Search

CONTEXT Preterm brain injuries are common; neurodevelopmental outcomes following contemporary neonatal care are continually evolving. OBJECTIVE To systematically review and meta-analyze neurodevelopmental outcomes among preterm infants after intraventricular hemorrhage (IVH) and white matter injury (WMI). DATA SOURCES Published and grey literature were searched across 10 databases between 2000 and 2021. STUDY SELECTION Observational studies reporting 3-year neurodevelopmental outcomes for preterm infants with IVH or WMI compared with preterm infants without injury. DATA EXTRACTION Study characteristics, population characteristics, and outcome data were extracted. RESULTS Thirty eight studies were included. There was an increased adjusted risk of moderate-severe neurodevelopmental impairment after IVH grade 1 to 2 (adjusted odds ratio 1.35 [95% confidence interval 1.05–1.75]) and IVH grade 3 to 4 (adjusted odds ratio 4.26 [3.25–5.59]). Children with IVH grade 1 to 2 had higher risks of cerebral palsy (odds ratio [OR] 1.76 [1.39–2.24]), cognitive (OR 1.79 [1.09–2.95]), hearing (OR 1.83 [1.03–3.24]), and visual impairment (OR 1.77 [1.08–2.9]). Children with IVH grade 3 to 4 had markedly higher risks of cerebral palsy (OR 4.98 [4.13–6.00]), motor (OR 2.7 [1.52–4.8]), cognitive (OR 2.3 [1.67–3.15]), hearing (OR 2.44 [1.42–4.2]), and visual impairment (OR 5.42 [2.77–10.58]). Children with WMI had much higher risks of cerebral palsy (OR 14.91 [7.3–30.46]), motor (OR 5.3 [3–9.36]), and cognitive impairment (OR 3.48 [2.18–5.53]). LIMITATIONS Heterogeneity of outcome data. CONCLUSIONS Mild IVH, severe IVH, and WMI are associated with adverse neurodevelopmental outcomes. Utilization of core outcome sets and availability of open-access study data would improve our understanding of the nuances of these outcomes.

Outcomes for patients with neonatal heart disease are affected by numerous noncardiac and genetic factors. These can include neonatal concerns, such as prematurity and low birth weight, and congenital anomalies, such as airway, pulmonary, gastrointestinal, and genitourinary anomalies, and genetic syndromes. This section will serve as a summary of these issues and how they may affect the evaluation and management of a neonate with heart disease. These noncardiac factors are heavily influenced by conditions common to neonatologists, making a strong argument for multidisciplinary care with neonatologists, cardiologists, surgeons, anesthesiologists, and cardiovascular intensivists. Through this section and this project, we aim to facilitate a comprehensive approach to the care of neonates with congenital heart disease.

OBJECTIVES Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP. METHODS Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function. RESULTS At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted β: −0.75, 95% confidence interval [CI]: −1.25 to −0.25), lower BMI z-score (adjusted β: −0.55, 95% CI: −1.09 to −0.01), and lower height z-score (adjusted β: −0.65, 95% CI: −1.16 to −0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes. CONCLUSIONS Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.

OBJECTIVES To determine the epidemiology, microbiology, and associated outcomes of late-onset sepsis among very preterm infants using a large and nationally representative cohort of NICUs across the United States. METHODS Prospective observational study of very preterm infants born 401 to 1500 g and/or 22 to 29 weeks’ gestational age (GA) from January 1, 2018, to December 31, 2020, who survived >3 days in 774 participating Vermont Oxford Network centers. Late-onset sepsis was defined as isolation of a pathogenic bacteria from blood and/or cerebrospinal fluid, or fungi from blood, obtained >3 days after birth. Demographics, clinical characteristics, and outcomes were compared between infants with and without late-onset sepsis. RESULTS Of 118 650 infants, 10 501 (8.9%) had late-onset sepsis for an incidence rate of 88.5 per 1000 (99% confidence interval [CI] [86.4–90.7]). Incidence was highest for infants born ≤23 weeks GA (322.0 per 1000, 99% CI [306.3–338.1]). The most common pathogens were coagulase negative staphylococci (29.3%) and Staphylococcus aureus (23.0%), but 34 different pathogens were identified. Infected infants had lower survival (adjusted risk ratio [aRR] 0.89, 95% CI [0.87–0.90]) and increased risks of home oxygen (aRR 1.32, 95% CI [1.26–1.38]), tracheostomy (aRR 2.88, 95% CI [2.47–3.37]), and gastrostomy (aRR 2.09, 95% CI [1.93–2.57]) among survivors. CONCLUSIONS A substantial proportion of very preterm infants continue to suffer late-onset sepsis, particularly those born at the lowest GAs. Infected infants had higher mortality, and survivors had increased risks of technology-dependent chronic morbidities. The persistent burden and diverse microbiology of late-onset sepsis among very preterm infants underscore the need for innovative and potentially organism-specific prevention strategies.

Retinopathy of prematurity (ROP) is a significant cause of potentially preventable blindness in preterm infants worldwide. It is a disease caused by abnormal retinal vascularization that, if not detected and treated in a timely manner, can lead to retinal detachment and severe long term vision impairment. Neonatologists and pediatricians have an important role in the prevention, detection, and management of ROP. Geographic differences in the epidemiology of ROP have been seen globally over the last several decades because of regional differences in neonatal care. Our understanding of the pathophysiology, risk factors, prevention, screening, diagnosis, and treatment of ROP have also evolved over the years. New technological advances are now allowing for the incorporation of telemedicine and artificial intelligence in the management of ROP. In this comprehensive update, we provide a comprehensive review of pathophysiology, classification, diagnosis, global screening, and treatment of ROP. Key historical milestones as well as touching upon the very recent updates to the ROP classification system and technological advances in the field of artificial intelligence and ROP will also be discussed.

