Journal of Perinatology (2014), 1–5 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Neurodevelopmental impact of hydrocortisone exposure in extremely low birth weight infants: outcomes at 1 and 2 years K Patra, MM Greene and JM Silvestri OBJECTIVE: Postnatal steroids are used in neonatal intensive care units despite known side effects. Hydrocortisone (HC) use persists as it is believed to have less deleterious effects on neurodevelopmental (ND) outcome compared to other steroids. The literature is sparse with respect to the ND impact of HC use in recent years. Hence, we sought to examine the effect of HC use on ND outcome in a contemporary cohort of extremely low birth weight (ELBW) infants. STUDY DESIGN: A total of 175 ELBW infants (86 HC exposed, 89 steroid naive) born in 2008 to 2010 were compared for mortality, morbidity and ND outcome at 8 and 20 months corrected age. Outcome measures included neurologic exam and results of the Bayley Scales of Infant and Toddler Development-III (BSITD-III). Multiple regression analyses adjusted for the effect of other risk factors on outcome. RESULT: Overall, 65 (75%) of the HC and 74 (83%) of the no-HC groups survived to discharge. HC infants were smaller (mean birth weight (BW) 719 ± 127 g vs 837 ± 99 g) and of lower gestational age (GA) (mean GA 26.0 ± 1.7 weeks vs 27.5 ± 1.8 weeks) compared to the no-HC group. Patients in the HC group were more likely to be a multiple, have a severely abnormal head ultrasound, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and receive treatment for patent ductus arteriosus and hypotension than those in the no-HC group. Of the HC group, the mean age at treatment was 20 ± 19 days, mean duration of treatment 49 ± 37 days. At 8 months, the HC group had lower mean motor (87 ± 18 vs 95 ± 15, P = 0.028) and fine motor (9 ± 2.9 vs 10.5 ± 2.6, P = 0.005) and higher rate of subnormal motor (44 vs 15%, P = 0.002) and fine motor scores (24 vs 6.5%, P = 0.017). In regression analyses, HC exposure 47 days was significantly related to worse outcome on fine motor scores at 8 months while cumulative days of HC exposure was a predictor of worse outcome on language at 8 months and motor outcome at 20 months. Each additional day of HC exposure increased the odds of subnormal receptive and expressive language in the first year of life by 4 and 2%, respectively, and increased odds of subnormal motor function by 2% in the 2nd year of life. CONCLUSION: HC exposure for 47 days is associated with worse performance in fine motor skills in the first year of life, while cumulative HC exposure negatively impacts receptive and expressive language skills in the first year and motor skills in the second year of life after adjusting for neonatal and social risk factors. Journal of Perinatology advance online publication, 31 July 2014; doi:10.1038/jp.2014.133
INTRODUCTION Postnatal corticosteroids are used commonly in neonatal intensive care units (NICUs) despite their known adverse effects on neurodevelopmental (ND) outcome in preterm infants.1–6 Concerns regarding early childhood neurologic outcome in preterm infants following dexamethasone exposure led the American Academy of Pediatrics to caution against the use of postnatal steroids altogether in the treatment and prevention of bronchopulmonary dysplasia (BPD).7,8 Since that time there has been a significant reduction in the use of dexamethasone while hydrocortisone (HC) use has increased.9,10 Cohort studies suggest that infants exposed to HC have ND outcomes superior to those of infants exposed to dexamethasone and similar to that of infants not treated with steroids.11–13 Prospective trials of 10 to 15 days of HC treatment for the prevention of BPD have found no increased incidence of cerebral palsy and ND impairment at 2 years.14,15 What is not clear, however, is the impact of variable doses and durations of HC therapy on ND outcome. This is relevant as HC use is increasing and treatment duration and weaning schedules will vary widely both across and within institutions. The literature is sparse with respect to ND outcome after HC exposure and no
study has examined the ND effect of HC on extremely low birth weight (ELBW) infants born since 2005. Neonatal management continues to evolve and HC use may have different effects now on short- and long-term morbidity. We therefore sought to examine the impact of HC exposure on the mortality, morbidity and ND outcome of a contemporary cohort of ELBW infants. METHODS Population and HC data This is a retrospective chart review of all ELBW infants (BWo1000 g) who were born in 2008 to 2010 and cared for in the Rush University Medical Center NICU. Exclusion criteria included presence of a major congenital malformation or genetic syndrome, exposure to postnatal dexamethasone and transport to another medical facility prior to hospital discharge. Remaining infants were categorized by exposure to HC. This resulted in a cohort of 175 ELBW infants (86 HC exposed and 89 steroid naive) who were compared in terms of mortality, morbidity and ND outcome at 8 and 20 months corrected age (CA). Sixty-five (76%) infants in the HC and 74 (83%) infants in the no-HC groups survived to hospital discharge. Of the survivors 55 (85%) infants in the HC and 46 (62%) infants in the no-HC groups had complete ND assessments at 8 months CA. One infant in the
Rush University Medical Center, Department of Pediatrics, Chicago, IL, USA. Correspondence: Dr K Patra, Rush University Medical Center, Department of Pediatrics, 1653W Congress Parkway, Murdock 622, Chicago, 60612 IL, USA. E-mail: [email protected] Received 17 March 2014; revised 19 May 2014; accepted 16 June 2014
HC exposure in ELBW infants K Patra et al
2 HC group died before the 20-month assessment leaving a final cohort of 64 infants in the HC group. At 20 months CA, 46 (72%) infants in the HC group and 44 (60%) infants in the no-HC group had complete ND assessments. Data collected regarding HC therapy included age at treatment initiation and discontinuation, indication for treatment, duration of therapy, cortisol levels prior to treatment and documentation of cosyntropin-stimulation testing post-treatment if performed. Indication for HC treatment was as documented by the attending physician in the medical record at the time of treatment initiation. This documentation was standard practice during the study years for quality improvement and treatments were categorized as being for respiratory status, blood pressure or other reasons that were clearly stated. Hypotension in our NICU was defined as mean arterial blood pressure (mmHg) less than the infant’s gestational age (GA) for greater than 30 min. The primary treatment algorithm of hypotension in the ELBW infant in the NICU during this time was treatment with fluid boluses, followed by dopamine. If hypotension persisted in spite of dopamine, infants were started on HC at 3 mg kg − 1 per day. During the study period, HC was started as a respiratory adjunct only in an intubated patient whom the attending physician deemed unable to successfully wean from mechanical ventilation, most commonly after 2 weeks of life. However, as there was no specific respiratory protocol in place to guide treatment initiation, there was much variation in level of respiratory support as well as treatment age among infants who received HC for respiratory reasons. During the period of study, the maximum daily dose of HC used was 3 mg kg − 1 per day divided every 8 h. This was the treatment dose for hypotension and the most common starting dose to facilitate weaning from the ventilator. HC was weaned for any infant requiring it for more than 2 to 5 days, and frequency of wean as well as returning to an increased dose was at the discretion of the attending physician. The most standard protocol for weaning of HC at that time was a tapering of dose once weekly from 3 mg kg − 1 per day to the following: 2 mg kg − 1 per day (divided every 8 h), 1 mg kg − 1 per day (divided every 8 h), 0.67 mg kg − 1 per day (divided every 12 h), 0.33 mg kg − 1 per day (every 24 h followed by every 48 h for 3 doses). If an infant was started on the maximum dose and weaned per protocol without re-escalation of therapy, the maximum number of days of initial HC therapy would be 38 days with a total dose of 50 mg kg − 1. Any infant previously exposed to HC received 3 mg kg − 1 per day of HC for 24 to 48 h for clinical deterioration or in preparation for surgery.
