Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Sample entropy correlates with intraventricular hemorrhage and mortality in premature infants early in life.

BACKGROUND: Mortality and intraventricular hemorrhage (IVH) are common adverse outcomes in preterm infants and are challenging to predict clinically. Sample entropy (SE), a measure of heart rate variability (HRV), has shown predictive power for sepsis and other morbidities in neonates. We evaluated associations between SE and mortality and IVH in the first week of life. METHODS: Participants were 389 infants born before 32 weeks of gestation for whom bedside monitor data were available. A total of 29 infants had IVH grade 3 or 4 and 31 infants died within 2 weeks of life. SE was calculated with the PhysioNet open-source benchmark. Logistic regressions assessed associations between SE and IVH and/or mortality with and without common clinical covariates over various hour of life (HOL) censor points. RESULTS: Lower SE was associated with mortality by 4 HOL, but higher SE was very strongly associated with IVH and mortality at 24-96 HOL. Bootstrap testing confirmed SE significantly improved prediction using clinical variables at 96 HOL. CONCLUSION: SE is a significant predictor of IVH and mortality in premature infants. Given IVH typically occurs in the first 24-72 HOL, affected infants may initially have low SE followed by a sustained period of high SE. IMPACT: SE correlates with IVH and mortality in preterm infants early in life. SE combined with clinical factors yielded ROC AUCs well above 0.8 and significantly outperformed the clinical model at 96 h of life. Previous studies had not shown predictive power over clinical models. First study using the PhysioNet Cardiovascular Toolbox benchmark in young infants. Relative to the generally accepted timing of IVH in premature infants, we saw lower SE before or around the time of hemorrhage and a sustained period of higher SE after. Higher SE after acute events has not been reported previously.

Mortality and extrauterine growth restriction of necrotizing enterocolitis in very preterm infants with heart disease: a multi-center cohort study.

Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases. This was an observational cohort study that enrolled VPIs (born between 24+0 and 31+6 weeks) admitted to 79 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC-related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome. A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD and 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, there was no significant increased risks in NEC-related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41-2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82-1.87), and increased risks in EUGR were identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31-4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16-2.01) in survivors. The composite outcome (death or EUGR) was also more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20-3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17-1.94) than that without heart diseases. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, and longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC.     Conclusion: In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR. What is Known: • CHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR. • NEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process. What is New: • CHD and isolated PDA are associated with increased risks of EUGR in VPIs with NEC. • Risk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes.

Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Donor human milk for preventing necrotising enterocolitis in very preterm or very low-birthweight infants.

BACKGROUND: When sufficient maternal milk is not available, donor human milk or formula are the alternative forms of enteral nutrition for very preterm or very low-birthweight (VLBW) infants. Donor human milk may retain the non-nutritive benefits of maternal milk and has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To assess the effectiveness of donor human milk compared with formula for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants when sufficient maternal milk is not available. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care (MIC) database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to February 2024. We searched clinical trials registries and examined the reference lists of included studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing feeding with donor human milk versus formula in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. DATA COLLECTION AND ANALYSIS: Two review authors evaluated the risk of bias in the trials, extracted data, and synthesised effect estimates using risk ratio, risk difference, and mean difference, with associated 95% confidence intervals. The primary outcomes were NEC, late-onset invasive infection, and all-cause mortality before hospital discharge. The secondary outcomes were growth parameters and neurodevelopment. We used the GRADE approach to assess the certainty of the evidence for our primary outcomes. MAIN RESULTS: Twelve trials with a total of 2296 infants fulfilled the inclusion criteria. Most trials were small (average sample size was 191 infants). All trials were performed in neonatal units in Europe or North America. Five trials were conducted more than 40 years ago; the remaining seven trials were conducted in the year 2000 or later. Some trials had methodological weaknesses, including concerns regarding masking of investigators and selective reporting. Meta-analysis showed that donor human milk reduces the risk of NEC (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.37 to 0.76; I² = 4%; risk difference (RD) -0.03, 95% CI -0.05 to -0.01; 11 trials, 2261 infants; high certainty evidence). Donor human milk probably has little or no effect on late-onset invasive infection (RR 1.12, 0.95 to 1.31; I² = 27%; RD 0.03, 95% CI -0.01 to -0.07; 7 trials, 1611 infants; moderate certainty evidence) or all-cause mortality (RR 1.00, 95% CI 0.76 to 1.31; I² = 0%; RD -0.00, 95% CI -0.02 to 0.02; 9 trials, 2116 infants; moderate certainty evidence). AUTHORS' CONCLUSIONS: The evidence shows that donor human milk reduces the risk of NEC by about half in very preterm or VLBW infants. There is probably little or no effect on late-onset invasive infection or all-cause mortality before hospital discharge.