OBJECTIVES To assess effects of enteral “low” dose (daily doses of ≤10 000 international unit) vitamin A supplementation compared with no vitamin A supplementation in human milk-fed preterm and low birth weight (LBW) infants. DATA SOURCES Cochrane Central Register of Controlled Trials; Medline, Embase, Scopus, Web of Science, CINAHL from inception to 16 March 2021. STUDY SELECTION Randomized trials were screened. Primary outcomes were mortality, morbidity, growth, neurodevelopment. Secondary outcomes were feed intolerance and duration of hospitalization. We also assessed the dose and timing of vitamin A supplementation. Data were extracted and pooled with fixed and random-effects models. RESULTS Four trials including 800 very LBW LIMITATIONS Heterogeneity and small sample size in the included studies. CONCLUSIONS Low-dose vitamin A increased serum retinol concentration among very LBW and very preterm infants but had no effect on other outcomes. More trials are needed to assess effects on clinical outcomes and to assess effects in infants 1.5 to 2.4 kg or 32 to 26 weeks’ gestation.

BACKGROUND AND OBJECTIVES Preterm and low birth weight (LBW) infants are often separated from parents during hospitalization. Our objective was to assess effects of interventions to increase family involvement in the routine newborn care of preterm or LBW infants compared with standard NICU care on infant and parental outcomes. METHODS Data sources include Medline, Embase, CINAHL, and World Health Organization Global Index Medicus to August 2021. The study selection included randomized controlled trials (RCTs) of family involvement intervention packages. Data were extracted and pooled with random-effects models. RESULTS We included 15 RCTs with 5240 participants. All interventions included direct parental bedside care; packages varied with respect to additional components. Family involvement interventions decreased retinopathy of prematurity (odds ratio 0.52, 95% confidence interval [CI]: 0.34, 0.80; 8 RCTs), length of hospital stay (mean difference [MD] −2.91 days; 95% CI: −5.15,−0.82; 11 RCTs), and parental stress and anxiety (Parental Stress Scale: MD −0.29 points, 95% CI: −0.56,−0.01, 2 RCTs; Anxiety State-Trait scale: MD −1.79, 95% CI: −3.11,−0.48; 2 RCTs). Family involvement increased weight gain velocity (MD 2.09 g/day; 95% CI: 1.27, 2.91; 3 RCTs), neurobehavioral exam scores (MD: 1.11; 95% CI: 0.21, 2.01; 2 RCTs) and predominant or exclusive breastmilk intake (odds ratio 1.34; 95% CI: 1.01, 1.65; 3 RCTs). It may decrease rates of bronchopulmonary dysplasia, infection, and intraventricular hemorrhage. There were no effects on mortality or necrotizing enterocolitis. Certainty of evidence ranged from low to moderate. CONCLUSIONS Family involvement has a beneficial role on several infant and parental outcomes.

OBJECTIVES To determine the epidemiology and microbiology of early-onset sepsis (EOS) among very preterm infants using a nationally representative cohort from academic and community hospitals to inform empirical antibiotic guidance, highlight risk factors for infection, and aid in prognostication for infected infants. METHODS Prospective observational study of very preterm infants born weighing 401 to 1500 g or at 22 to 29 weeks’ gestational age from January 2018 to December 2019 in 753 Vermont Oxford Network centers. EOS was defined as a culture-confirmed bacterial infection of the blood or cerebrospinal fluid in the 3 days after birth. Demographics, clinical characteristics, and outcomes were compared between infants with and without EOS. RESULTS Of 84 333 included infants, 1139 had EOS for an incidence rate of 13.5 per 1000 very preterm births (99% confidence interval [CI] 12.5–14.6). Escherichia coli (538 of 1158; 46.5%) and group B Streptococcus (218 of 1158; 18.8%) were the most common pathogens. Infected infants had longer lengths of stay (median 92 vs 66 days) and lower rates of survival (67.5% vs 90.4%; adjusted risk ratio 0.82 [95% CI 0.79–0.85]) and of survival without morbidity (26.1% vs 59.4%; adjusted risk ratio 0.66 [95% CI 0.60–0.72]). CONCLUSIONS In a nationally representative sample of very preterm infants with EOS from 2018 to 2019, approximately one-third of isolates were neither group B Streptococcus nor E coli. Three-quarters of all infected infants either died or survived with a major medical morbidity. The profoundly negative impact of EOS on very preterm infants highlights the need for novel preventive strategies.

Probiotic products in the United States are available for use in the general category of dietary supplements, bypassing the rigor of the US Food and Drug Administration (FDA) approval process in safety, efficacy, and manufacturing standards. As a result, currently available probiotics lack FDA-approved drug labeling and cannot be marketed to treat or prevent disease in preterm infants, including necrotizing enterocolitis and late-onset sepsis. Despite lack of availability of a pharmaceutical-grade product, the number of preterm infants receiving probiotics in the United States and Canada is steadily increasing. According to recent reports from large collaborative databases in the United States, approximately 10% of extremely low gestational age neonates receive a probiotic preparation during their stay in the NICU, with wide variation in practice among units. In sum, more than 10 000 preterm infants have been enrolled in randomized clinical trials of probiotic supplementation worldwide. Methodologic differences among study protocols included different strains and combinations of therapy, masking of trials, and a priori definitions of the primary outcome measure. Large meta-analyses of these trials have demonstrated the efficacy of multiple-strain probiotics in reducing necrotizing enterocolitis and all-cause mortality, whereas the efficacy of single-strain probiotic preparations is less certain. In the absence of an appropriate medical-grade product in the United States, dietary supplement–grade probiotics, some of which have been the subject of recent recalls for contamination, are being prescribed. Given the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of

CONTEXT Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES Medline was searched for all articles (up to June 2020). STUDY SELECTION All developed or externally validated prognostic models for mortality prediction in liveborn infants born DATA EXTRACTION Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS One hundred forty-four models from 36 studies reporting on model development and 118 models from 34 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 42% and 94% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83–0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81–0.92) for the Clinical Risk Index for Babies II score, 0.86 (95% CI: 0.78–0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score and 0.71 (95% CI 0.61–0.79) for the NICHD model. LIMITATIONS Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.