Neonatal and sociodemographic data Sociodemographic and birth data collected included maternal age, in-utero drug exposure, antenatal steroid administration, mode of and reason for delivery, infant BW and GA, race/ethnicity, type of medical insurance, transfer status, multiple gestation and small for gestational age status, defined as BW less than 10th percentile according to Fenton.16 Neonatal morbidity information collected included patent ductus arteriosus treated with medication and/or surgery, treated hypotension (treatment at the attending physician discretion with fluids, inotropes or HC), the presence of BPD, defined as oxygen dependence at 36 weeks’ CA, sepsis, defined as a positive blood or cerebrospinal fluid culture, necrotizing enterocolitis stages 2 to 3, defined according to Bells’ criteria, spontaneous intestinal perforation, retinopathy of prematurity and head ultrasound findings.17 Finally, for the NICU stay, data were collected on home oxygen therapy, diet and CA at discharge.
ND follow-up data During the period of study it was the policy to evaluate all ELBW infants in the Neonatal High Risk Follow-up Clinic, a multidisciplinary clinic that monitors the growth, neurologic and developmental status of infants cared for in the NICU. Outcome measures included neurologic exam and results of the Bayley Scales of Infant and Toddler Development-III (BSITD-III) at 8 and 20 months CA.18 Outcome measures on the BSITD-III included the cognitive, language and motor index scores and the receptive and expressive language and the fine and gross motor subscale scores. The mean for index scores is 100 ± 15 and for subscale scores is 10 ± 3. All index scores 41 standard deviation below the mean (o 85 for index scores and o7 for subscale scores) were classified as subnormal. Neurologic examination of muscle tone was performed according to Amiel-Tison and Stewart.19 Neurologic abnormalities were classified as hypertonia, hypotonia and cerebral palsy. Journal of Perinatology (2014), 1 – 5
Statistical analyses A series of chi-square or phi, point-biserial and Pearson correlations were calculated to analyze the following bivariate associations between HC and BSITD-II index and subscale scores at 8 and 20 months CA: any exposure (Y/N); total days of exposure (cumulative and 0 vs 1 to 7 vs 8+ days); and timing of exposure (started at o7 days, 14 to 29 days, or at 30+ day). Chisquare or phi, point-biserial and Pearson correlations were calculated to analyze bivariate associations between neonatal and sociodemographic data and 8- and 20-month BSITD-III index and subscale scores. Hierarchical, step-wise procedures were used for multiple linear and logistic regressions predicting the impact of HC on ND outcome after controlling for neonatal and social risk factors. Factors significantly associated with ND outcome in bivariate analyses (Po0.05) were entered in the first step, HC was entered in the second step and within each step variables with Po0.08 were retained. The study was reviewed and approved by the Institutional Review Board of Rush University Medical Center.
RESULTS Sociodemographic data and neonatal morbidities There were no significant differences in survival to hospital discharge between the HC and No-HC groups (76 vs 83%, respectively). Sociodemographic, birth and neonatal morbidity data of the survivors are presented in Table 1. Infants treated with HC were of significantly smaller BW (719 ± 127 vs 837 ± 99 g) and younger GA (26 ± 1.7 vs 27.5 ± 1.8 weeks) and more likely to be a multiple (37 vs 12%) compared to the no-HC group. ELBW in the HC group had a significantly higher rate of all major neonatal morbidities other than sepsis. Although the HC group had a significantly higher rate of the combined outcome of necrotizing enterocolitis and/or spontaneous intestinal perforation (23 vs 5%), there was no significant difference in the rate of spontaneous intestinal perforation between the two groups (P = 0.054). The most significant differences in neonatal morbidity between the HC and no-HC groups included higher rate of treatment for patent ductus arteriosus (85 vs 37%), treatment for hypotension (62 vs 28%), presence of any stage of retinopathy of prematurity (55 vs 10%) and a higher rate of BPD (85 vs 42%). Of the 40 patients in the HC group who were treated for hypotension, 2% were treated Table 1.
Sociodemographic, birth data and neonatal morbidities HC (N = 65)
Male gender
32 (49)
837 ± 99 27.5 ± 1.8 N (%) 28 (38)
Race White Black Hispanic
21 (32) 30 (46) 14 (22)
21 (28) 32 (43) 20 (27)
Multiple birth* Small for gestational age Antenatal steroids Caesarean section Maternal chorioamnionitis Public health insurance Bad head ultrasounda,* Treated patent ductus arteriosus** Treated hypotension** Sepsis NEC and/or intestinal perforation** Retinopathy of prematurity** Bronchopulmonary dysplasiab,**
24 14 53 48 13 42 15 55 40 17 15 36 55
9 15 60 49 10 52 4 27 21 15 4 7 31
Birth weight (g)** Gestational age (weeks)**
719 ± 127 26 ± 1.7
No-HC (N = 74)
(37) (22) (82) (74) (20) (65) (23) (85) (62) (26) (23) (55) (85)
(12) (20) (81) (66) (14) (70) (5) (37) (28) (20) (5) (10) (42)
a Grades 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, ventricular dilatation, hydrocephalus. bOxygen dependence at 36 weeks corrected gestational age. *Po0.01, **P o0.001.
© 2014 Nature America, Inc.
HC exposure in ELBW infants K Patra et al
3 with normal saline boluses alone, 43% were treated with inotropes after saline boluses and 17% were treated with HC therapy in addition to fluids and inotropes. Twenty percent of the HC and 3% of the no-HC groups were discharged home on oxygen therapy. Details of HC therapy Details of HC therapy are presented in Table 2. Eighty-eight percent of HC patients were started on HC to facilitate weaning from mechanical ventilation and 9% were started for inotroperefractory hypotension. Four patients were started on HC for the combined reason of respiratory decline and hypotension. Other reasons for treatment included presumed adrenal insufficiency, hypoglycemia and low cortisol level. Overall, the median cortisol level prior to treatment initiation was 3 mcg dl − 1 (25th to 75th percentile range: 1.55 to 3.55 mcg dl − 1). Almost half of the patients who received HC were started on it prior to 14 days of age. However, the age at which HC was started varied significantly
Table 2.
Details of hydrocortisone (HC) treatment HC (N = 65)
Baseline median cortisol level, mcg dl
−1
3 (1.55–5.35)a
Treatment reason, N (%) Respiratory Hypotension Hypoglycemia Other
57 6 2 4
(88) (9) (3) (6)
HC age at treatment start, days, N (%) o7 7–13 14–29 ⩾ 30
12 19 23 11
(19) (29) (35) (17)
49.0 ± 37.1 43.0 (24–61.5)a
Mean total duration of treatment, days Median total duration of treatment, days a
Median range refers to 25th–75th percentile.
Table 3.
