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
OBJECTIVE. Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.
METHODS. Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9–1.9, and ≥1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4–7).
RESULTS. Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.
CONCLUSIONS. Higher steroid dose was associated with increased neurodevelopmental impairment. There is no “safe” window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.
Postnatal steroid therapy was frequently prescribed during the 1990s to facilitate extubation and reduce bronchopulmonary dysplasia (BPD) by modifying lung inflammation.1–3 However, multiple reports suggest various short- and long-term adverse effects, including hyperglycemia, hypertension, gastrointestinal perforation, increased rates of infection, particularly fungal sepsis, cardiac hypertrophy, severe retinopathy of prematurity, reduced head circumference, and neurodevelopmental impairment (NDI).4–11 In response to these reports, the American Academy of Pediatrics and Canadian Paediatric Society issued a recommendation discouraging the use of postnatal corticosteroids (PNSs) for the treatment of BPD,12 thus resulting in a dramatic reduction in the use of the therapy.13 Controversy still exists regarding the possible beneficial effects of lower steroid doses and shorter durations of treatment. A recent study by Doyle et al14 suggests that low-dose dexamethasone after the first week of life shortens the duration of intubation among ventilator-dependent, extremely low birth weight (ELBW) infants, without any obvious short-term complications, reopening debate regarding the potential role of low-dose PNS therapy specifically for infants at high risk for BPD. Furthermore, a recent metaregression reported a significant effect modification by risk for BPD. With a risk for BPD below 35%, corticosteroid treatment increased the chance of death or cerebral palsy (CP), whereas with the risk for BPD exceeding 65%, it reduced this risk.15 Currently, no information is available to determine if there is a particular steroid drug, dose, or timing of exposure that results in improved short-term pulmonary outcomes without adverse long-term neurodevelopmental impact. We sought to evaluate the association of PNS dose, postmenstrual age (PMA) at time of exposure, and the interaction of BPD risk with neurodevelopmental outcomes at 18 to 22 months among inborn ELBW children born during 2000 to 2004, enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Benchmarking Trial, and exposed to PNSs after 7 days age compared with nonexposed ELBW children enrolled in the trial.
This study was a prospective cohort study nested within a randomized, controlled trial designed to assess the utility of multimodal quality improvement methods to improve survival free of BPD.16 Fourteen centers of the NICHD Neonatal Network enrolled 4093 neonates who were born in network centers between March 2001 and May 2004 with a birth weight of <1250 g. This study cohort included 2358 infants born at network centers with a birth weight of <1000 g, of whom 366 (16%) were PNS-exposed and 1992 (84%) were not exposed. Demographic characteristics of the study population are included in Table 1. The overall survival rate was 84% and did not differ according to steroid treatment status. Of the 1985 survivors, 306 (15%) infants were steroid-treated. Demographic and neonatal characteristics of infants followed (84%) did not differ from those lost to follow-up.
Detailed data on PNS treatments, including timing, corticosteroid type, dose strength, and duration were collected prospectively on all enrolled subjects. Corticosteroid dose was normalized to dexamethasone equivalents based on a published comparison of the relative potencies.17 Total dose exposure was expressed as mg/kg. All decisions to treat with PNSs were made at the discretion of the onsite neonatologist attending; treatment was not prescribed by protocol. Initial severity of illness was assessed at 24 hours of age by using the Score for Neonatal Acute Physiology II—Perinatal Extension.19 The score evaluates the most severe of 6 physiologic derangements and 3 perinatal factors assessed within the first 24 hours of life and ranges from 1 to 32, with higher scores being more severe. An additional measure of pulmonary illness severity was calculated by using the criteria proposed by Romagnoli et al20 The Romagnoli prediction score uses birth weight along with measures of respiratory illness severity including inspired oxygen concentration and peak inspiratory pressure received at 3 and 5 days of life to generate a predicted risk of BPD.
