Assessment of inflammatory biomarkers to identify surgical/death necrotizing enterocolitis in preterm infants without pneumoperitoneum.

BACKGROUND: Necrotizing enterocolitis (NEC) is a life-threatening disease that affects premature infants. However, the role of inflammatory biomarkers in identifying surgical/death NEC without pneumoperitoneum remains elusive. PURPOSE: We aimed to verify the value of platelet-to-lymphocyte ratio (PLR) and the combination of white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), neutrophil lymphocyte ratio (NLR), PLR, C reactive protein (CRP) and procalcitonin (PCT) in predicting the severity of NEC, and to construct a model to differ surgically NEC from non-surgically NEC. METHODS: A retrospective analysis was performed on 191 premature infants with NEC. Based on the inclusion and exclusion criteria, 90 infants with Stage II and IIIA NEC were enrolled in this study, including surgical/death NEC (n = 38) and medical NEC (n = 52). The values of inflammatory biomarkers were collected within 24 h of onset. RESULTS: The univariate analysis revealed that the values of WBC (p = 0.040), ANC (p = 0.048), PLR (p = 0.009), CRP (p = 0.016) and PCT (p < 0.01) in surgical/death NEC cohort were significantly higher than medical NEC cohort. Binary multivariate logistic regression analysis indicates that ANC, PLR, CRP, and PCT are capable of distinguishing infants with surgical/death NEC, and the AUC of the regression equation was 0.79 (95% CI 0.64-0.89; sensitivity 0.63; specificity 0.88), suggesting the equation has a good discrimination. IMPLICATIONS FOR PRACTICE AND RESEARCH: Elevated PLR is associated with severe inflammation in surgical/death NEC patients. The prediction modelling of combination of ANC, PLR, CRP and PCT can differentiate surgical/death NEC from infants with medical NEC, which may improve risk awareness and facilitate effective communication between nurses and clinicians. However, multicentre research is needed to verify these findings for better clinical management of NEC.

Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Receptor-interacting protein kinase-3 (RIPK3): a new biomarker for necrotising enterocolitis in preterm infants.

OBJECTIVE: This study aimed to evaluate the role of receptor-interacting protein kinase-3 (RIPK3) in the diagnosis, estimation of disease severity, and prognosis of premature infants with necrotising enterocolitis (NEC). METHODS: RIPK3, lactic acid (LA), and C-reactive protein (CRP) levels were measured in the peripheral blood of 108 premature infants between 2019 and 2023, including 24 with stage II NEC, 18 with stage III NEC and 66 controls. Diagnostic values of the indicators for NEC were evaluated via receiver operating characteristic (ROC) curve analysis. RESULTS: Plasma RIPK3 and LA levels upon NEC suspicion in neonates with stage III NEC were 32.37 ± 16.20 ng/mL. The ROC curve for the combination of RIPK3, LA, CRP for NEC diagnosis were 0.925. The time to full enteral feeding (FEFt) after recovery from NEC was different between two expression groups of plasma RIPK3 (RIPK3 < 20.06 ng/mL and RIPK3 ≥ 20.06 ng/mL). CONCLUSION: Plasma RIPK3 can be used as a promising marker for the diagnosis and estimation of disease severity of premature infants with NEC and for the guidance on proper feeding strategies after recovery from NEC.

Analysis of similarities and differences between transient symptomatic zinc deficiency and acrodermatitis enteropathica in children: a case report of a Chinese Yi-ethnic infant.