Unadjusted analyses of ND outcome at 8 and 20 months Mean Bayley Scores, neurologic exam findings and subnormal scores at 8 and 20 months are presented in Table 3. Patients in the HC group had a significantly lower mean motor index score at 8 months compared to those in the no-HC group. This was due to the significantly lower fine motor subscale score in the HC group at 8 months. Furthermore, a significantly higher percentage of infants in the HC groups had subnormal motor index (44 vs 15%, P o0.01) and fine motor subscale at 8 months (24 vs 7%, Po 0.05). There were no significant differences in cognitive and language scores or neurologic exam between the groups at 8 months. There were no differences in any ND outcome at 20 months between the HC and no-HC groups. Multivariate analyses of ND outcome at 8 and 20 months The results of regression analyses are shown in Table 4. Male gender and the total number of days of HC exposure were both significantly associated with worse language index scores and specifically worse receptive language scores at 8 months CA. Maternal chorioamnionitis, although a significant correlate of worse language in the first step of the model, did not remain significant in the final model alongside cumulative exposure to HC. Furthermore, the odds of having a subnormal receptive and expressive language subscale scores significantly increased with cumulative HC exposure. Each additional day of HC exposure increased the risk of subnormal receptive and expressive language by 4 and 2%, respectively. Male gender again was the only other covariate significantly associated with subnormal language with
20.1 ± 19.4 14 (8.5–25)a 65.1 ± 42.2 57.0 (38.5–80.0)a
Mean age at start of treatment, days Median age at start of treatment, days Mean age at stop of initial treatment, days Median age at stop of initial treatment, days
based upon the treatment indication. All infants who were started on HC solely for hypotension were less than 72 h old, whereas the median age at which infants were started on HC only to facilitate ventilator weaning was 15 days (25th to 75th percentile range: 10 to 25 days). Forty-eight percent of patients who received a HC course were restarted on it at another date, most commonly for preoperative stress steroid dosing (75%). Other indications for a repeat HC course included respiratory decline and airway edema. The mean duration of a 2nd HC course was 4 ± 14 days. Overall, the mean duration of HC therapy was 49 ± 37 days with a median of 43 days (25th to 75th percentile range: 24 to 61.5 days). Approximately 26% of patients received cosyntropin-stimulation testing at the completion of HC therapy.
Mean Bayley Scores, subnormal scores and neurologic exam at 8 and 20 months 8-Month outcome HC (N = 55)
Cognitive index Language index Receptive Expressive Motor index Fine motor Gross motor
20-Month outcome
No-HC (N = 46)
HC (N = 46)
No-HC (N = 44)
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
97 ± 15 89 ± 14 8.8 ± 2.5 7.7 ± 2.7 87 ± 18* 9.0 ± 2.9** 6.8 ± 3.7
13 35 17 37 44** 24* 46
102 ± 12 93 ± 13 9.5 ± 2.2 8.0 ± 3.2 95 ± 15 10.5 ± 2.6 7.6 ± 3.5
4 26 4 28 15 7 44
92 ± 12 82 ± 15 6.8 ± 2.3 6.9 ± 3.1 89 ± 11 9.3 ± 2.6 7.3 ± 1.8
15 59 50 48 28 17 30
96 ± 13 82 ± 19 6.9 ± 3.0 7.2 ± 3.9 91 ± 12 9.1 ± 2.7 7.5 ± 1.8
7 52 48 41 23 18 25
N (%) Neurologic abnormality Hypertonia Hypotonia Cerebral palsy
39 (71) 30 (55) 15 (27) 0
23 (50) 17 (40) 10 (22) 0
10 (22) 7 (15) 2 (4) 1 (2)
8 (18) 7 (16) 1 (2) 0 (0)
Abbreviation: HC, hydrocortisone. *Po0.05, **P o0.01.
© 2014 Nature America, Inc.
Journal of Perinatology (2014), 1 – 5
HC exposure in ELBW infants K Patra et al
4 Table 4.
Neurodevelopmental outcome at 8 and 20 months, multiple regression results 8 Months Language index
Receptive language
Fine motor
20 Months
Subnormal receptive language
β Male gender Chorioamnionitis CA at discharge Total days of HC HC (0 vs 1–7 days) HC (0 vs 8 ± days) Public insurance Sepsis
− 0.30** − 0.13 − 0.14 − 0.26* — — — —
− 0.29* − 0.10 — − 0.30* — — — —
Subnormal expressive language
Subnormal motor index
OR (95% CI) − 0.19 — — — 0.04 −0.29* — —
— — — 1.04 (1.02–1.06)** — — — 3.20 (0.71–14.40)
2.79 (1.11, 7.00)* — 1.07 (0.95–1.12) 1.02 (1.00–1.03)* — — — —
— — — 1.02 (1.002–1.033)* — — 4.05 (1.07–15.27)* —
Abbreviations: CA, corrected age; CI, confidence interval; HC, hydrocortisone; OR, odds ratio. *Po0.05, **Po 0.01.
nearly a threefold increase in low expressive language subscale score. Additionally, HC exposure (0, 1 to 7, 8+ days) was significantly associated with worse fine motor performance at 8 months CA. Specifically, relative to no-HC exposure, HC exposure greater than 7 days was associated with worse fine motor skills (P o 0.05). At 20 months, CA multivariate analyses revealed that total days of HC exposure as well as public health insurance significantly predicted subnormal motor index scores. Each additional day of HC exposure was associated with a 2% increase in subnormal motor scores. There were no significant predictors of language, cognitive or neurologic outcome at 20 months CA. DISCUSSION Concerns over the ND sequelae of dexamethasone have led to the evolution of HC as the postnatal steroid of choice in NICUs in the last decade.9,10 Although HC is employed for both cardiovascular and endocrine effects, its predominant role continues to be that of a respiratory adjunct utilized for the treatment of BPD, facilitation of extubation and rescue therapy in infants with life-threatening respiratory failure. To our knowledge this is the first study to report an adverse ND effect of HC in ELBW infants and the first to examine the relationship between HC exposure and language outcomes using the BSITD-III. We found that at 8 months CA HC exposure for 47 days negatively impacted fine motor performance and cumulative exposure significantly increased the odds of having subnormal expressive and receptive language scores. Although these deficits in language scores did not persist, ELBW infants with prolonged HC exposure were significantly more likely to have subnormal motor scores at 20 months CA compared to their no-HC counterparts even after adjusting for differences in neonatal and social risk factors. In contrast, retrospective studies of infants born in the late 1990s have found that HC does not negatively influence ND outcome.11–13 Van der Heide Jalving et al.11 studied two group of infants born in 1993 to 1996 at o 32 weeks GA, of whom one group was treated with HC at 5 mg kg − 1 per day tapered to 1 mg kg − 1 per day over 22 days vs a second group treated with dexamethasone at 0.5 mg kg − 1 per day tapered to 0.1 mg kg − 1 per day over 21 days. They found that at 5 to 7 years of age patients who were treated with HC had similar outcomes to steroid naive infants, and that both groups had superior neurologic outcome and school performance compared to children in the dexamethasone group. A separate study from the same institution reported outcomes of infants born in 1991 to 1993 treated with the same HC protocol (median age of treatment = day 19; median treatment duration = 27.5 days) and Journal of Perinatology (2014), 1 – 5
found that at 7 to 8 years of age there were no differences in intelligence quotients, visual motor skills, memory skills, and rates of cerebral palsy and MRI lesions between the HC and control groups.12 Needleman et al.20 followed a cohort of extremely preterm infants born from 1993 to 2005 who received HC (median age at treatment = day one; median treatment duration = 3.5 days) and found no differences in ND outcome at 6, 16 or 24 months CA between the HC and steroid-naive groups. Although the starting dose of HC was higher in at least two of the above studies, the median duration of HC therapy for our cohort was 43 days, much longer than the prior studies. Our patients were also of significantly smaller BW, GA and a generally sicker group of patients compared to the HC-treated cohorts of these studies.11–13,20 At 8 months, a significantly higher percentage our HC infants (85%) returned for follow-up as compared to the no-HC group (62%). Those who returned for 8-month follow-up were of lower GA and had a higher rate of BPD compared to those who did not return for follow-up. However, at 20 months there were no significant differences in the rate of follow-up between the two groups and no differences between those who did or did not come for follow-up. While eliminating the bias seen in the prior cohort studies, prospective randomized control trials have largely focused on early low-dose HC therapy for the treatment and/or prevention of BPD and have been terminated early due to concerns of higher rates of spontaneous intestinal perforation in infants who received HC.14,15 Peltoniemi et al.14 found no difference in ND outcome at 2 years for a cohort of 25 infants of BWo 1250 g treated for 10 days with a total of 11.5 mg kg − 1 per day of HC, as compared to infants not exposed to steroids. In the largest study to date Watterberg et al.15 found that in a cohort of ELBW infants treated for 15 days with total of 13.5 mg kg − 1 per day of HC there was no increased risk of cerebral palsy and that instead infants in the HC group had a significantly lower risk of having a mental developmental index o 70 and had better performance on tasks of object permanence. In both of these trials, however, the dose and duration of HC therapy was lower than what was used in our NICU and the indication for treatment was prevention of BPD, as opposed to facilitation of ventilator weaning, which was the primary indication for HC therapy in at least 88% of our patients who received HC. Although this study is retrospective we feel that it provides vital information to neonatologists who are increasingly treating smaller infants with severe lung disease, many of whom undergo what we consider to be ‘rescue therapy’ with HC in the first few weeks of life.10 The strengths of this study are that this was a very recent cohort of ELBW infants treated at a single center and there were not many significant practice changes over the 3-year period © 2014 Nature America, Inc.