BPD was assessed at 36 weeks' PMA using a validated physiologic definition that combined respiratory support and oxygen saturation.21 Secondary outcomes included death before hospital discharge, BPD severity (assessed by a modification of the National Institutes of Health consensus definition of BPD that included the physiologic definition), duration of mechanical ventilation, duration of continuous positive airway pressure, duration of oxygen supplementation, and length of hospital stay. Other measures of common neonatal comorbidities were specified before the trial began and included: severe intraventricular hemorrhage (stage 3 or 4),22 cystic periventricular leukomalacia, severe retinopathy of prematurity (stage 3 or more using the International Retinopathy Classification),23,24 pneumothorax, patent ductus arteriosus, necrotizing enterocolitis (stage 2 or more by modified Bell's criteria),25 and late-onset sepsis, defined as a positive blood culture with clinical signs of sepsis beyond 72 hours of age. All data were abstracted from the neonatal medical chart by trained research nurses using standardized definitions. Data were entered remotely with electronic submission. Quality-control procedures included range checking, internal comparisons for logic violations, and comparison of expected and observed values.
Neonates were evaluated in a standardized outcome assessment at 18 to 22 months' corrected age conducted by certified examiners. Assessments of pulmonary health, medication use, growth, neurologic examination of muscle tone according to the method described by Amiel-Tison and Stewart,26 and developmental outcomes (Bayley Scales of Infant Development II) were performed.27 CP was defined as a persistent disorder of movement and posture appearing in early life and attributable to a nonprogressive disorder of the brain, the result of interference during its development.28 CP was classified as “moderate” if the child could sit independently or with support, but an assistive device was required for ambulation, and “severe” if the child was unable to sit or walk even with support. The NICHD neuromotor and developmental examiners at each site met annually, followed standardized examination protocols, and submitted videos to ensure uniform examination techniques throughout the duration of the study. NDI was defined as 1 or more of the following: moderate or severe CP, bilateral blindness, deafness requiring amplification, Bayley MDI and/or Psychomotor Developmental Index (PDI) of <70. Of the 2358 eligible survivors, 1667 (84%) were evaluated in follow-up.
Human Subject Protection
This study was approved by the institutional review board of every institution. One center provided families with a letter of information and all others were given a waiver of consent to collect de-identified data. The main trial was registered at inception with the United States National Library of Medicine trial registry (NCT00067613).
Characteristics, treatments, and outcomes were compared between steroid-exposed and nonexposed neonates by using univariate methods. Continuous variables were compared with Student's t test, whereas dichotomous variables were assessed with the χ2 statistic with correction for multiple comparisons. Total steroid dose was expressed in tertiles with outcomes compared as a function of increasing dosage exposure. Logistic regression adjusted for birth weight, race, gender, antenatal steroids, small-for-gestational-age (SGA) status, severe intraventricular hemorrhage, and maternal education was used to test the relationship between NDI (Bayley MDI < 70, PDI < 70, disabling CP, or sensory impairment), total steroid dose (tertiles <0.9, 0.9–1.9, ≥1.9 mg/kg), and PMA at first dose. Separate logistic regression tested effect modification by BPD severity (Romagnoli risk probability > 0.5 defined as high risk, n = 2336 (99%) for days of life 4–7).
Steroid Treatment and Exposure
Three hundred sixty-six (16%) neonates were steroid-treated. Ninety-four percent of those exposed to steroids received dexamethasone, whereas the remainder received different steroid forms (betamethasone 0.5%, hydrocortisone 8%, mixed steroid exposure 5%, other 4%). The dose of steroid received by those treated averaged 1.99 ± 2.26 mg/kg dexamethasone equivalent units (range: 0.04–19.8 mg/kg); days treated averaged 10.4 ± 10.8 days (range: 1–75 days). Treated neonates were smaller (724 vs 807 g) and less mature (25.1 vs 26.6 weeks) (all P < .01) than untreated neonates (Table 1). Seventy-two percent of those treated were classified as high risk for BPD by the Romagnoli score (>50% predicted risk of BPD).
