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

2023

e2312277

05/2023

2574-3805

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.

10.1001/jamanetworkopen.2023.12277

JAMA Netw Open

37155165

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

2023

e2312277

05/2023

2574-3805

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.

10.1001/jamanetworkopen.2023.12277

JAMA Netw Open

37155165

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

2023

e2312277

05/2023

2574-3805

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.

10.1001/jamanetworkopen.2023.12277

JAMA Netw Open

37155165

Incidence of and Neurodevelopmental Outcomes After Late-Onset Meningitis Among Children Born Extremely Preterm.

2022

e2245826

12/2022

2574-3805

IMPORTANCE: Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.

OBJECTIVE: To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks' gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.

EXPOSURES: Culture-confirmed LOM.

MAIN OUTCOMES AND MEASURES: Incidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).

RESULTS: Among 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.

CONCLUSIONS AND RELEVANCE: In this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

10.1001/jamanetworkopen.2022.45826

JAMA Netw Open

36480199

Group B Streptococcus Infection in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years.

2022

1405-1415

10/2022

1537-6591

BACKGROUND: This study was performed to determine the incidence of group B Streptococcus (GBS) disease among extremely preterm infants and assess to risk of death or neurodevelopmental impairment (NDI) at a corrected age of 18-26 months.

METHODS: In this observational cohort study of infants enrolled in a multicenter registry, the incidence of GBS disease was assessed in infants born in 1998-2016 at 22-28 weeks' gestation and surviving for >12 hours. The composite outcome, death or NDI, was assessed in infants born in 1998-2014 at 22-26 weeks' gestation. Infection was defined as GBS isolation in blood or cerebrospinal fluid culture at ≤72 hours (early-onset disease [EOD]) or >72 hours (late-onset disease [LOD]) after birth. Using Poisson regression models, the outcome was compared in infants with GBS disease, infants infected with other pathogens, and uninfected infants.

RESULTS: The incidence of GBS EOD (2.70/1000 births [95% confidence interval (CI), 2.15-3.36]) and LOD (8.47/1000 infants [7.45-9.59]) did not change significantly over time. The adjusted relative risk of death/NDI was higher among infants with GBS EOD than in those with other infections (adjusted relative risk, 1.22 [95% CI, 1.02-1.45]) and uninfected infants (1.44 [1.23-1.69]). Risk of death/NDI did not differ between infants with GBS LOD and comparator groups. GBS LOD occurred at a significantly later age than non-GBS late-onset infection. Among infants surviving >30 days, the risk of death was higher with GBS LOD (adjusted relative risk, 1.90 [95% CI, 1.36-2.67]), compared with uninfected infants.

CONCLUSIONS: In a cohort of extremely preterm infants, the incidence of GBS disease did not change during the study period. The increased risk of death or NDI with GBS EOD, and of death among some infants with GBS LOD, supports the need for novel preventive strategies for disease reduction.

CLINICAL TRIALS REGISTRATION: NCT00063063.

10.1093/cid/ciac222

Clin Infect Dis

35323895

Impact of Early-Onset Sepsis and Antibiotic Use on Death or Survival with Neurodevelopmental Impairment at 2 Years of Age among Extremely Preterm Infants.

2020

39-46.e5

2020 Jun

1097-6833

OBJECTIVE: To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI.

STUDY DESIGN: Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants.

RESULTS: Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort.

CONCLUSIONS: Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.

10.1016/j.jpeds.2020.02.038

J. Pediatr.

32446491

Group B Streptococcal Infection in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years.

2022

2022 Mar 22

1537-6591

<p><strong>BACKGROUND: </strong>Determine the incidence of GBS disease among extremely preterm infants and assess risk of death or neurodevelopmental impairment (NDI) at 18-26 months' corrected age.</p>

<p><strong>METHODS: </strong>Observational cohort study of infants enrolled in a multicenter registry. GBS disease incidence was assessed in infants born 1998-2016 at 22-28 weeks' gestation surviving &gt;12 hours. The composite outcome, death or NDI, was assessed in infants born 1998-2014 at 22-26 weeks' gestation. Infection was defined as GBS isolation in blood/CSF culture at ≤72 hours (early-onset disease, EOD) and &gt;72 hours (late-onset disease, LOD) after birth. The outcome was compared in infants with GBS disease, infants infected with other pathogens, and uninfected infants using Poisson regression models.</p>