HC exposure in ELBW infants K Patra et al
as compared to prior studies.11–13,20 The majority of these infants had received antenatal steroids and although excluded from the study cohort, there was very little dexamethasone use in our NICU during the study period similar to what has occurred at other institutions in the last decade.10 As Fortin-Pellerin et al.10 acknowledge in their study of steroid practice there is the tendency to re-escalate steroid therapy once it has been started especially if the prior impact was positive in terms of gas exchange. Whether this ultimately results in any benefit to a patient in terms of survival without pulmonary disease and ND impairment, however, is debatable. Furthermore, although it is reassuring that there was no increased risk of cerebral palsy or Bayley Index scores o 70 in our HC cohort, it must be interpreted with caution as this is the only study on ND outcomes in HCexposed infants that utilized the BSITD-III, which is generally felt to result in higher test scores.21 Whether this is an underestimation of ND impairment or rather more predictive of later childhood outcome is unknown. Finally, it is not clear to us why language and fine motor skills were disproportionately affected at 8 months CA, although improved by 20 months. It is difficult to assess language skills at this age in general and unclear whether these language delays were really transient and/or less apparent as fewer HC infants returned for follow-up at the age of 2 years. There are several limitations of our study, namely that it is retrospective in nature and as such, one cannot determine an exact causal relationship between HC exposure and outcome. As in other cohort studies, our HC group was a smaller, sicker group of infants who would be expected to have a higher rate of developmental delay and ND impairment. However, even after adjusting for these variables, the rates of subnormal language and motor scores remained significantly higher in the HC group of infants. Although the maximum daily dose of HC we used was lower than in older studies, there was great heterogeneity in the duration of therapy, largely due to repeated re-escalation of stress dosing during clinical deterioration, which prevented weaning of HC per an existing protocol. However, we argue that as there is not a published standard protocol for HC treatment that NICU practices will vary widely particularly for infants on maximal ventilator support for whom there is great hesitation to wean steroids once they are started. Finally, we acknowledge that our follow-up rate for the HC cohort significantly declined from 85% at 8 months to 72% at 20 months, which may have impacted our 2-year findings but are relatively high compared to recent reports.10,20 CONCLUSION We have found that recently surviving ELBW infants treated with prolonged courses of HC are at significantly higher risk of fine motor and language delay at 8 months and motor delay at 20 months CA. These findings persist after adjusting for demographic and neonatal risk factors. As smaller infants continue to survive, there will be further utilization of what is considered to be rescue therapy in the treatment of preterm lung disease. This underscores the vital importance of randomized control trials that not only can determine ND outcome in survivors treated for this indication, but that can also determine safety profiles for duration of HC treatment. Until then, it is prudent to remain judicious with HC treatment and make every attempt to discontinue therapy particularly when there is no evidence of a clinical response.
© 2014 Nature America, Inc.
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CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 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. 2 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. 3 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–F181. 4 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 Engl J Med 2004; 350(13): 1304–1313. 5 Wilson-Costello D, Walsh MC, Langer JC, Guillet R, Laptook AR, Stoll BJ et al. 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 2009; 123: e430–e437. 6 Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001; 1–1. 7 Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002; 109: 330–338. 8 American Academy of Pediatrics. Policy statement: postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010; 126(4): 800–808. 9 Yoder BA, Harrison M, Clark RH. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics 2009; 124: 673–679. 10 Fortin-Pellerin É, Petersen C, Lefebvre F, Barrington KJ, Janvier A. Evolving neonatal steroid prescription habits and patient outcomes. Acta Paediatrica 2013; 102: 799–804. 11 Van der Heide-Jalving M, Kamphuis P, van der Laan M, Bakker J, Wiegant V, Heijnen C et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatrica 2003; 92: 827–835. 12 Rademaker KJ, Uiterwaal CS, Groenendaal F, Venema MM, van Bel F, Beek FJ et al. Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children. J Pediatr 2007; 150: 351–357. 13 Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F. Hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed 2008; 93(1): F58–F63. 14 Peltoniemi OM, Lano A, Puosi R, Yliherva A, Bonsante F, Kari MA et al. Neonatal Hydrocortisone Working Group. Trial of early neonatal hydrocortisone: two-year follow-up. Neonatology 2009; 95(3): 240–247. 15 Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ et al. Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007; 120: 40–48. 16 Fenton T. A new growth chart for preterm babies: Babson and Benda’s chart updated with recent data and new format. BMC Pediatr 2003; 3: 13. 17 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1979; 187(1): 1–7. 18 Bayley N. Bayley Scales of Infant DevelopmentThird ednSan Antonio, TX: The Psychological Corporation, 2006. 19 Amiel-Tison C, Stewart AL. Follow-up studies in the first five years of life: a pervasive assessment of neurologic function. Arch Dis Child 1989; 64: 496–502. 20 Needelman H, Hoskoppal A, Roberts H, Evans M, Bodensteiner JB. The effect of hydrocortisone on neurodevelopmental outcome in premature infants less than 29 weeks’ gestation. J Child Neurol 2010; 25: 448–452. 21 Vohr BR, Stephens BE, Higgins RD, Bann CM, Hintz SR, Das A et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr 2012; 161(2): 222–228.
