ABSTRACT BACKGROUND Extremely low birth weight (ELBW) infants comprise a fragile population at risk for neurodevelopmental disabilities (NDD). Systemic steroids were previously associated

with NDD, but more recent studies suggest hydrocortisone (HCT) may improve survival without increasing NDD. However, the effects of HCT on head growth adjusted for illness severity during

NICU hospitalization are unknown. Thus, we hypothesize that HCT will protect head growth, accounting for illness severity using a modified neonatal Sequential Organ Failure Assessment

(M-nSOFA) score. METHODS We conducted a retrospective study that included infants born at 23–29 weeks gestational age (GA) and < 1000 g. Our study included 73 infants, 41% of whom

such that infants exposed to HCT had better head growth compared to those not exposed to HCT when adjusted for illness severity. CONCLUSION These findings emphasize the importance of

considering patient illness severity and suggest that HCT use may offer additional benefits not previously considered. IMPACT * This is the first study to assess the relationship between

head growth and illness severity in extremely preterm infants with extremely low birth weights during their initial NICU hospitalization. * Infants exposed to hydrocortisone (HCT) were

overall more ill than those not exposed, yet HCT exposed infants had better preserved head growth relative to illness severity. * Better understanding of the effects of HCT exposure on this

vulnerable population will help guide more informed decisions on the relative risks and benefits for HCT use. You have full access to this article via your institution. Download PDF SIMILAR

CONTENT BEING VIEWED BY OTHERS PROPHYLACTIC EARLY LOW-DOSE HYDROCORTISONE AND SURVIVAL WITHOUT BRONCHOPULMONARY DYSPLASIA AMONG EXTREMELY PRETERM INFANTS BORN AT 22–27 WEEKS’ GESTATION

Article 08 March 2024 THE BENEFICIAL EFFECT OF PROPHYLACTIC HYDROCORTISONE TREATMENT IN EXTREMELY PRETERM INFANTS IMPROVES UPON ADJUSTMENT OF THE BASELINE CHARACTERISTICS Article Open access

31 August 2023 POST-NATAL STEROID EXPOSURE IN VERY LOW BIRTHWEIGHT NEONATES AND ASSOCIATIONS WITH ACUTE KIDNEY INJURY Article Open access 23 May 2024 INTRODUCTION Infants born extremely

premature ( < 29 weeks gestation) with extremely low birth weight (ELBW, < 1000 grams) are a population at high risk for disrupted brain development.1 While advances over the last few

decades have led to decreased mortality, there still exists significant long-term neurodevelopmental morbidity and disability in this population.2,3 For example, the ELGAN (Extremely Low

Gestational Age Newborns) study found that > 50% of their ELBW cohort had moderate to severe neurocognitive deficits by 10 years of age,4 likely affected by impaired brain growth and

altered connectivity. In support of this conclusion, brain MRI studies of ELBW infants at term-equivalent age show smaller brain volumes compared to full-term infants at the same corrected

gestational age (GA), and these differences persist into adolescence.5 Moreover, among extremely premature ELBW infants, smaller brain volumes are associated with worse developmental

outcomes.6 Many genetic and maternal-fetal-postnatal factors have been implicated in increasing risk for neurodevelopmental deficits in extremely premature ELBW infants. ELBW infants

routinely require invasive life-sustaining therapies, such as mechanical ventilation and medications that pose additional risks.7 One such commonly utilized therapy within this population is

systemic corticosteroids for treatment of hypotension at early ages and for treatment of chronic lung disease (CLD) dependent on mechanical ventilation at later ages.8,9 There is evidence

that steroids facilitate earlier extubation and reduce risk of CLD as well as improve overall survival.10 However, studies in the early 2000s associated use of steroids, largely

dexamethasone, in preterm infants with increased risk of neurodevelopmental disability and cerebral palsy.11,12 Dexamethasone has been additionally associated with reduced intracranial,

cerebral tissue, cortical gray matter, and cerebellar volumes.13 More recent studies suggest that steroid type along with factors such as dosing and timing affect the relative risk-benefit