BACKGROUND: Transient symptomatic zinc deficiency (TSZD), an acquired type of zinc deficiency, is a rare, but probably underrecognized disease, extremely in breastfed premature with low birthweight infants. Its clinical manefestations are similar to Acrodermatitis enteropathica (AE), which is a genetic zinc absorption disorder caused by SLC39A4 gene mutations. This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. TSZD is often misdiagnosed as AE because of their extremely similar manefestations, characterized by a typical rash. Therefore, the differention between them is still a clinical challenging. CASE PRESENTATION: Here, we present a case of TSZD in a 4 month and 23 days female Chinese Yi-ethnic premature with AE-like skin lesions, mainly presenting periorificial, perianal and perineal crusted, eroded, erythemato-squamous eruption. Laboratory examination showed the patient's blood zinc level was significantly decreased. Further sequencing of the SLC39A4 gene showed no mutation in the infant and her parents. Skin lesions significantly improved after 6 days of initial zinc supplementation (3 mg/kg/d), and maintenance treatment with 1 mg/kg/day of zinc was discontinued after 8 months without recurrence. CONCLUSIONS: The clinical manifestations of TSZD and AE are extremely similar, leading to a high rate of clinical misdiagnosis. While genetic analysis of the SLC39A4 gene is a reliable method for differentiating TSZD from AE. It is recommended that SLC39A4 gene test should be performed as far as possible in children with AE-like rash.

A novel useful marker in the early discrimination of transient hyperthyrotropinemia/hypothyroxinemia and congenital hypothyroidism in preterm infants: thyroid-stimulating hormone/free thyroxine ratio.

OBJECTIVES: Transient hyperthyrotropinemia/transient hypothyroxinaemia and congenital hypothyroidism (CH) have completely different treatment and clinical outcomes. However, a powerful, highly sensitive and cost-effective marker for the differentiation of these clinical entities in the early postnatal period is not available. Therefore, we aimed to test the potential, early predictive, diagnostic power of the thyroid-stimulating hormone (TSH)/free thyroxine (fT4) ratio for differentiation of the two clinical entities in the early period of life. METHODS: TSH and fT4 levels were recorded on the postnatal day 7 of premature infants<32 weeks of gestational age. TSH/fT4 ratio was calculated. The significance degree of TSH/fT4 ratio was analyzed for the differentiation of transient hyperthyrotropinemia or transient hypothyroxinaemia and CH. RESULTS: The study included 1,204 preterm infants<32 weeks of gestational age. Of the 1,204 infants, 978 (81.2 %) had normal thyroid function. Eighty-eight infants (7.3 %) were diagnosed with CH and 138 (11.5 %) with transient hyperthyrotropinemia or transient hypothyroxinemia. Initial TSH/fT4 ratio>4.8 was found to be an early diagnostic warning sign with high power in favor of transient hyperthyrotropinemia or transient hypothyroxinemia (AUC value: 0.947) and TSH/fT4 ratio>12.5 (AUC value: 0.999) was found to be an early diagnostic warning sign with high power in favor of CH (p=0.0001). CONCLUSIONS: We found for the first time that the TSH/fT4 ratio can be used for the early differentiation of transient hyperthyrotropinemia/transient hypothyroxinaemia and CH in preterm infants without additional cost and with high power.

Pulse oximetry signal loss during hypoxic episodes in preterm infants receiving automated oxygen control.

The aim of this study was to analyze signal loss (SL) resulting from low signal quality of pulse oximetry-derived hemoglobin oxygen saturation (SpO2) measurements during prolonged hypoxemic episodes (pHE) in very preterm infants receiving automatic oxygen control (AOC). We did a post hoc analysis of a randomized crossover study of AOC, programmed to set FiO2 to "back-up FiO2" during SL. In 24 preterm infants (median (interquartile range)) gestational age 25.3 (24.6 to 25.6) weeks, recording time 12.7 h (12.2 to 13.6 h) per infant, we identified 76 pHEs (median duration 119 s (86 to 180 s)). In 50 (66%) pHEs, SL occurred for a median duration of 51 s (33 to 85 s) and at a median frequency of 2 (1 to 2) SL-periods per pHE. SpO2 before and after SL was similar (82% (76 to 88%) vs 82% (76 to 87%), p = 0.3)).  Conclusion: SL is common during pHE and must hence be considered in AOC-algorithm designs. Administering a "backup FiO2" (which reflects FiO2-requirements during normoxemia) during SL may prolong pHE with SL.  Trial registration: The study was registered at www. CLINICALTRIALS: gov under the registration no. NCT03785899. WHAT IS KNOWN: • Previous studies examined SpO2 signal loss (SL) during routine manual oxygen control being rare, but pronounced in lower SpO2 states. • Oxygen titration during SL is unlikely to be beneficial as SpO2 may recover to a normoxic range. WHAT IS NEW: • Periods of low signal quality of SpO2 are common during pHEs and while supported with automated oxygen control (SPOC), FiO2 is set to a back-up value reflecting FiO2 requirements during normoxemia in response to SL, although SpO2 remained below target until signal recovery. • FiO2 overshoots following pHEs were rare during AOC and occurred with a delayed onset; therefore, increased FiO2 during SL does not necessarily lead to overshoots.