Journal of Perinatology (2014), 1 – 5
ORIGINAL ARTICLE
Neurodevelopmental impact of hydrocortisone exposure in extremely low birth weight infants: outcomes at 1 and 2 years K Patra, MM Greene and JM Silvestri OBJECTIVE: Postnatal steroids are used in neonatal intensive care units despite known side effects. Hydrocortisone (HC) use persists as it is believed to have less deleterious effects on neurodevelopmental (ND) outcome compared to other steroids. The literature is sparse with respect to the ND impact of HC use in recent years. Hence, we sought to examine the effect of HC use on ND outcome in a contemporary cohort of extremely low birth weight (ELBW) infants. STUDY DESIGN: A total of 175 ELBW infants (86 HC exposed, 89 steroid naive) born in 2008 to 2010 were compared for mortality, morbidity and ND outcome at 8 and 20 months corrected age. Outcome measures included neurologic exam and results of the Bayley Scales of Infant and Toddler Development-III (BSITD-III). Multiple regression analyses adjusted for the effect of other risk factors on outcome. RESULT: Overall, 65 (75%) of the HC and 74 (83%) of the no-HC groups survived to discharge. HC infants were smaller (mean birth weight (BW) 719 ± 127 g vs 837 ± 99 g) and of lower gestational age (GA) (mean GA 26.0 ± 1.7 weeks vs 27.5 ± 1.8 weeks) compared to the no-HC group. Patients in the HC group were more likely to be a multiple, have a severely abnormal head ultrasound, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis and receive treatment for patent ductus arteriosus and hypotension than those in the no-HC group. Of the HC group, the mean age at treatment was 20 ± 19 days, mean duration of treatment 49 ± 37 days. At 8 months, the HC group had lower mean motor (87 ± 18 vs 95 ± 15, P = 0.028) and fine motor (9 ± 2.9 vs 10.5 ± 2.6, P = 0.005) and higher rate of subnormal motor (44 vs 15%, P = 0.002) and fine motor scores (24 vs 6.5%, P = 0.017). In regression analyses, HC exposure 47 days was significantly related to worse outcome on fine motor scores at 8 months while cumulative days of HC exposure was a predictor of worse outcome on language at 8 months and motor outcome at 20 months. Each additional day of HC exposure increased the odds of subnormal receptive and expressive language in the first year of life by 4 and 2%, respectively, and increased odds of subnormal motor function by 2% in the 2nd year of life. CONCLUSION: HC exposure for 47 days is associated with worse performance in fine motor skills in the first year of life, while cumulative HC exposure negatively impacts receptive and expressive language skills in the first year and motor skills in the second year of life after adjusting for neonatal and social risk factors. Journal of Perinatology advance online publication, 31 July 2014; doi:10.1038/jp.2014.133
INTRODUCTION Postnatal corticosteroids are used commonly in neonatal intensive care units (NICUs) despite their known adverse effects on neurodevelopmental (ND) outcome in preterm infants.1–6 Concerns regarding early childhood neurologic outcome in preterm infants following dexamethasone exposure led the American Academy of Pediatrics to caution against the use of postnatal steroids altogether in the treatment and prevention of bronchopulmonary dysplasia (BPD).7,8 Since that time there has been a significant reduction in the use of dexamethasone while hydrocortisone (HC) use has increased.9,10 Cohort studies suggest that infants exposed to HC have ND outcomes superior to those of infants exposed to dexamethasone and similar to that of infants not treated with steroids.11–13 Prospective trials of 10 to 15 days of HC treatment for the prevention of BPD have found no increased incidence of cerebral palsy and ND impairment at 2 years.14,15 What is not clear, however, is the impact of variable doses and durations of HC therapy on ND outcome. This is relevant as HC use is increasing and treatment duration and weaning schedules will vary widely both across and within institutions. The literature is sparse with respect to ND outcome after HC exposure and no
study has examined the ND effect of HC on extremely low birth weight (ELBW) infants born since 2005. Neonatal management continues to evolve and HC use may have different effects now on short- and long-term morbidity. We therefore sought to examine the impact of HC exposure on the mortality, morbidity and ND outcome of a contemporary cohort of ELBW infants. METHODS Population and HC data This is a retrospective chart review of all ELBW infants (BWo1000 g) who were born in 2008 to 2010 and cared for in the Rush University Medical Center NICU. Exclusion criteria included presence of a major congenital malformation or genetic syndrome, exposure to postnatal dexamethasone and transport to another medical facility prior to hospital discharge. Remaining infants were categorized by exposure to HC. This resulted in a cohort of 175 ELBW infants (86 HC exposed and 89 steroid naive) who were compared in terms of mortality, morbidity and ND outcome at 8 and 20 months corrected age (CA). Sixty-five (76%) infants in the HC and 74 (83%) infants in the no-HC groups survived to hospital discharge. Of the survivors 55 (85%) infants in the HC and 46 (62%) infants in the no-HC groups had complete ND assessments at 8 months CA. One infant in the
Rush University Medical Center, Department of Pediatrics, Chicago, IL, USA. Correspondence: Dr K Patra, Rush University Medical Center, Department of Pediatrics, 1653W Congress Parkway, Murdock 622, Chicago, 60612 IL, USA. E-mail: [email protected] Received 17 March 2014; revised 19 May 2014; accepted 16 June 2014
HC exposure in ELBW infants K Patra et al
2 HC group died before the 20-month assessment leaving a final cohort of 64 infants in the HC group. At 20 months CA, 46 (72%) infants in the HC group and 44 (60%) infants in the no-HC group had complete ND assessments. Data collected regarding HC therapy included age at treatment initiation and discontinuation, indication for treatment, duration of therapy, cortisol levels prior to treatment and documentation of cosyntropin-stimulation testing post-treatment if performed. Indication for HC treatment was as documented by the attending physician in the medical record at the time of treatment initiation. This documentation was standard practice during the study years for quality improvement and treatments were categorized as being for respiratory status, blood pressure or other reasons that were clearly stated. Hypotension in our NICU was defined as mean arterial blood pressure (mmHg) less than the infant’s gestational age (GA) for greater than 30 min. The primary treatment algorithm of hypotension in the ELBW infant in the NICU during this time was treatment with fluid boluses, followed by dopamine. If hypotension persisted in spite of dopamine, infants were started on HC at 3 mg kg − 1 per day. During the study period, HC was started as a respiratory adjunct only in an intubated patient whom the attending physician deemed unable to successfully wean from mechanical ventilation, most commonly after 2 weeks of life. However, as there was no specific respiratory protocol in place to guide treatment initiation, there was much variation in level of respiratory support as well as treatment age among infants who received HC for respiratory reasons. During the period of study, the maximum daily dose of HC used was 3 mg kg − 1 per day divided every 8 h. This was the treatment dose for hypotension and the most common starting dose to facilitate weaning from the ventilator. HC was weaned for any infant requiring it for more than 2 to 5 days, and frequency of wean as well as returning to an increased dose was at the discretion of the attending physician. The most standard protocol for weaning of HC at that time was a tapering of dose once weekly from 3 mg kg − 1 per day to the following: 2 mg kg − 1 per day (divided every 8 h), 1 mg kg − 1 per day (divided every 8 h), 0.67 mg kg − 1 per day (divided every 12 h), 0.33 mg kg − 1 per day (every 24 h followed by every 48 h for 3 doses). If an infant was started on the maximum dose and weaned per protocol without re-escalation of therapy, the maximum number of days of initial HC therapy would be 38 days with a total dose of 50 mg kg − 1. Any infant previously exposed to HC received 3 mg kg − 1 per day of HC for 24 to 48 h for clinical deterioration or in preparation for surgery.