Strategies for cessation of caffeine administration in preterm infants.

BACKGROUND: Apnea and intermittent hypoxemia (IH) are common developmental disorders in infants born earlier than 37 weeks' gestation. Caffeine administration has been shown to lower the incidence of these disorders in preterm infants. Cessation of caffeine treatment is based on different post-menstrual ages (PMA) and resolution of symptoms. There is uncertainty about the best timing for caffeine discontinuation. OBJECTIVES: To evaluate the effects of early versus late discontinuation of caffeine administration in preterm infants. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trial registries in August 2023; we applied no date limits. We checked the references of included studies and related systematic reviews. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in preterm infants born earlier than 37 weeks' gestation, up to a PMA of 44 weeks and 0 days, who received caffeine for any indication for at least seven days. We compared three different strategies for caffeine cessation: 1. at different PMAs, 2. before or after five days without symptoms, and 3. at a predetermined PMA versus at the resolution of symptoms. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were: restarting caffeine therapy, intubation within one week of treatment discontinuation, and the need for non-invasive respiratory support within one week of treatment discontinuation. Secondary outcomes were: number of episodes of apnea in the seven days after treatment discontinuation, number of infants with at least one episode of apnea in the seven days after treatment discontinuation, number of episodes of intermittent hypoxemia (IH) within seven days of treatment discontinuation, number of infants with at least one episode of IH in the seven days after of treatment discontinuation, all-cause mortality prior to hospital discharge, major neurodevelopmental disability, number of days of respiratory support after treatment discontinuation, duration of hospital stay, and cost of neonatal care. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included three RCTs (392 preterm infants). Discontinuation of caffeine at PMA less than 35 weeks' gestation versus PMA equal to or longer than 35 weeks' gestation This comparison included one single completed RCT with 98 premature infants with a gestational age between 25 + 0 and 32 + 0 weeks at birth. All infants had discontinued caffeine treatment for five days at randomization. The infants received either an oral loading dose of caffeine citrate (20 mg/kg) at randomization followed by oral maintenance dosage (6 mg/kg/day) until 40 weeks PMA, or usual care (controls), during which caffeine was stopped before 37 weeks PMA. Early cessation of caffeine administration in preterm infants at PMA less than 35 weeks' gestation may result in an increase in the number of IH episodes in the seven days after discontinuation of treatment, compared to prolonged caffeine treatment beyond 35 weeks' gestation (mean difference [MD] 4.80, 95% confidence interval [CI] 2.21 to 7.39; 1 RCT, 98 infants; low-certainty evidence). Early cessation may result in little to no difference in all-cause mortality prior to hospital discharge compared to late discontinuation after 35 weeks PMA (risk ratio [RR] not estimable; 98 infants; low-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, number of episodes of apnea, number of infants with at least one episode of apnea in the seven days after discontinuation of treatment, or number of infants with at least one episode of IH in the seven days after discontinuation of treatment. Discontinuation based on PMA versus resolution of symptoms This comparison included two RCTs with a total of 294 preterm infants. Discontinuing caffeine at the resolution of symptoms compared to discontinuing treatment at a predetermined PMA may result in little to no difference in all-cause mortality prior to hospital discharge (RR 1.00, 95% CI 0.14 to 7.03; 2 studies, 294 participants; low-certainty evidence), or in the number of infants with at least one episode of apnea within the seven days after discontinuing treatment (RR 0.60, 95% CI 0.31 to 1.18; 2 studies; 294 infants; low-certainty evidence). Discontinuing caffeine based on the resolution of symptoms probably results in more infants with IH in the seven days after discontinuation of treatment (RR 0.38, 95% CI 0.20 to 0.75; 1 study; 174 participants; moderate-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, or number of episodes of IH in the seven days after treatment discontinuation. Adverse effects In the Rhein 2014 study, five of the infants randomized to caffeine had the caffeine treatment discontinued at the discretion of the clinical team, because of tachycardia. The Pradhap 2023 study reported adverse events, including recurrence of apnea of prematurity (15% in the short and 13% in the regular course caffeine therapy group), varying severities of bronchopulmonary dysplasia, hyperglycemia, extrauterine growth restriction, retinopathy of prematurity requiring laser treatment, feeding intolerance, osteopenia, and tachycardia, with no significant differences between the groups. The Prakash 2021 study reported that adverse effects of caffeine therapy for apnea of prematurity included tachycardia, feeding intolerance, and potential neurodevelopmental impacts, though most were mild and transient. We identified three ongoing studies. AUTHORS' CONCLUSIONS: There may be little or no difference in the incidence of all-cause mortality and apnea in infants who were randomized to later discontinuation of caffeine treatment. However, the number of infants with at least one episode of IH was probably reduced with later cessation. No data were found to evaluate the benefits and harms of later caffeine discontinuation for: restarting caffeine therapy, intubation within one week of treatment discontinuation, or need for non-invasive respiratory support within one week of treatment discontinuation. Further studies are needed to evaluate the short-term and long-term effects of different caffeine cessation strategies in premature infants.