The acute morbidities experienced by infants in this cohort are shown in Table 2. Infants treated with steroids were more likely to have been diagnosed with a patent ductus arteriosus (60% vs 48%; P < .001). Neonates selected for treatment had significantly poorer pulmonary outcomes. Despite steroid treatment, more of the treated infants were diagnosed with BPD at 36 weeks' PMA by the physiologic definition (72% vs 32%; P < .001), remained on ventilators longer (53 ± 28 vs 21 ± 28 days; P < .001), and had a longer duration of hospitalization (101 ± 13 vs 81 ± 20 days; P < .001). Similar to other reports, treated infants had a higher incidence of severe retinopathy of prematurity (39% vs 17%; P < .001) and a higher incidence of late-onset sepsis (52% vs 38%; P < .001).
Postnatal steroid exposure was associated with an increased risk of NDI or death (61% vs 44%; P < .0001) (Table 3). Higher steroid doses were associated with an increased percentage of survivors with NDI; 71% died or were impaired at the highest dose tertile. The dose effect of postnatal steroids on NDI was primarily due to an increase in CP (Fig 1). Each 1 mg/kg steroid dose exposure was associated with a 2.0-point decrease in the MDI and a 40% risk increase in disabling CP, (odds ratio [OR]: 1.4 [95% confidence interval (CI): 1.2–1.6]). There was no developmentally “safe” window for postnatal steroid use. The risk of NDI was greater for steroid-exposed infants than for those unexposed at every postnatal age evaluated. Older PMA at first dose did not mitigate the harm caused by steroid exposure (Fig 2). In fact, treatment after 33 weeks' PMA was associated with the greatest harm (NDI/death OR: 2.5 [95% CI: 1.1–5.5]) despite not having the highest total steroid dose. The relationship of postnatal steroids on NDI was modified by BPD risk (high-risk OR: 1.9 [95% CI: 1.4–2.6]; low-risk OR: 2.9 [95% CI: 1.8–4.8]). Infants at higher risk of BPD seemed to experience less harm from steroid exposure than those at lower risk. For example, the underlying rates of NDI when steroids were administered were 52% in the high-risk group and 53% in the low-risk group. The rates of NDI in the nonexposed groups were 36% in the high-risk group and 28% in the low-risk group. Thus, the higher OR for the low-risk group reflects the greater potential relative harm imposed by PNS use (28%–53%).
The use of postnatal steroids to treat evolving BPD is controversial. Although the use of PNSs has been reduced after recognition that deleterious effects may outweigh the benefits, our data and those of others have shown that ELBW infants continue to be treated with postnatal steroids, primarily dexamethasone.29–32 In this prospective study that collected detailed data on dosing and timing of open-label usage of PNSs for evolving or established BPD, we sought to determine the impact of cumulative dose, timing of exposure, and the interactions with predicted risk of BPD. We have shown that there is no safe window of development where PNS exposure is less detrimental to neurodevelopmental outcomes. In addition, increasing dosage exposure is associated with increased risk of lower MDI (loss of 2 points per 1 mg/kg of exposure) and increased risk of CP (40% risk increase for each 1 mg/kg of exposure). We hoped to examine the impact of steroid type on outcome; however, of those exposed to PNSs after the first week of life, 94% in this cohort were exposed to dexamethasone, thus we were unable to analyze the impact of other steroids. The exclusion of subjects treated before 7 days of life was necessary to determine the effect of postnatal steroids used only for BPD, rather than as treatment for adrenal insufficiency or hypotension.