Neonatal and sociodemographic data Sociodemographic and birth data collected included maternal age, in-utero drug exposure, antenatal steroid administration, mode of and reason for delivery, infant BW and GA, race/ethnicity, type of medical insurance, transfer status, multiple gestation and small for gestational age status, defined as BW less than 10th percentile according to Fenton.16 Neonatal morbidity information collected included patent ductus arteriosus treated with medication and/or surgery, treated hypotension (treatment at the attending physician discretion with fluids, inotropes or HC), the presence of BPD, defined as oxygen dependence at 36 weeks’ CA, sepsis, defined as a positive blood or cerebrospinal fluid culture, necrotizing enterocolitis stages 2 to 3, defined according to Bells’ criteria, spontaneous intestinal perforation, retinopathy of prematurity and head ultrasound findings.17 Finally, for the NICU stay, data were collected on home oxygen therapy, diet and CA at discharge.
ND follow-up data During the period of study it was the policy to evaluate all ELBW infants in the Neonatal High Risk Follow-up Clinic, a multidisciplinary clinic that monitors the growth, neurologic and developmental status of infants cared for in the NICU. Outcome measures included neurologic exam and results of the Bayley Scales of Infant and Toddler Development-III (BSITD-III) at 8 and 20 months CA.18 Outcome measures on the BSITD-III included the cognitive, language and motor index scores and the receptive and expressive language and the fine and gross motor subscale scores. The mean for index scores is 100 ± 15 and for subscale scores is 10 ± 3. All index scores 41 standard deviation below the mean (o 85 for index scores and o7 for subscale scores) were classified as subnormal. Neurologic examination of muscle tone was performed according to Amiel-Tison and Stewart.19 Neurologic abnormalities were classified as hypertonia, hypotonia and cerebral palsy. Journal of Perinatology (2014), 1 – 5
Statistical analyses A series of chi-square or phi, point-biserial and Pearson correlations were calculated to analyze the following bivariate associations between HC and BSITD-II index and subscale scores at 8 and 20 months CA: any exposure (Y/N); total days of exposure (cumulative and 0 vs 1 to 7 vs 8+ days); and timing of exposure (started at o7 days, 14 to 29 days, or at 30+ day). Chisquare or phi, point-biserial and Pearson correlations were calculated to analyze bivariate associations between neonatal and sociodemographic data and 8- and 20-month BSITD-III index and subscale scores. Hierarchical, step-wise procedures were used for multiple linear and logistic regressions predicting the impact of HC on ND outcome after controlling for neonatal and social risk factors. Factors significantly associated with ND outcome in bivariate analyses (Po0.05) were entered in the first step, HC was entered in the second step and within each step variables with Po0.08 were retained. The study was reviewed and approved by the Institutional Review Board of Rush University Medical Center.
RESULTS Sociodemographic data and neonatal morbidities There were no significant differences in survival to hospital discharge between the HC and No-HC groups (76 vs 83%, respectively). Sociodemographic, birth and neonatal morbidity data of the survivors are presented in Table 1. Infants treated with HC were of significantly smaller BW (719 ± 127 vs 837 ± 99 g) and younger GA (26 ± 1.7 vs 27.5 ± 1.8 weeks) and more likely to be a multiple (37 vs 12%) compared to the no-HC group. ELBW in the HC group had a significantly higher rate of all major neonatal morbidities other than sepsis. Although the HC group had a significantly higher rate of the combined outcome of necrotizing enterocolitis and/or spontaneous intestinal perforation (23 vs 5%), there was no significant difference in the rate of spontaneous intestinal perforation between the two groups (P = 0.054). The most significant differences in neonatal morbidity between the HC and no-HC groups included higher rate of treatment for patent ductus arteriosus (85 vs 37%), treatment for hypotension (62 vs 28%), presence of any stage of retinopathy of prematurity (55 vs 10%) and a higher rate of BPD (85 vs 42%). Of the 40 patients in the HC group who were treated for hypotension, 2% were treated Table 1.
Sociodemographic, birth data and neonatal morbidities HC (N = 65)
Male gender
32 (49)
837 ± 99 27.5 ± 1.8 N (%) 28 (38)
Race White Black Hispanic
21 (32) 30 (46) 14 (22)
21 (28) 32 (43) 20 (27)
Multiple birth* Small for gestational age Antenatal steroids Caesarean section Maternal chorioamnionitis Public health insurance Bad head ultrasounda,* Treated patent ductus arteriosus** Treated hypotension** Sepsis NEC and/or intestinal perforation** Retinopathy of prematurity** Bronchopulmonary dysplasiab,**
24 14 53 48 13 42 15 55 40 17 15 36 55
9 15 60 49 10 52 4 27 21 15 4 7 31
Birth weight (g)** Gestational age (weeks)**
719 ± 127 26 ± 1.7
No-HC (N = 74)
(37) (22) (82) (74) (20) (65) (23) (85) (62) (26) (23) (55) (85)
(12) (20) (81) (66) (14) (70) (5) (37) (28) (20) (5) (10) (42)
a Grades 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, ventricular dilatation, hydrocephalus. bOxygen dependence at 36 weeks corrected gestational age. *Po0.01, **P o0.001.
© 2014 Nature America, Inc.
HC exposure in ELBW infants K Patra et al
3 with normal saline boluses alone, 43% were treated with inotropes after saline boluses and 17% were treated with HC therapy in addition to fluids and inotropes. Twenty percent of the HC and 3% of the no-HC groups were discharged home on oxygen therapy. Details of HC therapy Details of HC therapy are presented in Table 2. Eighty-eight percent of HC patients were started on HC to facilitate weaning from mechanical ventilation and 9% were started for inotroperefractory hypotension. Four patients were started on HC for the combined reason of respiratory decline and hypotension. Other reasons for treatment included presumed adrenal insufficiency, hypoglycemia and low cortisol level. Overall, the median cortisol level prior to treatment initiation was 3 mcg dl − 1 (25th to 75th percentile range: 1.55 to 3.55 mcg dl − 1). Almost half of the patients who received HC were started on it prior to 14 days of age. However, the age at which HC was started varied significantly
Table 2.
Details of hydrocortisone (HC) treatment HC (N = 65)
Baseline median cortisol level, mcg dl
−1
3 (1.55–5.35)a
Treatment reason, N (%) Respiratory Hypotension Hypoglycemia Other
57 6 2 4
(88) (9) (3) (6)
HC age at treatment start, days, N (%) o7 7–13 14–29 ⩾ 30
12 19 23 11
(19) (29) (35) (17)
49.0 ± 37.1 43.0 (24–61.5)a
Mean total duration of treatment, days Median total duration of treatment, days a
Median range refers to 25th–75th percentile.
Table 3.
