Abstract
Objective
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Methods
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Results
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
Conclusion
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
Keywords: neurodevelopmental outcome, growth, bronchopulmonary dysplasia, cerebral palsy, neonatal follow-up
Introduction
Corticosteroid treatment before 8 days of age decreases the incidence of chronic lung disease (CLD) at 36 weeks postmenstrual age and facilitates weaning from mechanical ventilation (1). However, dexamethasone use is associated with serious short-term adverse effects and may increase the risk of neurodevelopmental impairment (NDI) (1,2,3).
We conducted a multicenter randomized trial of early dexamethasone treatment to prevent death or CLD in extremely low birth weight (ELBW) infants (4). Although we used a lower dose than in most previous trials, we observed frequent complications in the dexamethasone group, including a high rate of gastrointestinal perforation that resulted in early termination of the trial. We evaluated subjects enrolled in the trial at 18 to 22 months corrected age to assess the effect of early dexamethasone treatment on death or NDI and on growth. Although this study was completed following the trial, we present this information because of the relative paucity of data on outcomes of infants with early postnatal exposure to glucocorticoids.
Methods
Description of original trial
A randomized, double-masked, placebo controlled trial was conducted in 13 centers of the NICHD Neonatal Research Network between February 1998 and September 1999 (4). The trial protocol, including the follow-up component, was approved by the Institutional Review Board at each site, and written informed consent was obtained from a parent of each infant.
Inclusion criteria were a birth weight of 501 to 1000 g, treatment with mechanical ventilation within 12 hours after birth, and the presence of an indwelling vascular catheter. Additional inclusion criteria for infants with birth weight greater than 750 g were supplementation with a fraction of inspired oxygen of 0.3 or more and the administration of at least one dose of surfactant. In a two-by-two factorial design, infants were randomly assigned to one of four groups according to study medication (dexamethasone or placebo) and ventilator management (routine treatment or permissive hypercapnia). Study medication was started within 24 hours after birth. The dexamethasone-treated groups received an initial dose of 0.15 mg per kg per day for three days; the dose was tapered over the next seven days (0.1 mg per kg per day for three days, 0.05 mg per kg per day for two days, and 0.02 mg per kg per day for two days). The placebo groups received equivalent volumes of saline. The protocol allowed use of open-label dexamethasone if required for clinical management, but this was discouraged during the ten-day study period.
The trial was stopped early because of an unanticipated and unacceptable rate of gastrointestinal perforations in the dexamethasone group. Because the effect of dexamethasone treatment did not vary according to ventilator management, the two dexamethasone groups and two placebo groups were combined for analysis.
A total of 220 infants were enrolled; 111 received dexamethasone and 109 received placebo. Death or CLD (defined as the use of oxygen supplementation at 36 weeks postmenstrual age) was comparable (relative risk = 0.92, (95 percent confidence interval, 0.76 to 1.11). Weight and head circumference at 36 weeks postmenstrual age were significantly less in the dexamethasone group.
Follow-up evaluation
Parents of surviving infants were encouraged to participate in a comprehensive follow-up evaluation at 18 to 22 months corrected age (5). Contact was maintained with the families by interim visits, telephone, and/or letter, and an appointment was scheduled for the assessment.
The comprehensive neurodevelopmental evaluation included an interview with the primary care taker of the infant, assessments of mental and motor development with the Bayley Scales of Infant Development II, a neurologic examination, and ascertainment of hearing and vision impairment. Bayley Scale score of <70 (> 2 SD below the mean) in either the Mental Developmental Index (MDI) or Psychomotor Developmental Index (PDI) was considered to indicate significant delay. Neurologic examination was based on the Amiel-Tison method (6); the examination was considered abnormal if abnormalities were identified in tone, strength, reflexes, angles, or posture. Cerebral palsy was defined as a non-progressive disorder characterized by abnormal tone in≥ 1 extremity and abnormal control of movement and posture. Cerebral palsy was further classified as mild (impairment interfered only slightly with age-appropriate motor activities), moderate (no ambulation or ambulation only with assistive devices but can sit independently or with support), and severe (no ambulation or supported sitting). Blindness was defined as no useful vision in either eye. Deafness was defined as disability with bilateral hearing amplification. NDI, a composite measure, was defined as one or more of the following: moderate or severe cerebral palsy, MDI or PDI < 70, blindness, or deafness. Examiners whose reliability was established prior to the study and verified in subsequent videotapes of infant examinations performed both the neurologic and developmental assessments. Examiners were masked to treatment assignment.
