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Figure.
Flowchart of Follow-up Cohort
Flowchart of Follow-up Cohort
Table 1.  
Population Characteristics of Patients Assessed at 2 Years of Age and Their Mothers
Population Characteristics of Patients Assessed at 2 Years of Age and Their Mothers
Table 2.  
Anthropometric Characteristics and Respiratory Outcomes in Children Successfully Followed up at 2 Years of Age
Anthropometric Characteristics and Respiratory Outcomes in Children Successfully Followed up at 2 Years of Age
Table 3.  
Neurodevelopmental Outcomes at 2 Years of Age
Neurodevelopmental Outcomes at 2 Years of Age
1.
Kallapur  SG, Jobe  AH.  Contribution of inflammation to lung injury and development.  Arch Dis Child Fetal Neonatal Ed. 2006;91(2):F132-F135.PubMedGoogle ScholarCrossref
2.
Hagberg  H, Mallard  C, Ferriero  DM,  et al.  The role of inflammation in perinatal brain injury.  Nat Rev Neurol. 2015;11(4):192-208.PubMedGoogle ScholarCrossref
3.
Doyle  LW, Ehrenkranz  RA, Halliday  HL.  Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review.  Neonatology. 2010;98(3):217-224.PubMedGoogle ScholarCrossref
4.
Grier  DG, Halliday  HL.  Corticosteroids in the prevention and management of bronchopulmonary dysplasia.  Semin Neonatol. 2003;8(1):83-91.PubMedGoogle ScholarCrossref
5.
Committee on Fetus and Newborn.  Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.  Pediatrics. 2002;109(2):330-338.PubMedGoogle ScholarCrossref
6.
Yoder  BA, Harrison  M, Clark  RH.  Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants.  Pediatrics. 2009;124(2):673-679.PubMedGoogle ScholarCrossref
7.
Jobe  AH.  The new bronchopulmonary dysplasia.  Curr Opin Pediatr. 2011;23(2):167-172.PubMedGoogle ScholarCrossref
8.
Wright  CJ, Kirpalani  H.  Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies?  Pediatrics. 2011;128(1):111-126.PubMedGoogle ScholarCrossref
9.
Watterberg  KL.  Adrenocortical function and dysfunction in the fetus and neonate.  Semin Neonatol. 2004;9(1):13-21.PubMedGoogle ScholarCrossref
10.
Watterberg  KL, Gerdes  JS, Cole  CH,  et al.  Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.  Pediatrics. 2004;114(6):1649-1657.PubMedGoogle ScholarCrossref
11.
Bonsante  F, Latorre  G, Iacobelli  S,  et al.  Early low-dose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial.  Neonatology. 2007;91(4):217-221.PubMedGoogle ScholarCrossref
12.
Peltoniemi  O, Kari  MA, Heinonen  K,  et al.  Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.  J Pediatr. 2005;146(5):632-637.PubMedGoogle ScholarCrossref
13.
Baud  O, Maury  L, Lebail  F,  et al; PREMILOC Trial Study Group.  Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.  Lancet. 2016;387(10030):1827-1836.PubMedGoogle ScholarCrossref
14.
Sand  EA, Emery-Hauzeur  C.  The psychomotor development of the child during the first 2 years (Brunet-Lezine test) [in French].  Acta Neurol Psychiatr Belg. 1962;62:1087-1102.Google Scholar
15.
Charkaluk  ML, Truffert  P, Fily  A, Ancel  PY, Pierrat  V; Epipage Study Group.  Neurodevelopment of children born very preterm and free of severe disabilities: the Nord-Pas de Calais Epipage cohort study.  Acta Paediatr. 2010;99(5):684-689.PubMedGoogle ScholarCrossref
16.
Charkaluk  ML, Truffert  P, Marchand-Martin  L,  et al; Epipage Study Group.  Very preterm children free of disability or delay at age 2: predictors of schooling at age 8: a population-based longitudinal study.  Early Hum Dev. 2011;87(4):297-302.PubMedGoogle ScholarCrossref
17.
Brunet  O, Lézine  I.  Le développement psychologique de la première enfance, présentation d'une échelle française pour examen des tout petits.  Population. 1952;7(1):162.Google ScholarCrossref
18.
Lézine  I.  Le développement psychomoteur des jeunes prématurés.  Etud Neo-natales (Paris). 1958;7(1):1-50.Google Scholar
19.
Josse  D.  Brunet-Lézine Révisé: Echelle de Développement Psychomoteur de la Première Enfance. Paris, France: Etablissements d'applications Psychotechniques; 1997.
20.
Frankenburg  WK, Dodds  J, Archer  P, Shapiro  H, Bresnick  B.  The Denver II: a major revision and restandardization of the Denver Developmental Screening Test.  Pediatrics. 1992;89(1):91-97.PubMedGoogle Scholar
21.