We confirmed the previous observation by Doyle et al and others15,33 that the risk of the composite outcome of death or NDI was modified by the predicted risk of BPD. Neonates at >50% predicted risk of BPD experienced less harm than those at lower risk (high-risk OR: 1.9 [95% CI: 1.4–2.6]; low-risk OR: 2.9 [95% CI: 1.8–4.8]). Infants at even higher predicted risk of BPD cross a point where the risk of PNS treatment is offset by the risk of deteriorating pulmonary status and its associated detrimental effects. To assist clinicians faced with the decision of whether to treat individual infants with postnatal steroid therapy, we attempted to better define the BPD risk point where the benefit of postnatal steroid therapy might outweigh the harm of its use. Unfortunately, study subjects were not evenly distributed for analysis by either quartiles or deciles of risk. Rather, subject risk status tended to be bimodal in distribution with the majority of subjects classified as either high or low risk for BPD. The percentage of subjects treated with postnatal steroid therapy increased from 6% in the lowest BPD risk quartile to 25% in the highest risk quartile.
A potential shortcoming of this study involves the use of the Romagnoli risk score to classify BPD risk.20 The cohort studied by Romagnoli included infants of 23 to 34 weeks of age and 350 to 1250 g with a mortality rate of 35%, which is quite different from the cohort in this study. In addition, Romagnoli's prediction was for BPD by oxygen requirement at 28 days rather than by a physiologic definition at 36 weeks' PMA. Its relevance to our cohort is questionable; however, the Romagnoli system was selected because it was the only published model using comparable data with objective risk parameters readily available to clinicians. Controlling for the probability of BPD was necessary to derive ORs, which internalized the levels of perceived BPD risk, which could not be done using a measure of risk derived directly from our own data. Future research must be performed to validate the Romagnoli score and develop additional scoring systems for BPD risk.
Additional outcome studies support the concept of a potentially beneficial effect of postnatal steroid therapy for selected infants at high risk for chronic lung disease. The long-term, school-age follow-up of preterm infants previously treated at 2 weeks of age with 42 days of dexamethasone, 18 days of dexamethasone, or placebo suggests significantly improved neurodevelopmentally intact survival and pulmonary function for those treated with the longest course, suggesting that moderately early corticosteroid treatment may be advantageous for a select group of infants at high risk for BPD.34 In addition, recently reported increased rates of BPD and oxygen dependence among very low birth weight infants have been temporally related to the reduction in postnatal steroid use.30,35 Although infants at lower risk of BPD should not be exposed to treatment with PNSs, our data suggest that there may be a subpopulation that will benefit from PNS treatment.
Since the controversy of PNS use has been aired, many experts have recommended the use of lower doses of dexamethasone based on limited evidence. However, in studies of developing rats and lambs, dexamethasone treatment, even at doses below those used clinically, elicits selective changes in dopaminergic synaptic function, N-methyl-d-aspartate receptors, and neural cell development, suggesting that adverse neurobehavioral consequences of glucocorticoid therapy in preterm infants may be inescapable.36–38 Similar to our results showing worsened outcomes with increasing PNS dose, Powell et al39 reported that the risk of CP in preterm infants was related to the total cumulative dose of dexamethasone. Doyle and colleagues14 confirmed that a lower dose was effective in achieving extubation with an improved adverse effect profile. Unfortunately, the trial was terminated at only 10% of the planned sample size because of limited enrollment, in part because of concerns raised by the position statements of the American Academy of Pediatrics and the Canadian Paediatric Society.12 Our observational data provide additional support that total dose is of critical importance in mediating the detrimental impact of PNSs. In addition, the prospective data that the detrimental effect of PNSs is modified for those with the highest risk of BPD supports a future randomized trial in selected high-risk infants.