Statistical Analysis
Baseline data and treatment group differences for infants who have known and unknown primary outcome (death or NDI) were compared by t-tests for continuous data and chi-square tests for categorical data. Fisher's exact test was used for categorical outcomes with frequency counts less than six. Logistic regression analysis was used to analyze differences in neurodevelopmental findings, growth, and medical complications between treatment groups. Analyses were adjusted for center, birth weight (501-750 g; 751-1000 g), ventilator management group, and sex. For the outcome variables with sparse data, center was deleted from the logistic regression models in order to satisfy the convergence criteria of the models. For continuous outcomes, generalized least squares models were used.
Results
Death or NDI, the primary outcome, was known in 102 (92 percent) infants in the dexamethasone group and 92 (84 percent) in the placebo group (Table 1). Of the 220 infants enrolled in the trial, 164 infants were available for follow-up at 18 to 22 months corrected age. A total of 144 infants were seen (76 in the dexamethasone group, 68 in the placebo group), which comprised 88 percent of surviving infants, a rate similar for both groups. No MDI or PDI was recorded in 6 infants in the placebo group, so that NDI was calculated for only 62 infants, accounting for the reduced number with known outcome in that group.
Table 1. Outcome assessment among enrolled infants.
| Dexamethasone | Placebo | |
|---|---|---|
| Enrolled in trial – no. | 111 | 109 |
| Died before discharge – no. | 23 | 28 |
| Died after discharge – no. | 3 | 2 |
| Available for follow-up – no. | 85 | 79 |
| Seen at follow-up- no. (%) of available | 76 (89) | 68 (86) |
| Primary outcome known – no. (%) of enrolled) | 102 (92) | 92 (84)* |
No MDI or PDI was recorded for 6 infants in the placebo group so that NDI was available for 62 infants .
Baseline sociodemographic characteristics of the mothers of all infants enrolled were similar between groups. Of those evaluated at follow-up, the majority of mothers were 19 years old or more (84%) and unmarried (58%). Of the infants, 92 percent lived with their biologic mother. Annual income was less than $20,000 in 47% and 62% received Medicaid. The racial distribution was 51 percent black, 40 percent white, 7 percent Hispanic, and 2 percent other and was not different between groups. English was the primary language in 92% and Spanish in 6%. Baseline perinatal variables of the infants, including birth weight, gestational age, small for gestational age status, and sex were similar between treatment groups (Table 2). Among the infants seen at follow-up, 5 infants treated with early dexamethasone and 3 who received placebo had spontaneous gastrointestinal perforations during their hospital course. Fewer infants in the dexamethasone group received subsequent clinical treatment with corticosteroid (32 versus 49 percent, p = 0.02 among those with known outcome). Other neonatal outcomes, including CLD, intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity were similar. Infants with outcome known were similar to those with outcome not known, except for clinical steroid use.
Table 2. Characteristics of the infants with outcome known and not known according to treatment assignment*.
| Variable | Outcome Known | Outcome not known | Comparison | ||||
|---|---|---|---|---|---|---|---|
| Dex | Placebo | P1 | Dex | Placebo | P1 | P-value2 | |
| n = 102 | n = 92 | n = 9 | n = 17 | ||||
| Baseline variables | |||||||
| Birth weight – g. | 733±132 | 724±129 | 0.66 | 756±128 | 795±145 | 0.50 | 0.06 |
| Gestational age – wk. | 25±1.75 | 25±1.64 | 0.95 | 25±1 | 26±1 | 0.63 | 0.30 |
| Male – no. (%) | 54(53) | 49(53) | 0.97 | 5(56) | 6(35) | 0.42 | 0.30 |
| Inborn – no. (%) | 95(93) | 87(95) | 0.68 | 9(100) | 16(94) | 1.00 | 1.00 |
| SGA – no. (%) | 12(12) | 13(14) | 0.62 | 1(11) | 0(0) | 0.35 | 0.33 |
| Antenatal steroids - no. (%) | 75(74) | 70(76) | 0.68 | 7(78) | 12(71) | 1.00 | 0.81 |
| Neonatal Outcomes** | |||||||
| BPD – no./total no. (%) | 39/78(50) | 41/66(62) | 0.15 | 5(56) | 12(71) | 0.67 | 0.35 |
| Clinical steroid use – no. (%) | 33(32) | 45(49) | 0.02 | 5(56) | 11(65) | 0.69 | 0.04 |
| IVH | |||||||
| Any – no./total no. (%) | 42/101(42) | 28(30) | 0.11 | 2(22) | 9(53) | 0.22 | 0.55 |
| Severe (III or IV) – no./total no. (%) | 21/101(21) | 17(19) | 0.69 | 1(11) | 5(29) | 0.38 | 0.69 |
| PVL – no./total no. (%) | 6/101(6) | 6(7) | 1.00 | 0(0) | 1(6) | 1.00 | 1.00 |
| GI perforations – no. (%) | 14(14) | 7(8) | 0.17 | 2(22) | 1(6) | 0.27 | 1.00 |
| ROP (all grades) – no./total no.(%) | 67/80(84) | 53/64(83) | 0.88 | 6/8(75) | 13/16(81) | 1.00 | 0.57 |
Plus-minus values are means ± SD.