Clinical phenotype of pulmonary vascular disease requiring treatment in extremely preterm infants.

BACKGROUND: Pulmonary vascular disease (PVD) and pulmonary hypertension (PH) is a significant disorder affecting prognosis of extremely preterm infants. However, there is still a lack of a consensus on the definition and optimal treatments of PH, and there is also a lack of research comparing these conditions with persistent pulmonary hypertension of newborn (PPHN), early PH, and late PH. To investigate PH in extremely preterm infants, this study compared the baseline characteristics, short-term outcomes, and treatment duration, categorized by the timing of requiring PH treatment. METHODS: This study retrospectively analyzed extremely preterm infants admitted to a single tertiary center. Between 2018 and 2022, infants with clinical or echocardiographic diagnosis of PH who required treatment were divided into three groups based on the timing of treatment initiation: initial 3 days (extremely early-period), from day 4 to day 27 (early-period), and after day 28 (late-period). The study compared the outcomes, including mortality rates, bronchopulmonary dysplasia (BPD) severity, PH treatment duration, and oxygen therapy duration, among the three groups. RESULTS: Among the 157 infants, 67 (42.7%) were treated for PH during their stay. Of these, 39 (57.3%) were treatment in extremely early, 21 (31.3%) in early, and seven (11.4%) in late periods. No significant differences were observed in maternal factors, neonatal factors, or morbidity between the three groups. However, infants who received extremely early-period treatment had a higher mortality rate, but shorter duration of noninvasive respiratory support, oxygen therapy, and PH medication use. On the other hand, the late-period treatment group received longer durations of respiratory support and treatment. CONCLUSIONS: This study revealed differences in mortality rates, respiratory outcomes, and treatment duration between the three groups, suggesting varying pathophysiologies over time in extremely preterm infants.

A real-world study on the treatment of extremely preterm infants: a multi-center study in southwest area of Fujian Province in China.

BACKGROUND: Due to regional and cultural differences, the current status of extremely preterm infants(EPIs) treatment across different areas of mainland China remains unclear. This study investigated the survival rate and incidence of major diseases among EPIs in the southwest area of Fujian province. METHOD: This retrospective and multicenter study collected perinatal data from EPIs with gestational ages between 22-27+ 6w and born in the southwest area of Fujian province. The study population was divided into 6 groups based on gestational age at delivery. The primary outcome was the survival status at ordered hospital discharge or correct gestational age of 40 weeks, and the secondary outcome was the incidence of major diseases. The study analyzed the actual survival status of EPIs in the area. RESULT: A total of 2004 preterm infants with gestational ages of 22-27+ 6 weeks were enrolled in this study. Among them, 1535 cases (76.6%) were born in the delivery room but did not survive, 469 cases (23.4%) were transferred to the neonatal department for treatment, 101 cases (5.0%) received partial treatment, and 368 cases (18.4%) received complete treatment. The overall all-cause mortality rate was 84.4% (1691/2004). The survival rate and survival rate without major serious disease for EPIs who received complete treatment were 85.1% (313/368) and 31.5% (116/318), respectively. The survival rates for gestational ages 22-22+ 6w, 23-23+ 6w, 24-24+ 6w, 25-25+ 6w, 26-26+ 6w, and 27-27+ 6w were 0%, 0%, 59.1% (13/22), 83% (39/47), 88.8% (87/98), and 89.7% (174/198), respectively. The survival rates without major serious disease were 0%, 0%, 9.1% (2/22), 19.1% (9/47), 27.6% (27/98), and 40.2% (78/194), respectively. CONCLUSION: The all-cause mortality of EPIs in the southwest area of Fujian Province remains high, with a significant number of infants were given up after birth in the delivery room being the main influencing factor. The survival rate of EPIs who received complete treatment at 25-27 weeks in the NICU was similar to that in developed countries. However, the survival rate without major serious disease was significantly lower compared to high-income countries.