ratio.14,15,16,17 In a small randomized control trial among a small cohort of ELBW infants, Parikh et al. (2013)18 showed no difference in brain volume as measured by MRI between infants

treated with hydrocortisone (HCT) and controls. Furthermore, a recent randomized control trial of 800 ELBW infants randomized to a 10-day HCT or placebo treatment for BPD, notably with

open-label usage of dexamethasone in both groups, showed no difference in head circumference z-scores at 36wga.17 These studies have subsequently shifted clinical use of systemic

corticosteroids away from dexamethasone and towards HCT, which may be beneficial for survival without adverse effects on neurodevelopmental outcomes. Several limitations of these previous

studies still need to be addressed. First, the earliest brain MRIs were typically obtained at near term-equivalent age, which, for extremely premature ELBW infants, can be as late as four

months after birth. Thus, conclusions regarding head growth over the period between birth and term-equivalent age are not feasible, but this is when these infants are often most critically

ill and most likely to be exposed to corticosteroids. As such, longitudinal assessment of head growth is needed to determine risk factors for impaired brain growth and neurodevelopmental

deficits among ELBW infants over time. Second, prior studies have not adequately accounted for illness severity beyond GA and birth weight (BW).19,20 Compared to brain MRI measurements,

occipitofrontal circumference (OFC) measurement provides the added benefit of being able to be easily assessed early during the hospital course of extremely premature ELBW infants, when

these patients are often too unstable to obtain brain MRIs, and repeated measurements can be obtained over the entire hospital course. Multiple studies have also found that head size and

head growth correlate with neurodevelopmental outcomes.21,22 Therefore, OFC is an apt proxy for brain growth, particularly during the initial hospital course in patients without

ventriculomegaly or hydrocephalus. To date, no study has examined the effect of systemic HCT on the rate of head growth while at the same time adjusting for illness severity. We hypothesize

that HCT interacts with the relationship between head growth and illness severity. METHODS PATIENTS We conducted a retrospective cohort study that included infants recruited into the Adult

Biomarkers in Neonatal Injury and Development study. Infants were born between 23- and 29-weeks of gestation and < 1000 g, and were admitted to the level 4 neonatal intensive care unit

(NICU) at the Johns Hopkins Hospital (JHH), Baltimore, MD from 7/20/2016-8/19/2019. Infants with genetic syndromes, chromosomal abnormalities, and major congenital anomalies were not

approached for consent. The study received institutional review board approval (JHH IRB 00026068), and signed parental informed consent was obtained for each participant within the infant’s

first 30 days of life and prior to NICU discharge. The study included access to maternal and obstetrics data as well as neonatal data collected throughout their NICU hospitalization that

were obtained from electronic medical records. For our study purposes, exclusion criteria included: 1) less than 3 total OFC measurements, 2) use of a steroid other than HCT, and 3) patients

with larger than Grade 2 IVH (Fig. 1a). NUTRITION All patients received nutrition as per our unit protocol (Supplementary Table 1) and had similar proportions of breastmilk to formula feeds

(Supplementary Table 2). GROWTH MEASUREMENTS Growth measurements were made according to our standardized NICU protocol. This includes: 1) weighing infants naked on an infant scale prior to

feeds in the first set of cares daily, 2) measuring length from the top of their head to the bottom of one of their heels with extended lower extremities on the length board on admission and

then weekly, and 3) measuring OFC using a flexible and non-stretchable measuring tape around the most prominent part on the occiput and over the supraorbital ridge, on admission and then

weekly. Weight, length, and OFC measurements from birth to 50 weeks post menstrual age (PMA) were normalized to generate z-scores that account for GA and sex using the Fenton 2013 preterm

growth chart data.23 Normalized data were not available for length or head circumference of infants < 23.5 weeks GA, so z-scores for length or head circumference at younger ages were not

calculated. Outliers, defined as z-scores <-5 or > 3, were excluded, as these values were likely measurement or data entry errors. Only weights with corresponding lengths measured on

the same day were used. If multiple measurements were made on the same day, only the first value was included for analysis. Area under the curve (AUC) of z-scores were calculated using

linear interpolation using the composite trapezoid rule, relative to z-score at birth, such that increases in z-scores above the z-score at birth were calculated as positive areas and

decreases in z-scores were calculated as negative areas added to the total AUC. As such, a value of zero would reflect growth along the same percentile as their birth size, positive values

reflect greater than birth percentile growth, and negative values reflect lower than birth percentile growth. An example for a single patient is shown in Fig. 1b, c. CLINICAL SCORES FOR