Total number refers to the number of infants assessed for the outcome if different from the number in that group.
Dex = dexamethasone; SGA = small for gestational age; CLD = chronic lung disease, defined as oxygen supplementation at 36 weeks postmenstrual age; IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia; GI perforation = spontaneous gastrointestinal perforation within first 14 days; ROP = retinopathy of prematurity.
Comparison between dexamethasone and placebo groups with either known or unknown outcome.
Comparison between infants with known and unknown outcomes.
The mean corrected age at the time of follow-up evaluation was 20 ± 2.5 (SD) months for both the dexamethasone and placebo groups. Among the infants with known primary outcome, the proportion with death or NDI was similar in both groups (relative risk = 1.02 [95% CI = 0.84-1.23]) (Table 3). Six infants (8 percent) in the dexamethasone group and 8 infants (12 percent) in the placebo group were diagnosed with moderate to severe cerebral palsy. Of those, four in each group had quadriplegia; two in the dexamethasone group and four in the placebo group had diplegia. Nine additional infants had mild cerebral palsy, 5 in the dexamethasone and 4 in the placebo group. Mean MDI and PDI and the proportion of children in each group with MDI and PDI less than 70 were similar in both groups, as was the proportion of infants with an abnormal neurological examination. Among the 6 infants with no calculated NDI, one had mild cerebral palsy and none had blindness or hearing impairment. In a secondary analysis of infants in the placebo group, although the primary outcome was similar, surviving infants exposed to clinical steroid treatment tended to have worse outcomes (Table 4).
Table 3. Mortality and neurodevelopmental findings at 18 to 22 months according to treatment assignment (adjusted analysis).
| Variable | Dexamethasone | Placebo | RR (95% CI) | P-value |
|---|---|---|---|---|
| No. / total No. (%) | ||||
| Primary outcome | ||||
| Death or NDI | 66/102(65) | 61/92(66) | 1.00(0.83,1.21) | 0.99 |
| Specific outcomes in survivors | ||||
| Moderate to severe cerebral palsy | 6/76(8) | 8/68(12) | 0.68(0.25,1.81) | 0.43 |
| Bilateral blindness | 1/76(1.3) | 0/67(0) | - | - |
| Deafness* | 2/75(2.7) | 2/67(3.0) | 0.82(0.10,6.86) | 0.86 |
| Bayley MDI <70* | 35/76(46) | 25/62(40) | 1.11(0.76,1.62) | 0.60 |
| Bayley PDI <70 | 21/74(28) | 22/62(35) | 0.79(0.49,1.28) | 0.34 |
| NDI | 40/76(53) | 31/62(50) | 0.99(0.72,1.36) | 0.97 |
| Abnormal neurologic exam* | 20/76(26) | 17/68(25) | 1.02(0.59,1.78) | 0.94 |
NDI = Neurodevelopmental impairment (moderate/severe cerebral palsy, MDI or PDI less than 70, blindness or hearing impairment). MDI = Mental developmental index; PDI = Psychomotor developmental index; RR is the relative risk of the outcome in the dexamethasone group as compared with the placebo group. CI denotes confidence interval.
Not adjusted for center because of convergence issues.