BACKGROUND: Severe intraventricular hemorrhage (IVH) is a leading mortality risk factor among extremely premature neonates. Because other life-threatening conditions also occur in this population, it is unclear whether severe IVH is independently associated with death. The existence and potential implications of regional variation in severe IVH–associated mortality are unknown. METHODS: We performed a retrospective cohort study of mechanically ventilated neonates born at 22 to 29 weeks’ gestation who received care in 242 American NICUs between 2000 and 2014. After building groups composed of propensity score–matched and center-matched pairs, we used the Cox proportional hazards analysis to test our hypothesis that severe IVH would be associated with greater all-cause in-hospital mortality, defined as death before transfer or discharge. We also performed propensity score–matched subgroup analyses, comparing severe IVH–associated mortality among 4 geographic regions of the United States. RESULTS: In our analysis cohort, we identified 4679 patients with severe IVH. Among 2848 matched pairs, those with severe IVH were more likely to die compared with those without severe IVH (hazard ratio 2.79; 95% confidence interval 2.49–3.11). Among 1527 matched pairs still hospitalized at 30 days, severe IVH was associated with greater risk of death (hazard ratio 2.03; 95% confidence interval 1.47–2.80). Mortality associated with severe IVH varied substantially between geographic regions. CONCLUSIONS: The early diagnosis of severe IVH is independently associated with all-cause in-hospital mortality in extremely premature neonates. Regional variation in severe IVH–associated mortality suggests that shared decision-making between parents and neonatologists is strongly influenced by ultrasound-based IVH assessment and classification.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

* Abbreviations: NEC — : necrotizing enterocolitis NIRS — : near-infrared spectroscopy In this issue of Pediatrics, Howarth et al1 report on a completed longitudinal study of 46 preterm infants born at 15 million infants are born preterm (

The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006–April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.

OBJECTIVES: To examine trends in survival without major morbidity and its individual components among very low birth weight infants across California and assess remaining gaps that may be opportune targets for improvement efforts. METHODS: The study population included infants born between 2008 and 2017 with birth weights of 401 to 1500 g or a gestational age of 22 to 29 weeks. Risk-adjusted trends of survival without major morbidity and its individual components were analyzed. Survival without major morbidity was defined as the absence of death during birth hospitalization, chronic lung disease, severe peri-intraventricular hemorrhage, nosocomial infection, necrotizing enterocolitis, severe retinopathy of prematurity or related surgery, and cystic periventricular leukomalacia. Variations in adjusted rates and/or interquartile ranges were examined. To assess opportunities for additional improvement, all hospitals were reassigned to perform as if in the top quartile, and recalculation of predicted numbers were used to estimate potential benefit. RESULTS: In this cohort of 49 333 infants across 142 hospitals, survival without major morbidity consistently increased from 62.2% to 66.9% from 2008 to 2017. Network variation decreased, with interquartile ranges decreasing from 21.1% to 19.2%. The largest improvements were seen for necrotizing enterocolitis and nosocomial infection. Bronchopulmonary dysplasia rates did not change significantly. Over the final 3 years, if all hospitals performed as well as the top quartile, an additional 621 infants per year would have survived without major morbidity, accounting for an additional 6.6% annual improvement. CONCLUSIONS: Although trends are promising, bronchopulmonary dysplasia remains a common and persistent major morbidity, remaining a target for continued quality-improvement efforts.

BACKGROUND:Intraventricular hemorrhage (IVH) disproportionately affects black neonates. Other conditions that are more common in black neonates, including low birth weight and preterm delivery, have been linked with residential racial segregation (RRS). In this study, we investigated the association between RRS and IVH.METHODS:A retrospective cohort of neonates born between 24 and 32 weeks’ gestation was constructed by using birth certificates linked to medical records from California, Missouri, and Pennsylvania between 1995 and 2009. Dissimilarity, a measure of RRS indicating the proportion of minorities in the census tract of the mother in comparison to the larger metropolitan area, was linked to patient data, yielding a cohort of 70 775 infants. Propensity score analysis matched infants born to mothers living in high segregation to those living in less segregated areas on the basis of race, sociodemographic factors, and medical comorbidities to compare the risk of developing IVH.RESULTS:Infants born to mothers in the most segregated quartile had a greater risk of developing IVH compared with those in the lowest quartile (12.9% vs 10.4%; P < .001). In 17 918 pairs matched on propensity scores, the risk of developing IVH was greater in the group exposed to a segregated environment (risk ratio = 1.08, 95% confidence interval: 1.01–1.15). This effect was stronger for black infants alone (risk ratio = 1.16; 95% confidence interval: 1.03–1.30).CONCLUSIONS:RRS is associated with an increased risk of IVH in preterm neonates, but the effect size varies by race. This association persists after balancing for community factors and birth weight, representing a novel risk factor for IVH.