Several recent studies have explored the timing of postnatal steroid therapy. In a systematic review of randomized, controlled trials of dexamethasone to prevent chronic lung disease, initiation of dexamethasone in the first 15 days of life was associated with a marginally significant reduction in the risk of death and a very significant reduction in chronic lung disease at 36 weeks' postconceptional age, with the greatest reduction associated with initiation of therapy in the first 72 hours of life.40 Despite the apparent benefits of early postnatal steroids, research suggests that many of the short-term, yet serious complications of therapy are frequent during early treatment.1,41 Other long-term randomized, controlled studies of children treated with dexamethasone versus placebo have reported significantly higher rates of developmental delay and CP among the dexamethasone-treated infants.7,42 Two large, multicenter trials of early dexamethasone versus placebo for ventilated ELBW infants enrolled by 12 hours of age and randomly assigned to receive dexamethasone or placebo for 10 to 12 days were halted because of serious complications, such as hyperglycemia, gastrointestinal perforation, hypertension, and periventricular leukomalacia.4,43
In contrast to “preventative” corticosteroids given shortly after birth to reduce the risk of chronic lung disease, steroids given after 7 to 10 days of age, termed “moderately early treatment,” reduce time on the ventilator with less risk of neurosensory sequelae.44–45 A meta-analysis of randomized, controlled trials of delayed (>3 weeks' postnatal age) corticosteroid treatment demonstrated an increasing trend in CP, which was partly offset by a decreasing trend in death before late follow-up, resulting in no significant difference in the combined rate of death or neurosensory impairment.3 Our study does not support the use of delayed (>3 weeks) steroid therapy. In fact, infants exposed to postnatal steroids at older ages demonstrated the greatest risk for NDI. We found no difference in the timing of initiation of postnatal steroid therapy between high- and low-risk subjects in our study, suggesting that steroids were not given to prevent BPD. However, the decision to use postnatal steroid therapy was heavily influenced by study center, ranging from 2% to 35% of center subjects.
The question of the optimal steroid type to be used is unanswered. There is increasing data that dexamethasone, with or without the sulfite preservative, has differential effects on the brain compared with hydrocortisone.8 Cortisol occupies both mineralocorticoid and glucocorticoid receptors in the brain, binding preferentially to mineralocorticoid receptors at normal physiologic concentrations.46 Dexamethasone binds only to glucocorticoid receptors. It has been proposed that dexamethasone exerts its adverse effects on the hippocampus by causing a “chemical adrenalectomy.”47–48 Consistent with this hypothesis, administration of corticosterone to adrenalectomized adult rats was protective against the apoptotic effects of dexamethasone.49 In a study involving quantitative MRI evaluations and neurocognitive assessments of preterm and term-born children, those treated with perinatal hydrocortisone showed no long-term adverse effects on either neurostructural brain development or neurocognitive outcomes.50 To our knowledge, only a single, uncontrolled retrospective study has compared the effects of dexamethasone and hydrocortisone in the treatment of BPD.51 Both drugs were effective in reducing days on the ventilator and oxygen, but hydrocortisone had an improved adverse effect profile with less hyperglycemia, hypertension, and adverse growth. Hydrocortisone may also have less impact on brain growth and neurodevelopmental outcome.51,52 Together, these data suggest that a randomized trial of PNS treatment and a comparison of low-dose dexamethasone and hydrocortisone among infants with a high risk of BPD are both ethical and necessary to guide the treatment of future high-risk preterm infants.
This work was supported by Eunice Kennedy Shriver NICHD grants U10 HD34216, U10 HD21364, U10 HD27853, U10 HD27851, U01 HD36790, U10 HD27856, U10 HD21397, U10 HD27881, U10 HD27880, U10 HD21415, U10 HD21373, U10 HD21385, U10 HD27871, U10 HD34167, and U10 HD27904) and the National Institutes of Health General Clinical Research Center (grants M01 RR8084, M01 RR750, M01 RR997, M01 RR70, M01 RR6022, M01 RR2635, M01 RR2172, and M01 RR1032. The funding agency provided overall oversight for study conduct. All data analyses and interpretation were independent of the funding agency.