Table 4. Mortality and neurodevelopmental findings at 18 to 22 months in infants assigned to placebo group according to subsequent clinical steroid use (adjusted analysis).
| Variable | Placebo Steroid | Placebo No Steroid | RR (95% CI) | p-value |
|---|---|---|---|---|
| No. / total No. (%) | ||||
| Primary outcome | ||||
| Death or NDI | 31/45(69) | 30/47(64) | 0.85(0.64,1.13) | 0.27 |
| Specific outcomes in survivors | ||||
| Moderate to severe cerebral palsy | 7/39(18) | 1/29(3) | 2.58(0.20,33.2) | 0.47 |
| Bayley MDI <70 | 15/34(44) | 10/28(36) | 1.12(0.55,2.27) | 0.75 |
| Bayley PDI <70 | 16/34(47) | 6/28(21) | 1.78(0.70,4.50) | 0.22 |
| NDI | 20/34(59) | 11/28(39) | 1.22(0.65,2.31) | 0.53 |
| Abnormal neurologic exam | 16/39(41) | 1/29(3) | 11.02(1.21,100.33) | 0.03 |
NDI = Neurodevelopmental impairment (moderate/severe cerebral palsy, MDI or PDI less than 70, blindness or hearing impairment). MDI = Mental developmental index; PDI = Psychomotor developmental index; RR is the relative risk of the outcome in the placebo group treated with steroid as compared with the placebo group that did not receive steroid. CI denotes confidence interval. Not adjusted for center due to convergence issues.
Medical outcomes were similar in both groups although the 95% confidence intervals do not exclude clinically important differences (Table 5, online). Following the first hospital discharge, 58 and 59 percent of the infants in the dexamethasone and placebo groups, respectively, required at least one additional hospital admission, and 37 and 38 percent, respectively, received medications, such as diuretics or bronchodilators, to treat pulmonary disorders. Five infants in the dexamethasone group and four in the placebo group were receiving supplemental oxygen at the time of the visit.
Table 5. Medical complications at follow-up according to treatment assignment (adjusted analysis).
| Variable | Dexamethasone | Placebo | RR (95% CI) | P-value |
|---|---|---|---|---|
| No. / total No. (%) | ||||
| Re-hospitalization* | 44/76(58) | 40/68(59) | 0.96(0.74,1.26) | 0.77 |
| Pulmonary medications | 28/76(37) | 26/68(38) | 0.95(0.65,1.39) | 0.84 |
| Oxygen use at follow-up* | 5/74(7) | 4/67(6) | 1.09(0.29,4.07) | 0.79 |
RR is the relative risk of the outcome in the dexamethasone group as compared with the Placebo group. CI denotes confidence interval.
Not adjusted for center because of convergence issues.
Mean values for weight, length, and head circumference were similar in the dexamethasone and placebo groups (Table 6, online). The proportions of infants in both groups with measurements less than the tenth percentile for weight, length, and head circumference (7) were also comparable, although the 95% confidence intervals did not exclude clinically important differences.
Table 6. Growth at 18 to 22 months according to treatment assignment (adjusted analysis).
| Variable | Dexamethasone n=76 | Placebo n=68 | RR (95% CI) | P-value |
|---|---|---|---|---|
| Male – no. (%) | 38(50) | 33(49) | 0.86 | |
| Clinical steroid use – no. (%) | 28(37) | 39(57) | 0.01 | |
| Growth parameters | Mean ± S.D | |||
| Weight – kg. | 10.3±1.6 | 10.3±1.4 | 0.98 | |
| Length – cm. | 80.3±4.9 | 80.0±4.2 | 0.60 | |
| Head circumference - cm | 46.8±2.2 | 46.6±2.1** | 0.59 | |
| Growth < 10th percentile | ||||
| Weight – no. (%) | 38(50) | 27(40) | 1.16(0.81,1.66) | 0.42 |
| Length - no. (%)* | 19(25) | 21(31) | 0.76(0.45,1.27) | 0.29 |
| Head circumference – no. (%)* | 21(28) | 19(28)** | 0.96(0.57,1.63) | 0.88 |
RR is the relative risk of the outcome in the dexamethasone group as compared with the placebo group. CI denotes confidence interval.
Not adjusted for center because of convergence issues.
