Neonatal Research Network Research Articles

Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial

BackgroundBilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels.ObjectiveTo assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34–36 weeks gestational age in infants born ≤ 750 g or < 27 weeks’ gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered.MethodsPilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks’ gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34–36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22–26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis.DiscussionPragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing.Trial registrationClinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983Protocol version: Version 3.2 (10/5/2022).

How frequent is routine use of probiotics in UK neonatal units?

ObjectiveThere is a lack of UK guidance regarding routine use of probiotics in preterm infants to prevent necrotising enterocolitis, late-onset sepsis and death. As practices can vary, we aimed to...

Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial

Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death. To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death. This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023. Infants were randomized to 10 days of hydrocortisone or placebo treatment. Infants' baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up. Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4. In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death. ClinicalTrials.gov Identifier: NCT01353313.

Antenatal Steroids, Prophylactic Indomethacin, and the Risk of Spontaneous Intestinal Perforation

To estimate if the odds of spontaneous intestinal perforation (SIP) are increased when antenatal steroids (ANS) given close to delivery are combined with indomethacin on day 1 after birth (Indo-D1). A retrospective cohort study using the Neonatal Research Network (NRN) database of inborn infants, gestational age 220-286weeks or birth weight of 401-1000g, born between January 1, 2016 and December 31, 2019, and surviving >12hours. The primary outcome was SIP through 14days. Time of last ANS dose prior to delivery was analyzed as a continuous variable (using 169hours for durations >168hours or no steroid exposure). Associations between ANS, Indo-D1, and SIP were obtained from a multilevel hierarchical generalized linear mixed model after covariate adjustment. This yielded aOR and 95% CI. Of 6851 infants, 243 had SIP (3.5%). ANS exposure occurred in 6393 infants (93.3%) and IndoD1 was given to 1863 infants (27.2%). The time (median, IQR) from last dose of ANS to delivery was 32.5hours (6-81) vs 37.1hours (7-110) for infants with or without SIP, respectively (P=.10). Indo-D1 was given to 51.9 vs 26.3% of infants with SIP vs no SIP, respectively (P<.0001). Adjusted analysis indicated no interaction between time of last ANS dose and Indo-D1 for SIP (P=.7). Indo-D1 but not ANS was associated with increased odds of SIP (aOR: 1.73, 1.21-2.48, P = .003). The odds of SIP were increased after receipt of Indo-D1. Exposure to ANS prior to Indo-D1 was not associated with an increase in SIP.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants

The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. ClinicalTrials.gov ID: NCT01029353.

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

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. 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. 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. Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth. 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. 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%). 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.

Potential Missed Opportunities for Antenatal Corticosteroid Exposure and Outcomes Among Periviable Births: Observational Cohort Study

ABSTRACT Antenatal corticosteroid (ANCS) exposure reduces preterm infant death and morbidities, such as intracranial hemorrhage. Although observational studies suggest periviable infants may benefit from this treatment, many eligible women do not receive ANCSs due to unclear policies, lack of opportunity, or inconsistent care. Professional societies and the Eunice Kennedy Shriver National Institute of Child Health and Human Development recommend administering ANCSs at 24 weeks' gestation for all at-risk pregnancies and as early as 22 weeks with planned postnatal treatment. The aim of this study was to assess whether potential missed opportunities for ANCSs increase as gestational age decreases and are associated with higher rates of hospital mortality or severe brain injury. This was an observational cohort study of infants born at 24 National Institute of Child Health and Human Development Neonatal Research Network centers from 2006 to 2018. Included were infants at 220/7 to 256/7 weeks of gestation, without major birth defects, and a birth weight of 401 to 1000 g. Data were collected prospectively from birth to discharge, transfer, death, or 120 days. Antenatal corticosteroid exposure was defined as infants who received partial, complete, or repeat courses of the treatment. Potential missed opportunities for exposure were defined as infants who received no ANCSs, despite potentially having sufficient time to receive prenatal antibiotics, were administered magnesium sulfate, or experience prolonged rupture of membranes. Severe brain injury was defined as intracranial hemorrhage or periventricular leukomalacia on cranial imaging. The primary outcome was the rate of ANCS exposure and potential missed opportunities at each gestational age. Secondary outcomes included death and severe brain injury. A total of 7957 infants who were actively treated postnatally were included in the primary analysis. Of these, 87.6% had ANCS exposure, 5.7% had no exposure but potential missed opportunities for exposure, and 6.7% had no exposure and no potential missed opportunities. Potential missed opportunities for exposure were more common in infants born at 22 and 23 weeks versus 25 weeks (22 weeks: adjusted risk ratio [aRR], 11.06; 95% confidence interval [CI], 7.52–16.27; P &lt; 0.001); 23 weeks: aRR, 3.24; 95% CI, 2.44–4.29; P &lt; 0.001). No difference was observed between 24 and 25 weeks (24 weeks: aRR, 1.08; 95% CI, 0.82–1.42). From 2006 to 2018, infants at 22 weeks saw the largest increase in exposure to ANCSs (12.5%–87.2%) and a decrease in the rate of potential missed opportunities (68.8%–2.6%). Overall, the rate of mortality was 23% lower among infants in the exposure group than for those in the missed opportunities group (31% vs 54.8%; aRR, 0.77; 95% CI, 0.70–0.84; P &lt; 0.001). Infants in the exposure group had lower risk of severe brain injury than those in the missed opportunities group (25% vs 44.5%; aRR, 0.64; 95% CI, 0.55–0.73; P &lt; 0.001), with no significant variation by gestational age. In conclusion, the potential for missed opportunities for ANCS exposure was more common among periviable infants at 22 and 23 weeks compared with those at 25 weeks of gestation. Moreover, exposure to ANCSs was associated with lower rates of mortality and severe brain injury.