MEASURING SEVERITY OF ILLNESS Patient illness severity at birth was calculated using the Clinical Risk Index for Babies (CRIB II) score.24 Subsequent illness severity was calculated using

the neonatal sequential organ failure assessment (nSOFA) score, which has previously been shown to be an effective predictor of adverse outcomes and mortality for ELBW infants.20,25,26,27 As

we are studying the effects of HCT, the nSOFA score was modified to exclude the steroids component, which had a binary score range of 0–1 within the inotropic support category in the

original nSOFA score, hereon referred to as the modified-nSOFA score (M-nSOFA, Table 1). M-nSOFA scores were assessed at times of critical illness, identified as times when blood cultures

were obtained until 50 weeks post-menstrual age (PMA). To do so, M-nSOFA scores were computed at 0, 6, 12, 24, and 48 h before and after each blood culture draw for a total of 9 timepoints

per period. Then, the maximum M-nSOFA scores from each of these periods were summated to calculate a cumulative maximum M-nSOFA score per patient. An example of this calculation for a single

patient is shown in Fig. 1d. HEAD ULTRASOUND MEASUREMENTS Head ultrasounds (HUS) were obtained for every patient at approximately 1 month of age. Biparietal diameters and ventricle/brain

(V/B) ratios from coronal slices were measured by a pediatric neuroradiologist as previously described28 and depicted in Fig. 2a. V/B ratios were calculated using ventricular indices (VI),

where V/B = [VI(left) + VI(right)]/biparietal diameter. OFC measurements taken closest to the date of the HUS within one week were used for correlations between HUS and OFC measurements.

When comparing effects between groups we excluded those patients in the HCT group who had not yet been exposed to HCT at the time of the HUS. STATISTICAL ANALYSIS Statistical analysis was

performed using GraphPad Prism (GraphPad Software) and R Statistical Software (v5.0; R Core Team 2021). Correlations were fitted with a linear regression and assessed for significance using

Spearman correlation. Repeated measures correlation was conducted using the R package rmcorr29 and, where applicable, is reported as the correlation coefficient rrm. Comparisons of

correlations were made using ANCOVA. For group comparisons, normality was first assessed using the Shapiro-Wilk test. Parametric tests were used for normal distributions. In these cases,

pairwise statistical tests were performed using unpaired two-tailed _t_ tests, and multiple comparisons were performed by ANOVA. If distributions were not normally distributed, the

Mann-Whitney U test was used for pairwise comparisons, and the Kruskal-Wallis test was used for multiple comparisons. Comparisons of categorical variables were made using the Fisher’s exact

test for small sample sizes or Chi-square test for larger sample sizes. RESULTS PATIENT DEMOGRAPHICS – YOUNGER ELBW INFANTS WERE MORE LIKELY TO RECEIVE SYSTEMIC HCT We assessed 106 patients

for inclusion eligibility. Of those, 33 patients were excluded: 14 patients who had less than 3 OFC measurements due to death, 7 patients who had received a steroid other than HCT (in all

cases, dexamethasone), and 12 patients with severe intraventricular hemorrhage (IVH > Grade 230). In total, 73 patients met inclusion criteria. Of these 30 patients (41%) had received

HCT, and 43 control patients had received no steroids. HCT-treated infants were notably born at an earlier GA than controls (U = 318, _p_ < 0.001). While the HCT group had lower BW (_t_ =

