Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth

Baud, Olivier; Trousson, Clémence; Biran, Valérie; Leroy, E.; Mohamed, Damir; Alberti, Corinne

doi:10.1136/archdischild-2017-313756

Cited by 45 publications

(50 citation statements)

References 20 publications

(14 reference statements)

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“…These findings are in accordance with those of previous reports, showing that selective neonatal hydrocortisone treatment using higher doses (starting dose of 5 mg/kg/day tapered over a minimum of 3 weeks) had no detectable long-term effects on either neurostructural brain development at TEA, brain growth or neurocognitive outcomes at preschool age 17–20. They are also consistent with 2-year clinical outcomes of the population recruited in the trial, demonstrating that early low-dose hydrocortisone treatment was not associated with a statistically significant difference in neurodevelopment at 2 years of age 8 9. While waiting for preschool-age clinical assessment, the present data add further reassuring evidence supporting the neurodevelopmental safety of hydrocortisone use in extremely preterm infants, in particular in terms of the vulnerability of WM to postnatal steroids 21…”

Section: Discussionsupporting

confidence: 92%

“…Recently, the PREMILOC clinical trial tested early low-dose hydrocortisone as an alternative treatment, with potentially fewer neurodevelopmental consequences, in infants born extremely preterm at high risk of BPD. This trial showed a significant improvement in the rate of BPD-free survival at 36 weeks postmenstrual age (PMA),7 without detectable adverse neurodevelopmental outcomes at 2 years of age in hydrocortisone-treated infants 8 9. Although definitive proof of the neurodevelopmental safety of hydrocortisone requires further long-term assessment, early prediction of neurodevelopmental outcomes of very immature infants is still a critical point in prognostic discussions with families of infants born very preterm.…”

Section: Introductionmentioning

confidence: 99%

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Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality

Alison¹,

Tilea²,

Toumazi³

et al. 2020

Arch Dis Child Fetal Neonatal Ed

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ObjectiveTo determine whether early low-dose hydrocortisone treatment in extremely preterm infants is associated with brain damage assessed by MRI at term equivalent of age (TEA).Patients and outcomesThis is a predefined secondary analysis of brain abnormalities, observed by MRI at TEA, of patients randomly assigned to receive either placebo or hydrocortisone in the PREMILOC trial. Outcomes were based on brain abnormalities graded according to Kidokoro scores.ResultsAmong 412 survivors at TEA, 300 MRIs were performed and 295 were suitable for analysis. Kidokoro scoring was completed for 119/148 and 110/147 MRIs in the hydrocortisone and placebo groups, respectively. The distribution of the Kidokoro white matter (WM) subscore and other subscores was not significantly different between the two groups. There was, however, a significant association between a higher overall Kidokoro score and hydrocortisone treatment (5.84 (SD 3.51) for hydrocortisone and 4.98 (SD 2.52) for placebo; mean difference, 0.86; 95% CI 0.06 to 1.66; p=0.04). However, hydrocortisone was not statistically associated with moderate-to-severe brain lesions (Kidokoro overall score ≥6) in a multivariate logistic regression model accounting for potential confounding variables (adjusted OR (95% CI) 1.27 (0.75 to 2.14), p=0.38). Bronchopulmonary dysplasia at 36 weeks postmenstrual age significantly predicted both WM damage (adjusted OR (95% CI) 2.70 (1.03 to 7.14), p=0.04) and global brain damage (adjusted OR (95% CI) 2.18 (1.19 to 3.99), p=0.01).ConclusionsEarly hydrocortisone exposure in extremely preterm infants is not statistically associated with either WM brain damage or overall moderate-to-severe brain lesions when adjusted for other neonatal variables.Trial registration numberEudraCT number 2007-002041-20, NCT00623740

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality

Alison¹,

Tilea²,

Toumazi³

et al. 2020

Arch Dis Child Fetal Neonatal Ed

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“…14,15,17 Our analysis confirms an association between early lowdose hydrocortisone exposure and late-onset sepsis; nonetheless, treatment was associated with a significantly improved survival without BPD at 36 weeks PMA and survival to discharge, with no adverse effects on neurodevelopmental outcomes at 2 years. [16][17][18][19] Follow-up of a small number of children (n = 27) at age 5-7 years suggested a correlation between early hydrocortisone treatment and later neurocognitive impairment 34 ; however, the 2-year outcomes of 694 children enrolled in all these studies showed no adverse neurodevelopmental effects and identified possible benefits. Longer-term follow-up of previous cohort studies also have been reassuring.…”

Section: Discussionmentioning

confidence: 98%

“…[11][12][13][14][15] These trials extended hydrocortisone therapy beyond the first postnatal week and used a dose of 1-2 mg/kg/day, which has been shown to moderately but significantly increase serum cortisol concentrations in extremely preterm neonates compared with placebo. 12 Although 2-year follow-up data have been consistently reassuring, 7,[16][17][18][19] the effect of early hydrocortisone treatment on survival without BPD and potential side effects remain unclear. Therefore, we undertook an individual patient data metaanalysis of clinical trials to examine the effect of prophylaxis of early adrenal insufficiency on these outcomes.…”

mentioning

confidence: 99%

Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis

Shaffer

Baud

Lacaze‐Masmonteil

et al. 2019

The Journal of Pediatrics

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Objective To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis. Study design All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age. Results Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I 2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I 2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I 2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I 2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I 2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis. Conclusions This individual patient data meta-analysis showed that early low-dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants.

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“…There is anecdotal evidence that starting doses of dexamethasone as low as 0.05 mg/kg/day might be effective [136, 137] but the Minidex RCT failed to recruit enough participants to confirm this. Low-dose prophylactic hydrocortisone also reduced BPD [138] with improved neurological outcomes in a subgroup of infants of less than 25 weeks’ gestation [139]. …”

Section: Strategiesmentioning

confidence: 99%

European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update

et al. 2019

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As management of respiratory distress syndrome (RDS) advances, clinicians must continually revise their current practice. We report the fourth update of “European Guidelines for the Management of RDS” by a European panel of experienced neonatologists and an expert perinatal obstetrician based on available literature up to the end of 2018. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, need for appropriate maternal transfer to a perinatal centre and timely use of antenatal steroids. Delivery room management has become more evidence-based, and protocols for lung protection including initiation of CPAP and titration of oxygen should be implemented immediately after birth. Surfactant replacement therapy is a crucial part of management of RDS, and newer protocols for its use recommend early administration and avoidance of mechanical ventilation. Methods of maintaining babies on non-invasive respiratory support have been further developed and may cause less distress and reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation using caffeine and, if necessary, postnatal steroids are also important considerations. Protocols for optimising general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome.

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Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth

Abstract: In an exploratory analysis of neurodevelopmental outcomes from the PREMILOC trial, early low-dose hydrocortisone was associated with a statistically significant improvement in neurodevelopmental outcomes in infants born at 24 and 25 weeks of gestation.

Cited by 45 publications

References 20 publications

Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality

Prophylactic hydrocortisone in extremely preterm infants and brain MRI abnormality

Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis

European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update

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