Neonatal network database operated by the Neonatal Research Network of Japan

Neonatal network database operated by the Neonatal Research Network of Japan

Early-Life Outcomes in Relation to Social Determinants of Health for Children Born Extremely Preterm

To characterize the relationships between social determinants of health (SDOH) and outcomes for children born extremely preterm. This is a cohort study of infants born at 22-26weeks of gestation in National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2017) who survived to discharge. Infants were classified by 3 maternal SDOH: education, insurance, and race. Outcomes included postmenstrual age (PMA) at discharge, readmission, neurodevelopmental impairment (NDI), and death postdischarge. Regression analyses adjusted for center, perinatal characteristics, neonatal morbidity, ethnicity, and 2 SDOH (eg, group comparisons by education adjusted for insurance and race). Of 7438 children, 5442 (73%) had at least 1 risk-associated SDOH. PMA at discharge was older (adjusted mean difference 0.37weeks, 95% CL 0.06, 0.68) and readmission more likely (aOR 1.27, 95% CL 1.12, 1.43) for infants whose mothers had public/no insurance vs private. Neither PMA at discharge nor readmission varied by education or race. NDI was twice as likely (aOR 2.36, 95% CL 1.86, 3.00) and death 5 times as likely (aOR 5.22, 95% CL 2.54, 10.73) for infants with 3 risk-associated SDOH compared with those with none. Children born to mothers with public/no insurance were older at discharge and more likely to be readmitted than those born to privately insured mothers. NDI and death postdischarge were more common among children exposed to multiple risk-associated SDOH at birth compared with those not exposed. Addressing disparities due to maternal education, insurance coverage, and systemic racism are potential intervention targets to improve outcomes for children born preterm.

Policies Affecting Pregnant Women with Substance Use Disorder

Policies Affecting Pregnant Women with Substance Use Disorder

Neonatal Research Network of Japan and Neonatal Database

In 2004, the Neonatal Research Network of Japan initiated a database registration system for high-risk infants in Japan. Currently, 65% of all very low the birth weight infants or infants born at &lt;32 weeks of gestation are registered in the database. Approximately 4,000 new cases are registered annually. A unique feature of the database is that it includes outcome data at 1.5, 3, and 6 years after discharge from neonatal intensive care units. All registered data are fed back annually to the participating hospitals and used to benchmark neonatal care. Results from this database have also been published in many international journals. With the development of this database, neonatal medicine in Japan has progressed.

Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study

ObjectivesTo assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic...

Risk factor analyses for intraventricular hemorrhage in preterm infants: A retrospective cohort study.