Incidence of metabolic bone disease in neonates under 32 gestational weeks at the Hospital Universitario de Santander in Colombia. / Incidencia de enfermedad metabólica ósea en neonatos con menos de 32 semanas de gestación en el Hospital Universitario de Santander en Colombia

INTRODUCTION: Metabolic bone disease of premature infants is a rare complication characterized by a lower mineral content in bone tissue. OBJECTIVE: To establish the incidence of metabolic bone disease in premature infants and to determine associated risk factors. MATERIALS AND METHOD: We conducted a descriptive prospective cohort study for one year in all newborns under 32 gestational weeks, or 1,500 g, at the Hospital Universitario de Santander to determine the incidence of metabolic bone disease. We collected demographic data and prenatal histories of the selected patients, and later, we measured serum alkaline phosphatase and serum phosphorus at the third week of birth, having as reference values for diagnosis less than 5.6 mg/dl for the first one and more than 500 UI/L for the second one. We applied statistical tools for data analysis, such as average proportions, dispersion, distribution and association measures, and binomial regression. RESULTS: From a total of 58 patients, 7 had a diagnosis of metabolic bone disease, with an incidence of 12%. The weight was reported as an independent variable for the development of the disease, being significant in children under 1,160 g, as well as prolonged parenteral nutrition for more than 24 days. When performing the multivariate analysis, low weight and short time of parenteral nutrition appeared as risk factors; in the same way, maternal age below 22 years is associated with a higher relative risk, even more than a newborn weight inferior to 1,160 g. CONCLUSION: Establishing an early intervention in patients with metabolic bone disease enhancing risk factors, such as low weight and prolonged parenteral nutrition, is critical to prevent severe complications.

Introducción. La enfermedad metabólica ósea de neonatos prematuros es una complicación poco común que se caracteriza por una disminución del contenido mineral en el hueso. Objetivo. Establecer la incidencia de la enfermedad metabólica ósea en neonatos prematuros y los factores de riesgo asociados. Materiales y métodos. Durante un año, se realizó un estudio prospectivo de cohorte, descriptivo, con todos los neonatos nacidos con menos de 32 semanas de gestación o un peso menor de 1.500 g en el Hospital Universitario de Santander. Se recolectaron datos demográficos y antecedentes prenatales de los pacientes seleccionados. A la tercera semana de nacimiento, se midieron la fosfatasa alcalina y el fósforo sérico, tomando como valores de referencia diagnóstica aquellos inferiores a 5,6 mg/dl para el primero y aquellos mayores de 500 UI/L para la segunda. Para el análisis de la información, se emplearon herramientas estadísticas, como proporciones de promedios, medidas de dispersión, distribución y asociación, y regresión binomial. Resultados. De un total de 58 pacientes, 7 tuvieron diagnóstico de enfermedad metabólica ósea, con una incidencia del 12 %. De las variables estudiadas, el peso se reportó como una variable independiente para el desarrollo de la enfermedad, significativa en aquellos neonatos con peso menor de 1.160 g, al igual que la nutrición parenteral prolongada por más de 24 días. Al hacer el análisis multivariado, La edad materna menor de 22 años representó un riesgo relativo mayor, en comparación con un peso inferior a 1.160 g. Conclusión. Se estableció la importancia de una intervención temprana en pacientes con factores de riesgo para enfermedad metabólica ósea, como bajo peso (menor de 1.160 g) y nutrición parenteral prolongada (mayor de 24 días), con el fin de prevenir complicaciones graves.

Association of hypermagnesemia at birth and admission hypothermia in pre-term infants: A secondary analysis of a prospective cohort study.