As the technical ability for genetic diagnosis continues to improve, an increasing number of diagnoses are made in infancy or as early as the neonatal period. Many of these diagnoses are known to be associated with developmental delay and intellectual disability, features that would not be clinically detectable at the time of diagnosis. Others may be associated with cognitive impairment, but the incidence and severity are yet to be fully described. These neonates and infants with genetic diagnoses therefore represent an emerging group of patients who are at high risk for neurodevelopmental disabilities. Although there are well-established developmental supports for high-risk infants, particularly preterm infants, after discharge from the NICU, programs specifically for infants with genetic diagnoses are rare. And although previous research has demonstrated the positive effect of early developmental interventions on outcomes among preterm infants, the impact of such supports for infants with genetic disorders who may be born term, remains to be understood. We therefore review the literature regarding existing developmental assessment and intervention approaches for children with genetic disorders, evaluating these in the context of current developmental supports postdischarge for preterm infants. Further research into the role of developmental support programs for early assessment and intervention in high-risk neonates diagnosed with rare genetic disorders is needed.

OBJECTIVES: Children born very preterm (VPT) are at an increased risk of developing mental health (MH) disorders. Our aim for this study was to assess rates of MH disorders in children born VPT and term at 13 years of age and stability of MH disorders between ages 7 and 13 years by using a diagnostic measure. METHODS: Participants were from the Victorian Infant Brain Study longitudinal cohort and included 125 children born VPT ( RESULTS: Compared with term peers, 13-year-olds born VPT were more likely to meet criteria for any MH disorder (odds ratio 5.9; 95% confidence interval 1.71–20.03). Anxiety was the most common disorder in both groups (VPT = 14%; term = 4%), whereas attention-deficit/hyperactivity disorder carried the greatest differential elevated risk (odds ratio 5.6; 95% confidence interval 0.71–43.80). Overall rates of MH disorders remained stable between 7 and 13 years, although at an individual level, many participants shifted in or out of diagnostic categories over time. CONCLUSIONS: Children born VPT show higher rates of MH disorders than their term peers, with changing trajectories over time. Findings highlight the importance of early identification and ongoing assessment to support those with MH disorders in this population.

The advent of pulse oximetry as a widely adopted technology has transformed the overall clinical assessment of children with acute respiratory illness. One result of this transformation is a stronger clinical focus on treating hypoxemia in young children hospitalized with common respiratory illnesses, such as bronchiolitis, asthma, and pneumonia. For example, in acute viral bronchiolitis, international guidelines provide lower-limit oxygen saturation thresholds despite a weak evidence base and lack of consensus on the specific values. Nonetheless, advice to keep oxygen saturations above a precise threshold can be found in almost every bronchiolitis order set or hospital pathway. On the other hand, there has not been much debate about the opposite end of the spectrum: an upper saturation boundary once supplemental oxygen is administered for these common pediatric conditions. Pulse oximetry readings of 100% are not generally treated as abnormal, but they can represent a wide variety of Pao2 values and tissue oxygen delivery; thus, some readings of 100% while on supplemental oxygen will likely constitute tissue hyperoxia. Furthermore, nebulized therapies given in the hospital setting are typically driven by the flow of 100% oxygen from centralized supply lines, thus providing another source of exposure, which can be substantial for patients on continuously nebulized treatments. Nevertheless, there is a dearth of pediatric research on the scope of the exposure and the potential for harm from excess oxygen … Address correspondence to Shawn L. Ralston, MD, MS, Division of Quality and Safety, Johns Hopkins Children’s Center, 1800 N Orleans St, Baltimore, MD 21287. E-mail: sralsto3{at}jhmi.edu

Neonatal hyperglycemia is common in extremely low birth weight (ELBW) infants because of physiologic stress, exogenous glucose infusion, and postnatal corticosteroid therapy for hypotension, adrenal insufficiency, and pulmonary immaturity. The use of long-acting insulin glargine has been described in the treatment of transient neonatal diabetes in the premature infant, but in these reports is a lack of regard to its use in the treatment of iatrogenic neonatal hyperglycemia. We present the case of an ELBW infant with significant hyperglycemia that was refractory to usual treatment but demonstrated a favorable response to long-acting subcutaneous insulin glargine. The pharmacokinetics on regular insulin and long-acting insulin are different. Regular insulin is broken down into biologically active monomers after subcutaneous injection, and long-acting insulin forms microprecipitates and is gradually released to the body at a neutral physiologic pH after subcutaneous injection. Pharmacokinetics of both regular insulin and long-acting insulin are not clear in ELBW infants. However, with further research on long-acting insulin, it can be used safely to achieve consistent euglycemia with once-daily administration in neonatal hyperglycemia.

* Abbreviation: EP — : extremely premature In this issue of Pediatrics , O’Reilly et al1 report on neuropsychological outcomes at 19 years of age after extremely preterm (EP) birth using the 1995 EPICure birth cohort of infants born EP (50% loss to follow-up, O’Reilly et al1 provide compelling evidence for persistent effects of general cognitive impairments in their impressive longitudinal studies of EP birth to emerging adulthood. These findings are generally consistent with … Address correspondence to Louis A. Schmidt, PhD, Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, ON L8S 4K1, Canada. E-mail: schmidtl{at}mcmaster.ca