In the placebo group, n=67 for head circumference
Discussion
With the sample size evaluated in this trial, we detected no discernable difference between treatment assignments in death or NDI at 18 to 22 months corrected age. Our results differ from those of three randomized trials in which dexamethasone treatment using a higher dose and/or longer duration was associated with an increased incidence of neurological abnormality (8-11). Other trials of postnatal dexamethasone beginning either early in the first week (12-14) or at 7 or more days (15-18) did not show conclusive detrimental effects on neurodevelopmental outcome, similar to ours. However, all of these trials were smaller than our trial and thus more susceptible to type II error. Furthermore, although other trials have used low doses of dexamethasone (16,18), ours is the first to investigate the long-term effects of an early lower dose.
The likelihood of an adverse effect of dexamethasone on brain development is supported by studies in animals and humans. Pharmacological doses of glucocorticoids administered to neonatal animals during critical periods of brain development may impair brain cell division and differentiation, myelination, and electrophysiological reactions, and cause delayed behavioral changes (19,20,21). In preterm infants treated with dexamethasone for CLD, cerebral cortical gray matter volume measured with quantitative magnetic resonance imaging was reduced by 35 percent, compared to untreated infants (22).
The absence of a discernable effect on neurodevelopmental outcome may be due to our use of a lower dose and shorter duration of dexamethasone treatment than in many trials. The initial dose we used was approximately equivalent to five times the estimated physiologic cortisol secretion rate (23), in contrast to the higher doses typically used in trials and clinical practice at the time our study was conducted. However, this dose resulted in short term adverse effects, such as hypertension and hyperglycemia, similar to those observed with higher doses (1,2). The limited pharmacokinetic data available indicate that the half-life of dexamethasone is prolonged in ELBW infants compared to children and adults (24,25). Accumulation of the drug may have contributed to high levels of dexamethasone that increased the rate of early adverse effects.
Another explanation for the lack of a detectable difference in outcome between treatment groups is the frequent clinical use of dexamethasone (4). As observed in other trials of early dexamethasone treatment (26,27), clinical corticosteroid use was greater in the placebo than the dexamethasone group. This open-label use may have obscured any effects of early dexamethasone on neurodevelopmental outcome in the entire group. In addition, it is possible that dexamethasone may not increase the incidence of adverse neurologic outcomes in populations with the highest baseline risk of chronic lung disease (28). However, our secondary analysis of infants in the placebo group suggests poorer outcomes in those given open-label steroid treatment and is concerning, although the small sample size limits a definitive conclusion.
Our study is one of the largest studies reporting long-term outcome and the largest reporting long-term outcome for this relatively low early dexamethasone dose (8-18). We intended to enroll a sufficient number of infants to test whether early lower dose dexamethasone treatment reduced death or CLD, our primary outcome, and to exclude a clinically significant increase in cerebral palsy at 18 to 22 months corrected age. However, the trial was stopped early because of the increased rate of gastrointestinal perforation in the dexamethasone group. Nevertheless, the importance of long-term neurodevelopmental evaluation in subjects who have participated in trials of postnatal corticosteroids is well recognized (3). Furthermore, dexamethasone remains in clinical use for infants at high risk of CLD because of its beneficial pulmonary effects, underscoring the need for as much unbiased data as feasible regarding its long-term effects.
We observed a small but significant decrease in weight and head circumference at 36 postmenstrual weeks in the dexamethasone group compared to placebo, despite substantial clinical corticosteroid use in both groups. This difference was not sustained at 18 to 22 months, perhaps indicating greater catch-up growth in the dexamethasone-treated infants. However, a substantial rate of growth impairment was observed in the entire cohort. This likely reflects poor postnatal growth in hospitalized very low birth weight infants, especially those with severe illness (29), which may limit later catch-up growth (30).
Meta-analyses of trials of dexamethasone treatment initiated before 8 days and after 7 days show a decrease in CLD at 36 weeks postmenstrual age and more successful weaning from mechanical ventilation (1,2). However, dexamethasone administration does not affect the length of hospitalization or mortality. In addition, treatment results in many short-term adverse effects, although serious adverse events such as gastrointestinal perforation are largely observed with early use. Although not demonstrated in our study, in a systematic review of early postnatal dexamethasone, treatment appears to increase the incidence of cerebral palsy and neurodevelopmental impairment (1). Given the serious short-term adverse effects not offset by discernable long-term benefit, the available evidence does not support the routine use of postnatal dexamethasone, particularly early use, to prevent death or CLD in ELBW infants. Whether subgroups of infants, such as those at extremely high baseline risk for CLD (28), would benefit or whether the use of late low-dose dexamethasone (18) or other glucocorticoids such as hydrocortisone would improve outcome remain to be established in appropriate clinical trials.