Development of a Prediction Model for Surgery or Early Mortality at the Time of Initial Assessment for Necrotizing Enterocolitis.

OBJECTIVE: No available scale, at the time of initial evaluation for necrotizing enterocolitis (NEC), accurately predicts, that is, with an area under the curve (AUC) ≥0.9, which preterm infants will undergo surgery for NEC stage III or die within a week. STUDY DESIGN: This is a retrospective cohort study (n = 261) of preterm infants with <33 weeks' gestation or <1,500 g birth weight with either suspected or with definite NEC born at Parkland Hospital between 2009 and 2021. A prediction model using the new HASOFA score (Hyperglycemia, Hyperkalemia, use of inotropes for Hypotension during the prior week, Acidemia, Neonatal Sequential Organ Failure Assessment [nSOFA] score) was compared with a similar model using the nSOFA score. RESULTS: Among 261 infants, 112 infants had NEC stage I, 68 with NEC stage II, and 81 with NEC stage III based on modified Bell's classification. The primary outcome, surgery for NEC stage III or death within a week, occurred in 81 infants (surgery in 66 infants and death in 38 infants). All infants with pneumoperitoneum or abdominal compartment syndrome either died or had surgery. The HASOFA and the nSOFA scores were evaluated in 254 and 253 infants, respectively, at the time of the initial workup for NEC. Both models were internally validated. The HASOFA model was a better predictor of surgery for NEC stage III or death within a week than the nSOFA model, with greater AUC 0.909 versus 0.825, respectively, p < 0.001. Combining HASOFA at initial assessment with concurrent or later presence of abdominal wall erythema or portal gas improved the prediction surgery for NEC stage III or death with AUC 0.942 or 0.956, respectively. CONCLUSION: Using this new internally validated prediction model, surgery for NEC stage III or death within a week can be accurately predicted at the time of initial assessment for NEC. KEY POINTS: · No available scale, at initial evaluation, accurately predicts which preterm infants will undergo surgery for NEC stage III or die within a week.. · In this retrospective cohort study of 261 preterm infants with either suspected or definite NEC we developed a new prediction model (HASOFA score).. · The HASOFA-model had high discrimination (AUC: 0.909) and excellent calibration and was internally validated..

Exclusive Human Milk Diets and the Reduction of Necrotizing Enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is common in preterm infants, especially infants less than 32 weeks gestation. Mortality from NEC is 7% and occurs in 1 out of 1000 preterm infants. Studies have shown the efficacy of an exclusive milk from mother diet in decreasing rates of NEC and associated mortality. PURPOSE: To evaluate the effectiveness of an existing exclusive human milk diet (EHMD) protocol on the incidence of NEC in extremely premature infants. EHMD, for the purposes of this project is defined as breast milk of mother, with or without human milk-based fortifier. METHODS: A single-center retrospective quasi-experimental study. The sample included 201 infants born less than 32 weeks gestation, weighing less than 1250 grams, small for gestational age (SGA) and with low Apgar scores. Outcomes measured included incidences of NEC, mortality, and co-morbidities in infants pre- and postinitiation of an EHMD protocol. RESULTS: Just 4.8% of the EHMD group had a NEC diagnosis compared to 10.5% of the bovine-based (BOV) group. There was a 1% mortality rate of the EHMD group as compared to 6% in the BOV group. The EHMD group had a statistically significant greater weight gain during hospitalization as compared to infants fed BOV ( P = < .05). IMPLICATIONS FOR PRACTICE AND RESEARCH: Neonatal intensive care units should consider EHMDs for use in this infant population. Future research is needed to support dissemination of the use of EHMD as standard of practice.

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.

BACKGROUND: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. METHODS: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. RESULTS: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. CONCLUSIONS: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Hourly Kinetics of Critical Organ Dysfunction in Extremely Preterm Infants.