Study participants were as follows: advisory committee: M.C. Walsh, MD, MS, A.A. Fanaroff, MD, Case Western Reserve University (Cleveland, OH); A.H. Jobe, MD, PhD, University of Cincinnati (Cincinnati, OH); R.D. Higgins, MD, Eunice Kennedy Shriver NICHD (Bethesda, MD); N.N. Finer, MD, University of California, San Diego (San Diego, CA); W.K. Poole, PhD, Research Triangle Institute (Research Triangle Park, NC); training committee: Duncan Neuhauser, PhD, Case Western Reserve University (Cleveland, OH); Leslie Clarke, RN, MSN, MBA, Rainbow Babies and Children's Hospital (Cleveland, OH); Lynn Lostocco, RN, MSN, National Association of Children's Hospitals (Warwick, RI); Neil N. Finer, MD, University of California, San Diego (San Diego, CA); intervention centers: S.N. Kazzi, MD, MPH, K. Hayes-Hart, RN, M. Betts, RRT, S. Shankaran, MD, G. Muran, RN, BSN, Wayne State University (Detroit, MI); A.R. Laptook, MD, M. Martin, RN, J. Allen, RRT, University of Texas Southwestern (Dallas, TX); W.A. Engle, MD, L. Miller, RN, R. Hooper, RRT, J.A. Lemons, MD, Indiana University (Indianapolis, IN); W. Rhine, MD, C. Kibler, RN, J. Parker, RRT, D.K. Stevenson, MD, M.B. Ball, BS, CCRC, Stanford University (Palo Alto, CA); M.R. Rasmussen, MD, M. Grabarczyk, BSN, C. Joseph, RRT, K. Arnell, BSN, Sharp Mary Birch Hospital for Women (San Diego, CA); G. Heldt, MD, R. Bridge, RN, J. Goodmar, RRT, N.N. Finer, MD, C. Henderson, RCP, CRRT, University of California, San Diego (San Diego, CA); S. Buchter, MD, M. Berry, RN, I. Seabrook, RRT, B.J. Stoll, MD, E. Hale, RN, Emory University (Atlanta, GA); benchmark centers: S. Duara, MD, R. Everett, RN, BSN, University of Miami (Miami, FL); W.A. Carlo, MD, M.V. Collins, RN, University of Alabama at Birmingham (Birmingham, AL); W. Oh, MD, A. Hensman, BSN, RNC, Brown University (Providence, RI); control centers: M.T. O'Shea, MD, MPH, N. Peters, RN, Wake Forest University (Winston-Salem, NC); J.E. Tyson, MD, MPH, G. McDavid, RN, University of Texas (Houston, TX); A.A. Fanaroff, MD, M.C. Walsh, MD, MS, N.S. Newman, BA, RN, Case Western Reserve University (Cleveland, OH); D.L. Phelps, MD, R.A. Sinkin, MD, G. Myers, MD, L. Reubens, RN, D. Hust, PNP, R. Jensen, University of Rochester (Rochester, NY); R.A. Ehrenkranz, MD, P. Gettner, RN, Yale University (New Haven, CT); C.M. Cotton, MD, MHS, K. Auten, RN, Duke University (Durham, NC); E.F. Donovan, MD, C. Grisby, BSN, CCRC, University of Cincinnati (Cincinnati, OH); Statistical center: Q. Yao, PhD, W.K. Poole, PhD, Research Triangle Institute (Research Triangle Park, NC).
We thank the nursing and medical staff members and parents of the patients in the units for their diligent implementation of this complex trial. We also thank the Neonatal Research Network research coordinators and study nurses, without whom the trial could not have been completed.
- Accepted November 18, 2008.
- Address correspondence to Deanne Wilson-Costello, MD, Rainbow Babies and Children's Hospital, Division of Neonatology, 11100 Euclid Ave, Cleveland, OH 44106. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Postnatal steroids (PNS) were prescribed to facilitate extubation and reduce BPD. In response to reports of increased NDI, the American Academy of Pediatrics discouraged PNS, resulting in decreased use. Controversy exists regarding the possible beneficial effects of lower doses and shorter durations of treatment.
What This Study Adds
This prospective study determines the impact of postnatal steroid dose, timing of exposure, and interaction with predicted risk of BPD. It demonstrates no safe window of development where steroid use is less detrimental. Increasing dosage exposure is associated with increased risk of impairment.
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