BACKGROUND: Parents and clinicians caring for premature infants face high-stakes and time-sensitive decisions about care. We aimed to characterize how parents and clinicians discuss outcome in the context of decision-making for premature infants. METHODS: In this qualitative descriptive study, we used a case-based, prospective design. Cases of extreme prematurity were targeted. Parents and clinicians completed semistructured interviews about care decisions longitudinally in the first year of life. Interview data were analyzed by using directed content analysis. RESULTS: Sixteen parents and 53 clinicians of 10 infants completed 178 interviews (n = 115 parent; n = 63 clinician). Two primary themes emerged. First, parents and clinicians discussed prognostic information differently from each other. Parents focused on whether their infant would survive, whereas clinicians concentrated on neurologic outcome and the potential for life with disability. Parent discussion of the future was broad and rooted in hope and spirituality. Clinician prognostic language was narrowly focused and probabilistic. Second, we identified barriers and facilitators to a shared understanding of infant outcome. Clinicians perceived that parents were unaware of or unable to process important information about the big picture. Parents valued consistent therapeutic relationships; transitions of care and underused roles of the care team undermined this consistency. Clinical uncertainty forced parents and clinicians to “wait and see” about the future. CONCLUSIONS: Parents and clinicians discuss and weigh information about the future differently from each other as they consider choices for extremely premature infants. Future work should characterize the impact of these differences on prognostic communication and decision-making.

OBJECTIVES: To develop a nationwide, evidence-based framework to support prenatal counseling in extreme prematurity, focusing on organization, decision-making, content, and style aspects. METHODS: A nationwide multicenter RAND–modified Delphi method study was performed between November 2016 and December 2017 in the Netherlands. Firstly, recommendations were extracted from literature and previous studies. Secondly, an expert panel (n = 21) with experienced parents, obstetricians, and neonatologists rated the recommendations on importance for inclusion in the framework. Thirdly, ratings were discussed in a consensus meeting. The final set of recommendations was approved and transformed into a framework. RESULTS: A total of 101 recommendations on organization, decision-making, content, and style were included in the framework, including tools to support personalization. The most important recommendations regarding organization were to have both parents involved in the counseling with both the neonatologist and obstetrician. The shared decision-making model was recommended for deciding between active support and comfort care. Main recommendations regarding content of conversation were explanation of treatment options, information on survival, risk of permanent consequences, impossibility to predict an individual course, possibility for multiple future decision moments, and a discussion on parental values and standards. It was considered important to avoid jargon, check understanding, and provide a summary. The expert panel, patient organization, and national professional associations (gynecology and pediatrics) approved the framework. CONCLUSIONS: A nationwide, evidence-based framework for prenatal counseling in extreme prematurity was developed. It contains recommendations and tools for personalization in the domains of organization, decision-making, content, and style of prenatal counseling.

OBJECTIVES: We previously reported a clinical prediction rule to estimate the probability of rebound hyperbilirubinemia using gestational age (GA), age at phototherapy initiation, and total serum bilirubin (TSB) relative to the treatment threshold at phototherapy termination. We investigated (1) how a simpler 2-variable model would perform and (2) the absolute rebound risk if phototherapy were stopped at 2 mg/dL below the threshold for treatment initiation. METHODS: Subjects for this retrospective cohort study were infants born 2012–2014 at ≥35 weeks’ gestation at 1 of 17 Kaiser Permanente hospitals who underwent inpatient phototherapy before age 14 days. TSB reaching the phototherapy threshold within 72 hours of phototherapy termination was considered rebound. We simplified by using the difference between the TSB level at the time of phototherapy termination and the treatment threshold at the time of phototherapy initiation as 1 predictor, and kept GA as the other predictor. RESULTS: Of the 7048 infants treated with phototherapy, 4.6% had rebound hyperbilirubinemia. The area under the receiver operating characteristic curve was 0.876 (95% confidence interval, 0.854 to 0.899) for the 2-variable model versus 0.881 (95% confidence interval, 0.859 to 0.903) for the 3-variable model. The rebound probability after stopping phototherapy at 2 mg/dL below the starting threshold was 2.5% for infants ≥38 weeks’ GA and 10.2% for infants CONCLUSIONS: Rebound hyperbilirubinemia can be predicted by a simpler 2-variable model consisting of GA and the starting threshold–ending TSB difference. Infants

BACKGROUND AND OBJECTIVES: Avoidance of delivery room intubation (DRI) reduces death or bronchopulmonary dysplasia (BPD) in preterm neonates. Our objective with this quality improvement project was to decrease DRI rates by improving face mask positive pressure ventilation (Fm-PPV) among infants born ≤29 weeks’ gestation. METHODS: Key drivers of change were identified from a retrospective review of resuscitation records. A resuscitation bundle to optimize Fm-PPV including the use of a small round mask and end-tidal CO2 detectors, increasing peak inspiratory pressure when indicated, and debriefing after each intubation were implemented in consecutive plan-do-study-act cycles. The DRI rate was tracked by using a control chart. Resuscitation practice and outcomes of pre–quality improvement cohort (QIC) (January 2014–September 2015) were compared with post-QIC (October 2015–December 2016). RESULTS: Of the 314 infants who were resuscitated, 180 belonged to the pre-QIC and 134 to the post-QIC. The antenatal steroid administration rate was higher in the post-QIC (54% vs 88%). More infants in the post-QIC had resolution of bradycardia after Fm-PPV (56% vs 77%, P = .02). Infants in the post-QIC had lower DRI rates (58% vs 37%, P < .01), lower need for mechanical ventilation (85% vs 70%, P < .01), lower rates of BPD (26% vs 13%, P < .01), and severe retinopathy of prematurity (14% vs 5%, P = .01). Rates of DRI, BPD, and severe retinopathy of prematurity remained lower even after controlling for the potential confounders. CONCLUSIONS: Implementation of a resuscitation bundle decreased the DRI rate and improved outcomes of preterm infants.

