terms of the frequencyof intraventricular hemorrhage (any intraventricular hemorrhage,8 of 72 [11 percent] vs. 10 of 74 [14 percent]; intraventricularhemorrhage of grade 2 or worse, 3 of 72 [4 percent] vs. 2 of74 [3 percent]), retinopathy of prematurity (15 of 72 [21 percent]vs. 11 of 74 [15 percent], P=0.35), and infection (clinicalsuspicion of sepsis, bacteremia, or both: 14 of 72 [19 percent]vs. 8 of 74 [11 percent], P=0.22; bacteremia: 6 of 72 [8 percent]vs. 3 of 74 [4 percent], P=0.32; meningitis: 1 of 72 [1 percent]vs. 1 of 74 [1 percent]). Six infants in the dexamethasone group(8 percent) and seven in the control group (9 percent) who hadsevere chronic lung disease required open-label glucocorticoidtherapy after the completion of the initial study. Such therapy(0.25 mg per kilogram every 12 hours) was usually given forthree to five days at the discretion of the individual attendingphysician to infants who were dependent on a respirator in orderto facilitate extubation. Because of the relatively short durationof therapy, these infants were included in the analyses as membersof their initially assigned groups.
General Health and Physical Growth
The mean age at the time of follow-up was 8.3±0.9 yearsamong children in the dexamethasone group and 8.1±0.8years among children in the control group. The two groups weresimilar in terms of the frequency of upper respiratory infectionduring the year when follow-up assessments were conducted (6±6episodes per year in the dexamethasone group vs. 6±5episodes per year in the control group) and in terms of bloodpressure (systolic, 106±8 mm Hg vs. 108±8 mm Hg;diastolic, 59±8 mm Hg vs. 61±7 mm Hg).
The mean head circumference in the dexamethasone group (49.8±2.6cm) was significantly smaller than that in the control group(50.6±2.1 cm, P=0.04). There was no significant differencein body weight between the dexamethasone group and the controlgroup, either among boys or among girls (23.8±6.1 kgvs. 24.5±5.2 kg among boys, P=0.59; 23.0±3.2 kgvs. 24.4±5.7 kg among girls, P=0.21), but the mean heightin the dexamethasone group was significantly lower than thatin the control group (122.8±7.4 cm vs. 126.4±5.8cm among boys, P=0.03; 121.3±5.4 cm vs. 124.7±5.6cm among girls, P=0.01) (Figure 2 and Figure 3). Among bothboys and girls, a significantly greater proportion of childrenin the dexamethasone group than in the control group had a heightbelow the 10th percentile for their age group (Figure 2 andFigure 3).
Figure 2. Heights of the Boys, Plotted on the Growth Chart for Chinese Male Children 6 to 15 Years of Age.
At the time of the current study, the mean (±SD) height in the dexamethasone group was 122.8±7.4 cm, and the mean height in the control group was 126.4±5.8 cm (P=0.03). The heights of 12 of the 38 boys in the dexamethasone group were below the 10th percentile for age, as compared with 3 of the 36 boys in the control group (P=0.03).
Figure 3. Heights of the Girls, Plotted on the Growth Chart for Chinese Female Children 6 to 15 Years of Age.
At the time of the current study, the mean (±SD) height in the dexamethasone group was 121.3±5.4 cm, and the mean height in the control group was 124.7±5.6 cm (P=0.01). The heights of 13 of the 34 girls in the dexamethasone group were below the 10th percentile for age, as compared with 4 of the 38 girls in the control group (P=0.01).
Neurologic Examination and Assessment of Motor and Audiovisual Function
The results of the neurologic examination were categorized asnormal, borderline (defined as a delay in fine and gross motorskills or minor abnormalities in muscle tone), or abnormal (definedas the presence of cerebral palsy). The frequency of borderlineor abnormal results tended to be higher in the dexamethasonegroup than in the control group, although the difference wasnot statistically significant (20 of 72 [28 percent] vs. 14of 74 [19 percent], P=0.21) (Table 2).
Table 2. Results of Neurologic and Neuromotor Assessments and Audiovisual Function.
The dexamethasone group had significantly higher scores formanual dexterity, ball skills, balance, and total impairmentthan the control group, indicating that the motor performancein the dexamethasone group was poorer than that of controls(Table 2). A significantly greater proportion of children inthe dexamethasone group than in the control group had motor-performancescores below the 5th percentile for their age group (29 of 72[40 percent] vs. 15 of 74 [20 percent], P=0.01). Such a performanceusually indicates a definite motor problem and a need for additionalmedical help.
Children in the dexamethasone group had poorer motor coordination,visual perception, and visual–motor integration than childrenin the control group (Table 2). There was no significant differencebetween the groups in the frequency of visual and hearing impairment(Table 2).