BACKGROUND: Hypothermia on admission is associated with increased mortality in preterm infants. Drugs administered to pregnant women is implicated in its occurrence. Since magnesium sulfate has a myorelaxant effect, we aimed evaluating the association of hypermagnesemia at birth and admission hypothermia (axillary temperature <36.5°C) in preterm infants. METHODS: We performed a secondary analysis of a prospective cohort study database including inborn infants <34 weeks, without congenital malformations. Hypermagnesemia was considered if the umbilical magnesium level > 2.5 mEq/L. Maternal and neonatal variables were used to adjust the model, submitted to the multivariate hierarchical modelling process. RESULTS: We evaluated 249 newborns with median birth weight and gestational age of 1375 (IQR 1020-1375) g and 31 (IQR 28-32) weeks, respectively. Hypermagnesemia occurred in 28.5% and admission hypothermia occurred in 28.9%. In the univariate analysis, the following variables were identified as being associated with admission hypothermia: hypermagnesemia (OR 3.71; CI 2.06-6.68), resuscitation (OR 2.39; CI 1.37-4.19), small to gestational age (OR 1.91; CI1.03-3.53), general anesthesia (OR 3.34; CI 1.37-8.13), birth weight (OR 0.998; CI 0.998-0.999) and gestational age (OR 0.806; CI 0.725-0.895). In the hierarchical regression model, hypermagnesemia remained independent associated with admission hypothermia (OR 3.20; CI 1.66-6.15), as well as birth weight (OR 0.999; CI 0.998-0.999) and tracheal intubation (3.83; CI 1.88-7.80). CONCLUSION: Hypermagnesemia was associated with an increased risk of admission hypothermia, as did tracheal intubation and lower birth weight.

Screening for Delayed Thyroid Stimulation Hormone Rise and Atypical Congenital Hypothyroidism in Infants Born Very Preterm and Infants with Very Low Birth Weight.

OBJECTIVE: To determine among infants born very preterm (VPT) or with very low birth weight (VLBW) the incidence of alterations in thyroid function and associated comorbidities; the incidence of atypical congenital hypothyroidism (CH) requiring thyroxine therapy; and reference ranges for rescreening at 1 month of age. STUDY DESIGN: A retrospective review of infants born VPT or with VLBW and admitted to UC Irvine Medical Center between January 1, 2012, and December 31, 2020. Repeat thyroid screening was obtained at 1 month of life (+10 days). Infants with thyroid-stimulating hormone (TSH) >5 µIU/mL or free thyroxine <0.8 ng/dL underwent follow-up testing and endocrinology consultation. Initial newborn screening (NBS) and repeat thyroid screening data were collected via chart review. Demographic data and short-term outcomes were abstracted from the California Perinatal Quality Care Collaborative database. RESULTS: In total, 430 patients were included; 64 of 429 patients (14.9%) had TSH >5 µIU/mL and 20 of 421 patients (4.8%) had free thyroxine <0.8 ng/dL. Logistic regression analysis identified small for gestational age (P = .044), patent ductus arteriosus (P = .013), and late-onset sepsis (P = .026) as risk factors associated with delayed TSH rise. Atypical CH requiring treatment through neonatal intensive care unit discharge was diagnosed in 6 patients (incidence of 1.4%); none were identified by NBS. The 90th percentile TSH for infants with extremely low birth weight (<1000 g) was 7.2 µIU/mL, and the 95th percentile for those with birth weight of 1000-1500 g was 6.1 µIU/mL; using these cutoff values identified all infants diagnosed with atypical CH with 100% sensitivity and 90%-95% specificity. CONCLUSIONS: Abnormal thyroid function is common in infants born preterm. Those infants, including some with atypical CH, are missed by NBS. We recommend repeat thyroid screening with TSH at 1 month of age in infants born VPT or infants with VLBW to identify CH that may require therapy.

An Unknown Risk Factor for Sepsis in Very Low Birth Weight Preterms: ABO Blood Groups (BGaPS Study).