Rationale: Use of severity of illness scores to classify patients for clinical care and research is common outside of the neonatal ICU. Extremely premature (<29 weeks' gestation) infants with extremely low birth weight (<1,000 g) experience significant mortality and develop severe pathology during the protracted birth hospitalization. Objectives: To measure at high resolution the changes in organ dysfunction that occur from birth to death or discharge home by gestational age and time, and among extremely preterm infants with and without clinically meaningful outcomes using the neonatal sequential organ failure assessment score. Methods: A single-center, retrospective, observational cohort study of inborn, extremely preterm infants with extremely low birth weight admitted between January 2012 and January 2020. Neonatal sequential organ failure assessment scores were calculated every hour for every patient from admission until death or discharge. Measurements and Main Results: Longitudinal, granular scores from 436 infants demonstrated early and sustained discrimination of those who died versus those who survived to discharge. The discrimination for mortality by the maximum score was excellent (area under curve, 0.91; 95% confidence intervals, 0.88-0.94). Among survivors with and without adverse outcomes, most score variation occurred at the patient level. The weekly average score over the first 28 days was associated with the sum of adverse outcomes at discharge. Conclusions: The neonatal sequential organ failure assessment score discriminates between survival and nonsurvival on the first day of life. The major contributor to score variation occurred at the patient level. There was a direct association between scores and major adverse outcomes, including death.

Randomized Trial of Platelet-Transfusion Thresholds in Neonates.

BACKGROUND: Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia. METHODS: In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization. RESULTS: A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67). CONCLUSIONS: Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).

Neonatal morbidity and mortality by mode of delivery in very preterm neonates.

BACKGROUND: The safest mode of delivery to use for very preterm infants is an ongoing topic of debate. There are many reasons to perform a cesarean delivery in cases of extremely preterm and very preterm infants, including indication for labor, fetal distress, maternal indications, and malpresentation. OBJECTIVE: This study aimed to determine whether cesarean delivery is associated with a considerable improvement in neonatal morbidity. STUDY DESIGN: This study is a retrospective cohort study of all singleton pregnancies, delivered from 22 to 29 weeks' gestation between 2010 and 2015, admitted for preterm labor or preterm premature rupture of membranes and excluded neonates with a delivery weight ≤500 g, multiple gestations, cases with intrauterine fetal demise, and induced terminations. The primary outcome for the study was a neonatal morbidity composite (Apgar score of <5 at 5 minutes, prolonged ventilation (>28 days), intraventricular hemorrhage, necrotizing enterocolitis, coagulopathy, discharged on home ventilator support, or discharged with enteric feeding tube). Cesarean deliveries were performed for standard obstetrical indications. Regression models were used and adjusted for nulliparity, delivery year, and presentation at the time of delivery to determine whether cesarean delivery is associated with neonatal morbidity or neonatal death. RESULTS: There were 271 eligible deliveries, which included 128 cesarean deliveries and 143 vaginal deliveries. The cesarean delivery group had fewer nulliparous patients and more fetuses presenting in breech position at the time of delivery. The overall composite neonatal morbidity occurred in 202 of the 271 (74.5%) deliveries and mortality occurred in 26 of the 271 (9.59%) deliveries. When adjusting for nulliparity, delivery year, and fetal presentation at the time of delivery, cesarean delivery was associated with a decreased risk for death in the delivery room or within 24 hours after delivery (adjusted risk ratio, 0.18; 95% confidence interval, 0.05-0.63; P=.03). Cesarean delivery was associated with an increased use of exogenous surfactant (adjusted risk ratio, 1.20; 95% confidence interval, 1.05-1.38; P=.01) and bag mask ventilation (adjusted risk ratio, 1.17; 95% confidence interval, 1.01-1.37; P=.03). In a secondary analysis that included only patients who received a complete course of steroids, there were no differences in the composite morbidity or mortality. CONCLUSION: Cesarean delivery performed for standard obstetrical indications in cases of very preterm neonates is associated with a decreased risk for death in the delivery room or within 24 hours of delivery but is not associated with an improvement in the overall morbidity or mortality.

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).

Impact of Deferred Cord Clamping on Mortality and Severe Neurologic Injury in Twins Born at <30 Weeks of Gestation.