BACKGROUND AND OBJECTIVES: Exposure to negative social interactions (such as rudeness) has robust adverse implications on medical team performance. However, little is known regarding the effects of positive social interactions. We hypothesized that expressions of gratitude, a prototype of positive social interaction, would enhance medical teams’ effectiveness. Our objective was to study the performance of NICU teams after exposure to expressions of gratitude from alternative sources. METHODS: Forty-three NICU teams (comprising 2 physicians and 2 nurses) participated in training workshops of acute care simulations. Teams were randomly assigned to 1 of 4 conditions: (1) maternal gratitude (in which the mother of a preterm infant expressed gratitude to NICU teams, such as the one that treated her child), (2) expert gratitude (in which a physician expert expressed gratitude to teams for participating in the training), (3) combined maternal and expert gratitude, or (4) control (same agents communicated neutral statements). The simulations were evaluated (5-point Likert scale: 1 = failed and 5 = excellent) by independent judges (blind to team exposure) using structured questionnaires. RESULTS: Maternal gratitude positively affected teams’ performances (3.9 ± 0.9 vs 3.6 ± 1.0; P = .04), with most of this effect explained by the positive impact of gratitude on team information sharing (4.3 ± 0.8 vs 4.0 ± 0.8; P = .03). Forty percent of the variance in team information sharing was explained by maternal gratitude. Information sharing predicted team performance outcomes, explaining 33% of the variance in diagnostic performance and 41% of the variance in therapeutic performance. CONCLUSIONS: Patient-expressed gratitude significantly enhances medical team performance, with much of this effect explained by enhanced information sharing.

The incidence of neonatal early-onset sepsis (EOS) has declined substantially over the last 2 decades, primarily because of the implementation of evidence-based intrapartum antimicrobial therapy. However, EOS remains a serious and potentially fatal illness. Laboratory tests alone are neither sensitive nor specific enough to guide EOS management decisions. Maternal and infant clinical characteristics can help identify newborn infants who are at risk and guide the administration of empirical antibiotic therapy. The incidence of EOS, the prevalence and implications of established risk factors, the predictive value of commonly used laboratory tests, and the uncertainties in the risk/benefit balance of antibiotic exposures all vary significantly with gestational age at birth. Our purpose in this clinical report is to provide a summary of the current epidemiology of neonatal sepsis among infants born at ≥35 0/7 weeks’ gestation and a framework for the development of evidence-based approaches to sepsis risk assessment among these infants.

[Figure: see text] OBJECTIVES: Childhood blindness from retinopathy of prematurity (ROP) is increasing as a result of improvements in neonatal care worldwide. We evaluate the effectiveness of artificial intelligence (AI)–based screening in an Indian ROP telemedicine program and whether differences in ROP severity between neonatal care units (NCUs) identified by using AI are related to differences in oxygen-titrating capability. METHODS: External validation study of an existing AI-based quantitative severity scale for ROP on a data set of images from the Retinopathy of Prematurity Eradication Save Our Sight ROP telemedicine program in India. All images were assigned an ROP severity score (1–9) by using the Imaging and Informatics in Retinopathy of Prematurity Deep Learning system. We calculated the area under the receiver operating characteristic curve and sensitivity and specificity for treatment-requiring retinopathy of prematurity. Using multivariable linear regression, we evaluated the mean and median ROP severity in each NCU as a function of mean birth weight, gestational age, and the presence of oxygen blenders and pulse oxygenation monitors. RESULTS: The area under the receiver operating characteristic curve for detection of treatment-requiring retinopathy of prematurity was 0.98, with 100% sensitivity and 78% specificity. We found higher median (interquartile range) ROP severity in NCUs without oxygen blenders and pulse oxygenation monitors, most apparent in bigger infants (>1500 g and 31 weeks’ gestation: 2.7 [2.5–3.0] vs 3.1 [2.4–3.8]; P = .007, with adjustment for birth weight and gestational age). CONCLUSIONS: Integration of AI into ROP screening programs may lead to improved access to care for secondary prevention of ROP and may facilitate assessment of disease epidemiology and NCU resources.

CONTEXT:Periventricular/intraventricular hemorrhage (PIVH) is a common short-term morbidity in preterm infants, but its long-term neurodevelopmental impact, particularly with mild PIVH, remains unclear.OBJECTIVE:To systematically review and meta-analyze the neurodevelopmental outcomes of preterm infants ≤34 weeks’ gestation with mild and severe PIVH, compared with no PIVH.DATA SOURCES:Medline, Embase, CINAHL, and PsychINFO databases from January 2000 through June 2014.STUDY SELECTION:Studies reporting long-term neurodevelopmental outcomes based on severity of PIVH were included.DATA EXTRACTION:Study characteristics, inclusion/exclusion criteria, exposures, and outcome assessment data extracted independently by 2 coauthors.RESULTS:The pooled unadjusted odds ratios of the primary outcome of death or moderate-severe neurodevelopmental impairment (NDI) were higher with both mild (1.48, 95% CI 1.26–1.73; 2 studies) and severe PIVH (4.72, 4.21–5.31; 3 studies); no studies reported adjusted odds ratios. Among survivors, odds of moderate-severe NDI were higher with mild and severe PIVH in both unadjusted (1.75, 1.40–2.20; 3 studies; 3.36, 3.06–3.68; 5 studies) and adjusted (1.39, 1.09–1.77; 3 studies; 2.44, 1.73–3.42; 2 studies) pooled analyses. Adjusted odds of cerebral palsy and cognitive delay were higher with severe but not mild PIVH.LIMITATIONS:Only observational studies were included. Fifteen of 21 included studies had a moderate-high risk of bias.CONCLUSIONS:Mild and severe PIVH are associated with progressively higher odds of death or moderate-severe NDI compared with no PIVH, but no studies adjusted for confounders. Among survivors, mild PIVH was associated with higher odds of moderate-severe NDI compared with no PIVH.