Gosselin  J, Gahagan  S, Amiel-Tison  C.  The Amiel-Tison Neurological Assessment at Term: conceptual and methodological continuity in the course of follow-up.  Ment Retard Dev Disabil Res Rev. 2005;11(1):34-51.PubMedGoogle ScholarCrossref
22.
Bax  M, Goldstein  M, Rosenbaum  P,  et al; Executive Committee for the Definition of Cerebral Palsy.  Proposed definition and classification of cerebral palsy, April 2005.  Dev Med Child Neurol. 2005;47(8):571-576.PubMedGoogle ScholarCrossref
23.
Natalucci  G, Latal  B, Koller  B,  et al; Swiss EPO Neuroprotection Trial Group.  Effect of early prophylactic high-dose recombinant human erythropoietin in very preterm infants on neurodevelopmental outcome at 2 years: a randomized clinical trial.  JAMA. 2016;315(19):2079-2085.PubMedGoogle ScholarCrossref
24.
Ancel  PY, Goffinet  F, Kuhn  P,  et al; EPIPAGE-2 Writing Group.  Survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study [published correction appears in JAMA Pediatr. 2015;169(4):323].  JAMA Pediatr. 2015;169(3):230-238.PubMedGoogle ScholarCrossref
25.
Bassler  D, Plavka  R, Shinwell  ES,  et al; NEUROSIS Trial Group.  Early inhaled budesonide for the prevention of bronchopulmonary dysplasia.  N Engl J Med. 2015;373(16):1497-1506.PubMedGoogle ScholarCrossref
26.
Watterberg  KL, Shaffer  ML, Mishefske  MJ,  et al.  Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants.  Pediatrics. 2007;120(1):40-48.PubMedGoogle ScholarCrossref
27.
Peltoniemi  OM, Lano  A, Puosi  R,  et al; Neonatal Hydrocortisone Working Group.  Trial of early neonatal hydrocortisone: two-year follow-up.  Neonatology. 2009;95(3):240-247.PubMedGoogle ScholarCrossref
28.
Kersbergen  KJ, de Vries  LS, van Kooij  BJ,  et al.  Hydrocortisone treatment for bronchopulmonary dysplasia and brain volumes in preterm infants.  J Pediatr. 2013;163(3):666-71.e1, e661.PubMedGoogle ScholarCrossref
29.
Rademaker  KJ, Uiterwaal  CS, Groenendaal  F,  et al.  Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children.  J Pediatr. 2007;150(4):351-357.PubMedGoogle ScholarCrossref
30.
Rademaker  KJ, de Vries  WB.  Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart.  Semin Fetal Neonatal Med. 2009;14(3):171-177.PubMedGoogle ScholarCrossref
31.
Doyle  LW, Ehrenkranz  RA, Halliday  HL.  Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.  Cochrane Database Syst Rev. 2014;(5):CD001146.PubMedGoogle Scholar
32.
Moisiadis  VG, Matthews  SG.  Glucocorticoids and fetal programming part 2: mechanisms.  Nat Rev Endocrinol. 2014;10(7):403-411.PubMedGoogle ScholarCrossref
33.
Crochemore  C, Lu  J, Wu  Y,  et al.  Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation.  Mol Psychiatry. 2005;10(8):790-798.PubMedGoogle ScholarCrossref
34.
Slotkin  TA, Kreider  ML, Tate  CA, Seidler  FJ.  Critical prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems.  Neuropsychopharmacology. 2006;31(5):904-911.PubMedGoogle ScholarCrossref
35.
Heine  VM, Rowitch  DH.  Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11β-HSD2-dependent mechanism.  J Clin Invest. 2009;119(2):267-277.PubMedGoogle Scholar
36.
Janz-Robinson  EM, Badawi  N, Walker  K, Bajuk  B, Abdel-Latif  ME; Neonatal Intensive Care Units Network.  Neurodevelopmental outcomes of premature infants treated for patent ductus arteriosus: a population-based cohort study.  J Pediatr. 2015;167(5):1025-32.e3, e1023.PubMedGoogle ScholarCrossref
37.
Schmidt  B, Roberts  RS, Davis  P,  et al; Caffeine for Apnea of Prematurity Trial Group.  Long-term effects of caffeine therapy for apnea of prematurity.  N Engl J Med. 2007;357(19):1893-1902.PubMedGoogle ScholarCrossref
38.
Schmidt  B, Anderson  PJ, Doyle  LW,  et al; Caffeine for Apnea of Prematurity (CAP) Trial Investigators.  Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.  JAMA. 2012;307(3):275-282.PubMedGoogle ScholarCrossref
39.
Peltoniemi  OM, Lano  A, Yliherva  A, Kari  MA, Hallman  M; Neonatal Hydrocortisone Working Group.  Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age.  Acta Paediatr. 2016;105(2):159-164.PubMedGoogle ScholarCrossref
40.
Deary  IJ, Johnson  W.  Intelligence and education: causal perceptions drive analytic processes and therefore conclusions.  Int J Epidemiol. 2010;39(5):1362-1369.PubMedGoogle ScholarCrossref
Original Investigation
April 4, 2017

Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age

Author Affiliations
  • 1Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, Paris, France
  • 2Université Paris Diderot, Sorbonne Paris-Cité, Inserm U1141, Paris, France
  • 3Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, University Paris Diderot, Sorbonne Paris-Cité, Inserm U1123 and CIC-EC 1426, Paris, France
JAMA. 2017;317(13):1329-1337. doi:10.1001/jama.2017.2692
Key Points

Question  Is early hydrocortisone treatment of extremely preterm infants associated with neurodevelopmental impairment at 2 years of age?

Findings  In an exploratory analysis of 379 infants enrolled in the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial who survived to the age of 2 years, early low-dose hydrocortisone treatment was not associated with significantly worse neurodevelopmental impairment compared with placebo (hydrocortisone group: 73% without impairment, 20% with mild impairment, 7% with moderate to severe impairment; placebo group: 70% without impairment, 18% with mild impairment, and 11% with moderate to severe impairment).

Meaning  Early low-dose hydrocortisone treatment in extremely preterm infants was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants.

Abstract

Importance  Dexamethasone to prevent bronchopulmonary dysplasia in very preterm neonates was associated with adverse neurodevelopmental events. Early low-dose hydrocortisone treatment has been reported to improve survival without bronchopulmonary dysplasia but its safety with regard to neurodevelopment remains to be assessed.

Objective  To assess whether early hydrocortisone therapy in extremely preterm infants is associated with neurodevelopmental impairment at 2 years of age.

Design, Setting, and Participants  An exploratory secondary analysis of the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial conducted between 2008 and 2014 in 21 French neonatal intensive care units. Randomization was stratified by gestational age groups. Neurodevelopmental assessments were completed from 2010 to 2016.

Interventions  After birth, patients were randomly assigned to receive placebo or hydrocortisone (0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days).

Main Outcomes and Measures  The prespecified exploratory secondary outcome of neurodevelopmental impairment was based on a standardized neurological examination and the revised Brunet-Lézine scale (global developmental quotient score and subscores; mean norm, 100 [SD, 15]). The minimal clinically important difference on the global developmental quotient was 5 points.

Results  Of 1072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21-23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, −2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups.

Conclusions and Relevance  In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants.

Trial Registration  clinicaltrials.gov Identifier: NCT00623740

Introduction

Preterm birth is frequently associated with perinatal inflammation, a major risk factor for bronchopulmonary dysplasia, brain damage, and subsequent neurodevelopmental impairments.1,2 Because glucocorticoids alleviate systemic inflammation, they have been proposed as a therapeutic option in very preterm infants. Quiz Ref IDPostnatal dexamethasone therapy led to short-term benefits, including decreasing the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia, but was associated with cerebral palsy and other adverse neurodevelopmental events.3

Guidelines in Europe and North America in 2002 and 2003 recommended that early postnatal corticosteroid administration be avoided apart from controlled clinical trials.4,5 The incidence and severity of bronchopulmonary dysplasia increased concurrently with the decreased use of postnatal dexamethasone,6 and it remains a major public health challenge.7

A more physiologically based strategy was then proposed using low-dose hydrocortisone to maintain clinically relevant respiratory benefits while avoiding potential adverse effects on the developing brain.8,9 However, the first clinical trials of early prophylactic hydrocortisone were inconclusive.10-12

A larger multicenter, randomized trial of early, low-dose hydrocortisone therapy to prevent bronchopulmonary dysplasia, the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) trial,13 found that hydrocortisone therapy resulted in a significant increase of 9 percentage points (60% vs 51%) in the rate of bronchopulmonary dysplasia–free survival at 36 weeks of postmenstrual age. In this study, we assessed whether early hydrocortisone therapy is associated with neurodevelopmental impairment at 2 years of age in children enrolled in the PREMILOC trial.

Methods
Population and Study Protocol

Surviving infants enrolled in the PREMILOC trial conducted in France between 2008 and 2014 were eligible for the 2-year follow-up. The study protocol has been described previously13 and is available in Supplement 1. Briefly, this double-blind, multicenter, randomized, placebo-controlled trial enrolled infants born between 24 0/7 weeks and 27 6/7 weeks of gestation and before 24 hours of postnatal age and assigned them to receive either placebo or low-dose hydrocortisone (100 mg for injection [Upjohn]; 0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days [SERB Laboratoires]).

Randomization was stratified by gestational age group (24-25 weeks and 26-27 weeks of gestation) and randomization sequence in each stratum was generated electronically using nQuery version 6.01 (Statistical Solutions Ltd). Infants were randomly assigned 1:1 to either hydrocortisone or placebo via a central computer-generated list with block sizes of 2, 4, 6, or 8 chosen at random.

The trial was approved by the French national ethics committee (Comité de Protection des Personnes, Ile-de-France II, Necker), the French national drug safety agency (Agence Nationale de Sécurité du Médicament, EudraCT No. 2007-002041-20), and the French data protection authority (Commission Nationale de l’Informatique et des Libertés). Written informed consent was obtained from parents of all eligible infants before randomization.

Follow-up Study Procedures and Outcomes

The primary outcome of the trial, bronchopulmonary dysplasia–free survival at 36 weeks of postmenstrual age, has been reported.13 Of the 21 secondary end points, neurocognitive development at 18 to 24 months was selected for this analysis. Follow-up evaluation at 2 years of age was completed between 2010 and 2016 and included a medical history, anthropometric measures, respiratory status, standardized neurological examination based on specific definitions of disabilities, and quantitative neurodevelopmental assessment using the revised Brunet-Lézine (RBL) scale.