OBJECTIVE: To determine whether deferred cord clamping (DCC) compared with early cord clamping (ECC) was associated with reduction in death and/or severe neurologic injury among twins born at <30 weeks of gestation. STUDY DESIGN: We performed a retrospective cohort study including all liveborn twins of <30 weeks admitted to a tertiary-level neonatal intensive care unit (NICU) in Canada between 2015 and 2018 using the Canadian Neonatal/Preterm Birth Network database. We compared DCC ≥30 seconds vs ECC <30 seconds. Our primary outcome was a composite of death and/or severe neurologic injury (severe intraventricular hemorrhage grade III/IV and/or periventricular leukomalacia). Secondary outcomes included neonatal morbidity and health care utilization outcomes. We calculated aORs and ß coefficients for categorical and continuous variables, along with 95% CI. Models were fitted with generalized estimated equations accounting for twin correlation. RESULTS: We included 1597 twins (DCC, 624 [39.1%]; ECC, 973 [60.9%]). Death/severe neurologic injury occurred in 17.8% (n = 111) of twins who received DCC and in 21.7% (n = 211) of those who received ECC. The rate of death/severe neurologic injury did not differ significantly between the DCC and ECC groups (aOR 1.07; 95% CI, 0.78-1.47). DCC was associated with reduced blood transfusions (adjusted ß coefficient, -0.49; 95% CI, -0.86 to -0.12) and NICU length of stay (adjusted ß coefficient, -4.17; 95% CI, -8.15 to -0.19). CONCLUSIONS: The primary composite outcome of death and/or severe neurologic injury did not differ between twins born at <30 weeks of gestation who received DCC and those who received ECC, but DCC was associated with some benefits.

Outcomes for Infants Born in Perinatal Centers Performing Fewer Surgical Ligations for Patent Ductus Arteriosus: A Swiss Population-Based Study.

OBJECTIVE: To assess patent ductus arteriosus treatment variation between Swiss perinatal centers and to determine its effect on outcome in a population-based setting. STUDY DESIGN: This was a retrospective cohort study of infants born less than 28 weeks of gestation between 2012 and 2017. Outcomes between surgically ligated and pharmacologically treated infants as well as infants born in centers performing ≤10% ligation ("low" group) and >10% ("high" group) were compared using logistic regression and 1:1 propensity score matching. Matching was based on case-mix and preligation confounders: intraventricular hemorrhages grades 3-4, necrotizing enterocolitis, sepsis, and ≥28 days' oxygen supply. RESULTS: Of 1389 infants, 722 (52%) had pharmacologic treatment and 156 (11.2%) received surgical ligation. Compared with infants who received pharmacologic treatment, ligated infants had greater odds for major morbidities (OR 2.09, 95% CI 1.44-3.04) and 2-year neurodevelopmental impairment (OR 1.81, 95% CI 1.15-2.84). Mortality was comparable after restricting the cohort to infants surviving at least until day 10 to avoid survival bias. In the "low" group, 34 (4.9%) of 696 infants were ligated compared with 122 (17.6%) of 693 infants in the "high" group. Infants in the "high" group had greater odds for major morbidities (OR 1.49, 95% CI 1.11-2.0). CONCLUSIONS: Our analysis identified a burden on infants receiving surgical ligation vs pharmacologic treatment in a population-based setting where there was no agreed-on common procedure. These results may guide a revision of patent ductus arteriosus treatment practice in Switzerland.

Bloodstream Infections in Preterm Neonates and Mortality-Associated Risk Factors.

OBJECTIVE: To investigate the association of early (±4 hours after onset of bloodstream infection) clinical and laboratory variables with episode-related mortality (<7 days). STUDY DESIGN: This 2-site retrospective study included 142 neonates born at <35 weeks of gestational age with positive blood/cerebrospinal fluid (CSF) culture at >72 hours of age from organisms other than coagulase-negative Staphylococcus. Early variables were compared between those with bloodstream infection-related mortality and survivors. Multivariable analysis was conducted for the primary outcome, and the area under the curve (AUC) was estimated for relevant variables. RESULTS: The neonates who died were of lower gestational age at disease onset. After adjusting for relevant variables, lowest mean blood pressure (MBP) (aOR, 0.10; 95% CI, 1.02-1.19) and highest base deficit (aOR, 1.18; 95% CI, 1.06-1.32) were independently associated with mortality. The AUC was 0.87 (95% CI, 0.78-0.96) for base deficit, increasing to 0.91 (95% CI, 0.83-0.99) with the addition of MBP. CONCLUSION: Low MBP and high base deficit within ±4 hours of bloodstream infection onset identify preterm neonates at risk of mortality.