BACKGROUND AND OBJECTIVES: The importance of biological versus social influences on long-term outcomes of extremely preterm children is debatable. The goal of this study was to determine the relative contributions of biological and social exposures to outcomes into adolescence in extremely preterm survivors, hypothesizing that biological exposures would be more important early, but social exposures would dominate later. METHODS: The study included 298 consecutive survivors born at 2499 g) control subjects who were used to standardize outcomes for the preterm group. Cognitive ability was assessed at 2, 5, 8, and 18 years of age. Academic achievement was assessed at 8 and 18 years of age. RESULTS: The differences between the preterm and control groups for cognitive and academic scores remained relatively constant over time. The biological variables most associated with worse outcomes within the extremely preterm group were intraventricular hemorrhage and postnatal corticosteroid therapy. Of the social variables, being reared in a multilingual household was disadvantageous early, with social class and maternal education becoming more important for later outcomes. The strength of the biological associations mostly equaled or exceeded those of social exposures, even in late adolescence. CONCLUSIONS: Contrary to expectations, several perinatal biological exposures had large and persistent adverse associations with cognitive and academic outcomes among extremely preterm survivors. As expected, some social variables assumed increasing importance in later years but mostly did not diminish or exceed the important biological associations.

* Abbreviations: ASD — : autism spectrum disorder CLD — : chronic lung disease Children born preterm are known to be at higher risk for developing autism spectrum disorder (ASD) compared with their term-born counterparts, with an estimated 7% prevalence of ASD based on a recent large prospective study and a meta-analysis.1,2 This high prevalence is in contrast to the currently estimated prevalence of ASD in the United States of 1.8% in the general population.3 ASD has been shown to be associated with a variety of prenatal, perinatal, and neonatal risk factors, including a variety of maternal health risk factors and medications and neonatal risk factors such as seizures, birth asphyxia, and low birth weight.4 Previously identified perinatal risk factors for ASD specific to preterm infants include factors such as low birth gestational age and birth weight, intracranial hemorrhage, and acute and chronic lung disease (CLD).5 The article by Chen et al6 in this issue of Pediatrics provides the first prospectively obtained data regarding whether there is an early developmental trajectory of prematurely born children that predicts who will develop ASD. The authors tested 319 preterm … Address correspondence to Janet S. Soul, MDCM, Department of Neurology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: janet.soul{at}childrens.harvard.edu

CONTEXT: The effect of neonatal cerebellar hemorrhage on neurodevelopmental outcome (NDO) in the absence of supratentorial injury is still largely unknown. OBJECTIVE: To evaluate the influence of isolated neonatal cerebellar hemorrhage on cognitive, motor, language, and behavioral NDOs and assess the effect of location and size on outcome. DATA SOURCES: Embase, Medline, and Scopus were searched from inception to September 30, 2017. STUDY SELECTION: Studies in which a diagnosis of isolated cerebellar hemorrhage was reported in preterm infants ( DATA EXTRACTION: Patient characteristics, location, and size of bleeding and NDO (defined as severe [yes or no] on the basis of given cutoff points) in 4 domains were extracted. RESULTS: Of the 1519 studies identified, 8 were included in final analyses. Of infants with isolated cerebellar hemorrhage, 128 were described (cumulative incidence: 2.3%). The incidence of severe delay in cognition, motor, language, and behavioral development was 38%, 39%, 41%, and 38%, respectively. The overall incidence of severe neurodevelopmental delay in ≥1 domain ranged from 43% to 75% and was most seen in infants with vermis involvement (87%–93%) and with large bleeds (46%–82%). LIMITATIONS: Different neurodevelopmental scales lead to data heterogeneity, and reporting of data on a group level limited possibilities for an outcome description on an individual level. CONCLUSIONS: Of infants with isolated cerebellar hemorrhage, 43% to 75% were severely delayed in cognition, motor, language, and/or behavioral development, with the highest incidence with vermis involvement and with large bleeds.

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500–1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHODS: A cohort study of very preterm infants, born between 24 and 29 weeks’ gestation and weighing RESULTS: Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08–1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85–0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks’ gestation (range 35%–84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%–98% at 29 weeks’ gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSIONS: The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.

Recent literature confirms that, at the lower limit of extrauterine survival, substantial intercenter variability exists in resuscitation practice. The reasons for this variability are unclear, but may be related to disagreement on how to apply the best interests standard to extremely premature infants. Currently, both obstetric and pediatric societies recommend against assessing for viability or attempting resuscitation before 22 weeks’ gestation. In this context, we report the unimpaired 2-year outcome of a female infant resuscitated after delivery at 21 weeks’ 4 days’ gestation and 410 g birth weight. She may be the most premature known survivor to date. This infant had multiple risk factors for adverse outcome, including prolonged mechanical ventilation, bronchopulmonary dysplasia, and threshold retinopathy of prematurity. She achieved discharge from the hospital on low-flow oxygen at 39 weeks’ 4 days’ gestation and 2519 g. At 24 months’ and 8 days’ chronological age, she achieved cognitive, motor, and language Bayley III scores of 90, 89, and 88, equivalent to 105, 100, and 103 at 20 months 2 days corrected age. It is known that active intervention policies at 22 weeks’ gestation improves the outcome for those infants and it may be reasonable to infer that these benefits would extend, if to a lesser degree, into the 21st week. Ultimately, such limited data exist at this gestational age that the time may have arrived for obstetrical centers to begin systematically reporting fetal outcomes in the 21st week.