Acknowledgments
The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's SAVE Trial.
Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Drs. Abhik Das (DCC Principal Investigator) and Shampa Saha (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chairs: Alan H. Jobe, MD PhD, University of Cincinnati (2003-2006).
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Angelita M. Hensman, RN BSN; Bonnie E. Stephens, MD; Barbara Alksninis, PNP; Bill Cashore, MD; Dan Gingras, RRT; Regina A. Gargus, MD FAAP; Shabnam Lainwala, MD; Theresa M. Leach, MEd CAES; Martha R. Leonard, BA BS; Kalida Mehta; James R. Moore, MD; Lucy Noel; Suzy Ventura; Rachel V. Walden; Victoria E. Watson, MS CAS.
Brigham and Women's Hospital, Harvard Medical School (U10 HD34167, M01 RR1032, M01 RR2172, M01 RR2635) – Ann R Stark, MD; Kimberly Gronsman Lee, MD; Stacy Dow, RN; Colleen Driscoll; Kerri Fournier, RN
Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364, M01 RR80) – Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Nancy S. Newman, RN; Bonnie S. Siner, RN; Arlene Zadell RN; Julie DiFiore, BS; Monika Bhola, MD; Harriet G. Friedman, MA; Gulgun Yalcinkaya, MD.
Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – Kurt Schibler, MD; Vivek Narendran, MD MRCP; Kate Bridges, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Marcia Worley Mersmann, RN CCRC; Holly L. Mincey, RN BSN; Jody Hessling, RN; Teresa L. Gratton, PA.
Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 RR25008, M01 RR39) – Barbara J. Stoll, MD; Linda Black, MD; Sheena Carter, PhD; Elisabeth Dinkins, PNP; Ellen C. Hale, RN BS CCRC; Judson Miller, MD; Maureen Mulligan LaRossa, RN; Gloria V. Smikle, PNP MSN.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Linda L. Wright, MD.
RTI International (U10 HD36790) – Betty K. Hastings; Elizabeth M. McClure, MEd.
Stanford University and Lucile Packard Children's Hospital (U10 HD27880, UL1 RR25744, M01 RR70) – Krisa P. Van Meurs, MD; David K. Stevenson, MD; Barry E. Fleisher, MD; M. Bethany Ball, BS CCRC; Joan M. Baran, PhD; Barbara Bentley, PsychD MSEd; Lori E. Bond, PhD; Ginger K. Brudos, PhD; Elizabeth F. Bruno, PhD; Maria Elena DeAnda, PhD; Monica Hajdena-Dawson, MD; Jean G. Kohn, MD MPH; Carol G. Kuelper, PhD; Julie C. Lee-Ancajas, PhD; Melinda S. Proud, RCP; Renee P. Pyle, PhD; Dharshi Sivakumar, MD MRCP; Nicholas H. St. John, PhD.
University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32) – Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN. Vivien A. Phillips, RN BSN; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Kristen C. Johnston, MSN CRNP; Mary Beth Moses, PT MS PCS; Kathleen G. Nelson, MD; Cryshelle S. Patterson, PhD; Julie Preskitt, MSOT MPH; Richard V. Rector, PhD; Laurie Lou Smith, EdS NCSP; Sally Whitley, MA OTR-L FAOTA.
University of Miami, Holtz Children's Hospital (U10 HD21397, M01 RR16587) – Maria Calejo, MEd; Alexis N. Diaz, BA; Silvia M. Frade Eguaras, BA; Wendy Griffin, RN; Kasey Hamlin-Smith, PhD; Sylvia Hiriart-Fajardo, MD; Elaine O. Mathews, RN; Amy Mur-Worth, MSN.
University of New Mexico Health Sciences Center (U10 HD27881, M01 RR997) – LuAnn Papile, MD; Conra Backstrom Lacy, RN, Jean R. Lowe, PhD.