The RBL is a psychomotor developmental scale that evaluates 4 domains of development, including gross motor function, fine motor function and visuospatial coordination, language, and sociability. Four separate developmental quotient subscores can be calculated for children aged 2 to 30 months. A global developmental quotient score results from the combination of the RBL subscores, with a mean norm of 100 (SD, 15).14-18

The RBL was revised in 1994 and 1996 and adjusted based on a sample of 1055 French children born at term.19 It is routinely used in studies conducted in French-speaking countries. The RBL global developmental quotient was divided into 3 categories (<70 [moderate to severe disability], 70-84 [mild disability], and ≥85 [no disability]). All RBL examiners had been previously certified and were unaware of the treatment assignment, which remained masked throughout the follow-up period.

Motor function, cognitive skills, behavioral problems, and visual or auditory impairment were assessed by neurological examination using a scoring system adapted from the Amiel-Tison Neurological Assessment at Term and the Denver Developmental Screening Test.20,21 A disability severity scale was defined according to specific criteria as normal or no disability, mild disability, or moderate to severe disability (eTable 1 in Supplement 2), yielding a global qualitative score based on the lowest subscore.

As per protocol, neurocognitive development was classified into 3 categories using the RBL global developmental quotient and the standardized neurological examination. When the RBL developmental quotient was not available, the standardized neurological examination alone was used for qualitative assessment of neurodevelopment. The 3 categories were no neurodevelopmental impairment, mild neurodevelopmental impairment, or moderate to severe neurodevelopmental impairment.

Mild neurodevelopmental impairment was defined as either an RBL global developmental quotient score between 70 and 84 or mild disability according to the standardized neurological assessment. Quiz Ref IDModerate to severe neurodevelopmental impairment was defined as at least 1 of the following: cerebral palsy, an RBL global developmental quotient score of less than 70, or moderate to severe disability on the standardized neurological assessment. No children were blind or deaf.

Post hoc exploratory outcomes at 2 years included the following individual components of neurodevelopmental impairment: global developmental quotient score, RBL subscores, cerebral palsy evaluated according to the Executive Committee for the Definition of Cerebral Palsy,22 and other major neurodevelopmental impairments. A minimal clinically important difference between groups for the global developmental quotient score is 5 points based on the experience of the investigators and other study groups.23

Because randomization was stratified by gestational age groups (24-25 weeks and 26-27 weeks) and previous studies have found differences in survival, bronchopulmonary dysplasia, and neurodevelopmental impairment by gestational age, we tested for an interaction. A post hoc exploratory analysis was also performed to determine the incidence of survival free of bronchopulmonary dysplasia or neurodevelopmental impairment. Because use of postnatal steroids could change both lung and brain maturation, this outcome was considered clinically relevant to evaluate the overall effect of hydrocortisone therapy in the studied population.

Statistical Analysis

Data are expressed as means and 95% CIs for continuous variables and numbers and percentages for categorical variables. Between-group differences were computed when applicable. Comparisons between treatment groups were made using the t test for quantitative variables and the χ2 test or Cochran-Armitage trend test for categorical variables. Study power and sample size were primarily calculated for the outcome of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age but not for follow-up outcomes.

A log binomial regression model was built to study the relationship between the exploratory outcome of survival free of bronchopulmonary dysplasia or neurodevelopmental impairment and treatment that was adjusted for gestational age group. In this analysis, children lost to follow-up were omitted. Results are provided as risk difference and relative risk.

All statistical tests were 2-tailed with the significance level set at .05. The statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc).

Results
Characteristics of Patients

Of the 523 infants enrolled in the initial study, 406 survived to 2 years of age (Figure). Of 8 deaths occurring between 36 weeks of postmenstrual age and 2 years, 1 was in the hydrocortisone group (n = 208) and 7 were in the placebo group (n = 206) (P = .04 using the Fisher exact test). Five deaths were due to severe chronic lung disease (including the 1 patient who died in the hydrocortisone group), 2 to sepsis, and 1 to late-onset enterocolitis.

Of the 406 surviving infants, 379 (93%) were seen during follow-up at a median corrected age of 22 months (interquartile range, 21-23 months). Of those seen, 158 of 194 in hydrocortisone group (81%) and 146 of 185 in the placebo group (79%) were evaluated using both the RBL scale and the standardized neurological examination. The 75 remaining patients were assessed using the standardized neurological examination alone. The RBL scale outcome data were not obtained for these participants when either the infant was unable to be tested or the parents missed the appointment.

The main baseline characteristics of infants and their mothers seen during follow-up compared with those lost to follow-up appear in eTable 2 in Supplement 2 and were not significantly different between groups. The baseline characteristics and outcomes of patients at 36 weeks of postmenstrual age and at the 2-year follow-up were similar between the 2 groups (Table 1). Maternal characteristics were not significantly different for factors known to influence neurodevelopmental outcomes, including employment status and racial or ethnic group.

The 2 treatment groups were not significantly different in anthropometric measures or by respiratory symptoms recorded at follow-up (Table 2). Head circumference was similar, with a mean z score of −0.67 (SD, 1.55) in the hydrocortisone group and −0.79 (SD, 1.44) in the placebo group (P = .47).

Neurodevelopmental Outcomes

Table 3 presents the neurodevelopmental outcomes for all infants successfully reassessed at 2 years of age. Quiz Ref IDFor the prespecified exploratory outcome, the distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not found to be statistically significantly different between the 2 groups (P = .33). Qualitative assessment of patients using standardized neurological examination also was not statistically significantly different between groups (P = .87).