<p><strong>RESULTS: </strong>Incidence of GBS EOD (2.70/1000 births [95% CI: 2.15-3.36]) and LOD (8.47/1000 infants [7.45-9.59]) did not change significantly over time. The adjusted relative risk (aRR, 95% CI) of death/NDI was higher among GBS EOD cases compared to infants with other infections (1.22, [1.02-1.45]) and uninfected infants (1.44, [1.23-1.69]). Death/NDI did not differ between infants with GBS LOD and comparator groups. GBS LOD occurred at a significantly later age than non-GBS late-onset infection. Among infants surviving &gt;30 days, the risk of death was higher with GBS LOD (1.90, [1.36-2.67]), compared to uninfected infants.</p>

<p><strong>CONCLUSIONS: </strong>In a cohort of extremely preterm infants, incidence of GBS disease did not change during the study period. Increased risk of death/NDI with GBS EOD, and of death among some infants with GBS LOD, supports the need for novel preventive strategies for disease reduction.</p>

10.1093/cid/ciac222

Clin Infect Dis

35323895

Association between postmenstrual age and furosemide dosing practices in very preterm infants.

2022

2022 Jan 24

1476-5543

<p><strong>OBJECTIVE: </strong>Furosemide renal clearance is slow after very preterm (VP) birth and increases with postnatal maturation. We compared furosemide dose frequency and total daily dose between postmenstrual age (PMA) groups in VP infants.</p>

<p><strong>STUDY DESIGN: </strong>Observational cohort study of VP infants exposed to a repeated-dose course of furosemide in Pediatrix neonatal intensive care units (NICU) from 1997 to 2016.</p>

<p><strong>RESULTS: </strong>We identified 6565 furosemide courses among 4638 infants. There were no statistically significant differences between PMA groups on the odds of receiving more frequent furosemide dosing. Furosemide courses initiated at &lt;28 weeks PMA were associated with a higher total daily dose than those initiated at a later PMA.</p>

<p><strong>CONCLUSIONS: </strong>Furosemide dosing practices in the NICU are similar across PMA groups, despite maturational changes in drug disposition. Research is needed to identify and test rational dosing strategies across the PMA spectrum for this commonly used but unproven pharmacotherapy.</p>

10.1038/s41372-022-01320-w

J Perinatol

35075306

Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.

2021

2021 Jan 21

1468-2052

<p><strong>OBJECTIVE: </strong>Determine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC).</p>

<p><strong>DESIGN: </strong>Retrospective cohort study.</p>

<p><strong>SETTING: </strong>24 neonatal centres.</p>

<p><strong>PATIENTS: </strong>Infants born 1/1/2006-31/12/2014, at 22-26 weeks gestation, with birth weight 401-1000 g and surviving &gt;7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded.</p>

<p><strong>EXPOSURES: </strong>LOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition.</p>

<p><strong>OUTCOMES: </strong>Death or NDI was assessed at 18-26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age.</p>

<p><strong>RESULTS: </strong>Of 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants.</p>

<p><strong>CONCLUSIONS: </strong>Infants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.</p>

10.1136/archdischild-2020-320664

Arch Dis Child Fetal Neonatal Ed

33478957

Outcomes associated with surfactant in more mature and larger premature infants with respiratory distress syndrome.

2020

2020 Feb 20

1476-5543

<p><strong>OBJECTIVE: </strong>Examine the effect of off-label surfactant on mortality and morbidity in more mature and larger premature infants diagnosed with respiratory distress syndrome (RDS).</p>

<p><strong>STUDY DESIGN: </strong>Cohort study of premature infants born at 30-36 weeks, birth weight &gt; 2 kg, and a diagnosis of RDS. We compared the odds of mortality and morbidity between infants who were exposed vs unexposed to surfactant. We used a treatment effects model to balance covariates between groups.</p>

<p><strong>RESULTS: </strong>Of 54,964 included infants, 25,278 (46%) were exposed to surfactant. The frequency of mortality and morbidities were higher in the exposed group in unadjusted analyses. Following adjustment with a doubly robust treatment effects model, we found no significant treatment effect of surfactant on mortality or morbidity.</p>

<p><strong>CONCLUSION: </strong>Surfactant exposure is not associated with reduced or increased mortality or morbidity in more mature premature infants with RDS.</p>

10.1038/s41372-020-0625-1

J Perinatol

32080333