 5.26, df = 71, _p_ < 0.0001), BW z-scores were not significantly different (_t_ = 0.31, df = 71, _p_ = 0.76), suggesting the difference in BW was driven by the difference in GA. The

remainder of maternal and birth characteristics as well as other clinical characteristics were similar between groups (Table 2, Supplementary Table 2). Among the HCT group, HCT exposure

first occurred at a median age of 3 weeks of life, IQR = 2.39 (1.32, 3.71). 7/30 patients received HCT within the first week of life. HCT dose varied from 1 to 10 mg/kg/day with durations

varying from 1 to 36 days for a median cumulative dose of 74.88 mg/kg, IQR = 300.94 (24.38, 325.31). Per our NICU protocols, HCT was administered for the following indications and

accompanying doses: (1) physiologic replacement 7–9 mg/m2 per day in 2–3 doses; (2) stress dose 20–50 mg/m2 per day in 2–3 doses; (3) hypotension 1 mg/kg followed by 0.5 mg/kg q6-12 h; (4)

ventilator dependent CLD 72.5 mg/kg over 22-day course.31 Amongst the patients who received HCT, 12/30 (40%) received HCT for physiologic replacement, 10/30 (33%) as stress dose HCT, 12/30

(40%) for hypotension, and 18/30 (60%) for CLD. Several of these patients received HCT for multiple of these indications at different times during their initial NICU hospitalization: 6/30

(20%) received HCT for 2 of the above indications, 5/30 (17%) received HCT for 3 indications, and 2/30 (7%) received HCT for all 4 indications. As such, there was variability in the total

dosage of HCT given throughout the initial NICU admission. OFC MEASUREMENTS OF HEAD SIZE STRONGLY CORRELATED WITH HUS MEASUREMENTS OF BRAIN SIZE To evaluate the validity of our OFC

measurements, we compared them to measurements taken from HUS. HUS were obtained for every patient at approximately 1 month into the NICU hospitalization (mean ± SD = 33±8 days-of-life, 31 ±

 2 weeks PMA). As expected, there was a robust positive correlation between OFC and biparietal diameter on HUS (r2 = 0.57, _p_ < 0.0001, Fig. 2b) and a significant negative correlation

between OFC and V/B ratio (r2 = 0.15, _p_ < 0.001, Fig. 2c). There were no significant differences in these relationships between HCT and control groups, (OFC vs BPD: F(1, 63) = 0.05, _p_

 = 0.82; OFC vs V/B: F(1, 63) = 3.411, _p_ = 0.07). This supports the idea that head size as measured by OFC closely reflects underlying brain size. On review of HUS clinical impressions by

our pediatric neuroradiologists, 4 patients in the HCT group and 1 patient in the control group were noted to have increased white matter echogenicity. We compared this data with available

near-term MRIs, which were performed on 17/73 of included patients, of which 71% (12/17) received HCT, and 29% (5/17) did not. On review of MRI clinical impressions, within the HCT group,

42% (5/12) were unremarkable, 42% (5/12) demonstrated evidence of remote IVH, 17% (2/12) had mild ventriculomegaly, one had white matter abnormalities, and one had moderate ventriculomegaly.

Within the control group, 60% (3/5) were unremarkable, 40% (2/5) had white matter abnormalities, and one had mild ventriculomegaly. A complete summary of MRI interpretations is available in

Supplemental Table 3. Due to the limited sample size of available MRIs, we were not able to make group comparisons using this data. DEFICIENT POSTNATAL GROWTH DURING NICU HOSPITALIZATION

While there was significant growth with age, as measured by weight-to-length ratio (Fig. 3a, rrm(911) = 0.98, 95% CI [0.978, 0.984], _p_ < 0.001), normalized weight and length, and

z-scores showed significant negative correlations with PMA (Fig. 3b–d, rrm, weight(911) = −0.29, 95% CI[−0.350, −0.231], _p_ < 0.001; rrm, length(911) = −0.49, 95% CI[−0.540, −0.441], _p_

 < 0.001). Normalized OFC z-scores did not significantly correlate with PMA (rrm(972) = 0.06, 95% CI[−0.005, 0.120], p0.072). We further assessed overall growth for each patient during

this period by calculating the weight, length, and OFC z-score AUC as a function of the chronological age of the patient when the last measurements included were taken, which reflects the

length of hospitalization. In all growth domains, there was a negative association between AUC and the last measurement age (weight R2 = 0.13, _p_ < 0.01; length R2 = 0.41, _p_ < 