Quiz Ref IDFor the post hoc outcomes using the RBL scale, the mean global developmental quotient score was not statistically significantly different between treatment groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, −2.7 to 3.4]; P = .83). Subscores evaluating the 4 domains of development, cerebral palsy incidence, and other major neurodevelopmental impairments also were not statistically significantly different between groups. Because randomization was initially stratified by gestational age groups (24-25 weeks and 26-27 weeks), tests were performed to assess the neurodevelopmental impairment and treatment group × gestational age group interactions. No statistically significant interaction was observed (P = .09), therefore, subgroup results were not reported.

In a post hoc analysis, the relationship between the exploratory outcome of survival free of bronchopulmonary dysplasia or neurodevelopmental impairment and treatment group, adjusted for gestational age group, was studied. From the 523 initially randomized, 2 withdrew consent and 27 infants were lost to follow-up at 2 years of age. Among these 27 infants, 5 had bronchopulmonary dysplasia at 36 weeks of postmenstrual age and were classified as having experienced treatment failure. The number of patients with data on the composite outcome is therefore 499.

Hydrocortisone was associated with survival free of neonatal bronchopulmonary dysplasia or neurodevelopmental impairment at 22 months compared with placebo (46.1% vs 36.2%, respectively; risk difference, 9.4 [95% CI, 1.2-17.6]; relative risk, 1.27 [95% CI, 1.03-1.57]; P = .03). After adjustment for gestational age group, the number of patients needed to treat to gain 1 patient surviving free of bronchopulmonary dysplasia and neurodevelopmental impairment was 11 (95% CI, 6-83).

Discussion

In this follow-up study of premature infants who were randomly assigned at birth to receive low-dose hydrocortisone or placebo for 10 days, hydrocortisone treatment was not associated with any adverse effects on neurodevelopmental outcomes at 22 months of corrected age. The mean global developmental quotient score was 91.7 in hydrocortisone group and 91.4 in the placebo group, which was not significantly different. The 95% CI for the observed difference of −2.7 to 3.4 fell between −5 and 5 points; this suggests the true difference between these scores is unlikely to be clinically relevant.

A strength of this study is the small number of children lost to follow-up (7%); 93% of the eligible children returned for evaluation. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age observed in the placebo group in PREMILOC trial (51%) was similar to rates reported in 2 other large studies of extremely preterm infants: the EPIPAGE 2 (Etude Épidémiologique sur les Petits Âges Gestationnels 2) population-based cohort in France in 2011 (53%)24 and the European NEUROSIS (Neonatal European Study of Inhaled Steroids) trial between 2010 and 2013 (54%).25

In addition, the rate of cerebral palsy at 2 years of age was similar in both the PREMILOC trial (6%) and the EPIPAGE 2 study (7%). These findings suggest that the population included in the present trial was comparable with larger national and multinational cohorts.

Results from the present follow-up study are consistent with those reported by Watterberg et al26 who showed that fewer hydrocortisone-treated infants had a Mental Development Index below 70. These findings contrast with previously reported effects of early postnatal dexamethasone (beneficial respiratory but adverse neurocognitive effects) and, to a lesser extent, previous uncompleted clinical trials using early hydrocortisone (inconclusive effects on bronchopulmonary dysplasia and conflicting neurocognitive outcomes).26-31 In addition, the present study reports 2-year outcomes of the largest randomized trial, to our knowledge, of early hydrocortisone in extremely preterm infants with the lowest loss to follow-up to date.

Observed differences between the effects of hydrocortisone and dexamethasone could be related to dose because higher-dose corticosteroids are known to be deleterious to the developing brain.32 However, several preclinical findings also argue against the use of dexamethasone, a 11β-HSD2–insensitive glucocorticoid, even at low dosages.

Postnatal dexamethasone has been shown to induce hippocampal neuronal apoptotic cell death, a property that could be reversed by survival-promoting actions mediated by mineralocorticoid receptors and hydrocortisone.33 Dexamethasone perturbs serotoninergic and dopaminergic systems and the expression of glucocorticoid receptors.34 Dexamethasone inhibits sonic hedgehog–smoothened signaling, the major mitogenic pathway for granule neuron precursors in the cerebellum, a brain region critical for the coordination of movement.35

In contrast, a number of the effects of hydrocortisone could explain its lack of association with neurodevelopmental impairment. In addition to the direct anti-inflammatory effect on the brain, hydrocortisone therapy was associated in the PREMILOC study with a lower rate of bronchopulmonary dysplasia and patent ductus arteriosus ligation (19% vs 33% in the placebo group), which are risk factors for neurodevelopmental impairment.36 Also, hydrocortisone consistently increases blood pressure, which could improve cerebral blood flow.13

Other than hydrocortisone, caffeine citrate is the only therapy that has been shown to exert a beneficial effect on both bronchopulmonary dysplasia and neurodevelopmental impairment at 18 months of age in very low-birth-weight infants,37 but not at 5 years of age.38 In the PREMILOC trial, all recruiting centers used caffeine as a standard of care for treating apnea of prematurity; therefore, hydrocortisone appears to be additionally beneficial. Until other potential interventions, such as those targeting lung angiogenesis or using mesenchymal stem cells, can be tested, caffeine and hydrocortisone appear to be the most reasonable options for preventing bronchopulmonary dysplasia and improving long-term outcomes.