OBJECTIVE: There is insufficient study of the association of blood groups with neonatal diseases. The aim of this study was to evaluate the blood groups associated with sepsis and blood groups in preterm infants. STUDY DESIGN: This retrospective study was conducted between January 1, 2010 and November 31, 2018 in the neonatal intensive care unit (NICU). This study was done in single-center tertiary NICU. Infants born at gestational age (GA) <32 weeks with birth weight (BW) <1,500 g were included in the study. RESULTS: A total of 2,548 infants were included. The culture-proven sepsis ratio (30.2%) was the lowest in the O blood group and the highest in the AB blood group (37.5%) (p = 0.045). Meningitis ratio (6.5%) was significantly higher, and hospital stay (64.1 ± 33.9 days) was significantly longer in B blood group (respectively, p = 0.005, p < 0.001). In the AB blood group, GA (27.68 ± 1.12 weeks) was the lowest and early onset sepsis (EOS) (40.1%) and mortality (28.9%) ratio were found to be statistically higher (p < 0.001 for all groups). The AB group was significantly related to higher frequency of EOS (odds ratio [OR] = 2.93, 95% confidence interval [CI] = 1.68-5.12, p = 0.000), in addition to mortality (OR = 1.1, 95% CI = 0.55-2.19, p = 0.001). The O group was found to be associated with lower risk of late onset sepsis (LOS) (OR = 1.67, 95% CI = 1.06-3.058, p = 0.003) according to the model with corrected risk factor including GA, BW, and time of hospitalization. CONCLUSION: Our study was the first study showing a relationship between certain blood groups and EOS/LOS in premature infants as well as meningitis.

Very preterm birth results in later lower platelet activation markers.

BACKGROUND: Premature birth entails an adverse cardiovascular risk profile, but the underlying mechanisms are insufficiently understood. Here, we employed an unbiased cardiovascular proteomics approach to profile former very preterm-born preschoolers. METHODS: This observational study investigated differences in plasma concentrations of 79 proteins, including putative cardiovascular biomarkers between very preterm- and term-born children on average 5.5 years old (53.1% male) using multiple-reaction monitoring mass spectrometry. RESULTS: Very preterm-born (n = 38; median gestational age 29.6 weeks) compared to term-born (n = 26; 40.2 weeks) children featured lower plasma concentrations of platelet factor 4 (PLF4; -61.6%, P < 0.0001), platelet basic protein (CXCL7; -57.8%, P < 0.0001), and hemoglobin subunit beta (-48.3%, P < 0.0001). Results remained virtually unchanged when adjusting for complete blood count parameters, including platelet count. Conversely, whole blood hemoglobin was higher (+7.62%, P < 0.0001) in preterm-born children. CONCLUSIONS: Very preterm birth was associated with decreased markers of platelet activation among preschoolers. These findings are consistent with reduced platelet reactivity persisting from very preterm birth to a preschool age. IMPACT: Former very preterm-born preschoolers featured reduced levels of platelet activation markers. While lower platelet reactivity in very preterm-born compared to term-born infants in the first days of life was established, it was unknown when, if at all, reactivity normalizes. The current study suggests that platelet hyporeactivity due to very preterm birth persists at least up to a preschool age. "Immaturity of the hemostatic system" may be a persistent sequel of preterm birth, but larger studies are needed to investigate its potential clinical implications.

Necrotising enterocolitis in newborns receiving diazoxide.

BACKGROUND: Frequent and severe gastrointestinal disturbances have been reported with the use of diazoxide in adults and older children. However, no studies have investigated the incidence of necrotising enterocolitis (NEC) in diazoxide-exposed newborns. OBJECTIVE: To evaluate a possible association between diazoxide treatment for neonatal hypoglycaemia and the occurrence of NEC. DESIGN: Multicentre retrospective cohort study. SETTING: Three tertiary neonatal intensive care units in Toronto, Canada. PATIENTS: All patients treated with diazoxide for persistent hypoglycaemia between July 2012 and June 2017 were included. Overall incidence of NEC during those years on the participating units was obtained for comparison from the Canadian Neonatal Network database. MAIN OUTCOME: Incidence of NEC after diazoxide exposure. RESULTS: Fifty-five neonates were exposed to diazoxide during the study period. Eighteen patients (33%) showed signs of feeding intolerance, and 7 developed NEC (13%). A diagnosis of NEC was more prevalent in the diazoxide-exposed, as compared with non-exposed infants of similar gestational age (OR 5.07, 95% CI 2.27 to 11.27; p<0.001), and greatest among infants born at 33-36 weeks' gestation (OR 13.76, 95% CI 3.77 to 50.23; p<0.001). All but one of the neonates diagnosed with NEC developed the disease within 7 days from initiation of diazoxide treatment. CONCLUSION: The present data suggest a possible association between diazoxide exposure and the development of NEC in neonates. Further evaluation of the diazoxide-associated risk of NEC in neonates treated for persistent hypoglycaemia is warranted.