Cognitive Function
Children in the dexamethasone group had significantly lowerfull IQ, verbal IQ, and performance IQ scores and had significantlylower scores for perceptual organization, freedom from distractibility,and processing speed (Table 3).
Seven children in the dexamethasone group and eight in the controlgroup attended a special school for handicapped children. Childrenin the dexamethasone group had significantly lower scores ontests of arithmetic, phonetic transcription and perception,and grammar than those in the control group (Table 3). Therewas no significant difference between the groups on other languagetests or in terms of various forms of adaptive behavior.
Frequency of Disability
A significantly greater proportion of children in the dexamethasonegroup than in the control group had a clinically significantdisability (Figure 4).
Figure 4. Children with Clinically Significant Disability at School Age.
Clinically significant disability was defined as any one of the following: cerebral palsy, visual acuity of less than 20/60, cognitive delay (WISC-III total IQ <5th percentile for age), and hearing impairment requiring a hearing aid. Numbers of children are shown on the bars.
Correlation of Disability with Perinatal Events
Within each group, there was no significant difference in perinatalcharacteristics or neonatal course, including the rate of prenatalglucocorticoid therapy and the Apgar score, between infantswith clinically significant disability and those without suchdisability. However, there were significant correlations betweenthe presence of clinically significant disability at schoolage and the severity of the early respiratory distress syndrome(P=0.02).
Discussion
The present report summarizes the data from a group of school-agechildren who had participated in a placebo-controlled, double-blindtrial of dexamethasone therapy begun within 12 hours after birthfor the prevention of chronic lung disease.1 Children who receivedearly dexamethasone therapy (0.25 mg per kilogram every 12 hours)for one week, with a tapering of the dose over the course ofthe next three weeks, were more likely to have delays in somaticgrowth, impaired neuromotor and cognitive function, and disabilityat school age.
Glucocorticoids have been used for years to treat preterm infantswho have or are at risk for chronic lung disease.1,2,3,4,5,6,7,8These agents often have the short-term benefits of improvinglung compliance and facilitating early weaning from mechanicalventilation. In the past 20 years, dexamethasone has been givenat various postnatal ages for a variety of reasons. The immediateresults and the outcomes in early childhood have varied fromstudy to study.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21It is difficult to interpret these results, because each ofthese studies was designed differently, not only in terms ofthe time at which therapy was initiated, but also in terms ofthe dose and duration of therapy and the sample size. In a systematicreview, Barrington13 reported an increase in the risk of cerebralpalsy and neurodevelopmental impairment associated with glucocorticoidtherapy. Halliday and Ehrenkranz11,12,16 reviewed the resultsof randomized, controlled trials from various data bases (studiesin early childhood) and concluded that the benefits of postnatalglucocorticoid therapy, either early (initiated within 96 hoursafter birth) or delayed (initiated after three weeks), may notoutweigh the actual or potential adverse effects on neurologicoutcome.
Our study was conducted in a double-blind fashion and involveda population that was relatively homogeneous with respect torace and family socioeconomic background. The size of the samplewas appropriate, and the proportions of infants in each groupwho subsequently received open-label glucocorticoid therapywere similar. Even if we had excluded from the analysis theinfants who received such therapy, the incidence of disabilitywould still have been significantly higher in the dexamethasonegroup than in the control group (27 of 66 [41 percent] vs. 14of 67 [21 percent], P=0.02).
Our results show consistent adverse effects of dexamethasoneat school age. Among the 42 children (26 in the dexamethasonegroup and 16 in the control group) who had had neuromotor dysfunctionat two years of age, most of those with mild dysfunction showedsome improvement at school age (5 of 8, or 62 percent, in thedexamethasone group and 6 of 9, or 67 percent, in the controlgroup). In contrast, none of the children who had had severeneuromotor dysfunction at two years of age showed significantimprovement.
Children in the dexamethasone group tended to have more abnormalitiesof neurologic development and significantly poorer motor performancethan children in the control group. This poor motor performancemay be responsible for their poor motor coordination and poorvisual–motor integration. Our results are consistent withobservations by Bos et al.30 in that dexamethasone may impairmotility and the quality of general movement in preterm infants.The mechanism behind the neuromotor abnormalities is not completelyclear. In experiments in neonatal animals, pharmacologic dosesof dexamethasone have resulted in adverse effects on brain-celldivision, differentiation, myelination, and electrophysiologicalreactions.31,32,33
A recent study by Murphy et al.34 suggested that postnatal dexamethasonetherapy may cause a decrease in the volume of cerebral graymatter. Such a decrease could explain our finding of subnormalhead circumference in the children in the dexamethasone group.Subnormal head size has been shown to be associated with poorcognitive outcome.35 In our study, the children with clinicallysignificant disability had significantly smaller head circumferencethan those without disability (49.1±3.0 vs. 50.8±2.5,P<0.001). The Vermont Oxford Network Steroid Study8 and thestudy by Shinwell et al.10 have shown a trend toward an increasedrisk of periventricular leukomalacia associated with dexamethasonetherapy.