Limitations

Quiz Ref IDA limitation of the present study is the lack of multiple comparisons adjustment for exploratory outcomes. Also, the analysis did not account for death as a competing risk because neurodevelopmental impairment could only be studied in survivors. Fewer deaths occurred in the hydrocortisone group (47 deaths before 36 weeks of postmenstrual age and 1 death after 36 weeks of postmenstrual age in the hydrocortisone group vs 60 and 7, respectively, in the placebo group).

In addition, a substantial number of children (20%) were only assessed with the standardized neurological examination. However, baseline characteristics were similar between children evaluated with the RBL and those evaluated with the standardized neurological examination only.

The end point (22 months of corrected age) of the population assessment was relatively short. Study participants will be reassessed at the ages of 5 to 7 years. A report on the neurodevelopment of 5- to 7-year-old children exposed to early hydrocortisone39 has suggested a lower full-scale intelligence quotient at preschool age compared with placebo-treated infants. These data should be interpreted with caution because only 16 to 18 patients in each group had a complete neuropsychological examination. Nevertheless, the safety of hydrocortisone should be assessed at preschool age because neurodevelopment assessment at this age better reflects a child’s general intellectual ability and identifies more specific learning disabilities.40

Conclusions

In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants.

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Article Information

Corresponding Author: Olivier Baud, MD, PhD, Réanimation et Pédiatrie Néonatales, Inserm U1141, Hôpital Robert Debré, 48 Blvd Sérurier, Paris 75019, France (olivier.baud@rdb.aphp.fr).

Author Contributions: Drs Baud and Alberti had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Baud, Biran, Mohamed, Alberti.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Baud, Trousson, Leroy, Mohamed, Alberti.

Statistical analysis: Mohamed, Alberti.

Obtained funding: Baud, Alberti.

Administrative, technical, or material support: Trousson, Biran, Leroy, Mohamed, Alberti.

Supervision: Baud, Alberti.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by a research grant from the French Ministry of Health and sponsored by the Département de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris (AOM 06 025 and AOM 11 129).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The funders coordinated the collection and management of the data.

Group Information: The PREMILOC Trial Group members were Caroline Farnoux, MD, Laure Maury, MD, and Sophie Soudée, MD (Neonatal Intensive Care Unit and INSERM U1141, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré, Paris, France); Michèle Granier, MD, and Florence Lebail, MD (Neonatal Intensive Care Unit, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France); Duksha Ramful, MD, and Sylvain Samperiz, MD (Neonatal and Pediatric Intensive Care Unit, CHR Saint-Denis, La Réunion, France); Alain Beuchée, MD, PhD, and Karine Guimard, MD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire, Rennes, France); Pascal Boileau, MD, PhD, Florence Castela, MD, and Fatima El Moussawi, MD (Neonatal Intensive Care Unit, CHI Poissy Saint-Germain-en-Laye, Poissy, France); Claire Nicaise, MD, and Renaud Vialet, MD (Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Hôpital Nord, Marseille, France); Pierre Andrini, MD, and Thierry Debillon, MD, PhD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire, Grenoble, France); Hasinirina, Razafimahefa, MD, and Véronique Zupan-Simunek, MD (Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Antoine Béclère, Paris, France); Anne Coursol, MD, and Saïd Merbouche, MD (Neonatal Intensive Care Unit, Centre Hospitalier de Pontoise, Pontoise, France); Pascal Bolot, MD, and Jean-Marc Kana, MD (Neonatal Intensive Care Unit, Centre Hospitalier Delafontaine, Saint-Denis, France); Julie Guichoux, MD, and Olivier Brissaud, MD, PhD (Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France); Gérard Thiriez, MD, PhD, and Olivier Schulze, MD (Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire de Besançon, Besançon, France); Mickael Pomedio, MD, and Patrice Morville, MD (Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire de Reims, Reims, France); Thierry Blanc, MD, and Stéphane Marret, MD, PhD (Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire Rouen, Rouen, France); Bernard Guillois, MD, PhD, and Cénéric Alexandre, MD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire de Caen, Caen, France); Stéphane Le Bouëdec, MD, and Bertrand Leboucher, MD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire d’Angers, Angers, France); Umberto Simeoni, MD, PhD, and Valérie Lacroze, MD (Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Conception, Marseille, France); Pierre Kuhn, MD, PhD, and Stéphanie Litzler-Renaud, MD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France); Elodie Zana-Taïeb, MD, PhD, and Pierre-Henri Jarreau, MD, PhD (Neonatal Intensive Care Unit Port-Royal, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Cochin-Broca-Hôtel Dieu, Paris, France); Sylvain Renolleau, MD, PhD, and Virginie Meau-Petit, MD (Neonatal and Pediatric Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Hôpital Armand-Trousseau, Paris, France); Gilles Cambonie, MD, PhD, and Aline Rideau Batista Novais, MD, PhD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire de Montpellier, Montpellier, France); Annick Tibi, PharMD (Département de la Santé Publique, Université Paris-Descartes, Département des Essais Cliniques, Agence Générale des Equipements et des Produits de Santé, Assistance Publique-Hôpitaux de Paris, Paris, France); Thierry Lacaze-Masmonteil, MD, PhD (Section Head Neonatology, University of Calgary, Calgary, Alberta, Canada); Kristi Watterberg, MD (University of New Mexico School of Medicine, Albuquerque); Amel Ouslimani and Elodie Soler (Direction de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris, Paris, France); Sandra Argues, Tania Rilcy, Adyla Yacoubi, and Sabrina Verchere (Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, Paris, France); Elena Bombled, MSc, Jennifer Gallard, MSc, and Anne Ménard, MSc (neuropsychologists at Direction de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris, Paris, France); and Isabelle Husson, MD, PhD (Pediatric Neurology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré, Paris, France).