Unadjusted analyses of ND outcome at 8 and 20 months Mean Bayley Scores, neurologic exam findings and subnormal scores at 8 and 20 months are presented in Table 3. Patients in the HC group had a significantly lower mean motor index score at 8 months compared to those in the no-HC group. This was due to the significantly lower fine motor subscale score in the HC group at 8 months. Furthermore, a significantly higher percentage of infants in the HC groups had subnormal motor index (44 vs 15%, P o0.01) and fine motor subscale at 8 months (24 vs 7%, Po 0.05). There were no significant differences in cognitive and language scores or neurologic exam between the groups at 8 months. There were no differences in any ND outcome at 20 months between the HC and no-HC groups. Multivariate analyses of ND outcome at 8 and 20 months The results of regression analyses are shown in Table 4. Male gender and the total number of days of HC exposure were both significantly associated with worse language index scores and specifically worse receptive language scores at 8 months CA. Maternal chorioamnionitis, although a significant correlate of worse language in the first step of the model, did not remain significant in the final model alongside cumulative exposure to HC. Furthermore, the odds of having a subnormal receptive and expressive language subscale scores significantly increased with cumulative HC exposure. Each additional day of HC exposure increased the risk of subnormal receptive and expressive language by 4 and 2%, respectively. Male gender again was the only other covariate significantly associated with subnormal language with
20.1 ± 19.4 14 (8.5–25)a 65.1 ± 42.2 57.0 (38.5–80.0)a
Mean age at start of treatment, days Median age at start of treatment, days Mean age at stop of initial treatment, days Median age at stop of initial treatment, days
based upon the treatment indication. All infants who were started on HC solely for hypotension were less than 72 h old, whereas the median age at which infants were started on HC only to facilitate ventilator weaning was 15 days (25th to 75th percentile range: 10 to 25 days). Forty-eight percent of patients who received a HC course were restarted on it at another date, most commonly for preoperative stress steroid dosing (75%). Other indications for a repeat HC course included respiratory decline and airway edema. The mean duration of a 2nd HC course was 4 ± 14 days. Overall, the mean duration of HC therapy was 49 ± 37 days with a median of 43 days (25th to 75th percentile range: 24 to 61.5 days). Approximately 26% of patients received cosyntropin-stimulation testing at the completion of HC therapy.
Mean Bayley Scores, subnormal scores and neurologic exam at 8 and 20 months 8-Month outcome HC (N = 55)
Cognitive index Language index Receptive Expressive Motor index Fine motor Gross motor
20-Month outcome
No-HC (N = 46)
HC (N = 46)
No-HC (N = 44)
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
Mean ± s.d.
%Subnormal
97 ± 15 89 ± 14 8.8 ± 2.5 7.7 ± 2.7 87 ± 18* 9.0 ± 2.9** 6.8 ± 3.7
13 35 17 37 44** 24* 46
102 ± 12 93 ± 13 9.5 ± 2.2 8.0 ± 3.2 95 ± 15 10.5 ± 2.6 7.6 ± 3.5
4 26 4 28 15 7 44
92 ± 12 82 ± 15 6.8 ± 2.3 6.9 ± 3.1 89 ± 11 9.3 ± 2.6 7.3 ± 1.8
15 59 50 48 28 17 30
96 ± 13 82 ± 19 6.9 ± 3.0 7.2 ± 3.9 91 ± 12 9.1 ± 2.7 7.5 ± 1.8
7 52 48 41 23 18 25
N (%) Neurologic abnormality Hypertonia Hypotonia Cerebral palsy
39 (71) 30 (55) 15 (27) 0
23 (50) 17 (40) 10 (22) 0
10 (22) 7 (15) 2 (4) 1 (2)
8 (18) 7 (16) 1 (2) 0 (0)
Abbreviation: HC, hydrocortisone. *Po0.05, **P o0.01.
© 2014 Nature America, Inc.
Journal of Perinatology (2014), 1 – 5
HC exposure in ELBW infants K Patra et al
4 Table 4.
Neurodevelopmental outcome at 8 and 20 months, multiple regression results 8 Months Language index
Receptive language
Fine motor
20 Months
Subnormal receptive language
β Male gender Chorioamnionitis CA at discharge Total days of HC HC (0 vs 1–7 days) HC (0 vs 8 ± days) Public insurance Sepsis
− 0.30** − 0.13 − 0.14 − 0.26* — — — —
− 0.29* − 0.10 — − 0.30* — — — —
Subnormal expressive language
Subnormal motor index
OR (95% CI) − 0.19 — — — 0.04 −0.29* — —
— — — 1.04 (1.02–1.06)** — — — 3.20 (0.71–14.40)
2.79 (1.11, 7.00)* — 1.07 (0.95–1.12) 1.02 (1.00–1.03)* — — — —
— — — 1.02 (1.002–1.033)* — — 4.05 (1.07–15.27)* —
Abbreviations: CA, corrected age; CI, confidence interval; HC, hydrocortisone; OR, odds ratio. *Po0.05, **Po 0.01.
nearly a threefold increase in low expressive language subscale score. Additionally, HC exposure (0, 1 to 7, 8+ days) was significantly associated with worse fine motor performance at 8 months CA. Specifically, relative to no-HC exposure, HC exposure greater than 7 days was associated with worse fine motor skills (P o 0.05). At 20 months, CA multivariate analyses revealed that total days of HC exposure as well as public health insurance significantly predicted subnormal motor index scores. Each additional day of HC exposure was associated with a 2% increase in subnormal motor scores. There were no significant predictors of language, cognitive or neurologic outcome at 20 months CA. DISCUSSION Concerns over the ND sequelae of dexamethasone have led to the evolution of HC as the postnatal steroid of choice in NICUs in the last decade.9,10 Although HC is employed for both cardiovascular and endocrine effects, its predominant role continues to be that of a respiratory adjunct utilized for the treatment of BPD, facilitation of extubation and rescue therapy in infants with life-threatening respiratory failure. To our knowledge this is the first study to report an adverse ND effect of HC in ELBW infants and the first to examine the relationship between HC exposure and language outcomes using the BSITD-III. We found that at 8 months CA HC exposure for 47 days negatively impacted fine motor performance and cumulative exposure significantly increased the odds of having subnormal expressive and receptive language scores. Although these deficits in language scores did not persist, ELBW infants with prolonged HC exposure were significantly more likely to have subnormal motor scores at 20 months CA compared to their no-HC counterparts even after adjusting for differences in neonatal and social risk factors. In contrast, retrospective studies of infants born in the late 1990s have found that HC does not negatively influence ND outcome.11–13 Van der Heide Jalving et al.11 studied two group of infants born in 1993 to 1996 at o 32 weeks GA, of whom one group was treated with HC at 5 mg kg − 1 per day tapered to 1 mg kg − 1 per day over 22 days vs a second group treated with dexamethasone at 0.5 mg kg − 1 per day tapered to 0.1 mg kg − 1 per day over 21 days. They found that at 5 to 7 years of age patients who were treated with HC had similar outcomes to steroid naive infants, and that both groups had superior neurologic outcome and school performance compared to children in the dexamethasone group. A separate study from the same institution reported outcomes of infants born in 1991 to 1993 treated with the same HC protocol (median age of treatment = day 19; median treatment duration = 27.5 days) and Journal of Perinatology (2014), 1 – 5
found that at 7 to 8 years of age there were no differences in intelligence quotients, visual motor skills, memory skills, and rates of cerebral palsy and MRI lesions between the HC and control groups.12 Needleman et al.20 followed a cohort of extremely preterm infants born from 1993 to 2005 who received HC (median age at treatment = day one; median treatment duration = 3.5 days) and found no differences in ND outcome at 6, 16 or 24 months CA between the HC and steroid-naive groups. Although the starting dose of HC was higher in at least two of the above studies, the median duration of HC therapy for our cohort was 43 days, much longer than the prior studies. Our patients were also of significantly smaller BW, GA and a generally sicker group of patients compared to the HC-treated cohorts of these studies.11–13,20 At 8 months, a significantly higher percentage our HC infants (85%) returned for follow-up as compared to the no-HC group (62%). Those who returned for 8-month follow-up were of lower GA and had a higher rate of BPD compared to those who did not return for follow-up. However, at 20 months there were no significant differences in the rate of follow-up between the two groups and no differences between those who did or did not come for follow-up. While eliminating the bias seen in the prior cohort studies, prospective randomized control trials have largely focused on early low-dose HC therapy for the treatment and/or prevention of BPD and have been terminated early due to concerns of higher rates of spontaneous intestinal perforation in infants who received HC.14,15 Peltoniemi et al.14 found no difference in ND outcome at 2 years for a cohort of 25 infants of BWo 1250 g treated for 10 days with a total of 11.5 mg kg − 1 per day of HC, as compared to infants not exposed to steroids. In the largest study to date Watterberg et al.15 found that in a cohort of ELBW infants treated for 15 days with total of 13.5 mg kg − 1 per day of HC there was no increased risk of cerebral palsy and that instead infants in the HC group had a significantly lower risk of having a mental developmental index o 70 and had better performance on tasks of object permanence. In both of these trials, however, the dose and duration of HC therapy was lower than what was used in our NICU and the indication for treatment was prevention of BPD, as opposed to facilitation of ventilator weaning, which was the primary indication for HC therapy in at least 88% of our patients who received HC. Although this study is retrospective we feel that it provides vital information to neonatologists who are increasingly treating smaller infants with severe lung disease, many of whom undergo what we consider to be ‘rescue therapy’ with HC in the first few weeks of life.10 The strengths of this study are that this was a very recent cohort of ELBW infants treated at a single center and there were not many significant practice changes over the 3-year period © 2014 Nature America, Inc.