Very-low-birthweight (VLBW) infants can experience severe intraventricular hemorrhage (IVH) that can lead to life-long disability by impairing neurodevelopment. The aim of this study was to identify the risk and protective factors for severe IVH in VLBW infants. A retrospective, cross-sectional review of VLBW infants born at 22-28 weeks' gestation between January 2003 and December 2012 and listed in the Database of Neonatal Research Network in Japan was performed using a statistical model incorporating an odds ratio (OR) and medical center variation as a center variance ratio (CVR). A two-dimensional analysis using a combination of OR and the CVR described evolving measures of a clinical trial (for OR > 1) and standardization (for CVR > 1) concerning a factor of interest. The noteworthy significant protective factors were antenatal steroids (ANS) with and without premature rupture of membrane (OR: 0.43, CVR: 1.08, and OR: 0.68, CVR: 1.14, respectively) and the number of neonatal beds (OR: 0.94, CVR: 0.99) and staff nurses per neonatal bed (OR: 0.89, CVR: 0.99). Active promotion of ANS administration and consolidation of perinatal medical centers can mitigate the development of severe IVH in VLBW infants.

Comparison of mortality and survival without major morbidities of very preterm infants with very low birth weight from Japan and Brazil.

Objective:This study was carried out to understand the disparities in mortality and survival without major morbidities among very premature and very low birth weight infants between participating Neonatal Intensive Care Units (NICUs) from the Brazilian Network on Neonatal Research (RBPN) and the Neonatal Research Network of Japan (NRNJ).Methods:Secondary data analysis of surveys by the RBPN and NRNJ was performed. The surveys were conducted in 2014 and 2015 and included 187 NICUs. Primary outcome was mortality or survival without any major morbidity. Logistic regression analysis adjustment for confounding factors was used.Results:The study population consisted of 6,406 infants from the NRNJ and 2,319 from the RBPN. Controlling for various confounders, infants from RBPN had 9.06 times higher adjusted odds of mortality (95%CI 7.30–11.29), and lower odds of survival without major morbidities (AOR 0.36; 95%CI 0.32–0.41) compared with those from the NRNJ. Factors associated with higher odds of mortality among Brazilian NICUs included: Air Leak Syndrome (AOR 4.73; 95%CI 1.26–15.27), Necrotizing Enterocolitis (AOR 3.25; 95%CI 1.38–7.26), and Late Onset Sepsis (LOS) (AOR 4.86; 95%CI 2.25–10.97).Conclusions:Very premature and very low birth weight infants from Brazil had significantly higher odds for mortality and lower odds for survival without major morbidities in comparison to those from Japan. Additionally, we identified the factors that increased the odds of in-hospital neonatal death in Brazil, most of which was related to LOS.

Antenatal prediction models for outcomes of extremely and very preterm infants based on machine learning.

Predicting individual risks for adverse outcomes in preterm infants is necessary for perinatal management and antenatal counseling for their parents. To evaluate whether a machine learning approach can improve the prediction of severe infant outcomes beyond the performance of conventional logistic models, and to identify maternal and fetal factors that largely contribute to these outcomes. A population-based retrospective study was performed using clinical data of 31,157 infants born at < 32weeks of gestation and weighing ≤ 1500g, registered in the Neonatal Research Network of Japan between 2006 and 2015. We developed a conventional logistic model and 6 types of machine learning models based on 12 maternal and fetal factors. Discriminative ability was evaluated using the area under the receiver operating characteristic curves (AUROCs), and the importance of each factor in terms of its contribution to outcomes was evaluated using the SHAP (SHapley Additive exPlanations) value. The AUROCs of the most discriminative machine learning models were better than those of the conventional models for all outcomes. The AUROCs for in-hospital death and short-term adverse outcomes in the gradient boosting decision tree were significantly higher than those in the conventional model (p = 0.015 and p = 0.002, respectively). The SHAP value analyses showed that gestational age, birth weight, and antenatal corticosteroid treatment were the three most important factors associated with severe infant outcomes. Machine learning models improve the prediction of severe infant outcomes. Moreover, the machine learning approach provides insight into the potential risk factors for severe infant outcomes.

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

Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm. To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age. 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. Culture-confirmed LOM. 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). 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. 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.

Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the United States, 2013-2018

(JAMA. 2022;327:248–263. doi: 10.1001/jama.2021.2358) While mortality rates of preterm infants have decreased over time, differences in age assessment, assessment instruments, and other factors have made determining neurodevelopmental outcomes difficult. This study used data collected from preterm infants born before the gestational age of 29 weeks between January 1, 2013 and December 31, 2018 from 19 network centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.

Antenatal corticosteroids and outcomes of small for gestational age infants born at 24-31 gestational weeks: a population-based propensity score matching analysis.