Interleukin 8 may predict surgical necrotizing enterocolitis in infants born less than 1500 g.

Necrotizing enterocolitis (NEC) often leads to gastrointestinal emergency resulting high mortality in very low birth weight infants (VLBWIs) requiring surgery. To date, few studies have explored the role of serum cytokines in the development of feeding intolerance (FI) or NEC outcomes in VLBWIs. Infants born weighing <1500 g or of 32 weeks of gestational age were prospectively enrolled from May 2018 to Dec 2019. We measured several cytokines routinely within 72 h of life, even before NEC-like symptoms developed. NEC or FI group comprised 17 (27.4%) infants, and 6 (9.7%) infants had surgical NEC. The gestational age and birth weight were significantly lower in the NEC or FI group with more prematurity-related complications. The surgical NEC group also demonstrated significantly lower gestational age and birth weight along with more infants experiencing refractory hypotension within a 1 week of life, pulmonary hypertension, and patent ductus arteriosus. IL-10 levels were significantly higher in the NEC or FI group, whereas IL-8 levels were significantly higher in the infants with surgical NEC. Our findings indicated to IL-8 can predict surgical NEC while increased IL-10 can predict NEC development in VLBWIs.

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.).

Modified Serum ALP Values and Timing of Apparition of Knee Epiphyseal Ossification Centers in Preterm Infants with Cholestasis and Risk of Concomitant Metabolic Bone Disease of Prematurity.

The usefulness of serum alkaline phosphatase (ALP) and phosphorous in screening and monitoring of metabolic bone disease of prematurity (MBDP) still has some limitations, especially in preterm infants with concomitant conditions such as cholestasis. We aimed to assess a modification of serum ALP (M-ALP) as a biomarker for MBDP in preterm infants, and the use of ultrasound monitoring for the apparition of knee ossification centers as marker of bone mineralization. Biochemical and clinical registers were taken from 94 preterm newborns <32 weeks. A significant correlation existed between serum ALP and direct bilirubin (DB), expressed by the regression equation: M-ALP (IU/L) = 302.1 + 96.9 (DB (mg/dL)). The ratio ALP/M-ALP > 1 was demonstrated to be more specific (87.5%) in the diagnosis of MBDP than the cut-off value of serum ALP > 500 IU/L (62.5%). ALP/M-ALP > 1 showed 100% sensitivity and specificity for the diagnosis of MBDP, and a good correlation with specific bone ALP (B-ALP). Patients with the knee nucleus by post-menstrual week 37 had lower B-ALP compared to patients with no nucleus, and no patients with MBDP presented the nucleus by the 40th week. In the absence of reliable specific B-ALP, reinterpreting serum ALP values by M-ALP plus monitoring of knee ossification centers contribute to better management of MBDP in preterm infants with cholestasis.

Vitamin D in Preterm and Full-Term Infants.