HC exposure in ELBW infants K Patra et al
as compared to prior studies.11–13,20 The majority of these infants had received antenatal steroids and although excluded from the study cohort, there was very little dexamethasone use in our NICU during the study period similar to what has occurred at other institutions in the last decade.10 As Fortin-Pellerin et al.10 acknowledge in their study of steroid practice there is the tendency to re-escalate steroid therapy once it has been started especially if the prior impact was positive in terms of gas exchange. Whether this ultimately results in any benefit to a patient in terms of survival without pulmonary disease and ND impairment, however, is debatable. Furthermore, although it is reassuring that there was no increased risk of cerebral palsy or Bayley Index scores o 70 in our HC cohort, it must be interpreted with caution as this is the only study on ND outcomes in HCexposed infants that utilized the BSITD-III, which is generally felt to result in higher test scores.21 Whether this is an underestimation of ND impairment or rather more predictive of later childhood outcome is unknown. Finally, it is not clear to us why language and fine motor skills were disproportionately affected at 8 months CA, although improved by 20 months. It is difficult to assess language skills at this age in general and unclear whether these language delays were really transient and/or less apparent as fewer HC infants returned for follow-up at the age of 2 years. There are several limitations of our study, namely that it is retrospective in nature and as such, one cannot determine an exact causal relationship between HC exposure and outcome. As in other cohort studies, our HC group was a smaller, sicker group of infants who would be expected to have a higher rate of developmental delay and ND impairment. However, even after adjusting for these variables, the rates of subnormal language and motor scores remained significantly higher in the HC group of infants. Although the maximum daily dose of HC we used was lower than in older studies, there was great heterogeneity in the duration of therapy, largely due to repeated re-escalation of stress dosing during clinical deterioration, which prevented weaning of HC per an existing protocol. However, we argue that as there is not a published standard protocol for HC treatment that NICU practices will vary widely particularly for infants on maximal ventilator support for whom there is great hesitation to wean steroids once they are started. Finally, we acknowledge that our follow-up rate for the HC cohort significantly declined from 85% at 8 months to 72% at 20 months, which may have impacted our 2-year findings but are relatively high compared to recent reports.10,20 CONCLUSION We have found that recently surviving ELBW infants treated with prolonged courses of HC are at significantly higher risk of fine motor and language delay at 8 months and motor delay at 20 months CA. These findings persist after adjusting for demographic and neonatal risk factors. As smaller infants continue to survive, there will be further utilization of what is considered to be rescue therapy in the treatment of preterm lung disease. This underscores the vital importance of randomized control trials that not only can determine ND outcome in survivors treated for this indication, but that can also determine safety profiles for duration of HC treatment. Until then, it is prudent to remain judicious with HC treatment and make every attempt to discontinue therapy particularly when there is no evidence of a clinical response.
© 2014 Nature America, Inc.
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CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 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. 2 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. 3 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–F181. 4 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 Engl J Med 2004; 350(13): 1304–1313. 5 Wilson-Costello D, Walsh MC, Langer JC, Guillet R, Laptook AR, Stoll BJ et al. 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 2009; 123: e430–e437. 6 Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001; 1–1. 7 Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002; 109: 330–338. 8 American Academy of Pediatrics. Policy statement: postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010; 126(4): 800–808. 9 Yoder BA, Harrison M, Clark RH. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics 2009; 124: 673–679. 10 Fortin-Pellerin É, Petersen C, Lefebvre F, Barrington KJ, Janvier A. Evolving neonatal steroid prescription habits and patient outcomes. Acta Paediatrica 2013; 102: 799–804. 11 Van der Heide-Jalving M, Kamphuis P, van der Laan M, Bakker J, Wiegant V, Heijnen C et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatrica 2003; 92: 827–835. 12 Rademaker KJ, Uiterwaal CS, Groenendaal F, Venema MM, van Bel F, Beek FJ et al. Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children. J Pediatr 2007; 150: 351–357. 13 Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F. Hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed 2008; 93(1): F58–F63. 14 Peltoniemi OM, Lano A, Puosi R, Yliherva A, Bonsante F, Kari MA et al. Neonatal Hydrocortisone Working Group. Trial of early neonatal hydrocortisone: two-year follow-up. Neonatology 2009; 95(3): 240–247. 15 Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ et al. Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007; 120: 40–48. 16 Fenton T. A new growth chart for preterm babies: Babson and Benda’s chart updated with recent data and new format. BMC Pediatr 2003; 3: 13. 17 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1979; 187(1): 1–7. 18 Bayley N. Bayley Scales of Infant DevelopmentThird ednSan Antonio, TX: The Psychological Corporation, 2006. 19 Amiel-Tison C, Stewart AL. Follow-up studies in the first five years of life: a pervasive assessment of neurologic function. Arch Dis Child 1989; 64: 496–502. 20 Needelman H, Hoskoppal A, Roberts H, Evans M, Bodensteiner JB. The effect of hydrocortisone on neurodevelopmental outcome in premature infants less than 29 weeks’ gestation. J Child Neurol 2010; 25: 448–452. 21 Vohr BR, Stephens BE, Higgins RD, Bann CM, Hintz SR, Das A et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr 2012; 161(2): 222–228.
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