Additional Contributions: We thank Sowmyalakshmi Rasika, PhD (Inserm U1141, Paris, France), for editing an earlier draft. We also thank the members of the data and safety monitoring board: Elizabeth Autret MD, PhD (Unit of Clinical Pharmacology, Centre Hospitalier Universitaire de Tours, Tours, France), Charlotte Casper, MD, PhD (Neonatal Intensive Care Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France), Bruno Giraudeau, PhD (National Institute of Health and Medical Research, CIC 1415, Hôpital Bretonneau, Tours, France), and Pierre-Henri Jarreau, MD, PhD (Neonatal Intensive Care Unit, Port Royal Maternity, Assistance Publique-Hôpitaux de Paris, Paris, France). None of the persons listed received compensation for his or her contribution.

References
1.
Kallapur  SG, Jobe  AH.  Contribution of inflammation to lung injury and development.  Arch Dis Child Fetal Neonatal Ed. 2006;91(2):F132-F135.PubMedGoogle ScholarCrossref
2.
Hagberg  H, Mallard  C, Ferriero  DM,  et al.  The role of inflammation in perinatal brain injury.  Nat Rev Neurol. 2015;11(4):192-208.PubMedGoogle ScholarCrossref
3.
Doyle  LW, Ehrenkranz  RA, Halliday  HL.  Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review.  Neonatology. 2010;98(3):217-224.PubMedGoogle ScholarCrossref
4.
Grier  DG, Halliday  HL.  Corticosteroids in the prevention and management of bronchopulmonary dysplasia.  Semin Neonatol. 2003;8(1):83-91.PubMedGoogle ScholarCrossref
5.
Committee on Fetus and Newborn.  Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.  Pediatrics. 2002;109(2):330-338.PubMedGoogle ScholarCrossref
6.
Yoder  BA, Harrison  M, Clark  RH.  Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants.  Pediatrics. 2009;124(2):673-679.PubMedGoogle ScholarCrossref
7.
Jobe  AH.  The new bronchopulmonary dysplasia.  Curr Opin Pediatr. 2011;23(2):167-172.PubMedGoogle ScholarCrossref
8.
Wright  CJ, Kirpalani  H.  Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies?  Pediatrics. 2011;128(1):111-126.PubMedGoogle ScholarCrossref
9.
Watterberg  KL.  Adrenocortical function and dysfunction in the fetus and neonate.  Semin Neonatol. 2004;9(1):13-21.PubMedGoogle ScholarCrossref
10.
Watterberg  KL, Gerdes  JS, Cole  CH,  et al.  Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.  Pediatrics. 2004;114(6):1649-1657.PubMedGoogle ScholarCrossref
11.
Bonsante  F, Latorre  G, Iacobelli  S,  et al.  Early low-dose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial.  Neonatology. 2007;91(4):217-221.PubMedGoogle ScholarCrossref
12.
Peltoniemi  O, Kari  MA, Heinonen  K,  et al.  Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.  J Pediatr. 2005;146(5):632-637.PubMedGoogle ScholarCrossref
13.
Baud  O, Maury  L, Lebail  F,  et al; PREMILOC Trial Study Group.  Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.  Lancet. 2016;387(10030):1827-1836.PubMedGoogle ScholarCrossref
14.
Sand  EA, Emery-Hauzeur  C.  The psychomotor development of the child during the first 2 years (Brunet-Lezine test) [in French].  Acta Neurol Psychiatr Belg. 1962;62:1087-1102.Google Scholar
15.
Charkaluk  ML, Truffert  P, Fily  A, Ancel  PY, Pierrat  V; Epipage Study Group.  Neurodevelopment of children born very preterm and free of severe disabilities: the Nord-Pas de Calais Epipage cohort study.  Acta Paediatr. 2010;99(5):684-689.PubMedGoogle ScholarCrossref
16.
Charkaluk  ML, Truffert  P, Marchand-Martin  L,  et al; Epipage Study Group.  Very preterm children free of disability or delay at age 2: predictors of schooling at age 8: a population-based longitudinal study.  Early Hum Dev. 2011;87(4):297-302.PubMedGoogle ScholarCrossref
17.
Brunet  O, Lézine  I.  Le développement psychologique de la première enfance, présentation d'une échelle française pour examen des tout petits.  Population. 1952;7(1):162.Google ScholarCrossref
18.
Lézine  I.  Le développement psychomoteur des jeunes prématurés.  Etud Neo-natales (Paris). 1958;7(1):1-50.Google Scholar
19.
Josse  D.  Brunet-Lézine Révisé: Echelle de Développement Psychomoteur de la Première Enfance. Paris, France: Etablissements d'applications Psychotechniques; 1997.
20.
Frankenburg  WK, Dodds  J, Archer  P, Shapiro  H, Bresnick  B.  The Denver II: a major revision and restandardization of the Denver Developmental Screening Test.  Pediatrics. 1992;89(1):91-97.PubMedGoogle Scholar
