Assessment of Corticosteroid Therapy and Death or Disability According to Pretreatment Risk of Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants.

Importance: Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended. Objective: To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants. Design, Setting, and Participants: This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022. Exposure: Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth. Main Outcomes and Measures: The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age. Results: A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%). Conclusions and Relevance: Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Model for severe intracranial hemorrhage and role of early indomethacin in extreme preterm infants.

BACKGROUND: To develop a model for prediction of severe intracranial hemorrhage (ICH) or death based on variables from the first 12 h of age and to compare mortality and morbidities with and without exposure to early indomethacin. METHODS: This retrospective cohort study included extreme preterm (220/7-266/7 weeks) infants born at National Institute of Child Health and Human Development Neonatal Research Network sites. Primary outcome was a composite of severe ICH and/or death. RESULTS: Of 4624 infants, 1827 received early indomethacin. Lower gestation, lack of antenatal steroids exposure, lower 1-min Apgar, male sex, and receipt of epinephrine were associated with severe ICH or death. Early indomethacin was associated with a lower risk of patent ductus arteriosus, bronchopulmonary dysplasia, and higher risk of spontaneous intestinal perforation. CONCLUSIONS: A model for early prediction of severe ICH/death was developed and validated. Early indomethacin was associated with a lower risk of patent ductus arteriosus and bronchopulmonary dysplasia and a higher risk of spontaneous intestinal perforation. CLINICAL TRIAL REGISTRATION: Not applicable. IMPACT: Modern data on severe ICH and neonatal morbidities in relation to prophylactic indomethacin are scarce in the published literature. Prophylactic indomethacin was associated with a lower risk of patent ductus arteriosus and bronchopulmonary dysplasia and a higher risk of intestinal perforation. A risk estimator for severe intracranial hemorrhage/death was developed in a large cohort of extremely preterm infants. The risk estimator developed based on a large cohort of patients provides an estimate of severe intracranial bleeding for an individual infant.

The relationship of neurodevelopmental impairment to concurrent early childhood outcomes of extremely preterm infants.

OBJECTIVE: Determine how neurodevelopmental impairment (NDI) relates to concurrent outcomes for children born extremely preterm. STUDY DESIGN: Retrospective cohort study children born 22 0/7-26 6/7 weeks' gestation at NICHD Neonatal Research Network hospitals. Outcomes were ascertained at 18-22 months' corrected age. RESULT: Of 6562 children, 2618 (40%) died and 441 (7%) had no follow-up. Among the remaining 3483 children, 825 (24%), 1576 (45%), 657 (19%), and 425 (12%) had no, potential/mild, moderate, and severe NDI, respectively. Rehospitalization, respiratory medications, surgery, and medical support services were associated with greater NDI severity but affected >10% of children without NDI. Rehospitalization occurred in 40% of children with no NDI (mean (SD): 1.7 (1.3) episodes). CONCLUSION: Medical, functional, and social outcomes at 18-22 months' corrected age were associated with NDI; however, many children without NDI were affected. These data should contribute to counseling families and the design of studies for childhood outcomes beyond NDI.

Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes.

OBJECTIVE: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). STUDY DESIGN: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks' postmenstrual age was used to produce adjusted odds ratios (aOR). RESULTS: Compared with infants in the reference group (22-28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50-63 (aOR 1.77, 95% CI 1.03-3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44-6.48). The aOR for NDI did not vary significantly by age of PNS exposure. CONCLUSION: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.