University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas (U10 HD40689, M01 RR633) – Pablo J. Sánchez, MD; Charles R. Rosenfeld, MD; Walid A. Salhab, MD; Abbot R. Laptook, MD; Sally S. Adams, MS RN CPNP; James Allen, RRT; Laura Grau, RN; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, PsyD PA-C; Melissa H. Lepps, RN; Linda A. Madden, RN CPNP; Melissa Martin, RN; Nancy A. Miller, RN; Janet S. Morgan, RM; Araceli Solis, RRT; Lizette E. Torres, RN; Catherine Twell Boatman, MS CIMI; Diana M Vasil, RNC-NIC; Kerry Wilder, RN.
Wayne State University, University of Michigan, Hutzel Women's Hospital, and Children's Hospital of Michigan (U10 HD21385) – Yvette R Johnson, MD, MPH; Rebecca Bara, RN BSN.
Yale University and Yale-New Haven Children's Hospital (U10 HD27871, M01 RR125) – Richard A. Ehrenkranz, MD; Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Nancy Close, PhD; Walter Gilliam, PhD; Elaine Romano, MSN.
Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Multicenter Neonatal Research Network and the General Clinical Research Centers Program
List of Abbreviations
- NDI
Neurodevelopmental impairment
- MDI
Mental Developmental Index
- PDI
Psychomotor Developmental Index
- CLD
Chronic lung disease
- ELBW
Extremely low birthweight
References
- 1.Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<8 days) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2010;(1):CD001146. doi: 10.1002/14651858.CD001146.pub3. [DOI] [PubMed] [Google Scholar]
- 2.Halliday HL, Ehrenkranz RA, Doyle LW. Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2009;(1):CD001145. doi: 10.1002/14651858.CD001145.pub2. [DOI] [PubMed] [Google Scholar]
- 3.American Academy of Pediatrics Committee on Fetus and Newborn. Policy statement -Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(2):800–8. doi: 10.1542/peds.2010-1534. [DOI] [PubMed] [Google Scholar]
- 4.Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, et al. Adverse effects of early dexamethasone in extremely low birth weight infants. N Engl J Med. 2001;344:95–101. doi: 10.1056/NEJM200101113440203. [DOI] [PubMed] [Google Scholar]
- 5.Vohr BR, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994. Pediatrics. 2000;105:1215–1226. doi: 10.1542/peds.105.6.1216. [DOI] [PubMed] [Google Scholar]
- 6.Amiel-Tison C. Neuromotor Status. In: Taeusch HW, Yogman MW, editors. Follow-up management of the high-risk infant. Boston: Little, Brown and Company; 1987. pp. 115–126. [Google Scholar]
- 7.Hamill PV, Drizd TA, Johnson TA, Reed RB, Roche AF, Moor WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607–629. doi: 10.1093/ajcn/32.3.607. [DOI] [PubMed] [Google Scholar]
- 8.Yeh TF, Lin YJ, Huang CC, Chen YJ, Lin CH, Lin HC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics. 1998;101(5):e7. doi: 10.1542/peds.101.5.e7. [DOI] [PubMed] [Google Scholar]
- 9.Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Eng J Med. 2004;350:1304. doi: 10.1056/NEJMoa032089. [DOI] [PubMed] [Google Scholar]
- 10.Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000;83:F177–181. doi: 10.1136/fn.83.3.F177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.O'Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver RG, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: Outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104:15–21. doi: 10.1542/peds.104.1.15. [DOI] [PubMed] [Google Scholar]
- 12.Subhedar NV, Bennett AJ, Wardle SP, Shaw NJ. More trials on early treatment with corticosteroids are needed (Letter) BMJ. 2000;320:941. [PMC free article] [PubMed] [Google Scholar]
- 13.Romagnoli C, Zecca E, Luciano R, Torrioli G, Tortorolo G. Controlled trial of early dexamethasone treatment for the prevention of chronic lung disease in preterm infants: a 3-year follow-up. Pediatrics. 2002;109(6):e85. doi: 10.1542/peds.109.6.e85. [DOI] [PubMed] [Google Scholar]