0.0001; OFC R2 = 0.05, _p_ = 0.06). No differences in these relationships were observed between HCT and control groups (Fig. 3a–g right panels, statistics in Supplemental Table 4). This data

suggests that patients had difficulty attaining appropriate weight and length gain during NICU hospitalization with relatively preserved head growth. HCT EXPOSED PATIENTS HAD HIGHER

SEVERITY OF ILLNESS THAN CONTROLS Illness severity was assessed at birth using CRIB II scores.24 The HCT group had significantly higher CRIB II scores than the control group, suggesting

higher illness severity at birth (Table 2). We measured subsequent illness severity during hospitalization using M-nSOFA scores. The HCT group had higher illness severity as measured by

cumulative M-nSOFA score (U = 124, _p_ < 0.0001; Fig. 4a), which likely reflects the clinical rationale for use of HCT in the first place. This in part may be due to the HCT group being

born at younger GAs than the control group, as we found a negative correlation between GA and cumulative M-nSOFA scores (R2 = 0.21, _p_ < 0.0001; Fig. 4b), suggesting that being born at

younger GA was associated with higher illness severity. Accordingly, HCT patients also had significantly longer lengths of stay (LOS) with a median LOS of 120 days compared to control

patients at 56 days (U = 167, _p_ < 0.0001; Fig. 4c). This, again, is likely in part due to younger gestational ages at birth (R2 = 0.23, _p_ < 0.0001; Fig. 4d) and greater illness

severity as measured by cumulative M-nSOFA score (R2 = 0.65, _p_ < 0.0001; Fig. 4e). HCT EXPOSURE MODULATES THE EFFECT OF ILLNESS SEVERITY ON HEAD GROWTH Given that HCT and control

patients had similar growth trajectories throughout hospitalization despite notably different degrees of illness severity, we then sought to understand whether HCT exposure may modulate the

effect of illness severity on growth, particularly head growth. We first evaluated the correlations between overall growth, measured by weight, length, and OFC AUCs, and illness severity,

measured by cumulative M-nSOFA scores for all study patients (Fig. 5a–c left panels). We found negative correlations between growth and illness severity. While the correlation between length

AUC and cumulative M-nSOFA scores (R2 = 0.11, _p_ < 0.01) as well as the correlation between OFC AUC and cumulative M-nSOFA scores (R2 = 0.10, _p_ < 0.01) were statistically

significant, the correlation between weight AUC and cumulative M-nSOFA scores showed only a trend (R2 = 0.04, _p_ = 0.09). Interestingly, we found that this relationship differed for

patients exposed to HCT compared to controls (Fig. 5a–c right panels, statistics in Supplementary Table 5). Specifically, there was a significant negative correlation between length AUC and

cumulative M-nSOFA scores in the HCT group (R2 = 0.18, _p_ < 0.05) but not in the control group (R2 = 0.01, _p_ = 0.57, Fig. 4b), though direct comparison of these correlations was not

statistically significant (F(1,69) = 0.26, _p_ = 0.61). Meanwhile there remained no significant correlation between weight AUC and cumulative M-nSOFA scores in either HCT or control groups

(HCT R2 = 0.06, _p_ = 0.20; Control R2 = 0.06, _p_ = 0.12; Fig. 5a). This suggests that HCT exposure may slightly worsen the effect of illness severity on growth in length but not weight.

Moreover, there was a significant negative correlation between OFC AUC and cumulative M-nSOFA scores only for the control group (R2 = 0.26, _p_ < 0.001), not the HCT group (R2 = 0.04, _p_

 = 0.32; Fig. 5c). Direct comparison of these correlations was statistically significant (F(1,69) = 5.79, _p_ < 0.05), suggesting that HCT exposure is associated with an attenuated effect

of illness severity on head growth. Within the HCT group, we found that cumulative HCT dosage did not have a significant interaction with the effect of illness severity on head growth