Vitamin D is necessary for the active (transcellular) absorption of calcium and for skeletal health. Inadequate vitamin D in infants leads to increased risks of poor bone mineralization and ultimately rickets. Rickets is uncommon in full-term infants with a much higher risk in very premature infants. However, the primary cause of rickets in premature infants is a deficiency of calcium and phosphorus, not vitamin D. Available research, as well as most guidelines, recommend an intake of 400 IU daily of vitamin D as adequate for bone health in preterm and full-term infants. Higher doses have not been consistently shown to have specific clinical benefits for healthy infants. There are no strong data to support either routine testing of serum 25-hydroxyvitamin D or targeting high serum 25-hydroxyvitamin D levels (e.g., 30 ng/mL) in healthy preterm or full-term infants. Vitamin D is commonly provided to infants via drops for breastfed babies or via infant formula, although alternative dosing approaches exist for breastfed infants, which some families may prefer. These include the use of drops placed on the mother's breast, dissolvable doses, and high maternal doses (approximately 6,400 IU daily). Infant formula contains vitamin D, and most infants will reach an intake from formula of about 400 IU daily within the first 2 months of life if they are consuming routine cow milk-based formula. Although vitamin D toxicity is very uncommon, caution should be used to avoid extremely concentrated high doses found in some commercially available drops. Infants with liver or kidney disease may need special attention to vitamin D intake and status. Further research is needed to define the role of vitamin D in non-bone health outcomes of infants and to identify methods to enhance compliance with current recommendations for vitamin D intake in infants.

Unbound bilirubin levels in phototherapy-treated preterm infants receiving soy-based lipid emulsion.

BACKGROUND: Phototherapy is an effective treatment for neonatal jaundice. Treatment indication uses total serum bilirubin (TSB), although unbound bilirubin (Bf) more accurately predicts disability risk. The goals of this investigation were to examine the response of Bf and TSB to phototherapy in preterm infants, and we hypothesized that (i) TSB and Bf respond differently; (ii) the relationship between TSB and Bf is altered; and (iii) unexpected Bf elevations are found. METHODS: One hundred and seventeen preterm infants <2 kg at birth and receiving (IL) were enrolled; and measurements of TSB and Bf were obtained. TSB was measured by the diazo method and Bf with a fluorescent Bf sensor BL22P1B11-Rh. RESULTS: Initial mean (± SD) TSB and Bf levels (41.4 ± 6.9 h) were 8.0 ± 9.0 mg/dL and 16.9 ± 12.4 nmol/L (P < 0.05). The rates of rise (ROR) were 0.21 ± 0.10 mg/dL/h for TSB and 0.38 ± 0.33 nmol/L/h for Bf. Phototherapy reduced TSB from 8.0 ± 9.0 to 5.8 ± 9.4 mg/dL (P = 0.068) but Bf did not change (16.9 ± 12.4 to 14.1 ± 9.4 nmol/L P = n.s.). Bf levels were >11 nmol/L in 64, >17 nmol/L in 18, and >22 nmol/L in 7 infants. CONCLUSIONS: Bf and TSB responded differently. While TSB and Bf correlated well before phototherapy, they did not correlate during phototherapy. TSB showed a trend toward a reduction with treatment, Bf did not. While TSB ROR information is not helpful, ROR Bf data can be utilized to anticipate treatment. Potentially high Bf levels existed before and after phototherapy and the mean Bf level at phototherapy termination remained elevated in a significant proportion of infants.

Plasma cytokine profiles in very preterm infants with late-onset sepsis.

INTRODUCTION: Deficiencies in innate immune responses may contribute to the increased susceptibility to infection in preterm infants. In vivo cytokine profiles in response to sepsis in very preterm infants are not fully understood. AIMS: To characterise plasma pro- and anti-inflammatory cytokine concentrations and pre-defined ratios in very preterm infants with late-onset sepsis (LOS). METHODS: In this observational study, peripheral blood samples were collected at the time of evaluation for suspected LOS from 31 preterm infants (<30 weeks gestational age). Plasma cytokine concentrations were determined by 12-plex immunoassay. RESULTS: IL-10, IFN-γ, IL-12p70, IP-10, IL-6 and CCL2 were elevated in the majority infants with LOS (n = 12) compared to those without LOS (n = 19). There was no difference in TNF-α, IL-1ß, IL-17AF, IL-8 and IL-15 concentrations between groups. IL-10/TNF-α ratios were increased, while CCL2/IL-10 and IL-12p70/IL-10 ratios were decreased in infants with LOS compared to those without. CONCLUSION: Very preterm infants have a marked innate inflammatory response at the time of LOS. The increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness. Longitudinal studies with a larger number of participants are required to understand immune responses and clinical outcomes following LOS in preterm infants.