- 14.Wilson TT, Waters L, Patterson CC, McCusker CG, Rooney NM, Marlow N, et al. Neurodevelopmental and respiratory follow-up at 7 years for children from the United Kingdom and Ireland enrolled in a randomized trial of early and late postnatal corticosteroid treatment, systemic and inhaled. The Open Study of Early Corticosteroid Treatment Pediatrics. 2006;117(6):2196–2205. doi: 10.1542/peds.2005-2194. [DOI] [PubMed] [Google Scholar]
- 15.Cummings JJ, D'Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med. 1989:1505–1510. doi: 10.1056/NEJM198906083202301. [DOI] [PubMed] [Google Scholar]
- 16.McEvoy C, Bowling S, Williamson K, McGaw P, Durand M. Randomized, double-blinded trial of low-dose dexamethasone: II. Functional residual capacity and pulmonary outcome in very low birth weight infants at risk for bronchopulmonary dysplasia. Pediatr Pulmonol. 2004;38(1):55–63. doi: 10.1002/ppul.20037. [DOI] [PubMed] [Google Scholar]
- 17.Armstrong DL, Penrice J, Bloomfield FH, Knight DB, Dezoete JA, Harding JE. Follow up of a randomized trial of two different courses of dexamethasone for preterm babies at risk of chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):F102–F107. doi: 10.1136/fn.86.2.F102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, DART Study Investigators Outcome at 2 years of age of infants from the DART study: a multicenter, international, randomized, controlled trial of low-dose dexamethasone. Pediatrics. 2007;119(4):716–721. doi: 10.1542/peds.2006-2806. [DOI] [PubMed] [Google Scholar]
- 19.Weischsel ME. The therapeutic use of glucocorticoid hormones in the perinatal period: potential neurological hazards. Ann Neurol. 1977;2:364–366. doi: 10.1002/ana.410020503. [DOI] [PubMed] [Google Scholar]
- 20.Benesova O, Pavlik A. Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain. Neuropharmacology. 1989;28:89–97. doi: 10.1016/0028-3908(89)90073-7. [DOI] [PubMed] [Google Scholar]
- 21.He J, Varma A, Weissfeld LA, Devaskar SU. Postnatal glucocorticoid exposure alters the adult phenotype. Am J Physiol Regul Integr Comp Physiol. 2004;287:R198–208. doi: 10.1152/ajpregu.00349.2003. [DOI] [PubMed] [Google Scholar]
- 22.Murphy BP, Inder TE, Huppi PS, Warfield S, Zientara GP, Kikinis R, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics. 2001;107:217–21. doi: 10.1542/peds.107.2.217. [DOI] [PubMed] [Google Scholar]
- 23.Metzger DL, Wright NM, Veldhuis JD, Rogol AD, Kerrigan JR. Characterization of pulsatile secretion and clearance of plasma cortisol in premature and term neonates using deconvolution analysis. J Clin Endocrinol Metab. 1993;77:458–463. doi: 10.1210/jcem.77.2.8345052. [DOI] [PubMed] [Google Scholar]
- 24.Charles B, Schild P, Steer P, Cartwright D, Donovan T. Pharmacokinetics of dexamethasone following single-dose intravenous administration to extremely low birth weight infants. Dev Pharmacol Ther. 1993;20:205–210. doi: 10.1159/000457564. [DOI] [PubMed] [Google Scholar]
- 25.Lugo RA, Nahata MC, Menke JA, McClead RE., Jr Pharmacokinetics of dexamethasone in premature neonates. Eur J Clin Pharmacol. 1996;49:477–483. doi: 10.1007/BF00195934. [DOI] [PubMed] [Google Scholar]
- 26.Garland JS, Alex CP, Pauly TH, Whitehead VL, Brand J, Winston JF, et al. A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial. Pediatrics. 1999;104:91–99. doi: 10.1542/peds.104.1.91. [DOI] [PubMed] [Google Scholar]
- 27.The Vermont Oxford Network Steroid Study Group. Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics. 2001;108:741–748. doi: 10.1542/peds.108.3.741. [DOI] [PubMed] [Google Scholar]
- 28.Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics. 2005;115:655–61. doi: 10.1542/peds.2004-1238. [DOI] [PubMed] [Google Scholar]
- 29.Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics. 1999;104:280–289. doi: 10.1542/peds.104.2.280. [DOI] [PubMed] [Google Scholar]
- 30.Saigal S, Stoskopf BL, Streiner DL, Burrows E. Physical growth and current health status of infants who were of extremely low birth weight and controls at adolescence. Pediatrics. 2001;108:407–415. doi: 10.1542/peds.108.2.407. [DOI] [PubMed] [Google Scholar]