The WISC-III scores obtained in this study were lower than thosethat have been reported in other studies.29,35,36 We did nothave an established standard for Chinese children; the racial,ethnic, or cultural bias of the tests might explain the lowscores in our population. However, the IQ scores in the dexamethasonegroup were significantly lower than those in the control group.This difference between the groups was not detected in our earlierfollow-up study at two years of age, when the children wereassessed with use of the Bayley Scales of Infant Development.This discrepancy could be due to a difference in the contentsof the tests: the Bayley test focuses much more on motor skills,whereas the IQ test for school-age children focuses much moreon cognition. The difference in cognitive function between thetwo groups could become larger as the children get older. Poormotor function in the dexamethasone-treated children might alsoaffect their cognitive performance.
Neonatal infection and hypertension secondary to dexamethasonetherapy could also lead to delayed cognitive function. Duringthe initial study, the incidence of neonatal infection was higherin the dexamethasone group than in the control group. However,among the children included in the current study, the proportionsin each group who had had neonatal infections were similar,because many of the infants in the dexamethasone group who hadneonatal infections died during the course of the initial study.Neonatal hypertension in the dexamethasone group was usuallytransient. It is unlikely that neonatal infection or hypertensioncould account for the higher incidence of cognitive delay inthe dexamethasone group in the current study population.
Concern has been expressed regarding the effects of early dexamethasonetherapy on somatic growth, because glucocorticoids have beenshown to alter cell size and DNA synthesis in animal models.32,33Moreover, Weiler et al.37 and Gibson et al.38 have found thatdexamethasone therapy may compromise the accretion of bone mineraland thus affect the velocity of bone growth, even when energyintake increases. Interestingly, the majority of the childrenwho had a delay in growth at school age (26 of 32, or 81 percent)were already short (with a height below the 10th percentile)at two years of age. It appears that the primary or secondaryeffects of dexamethasone on growth still prevail at school age.Whether dexamethasone can alter the normal acceleration of growthat puberty and ultimately affect the adult stature remains tobe clarified.
The dexamethasone-treated children also had lower scores onarithmetic tests and on tests of phonetic transcription andgrammar — findings that are consistent with poorer cognitivefunction. The testing of Chinese language skills is quite complicated,since spelling ability, pronunciation, and character drawingmust be evaluated independently. Moreover, many factors mayinfluence the language and school performance of a child. Themost important factor in our society is probably the pressureand expectations of academic excellence on the part of the family.Many families, particularly those who have disabled children,employ tutors or send their children to special classes to improvetheir academic performance; therefore, the performance shownin this study might not reflect the children's mental developmentas accurately as it would have without these aids.
In conclusion, although dexamethasone therapy initiated soonafter birth, given at the initial dose for one week and taperedover the next three weeks, significantly reduced the incidenceof chronic lung disease in preterm infants with severe respiratorydistress syndrome,1 this therapeutic regimen should not be recommendedbecause of its adverse effects on neuromotor and cognitive functionand somatic growth at school age. Our data support the recommendationsof the European Association of Perinatal Medicine39 and thoseof the American Academy of Pediatrics and the Canadian PaediatricSociety40: routine systemic dexamethasone should not be usedpostnatally to prevent or treat chronic lung disease of prematurity.
Supported in part by grants (NSC91-2314-B-039-036 and NSC92-2314-B-039-005)from the National Science Council of Taiwan.
Presented in part at the annual meeting of the Pediatric AcademicSocieties, Seattle, May 5, 2003.
We are indebted to Ming-F. Chiu, Su-Y. Chuang, and Hsiang-C.Kuo from the Tainan special school for handicapped childrenfor the assessment of school performance; to Dr. Tsai-C. Leefor assistance with statistical analysis; to Dr. N.S. Wang andDr. R.S. Pildes for reviewing the manuscript; and to Miss Chieh-W.Chen and Su-Y. Chen for assistance in the preparation of themanuscript.
Source Information
From the Department of Pediatrics, China Medical University, Taichung (T.F.Y., H.C.L.); the National Chung-Kung University Hospital, Tainan (Y.J.L., C.C.H., C.H.L., C.H.T.); and the National Taiwan University Hospital, Taipei (W.S.H.) — all in Taiwan.
Address reprint requests to Dr. Yeh at the Department of Pediatrics, College of Medicine, China Medical Univeristy, 91 Hsueh-Shih Rd., Taichung 40421, Taiwan, or at master{at}mail.cmu.edu.tw.
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(2009). Impact of Postnatal Corticosteroid Use on Neurodevelopment at 18 to 22 Months' Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants. Pediatrics
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12 years of education). 
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