(Supplementary Table 6). DISCUSSION The use of steroids for extremely premature ELBW infants in the NICU remains controversial despite multi-center randomized clinical trials.14,15,16 Thus,

better understanding of the risks and benefits of steroid use is necessary to guide informed clinical decision-making for this vulnerable population. This study of extremely premature ELBW

infants is the first to report the relationship between HCT exposure and growth for whom individualized patient level severity of illness was calculated during the initial NICU

hospitalization. In our cohort, the patients who received HCT were significantly more premature and had significantly greater severity of illness from birth to discharge, as demonstrated by

higher CRIB II scores at admission, increased LOS, and higher cumulative maximum M-nSOFA scores. We found that in terms of growth, there were weak but significant negative correlations

between weight, length, but not OFC z-scores with age, suggesting overall subpar growth with relative preservation of head growth over the time course of hospitalization. This was not

different between HCT and control groups. These data are consistent with larger population studies, though it should be noted that these larger studies included patients who received

dexamethasone or other glucocorticoids in addition to HCT and utilized different dosing and duration of HCT treatment.16,17,32 We also found significant negative correlations between length

AUC and OFC AUC but not weight AUC with illness severity. Interestingly, we found that HCT exposure interacts with these relationships. Specifically, HCT exposure may mitigate the effect of

severity of illness on head growth, suggesting that it may provide support for better brain growth in this population. While we did not find cumulative HCT dose to be a significant mediator

of illness severity on head growth amongst HCT exposed patients, we acknowledge that we may lack the statistical power or spread in our data to identify a more subtle effect. As we found a

very strong correlation between head size measured by OFC and brain size measured by HUS, consistent with prior studies,21 we expect that these finding for head growth reflect trajectories

of underlying brain tissue growth. These findings emphasize the importance of considering patient illness severity and suggest that HCT use may offer additional benefits not previously

considered, although larger studies are needed to confirm these associations. Additionally, larger studies may also allow us to better understand whether the indication for HCT use may be

associated with different effects. Further investigation is necessary to better understand the mechanisms by which HCT may modulate effects of illness severity on head growth, as well as

what differentiates HCT and dexamethasone. One possibility is that HCT and dexamethasone have differential effects directly on neuronal survival and maturation. In animal models, endogenous

steroids have been shown to affect neurogenesis, neuronal survival, and neuronal morphology.33,34 This may in part be due to its interactions with TrkB receptors to mediate brain derived

neurotrophic factor (BDNF)-dependent pathways of glutamatergic activity and neuroprotection.35,36 Anti-inflammatory effects of steroids may also protect against excitotoxicity.37 Exogenous

steroid administration have also been shown to affect synaptic maintenance through dendritic spine turnover.38,39 Another possibility is that HCT and dexamethasone have differential

secondary effects, such as the ability to promote improved cardiorespiratory physiology, that in turn better facilitates brain perfusion and oxygenation. Akin to intrauterine growth

restricted (IUGR) infants who have preferential perfusion to vital organs during fetal development (i.e., brain vs. gastrointestinal tract), extremely premature, ELBW infants with high

illness severity (i.e. those requiring HCT) may have preferential perfusion of their brain (reflected in their OFC) over their gastrointestinal tract (reflected in their weight) or skeletal

system (reflected in their length).40 Past studies have implicated steroids in upregulating expression of cardiovascular adrenergic receptors, which may be downregulated during critical

illness.41 Steroids may also inhibit catecholamine metabolism, release vasoactive factors, and increase intracellular calcium availability in cardiac and vascular smooth muscles that

increase responsiveness to catecholamines.42 This study has limitations inherent to all single-center, retrospective, pilot analyses. First, for these extremely premature ELBW infants, we

did not have longer term follow-up data available at the time of analysis. Second, institution-specific practices, including use of systemic steroids and unit specific feeding guidelines,

may modify both severity of illness metrics and growth, thus affecting the generalizability of our results. Moreover, as the HCT and control groups were not matched, and the HCT cohort was

significantly more premature than the control group, there are likely other confounds for which we could not account. For instance, the effects of HCT were noted in surviving patients, so

they may represent a subgroup of patients who were inherently more responsive to steroids. Nevertheless, the proportion of our cohort exposed to steroids and the differential characteristics

between HCT and control groups were comparable to larger, multi-center cohort studies regarding this population.43 Our results highlight the need for a more nuanced understanding of factors

that modulate risk for neurodevelopmental outcomes in extremely premature ELBW infants. Ultimately, additional studies that account for individual patient level severity of illness relative

to therapies, such as HCT, are needed to better tailor treatments to patients in the era of precision medicine. DATA AVAILABILITY The datasets generated and analyzed during the current