This report describes a temporary retrograde occlusion technique for control of a high-flow tracheo-esophageal fistula in a critically ill, premature infant born at 29 weeks’ gestational age, with a diagnosis of type C (Gross) esophageal atresia and tetralogy of Fallot (TOF). This procedure is a useful bridging maneuver before definitive surgical correction for extremely low birth weight, unstable neonates with tracheo-esophageal fistula who are suffering from associated malformations.

BACKGROUND AND OBJECTIVE:Car seat tolerance screening (CSTS) is a common predischarge assessment of neonates. Almost half of nurseries and NICUs have low birth weight (LBW, METHODS:This was a retrospective medical record review of 220 full-term LBW infants qualifying for CSTS over a 4-year period between January 2010 to December 2013. We described CSTS results and performed bivariate analyses to evaluate for predictors of failure.RESULTS:Overall failure incidence was 4.8%. There were no differences between those who passed and those who failed based on birth weight, birth GA, race, gender, Apgar scores, respiratory support requirements, magnesium exposure, corrected GA, or weight at the time of CSTS. Maternal urine toxicology positive for opiates was found to be a significant predictor of CSTS failure. Of the 9 subjects who failed, 2 had a specific diagnosis identified (Prader–Willi syndrome and long QT syndrome) after a failed CSTS prompted closer examination and workup before discharge.CONCLUSIONS:We found a similar incidence of failure for full-term LBW infants as has been previously reported for preterm infants. The infants who failed were more likely to have mothers who tested positive for opiates before delivery. Epidemiologic data are provided to help guide future CSTS policies and protocol development for this group.

Symptomatic pulmonary thromboembolism (PTE) is rare in neonates, and the diagnosis is often made only postmortem. The true incidence is probably underestimated because of its varying presentations, ranging from mild respiratory distress to acute right-heart failure and cardiovascular collapse. We report a sudden cardiorespiratory collapse on day 10 of life in a preterm neonate who was subsequently diagnosed as having a saddle pulmonary embolus. The patient underwent an emergency surgical embolectomy as a salvage procedure. Considering the potentially lethal complications of PTE, neonatologists and pediatricians should maintain a high degree of suspicion in infants with sudden inexplicable deterioration in cardiorespiratory status. Surgical removal of the thrombus is an invasive procedure and potentially carries a high mortality rate. Two term neonatal survivors of surgical intervention have been reported in the medical literature so far. However, we believe that this is the first documented preterm neonatal survivor after surgical intervention for a massive saddle PTE.

BACKGROUND AND OBJECTIVES: Echocardiogram is the gold standard for the diagnosis of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. A simple blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA. Our objectives were to determine the diagnostic accuracy of BNP and NT-proBNP for hsPDA in preterm neonates and to explore heterogeneity by analyzing subgroups. METHODS: The systematic review was performed as recommended by the Cochrane Diagnostic Test Accuracy Working Group. Electronic databases, conference abstracts, and cross-references were searched. We included studies that evaluated BNP or NT-proBNP (index test) in preterm neonates with suspected hsPDA (participants) in comparison with echocardiogram (reference standard). A bivariate random effects model was used for meta-analysis, and summary receiver operating characteristic curves were generated. RESULTS: Ten BNP and 11 NT-proBNP studies were included. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age, and whether the assay was used to initiate medical or surgical therapy. Sensitivity and specificity for BNP at summary point were 88% and 92%, respectively, and for NT-proBNP they were 90% and 84%, respectively. CONCLUSIONS: The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDA varied widely by assay characteristics (assay kit and threshold) and patient characteristics (gestational and chronological age); therefore, generalizability between centers is not possible. We recommend that BNP or NT-proBNP assays be locally validated for specific patient population and outcomes, to initiate therapy or follow response to therapy.

BACKGROUND:Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids.METHODS:Women were randomized to betamethasone or placebo treatment, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at RESULTS:Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI −2 to 2; diastolic 0 mm Hg, 95% CI −1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73m2, 95% CI −3.2 to 5.6).CONCLUSIONS:Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age.

BACKGROUND:Late-onset sepsis (LOS) is among the leading causes of morbidity and mortality in preterm newborns, and currently available diagnostic tools are inadequate. The objective of this study was to evaluate the accuracy of presepsin (P-SEP) as novel biomarker of bacterial infection for the diagnosis of LOS in preterm newborns.METHODS:We prospectively studied newborns ≤32 weeks’ gestational age with LOS (n = 19) and noninfected controls (n = 21) at 4 to 60 days’ postnatal age. At enrollment, and 1, 3, and 5 days later, we ascertained the C-reactive protein, procalcitonin, and P-SEP in the LOS group, whereas P-SEP alone was ascertained in the control group.RESULTS:P-SEP at enrollment was higher in the LOS than the control group (median 1295 vs 562 ng/L, P = .00001) and remained higher throughout the study period. In the LOS group, P-SEP had a borderline reduction at day 1 versus values at enrollment (median 1011 vs 1295 ng/L, P = .05), whereas C-reactive protein and procalcitonin at day 1 did not differ from baseline values. The receiver operating characteristic curve of P-SEP at enrollment shows an area under the curve of 0.972. The best calculated cutoff value was 885 ng/L, with 94% sensitivity and 100% specificity. Negative likelihood ratio was 0.05, and positive likelihood ratio was infinity.CONCLUSIONS:We demonstrated for the first time in a cohort of preterm newborns that P-SEP is an accurate biomarker for the diagnosis of possible LOS and may also provide useful information for monitoring the response to therapeutic interventions.