21.
Gosselin  J, Gahagan  S, Amiel-Tison  C.  The Amiel-Tison Neurological Assessment at Term: conceptual and methodological continuity in the course of follow-up.  Ment Retard Dev Disabil Res Rev. 2005;11(1):34-51.PubMedGoogle ScholarCrossref
22.
Bax  M, Goldstein  M, Rosenbaum  P,  et al; Executive Committee for the Definition of Cerebral Palsy.  Proposed definition and classification of cerebral palsy, April 2005.  Dev Med Child Neurol. 2005;47(8):571-576.PubMedGoogle ScholarCrossref
23.
Natalucci  G, Latal  B, Koller  B,  et al; Swiss EPO Neuroprotection Trial Group.  Effect of early prophylactic high-dose recombinant human erythropoietin in very preterm infants on neurodevelopmental outcome at 2 years: a randomized clinical trial.  JAMA. 2016;315(19):2079-2085.PubMedGoogle ScholarCrossref
24.
Ancel  PY, Goffinet  F, Kuhn  P,  et al; EPIPAGE-2 Writing Group.  Survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study [published correction appears in JAMA Pediatr. 2015;169(4):323].  JAMA Pediatr. 2015;169(3):230-238.PubMedGoogle ScholarCrossref
25.
Bassler  D, Plavka  R, Shinwell  ES,  et al; NEUROSIS Trial Group.  Early inhaled budesonide for the prevention of bronchopulmonary dysplasia.  N Engl J Med. 2015;373(16):1497-1506.PubMedGoogle ScholarCrossref
26.
Watterberg  KL, Shaffer  ML, Mishefske  MJ,  et al.  Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants.  Pediatrics. 2007;120(1):40-48.PubMedGoogle ScholarCrossref
27.
Peltoniemi  OM, Lano  A, Puosi  R,  et al; Neonatal Hydrocortisone Working Group.  Trial of early neonatal hydrocortisone: two-year follow-up.  Neonatology. 2009;95(3):240-247.PubMedGoogle ScholarCrossref
28.
Kersbergen  KJ, de Vries  LS, van Kooij  BJ,  et al.  Hydrocortisone treatment for bronchopulmonary dysplasia and brain volumes in preterm infants.  J Pediatr. 2013;163(3):666-71.e1, e661.PubMedGoogle ScholarCrossref
29.
Rademaker  KJ, Uiterwaal  CS, Groenendaal  F,  et al.  Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children.  J Pediatr. 2007;150(4):351-357.PubMedGoogle ScholarCrossref
30.
Rademaker  KJ, de Vries  WB.  Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart.  Semin Fetal Neonatal Med. 2009;14(3):171-177.PubMedGoogle ScholarCrossref
31.
Doyle  LW, Ehrenkranz  RA, Halliday  HL.  Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.  Cochrane Database Syst Rev. 2014;(5):CD001146.PubMedGoogle Scholar
32.
Moisiadis  VG, Matthews  SG.  Glucocorticoids and fetal programming part 2: mechanisms.  Nat Rev Endocrinol. 2014;10(7):403-411.PubMedGoogle ScholarCrossref
33.
Crochemore  C, Lu  J, Wu  Y,  et al.  Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation.  Mol Psychiatry. 2005;10(8):790-798.PubMedGoogle ScholarCrossref
34.
Slotkin  TA, Kreider  ML, Tate  CA, Seidler  FJ.  Critical prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems.  Neuropsychopharmacology. 2006;31(5):904-911.PubMedGoogle ScholarCrossref
35.
Heine  VM, Rowitch  DH.  Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11β-HSD2-dependent mechanism.  J Clin Invest. 2009;119(2):267-277.PubMedGoogle Scholar
36.
Janz-Robinson  EM, Badawi  N, Walker  K, Bajuk  B, Abdel-Latif  ME; Neonatal Intensive Care Units Network.  Neurodevelopmental outcomes of premature infants treated for patent ductus arteriosus: a population-based cohort study.  J Pediatr. 2015;167(5):1025-32.e3, e1023.PubMedGoogle ScholarCrossref
37.
Schmidt  B, Roberts  RS, Davis  P,  et al; Caffeine for Apnea of Prematurity Trial Group.  Long-term effects of caffeine therapy for apnea of prematurity.  N Engl J Med. 2007;357(19):1893-1902.PubMedGoogle ScholarCrossref
38.
Schmidt  B, Anderson  PJ, Doyle  LW,  et al; Caffeine for Apnea of Prematurity (CAP) Trial Investigators.  Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.  JAMA. 2012;307(3):275-282.PubMedGoogle ScholarCrossref
39.
Peltoniemi  OM, Lano  A, Yliherva  A, Kari  MA, Hallman  M; Neonatal Hydrocortisone Working Group.  Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age.  Acta Paediatr. 2016;105(2):159-164.PubMedGoogle ScholarCrossref
40.
Deary  IJ, Johnson  W.  Intelligence and education: causal perceptions drive analytic processes and therefore conclusions.  Int J Epidemiol. 2010;39(5):1362-1369.PubMedGoogle ScholarCrossref
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