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Extremely Preterm Infants. _JAMA Netw. Open_ 5, e221947 (2022). Article  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We thank the families of the

participants and the staff at Johns Hopkins Hospital and laboratory for their willingness to participate in this study. FUNDING Supported by National Institutes of Health RO1HD086058 (A.E.,

F.J.N.); R01 HD110091 (F.J.N., A.D.E., K.Z., R.C-V.); RO1HD070996, AG061643, and NS109029, HD074593-07 (F.J.N.); KO8NS096115 (R.C-V.), and the Thomas Wilson Foundation (R.-V.). AUTHOR

INFORMATION Author notes * These authors contributed equally: Haiwen Chen, Khyzer B. Aziz. AUTHORS AND AFFILIATIONS * Division of Pediatric Neurology, Department of Neurology, Johns Hopkins

University School of Medicine, Baltimore, MD, USA Haiwen Chen & Carl E. Stafstrom * Division of Neonatology – Neuroscience Intensive Care Nursery, Johns Hopkins University School of

Medicine, Baltimore, MD, USA Khyzer B. Aziz, Harisa Spahic, Sarah Miller, Alison Kilborn, Frances J. Northington, Carl E. Stafstrom & Raul Chavez-Valdez * Division of Pediatric

Neuroradiology, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Melike Guryildirim * Division of Neonatology, Johns Hopkins All Children’s Hospital,

St. Petersburg, FL, USA Austin Sellers & Sandra Brooks * Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Allen D. Everett Authors *

Haiwen Chen View author publications You can also search for this author inPubMed Google Scholar * Khyzer B. Aziz View author publications You can also search for this author inPubMed Google

Scholar * Harisa Spahic View author publications You can also search for this author inPubMed Google Scholar * Sarah Miller View author publications You can also search for this author

inPubMed Google Scholar * Melike Guryildirim View author publications You can also search for this author inPubMed Google Scholar * Austin Sellers View author publications You can also

search for this author inPubMed Google Scholar * Sandra Brooks View author publications You can also search for this author inPubMed Google Scholar * Alison Kilborn View author publications

You can also search for this author inPubMed Google Scholar * Allen D. Everett View author publications You can also search for this author inPubMed Google Scholar * Frances J. Northington

View author publications You can also search for this author inPubMed Google Scholar * Carl E. Stafstrom View author publications You can also search for this author inPubMed Google Scholar

* Raul Chavez-Valdez View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS H.C., K.B.A., R.C-V. conceived and designed the study, analyzed the

data, and drafted the article. H.C., K.B.A, H.S., S.M., A.S., S.B., A.D.E., F.J.N and R.C-V. contributed to acquisition of the data. M.G. and A.K. performed the HUS measurements. H.C.,

K.B.A., A.S., S.B., A.D.E., C.E.S., and R.C-V. provided critical revisions. All authors provided final approval of the version to be published. CORRESPONDING AUTHOR Correspondence to Raul

Chavez-Valdez. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ETHICAL APPROVAL The study received institutional review board approval (JHH IRB 00026068),

and signed parental informed consent was obtained for each participant within the infant’s first 30 days of life and prior to NICU discharge. ADDITIONAL INFORMATION PUBLISHER’S NOTE

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CITE THIS ARTICLE Chen, H., Aziz, K.B., Spahic, H. _et al._ Interaction of hydrocortisone and illness severity on head growth in cohort of ELBW infants. _Pediatr Res_ 94, 1958–1965 (2023).

https://doi.org/10.1038/s41390-023-02689-w Download citation * Received: 21 December 2022 * Revised: 06 May 2023 * Accepted: 15 May 2023 * Published: 20 June 2023 * Issue Date: December 2023

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