To evaluate the effect of antenatal corticosteroid (ACS) treatment on neonatal outcomes in small for gestational age (SGA) infants born at 24-31 gestational weeks compared with non-SGA infants. A population-based retrospective study was conducted that analyzed clinical data from the Neonatal Research Network of Japan database, which enrolls neonates born at < 32 gestational weeks and weighing 1500g or less (n = 22,414). Propensity score matching (with the ratio of ACS to no-ACS groups of 1:1) was performed in SGA (n = 7028) and non-SGA (n = 15,386) infants, respectively. Univariate logistic and interaction analyses were performed to compare the short-term neonatal outcomes of infants with and without ACS treatment in utero. In the SGA and non-SGA infants, ACS treatment significantly reduced in-hospital mortality (odds ratio 0.67 95% confidence interval [0.50-0.88] and 0.62 [0.50-0.78], respectively), respiratory distress syndrome (0.77 [0.69-0.87] and 0.63 [0.58-0.68], respectively), and composite adverse outcomes (0.73 [0.58-0.91] and 0.57 [0.50-0.65], respectively). ACS treatment also significantly reduced intraventricular hemorrhage (grade III/IV), periventricular leukomalacia, and sepsis in the non-SGA infants, but not in the SGA infants. However, interaction analyses revealed no significant differences between the SGA and non-SGA infants in the efficacy of ACS treatment on short-term outcomes except for respiratory distress syndrome. ACS treatment was associated with beneficial effects on mortality, respiratory distress syndrome, and adverse composite outcomes in extremely and very preterm SGA infants, with similar efficacy on all neonatal outcomes except for respiratory distress syndrome observed in the non-SGA infants.

Comparison of definitions of bronchopulmonary dysplasia to reflect the long-term outcomes of extremely preterm infants

Survivors of neonatal bronchopulmonary dysplasia (BPD) have persistent respiratory, neurodevelopmental, and growth impairment over the first few years of life and later childhood, which represents an emerging burden for health systems. Therefore, there is an increasing need for a new definition and grading system of BPD that predicts long-term outcomes of high-risk infants who need timely and proper intervention to improve outcomes. We compared new definitions of BPD (National Institute of Child Health and Human Development [NICHD] 2018 and Neonatal Research Network [NRN] 2019) to the original NICHD 2001 definition at 3 years of age using a nationwide cohort of extreme preterm infants. New definitions and severity grading were clearly related to respiratory, neurodevelopmental, and growth impairments at 3 years of age and at 18–24 months corrected age (CA), whereas the original NICHD 2001 definition was not. Furthermore, the negative effect of BPD on growth was ameliorated at 3 years of age compared to 18–24 months CA. However, the negative effect of BPD in neonates on the respiratory system and neurodevelopment persisted at 3 years of age. These new definitions should be adopted to identify high-risk infants and improve long-term outcomes by exact diagnosis and BPD severity classification.

Validation of eligibility criteria for the Japan Obstetric Compensation System for Cerebral Palsy in preterm infants: A case-control cohort study.

To verify validity of the criteria used for the Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP) in preterm infants, the association between the criteria and the development of CP was studied using a neonatal database. Our hypothesis was that the criteria would not be sufficient due to the recent advances made in perinatal care. Preterm infants born between 2003 and 2019 and registered in the Neonatal Research Network of Japan database with a birth weight of 1500 g or less or a gestational age of less than 32 weeks were analyzed. The database included the clinical information of registered infants during their stay in NICUs and outcomes at 3 years of age. The database included 73 615 infants. After excluding those with an unknown outcome at discharge, 73 464 infants were analyzed for short-term outcomes, including mortality and morbidities. The incidence of CP at 3 years of age was analyzed in 36 151 infants. Furthermore, 16 467 infants born between 28 and 31 weeks of gestation were examined in terms of the validity of the current eligibility criteria. The mortality and incidences of severe intraventricular hemorrhage and periventricular leukomalacia significantly decreased during the study period (Cochrane-Armitage test, p < 0.01). Furthermore, the eligibility criteria were not sufficiently nor strongly associated with indicators for detecting perinatal hypoxia-ischemia resulting in CP. The existing eligibility criteria of the JOCS-CP used for preterm infants born between 28 and 31 weeks were no longer suitable because of the advances in perinatal care in Japan.