Distinct protein patterns related to postnatal development in small for gestational age preterm infants.

BACKGROUND: Preterm infants, especially those born small for gestational age (SGA), are at risk of short-term and long-term health complications. Characterization of changes in circulating proteins postnatally in preterm infants may provide valuable fundamental insights into this population. Here, we investigated postnatal developmental patterns in preterm infants and explored protein signatures that deviate between SGA infants and appropriate for gestational age (AGA) infants using a mass spectrometry (MS)-based proteomics workflow. METHODS: Longitudinal serum samples obtained at postnatal days 0, 3, 7, 14, and 28 from 67 preterm infants were analyzed using unbiased MS-based proteomics. RESULTS: 314 out of 833 quantified serum proteins change postnatally, including previously described age-related changes in immunoglobulins, hemoglobin subunits, and new developmental patterns, e.g. apolipoproteins (APOA4) and terminal complement cascade (C9) proteins. Limited differences between SGA and AGA infants were found at birth while longitudinal monitoring revealed 69 deviating proteins, including insulin-sensitizing hormone adiponectin, platelet proteins, and 24 proteins with an annotated function in the immune response. CONCLUSIONS: This study shows the potential of MS-based serum profiling in defining circulating protein trajectories in the preterm infant population and its ability to identify longitudinal alterations in protein levels associated with SGA. IMPACT: Postnatal changes of circulating proteins in preterm infants have not fully been elucidated but may contribute to development of health complications. Mass spectrometry-based analysis is an attractive approach to study circulating proteins in preterm infants with limited material. Longitudinal plasma profiling reveals postnatal developmental-related patterns in preterm infants (314/833 proteins) including previously described changes, but also previously unreported proteins. Longitudinal monitoring revealed an immune response signature between SGA and AGA infants. This study highlights the importance of taking postnatal changes into account for translational studies in preterm infants.

Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia.

Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.

Early red blood cell transfusion and the occurrence of intraventricular hemorrhage in very preterm infants.

BACKGROUND: Preterm infants are at risk of developing both intraventricular hemorrhage (IVH) and anemia of prematurity. Several studies reported an association between early postnatal red blood cell (RBC) transfusion and IVH, however the timing and causality between these two remains unclear. AIMS: To describe the temporal sequence between administration of early RBC transfusion (within the first week of life) and diagnosis of IVH in very preterm infants. STUDY DESIGN: Retrospective single center case-series. SUBJECTS: 132 very preterm infants (<32 weeks' gestation), admitted to a level III neonatal intensive care unit, studied with serial cranial ultrasound (CUS), and diagnosed with any grade of IVH. OUTCOME MEASURES: Number and timing of early RBC transfusions in relation to the timing of IVH. RESULTS: Median time of IVH diagnosis was 20.5 h after birth (interquartile range [IQR], 6.25-49.00 h). Of those who received an early RBC transfusion (36 %, 47/132), only 15 % (20/132) received it before the IVH diagnosis. Infants with RBC transfusion before IVH more frequently had lower birth weight, received less fequently antenatal steroids, required more often invasive mechanical ventilation and surfactant administration, had more often hypo- and hypercapnia, and received more fluid boluses, NaHCO3, and inotropes compared to the rest. CONCLUSIONS: In the majority of infants, IVH was already present at the time of the first RBC transfusion. Studies including pre- and post RBC transfusion CUS are needed to assess the effect of early RBC transfusions on the development of IVH in preterm neonates.

Most major bleeds in preterm infants occur in the absence of severe thrombocytopenia: an observational cohort study.

OBJECTIVE: To describe the incidence of major bleeds according to different platelet counts in very preterm infants, and to explore whether this association is influenced by other risk factors for bleeding. DESIGN: Observational cohort study. SETTING: A Dutch tertiary care neonatal intensive care unit. PATIENTS: All consecutive infants with a gestational age at birth <32 weeks admitted between January 2004 and July 2022. EXPOSURE: Infants were stratified into nine groups based on their nadir platelet count (×109/L) during admission (<10, 10-24, 25-49, 50-99, 100-149, 150-199, 200-249, 250-299 and ≥300), measured before the diagnosis of a major bleed and before any platelet transfusion was administered. MAIN OUTCOME MEASURE: Incidence of major bleeds during admission. Logistic regression analysis was used to quantify the relationship between nadir platelet count and incidence of major bleeds. RESULTS: Among 2772 included infants, 224 (8%) developed a major bleed. Of the infants with a major bleed, 92% (206/224) had a nadir platelet count ≥50×109/L. The incidence of major bleeds was 8% among infants with and without severe thrombocytopenia (platelet count <50×109/L), 18/231 (95% CI 5 to 12) and 206/2541 (95% CI 7 to 9), respectively. Similarly, after adjustment for measured confounders, there was no notable association between nadir platelet counts below versus above 50×109/L and the occurrence of major bleeds (OR 1.09, 95% CI 0.61 to 1.94). CONCLUSION: In very preterm infants, the vast majority of major bleeds occur in infants without severe thrombocytopenia.

Prophylactic Platelet Transfusions: Why Less Is More.

Preterm neonates are a highly transfused patient group, with platelet transfusions being the second most transfused cellular blood component. Historically, however, evidence to inform optimal platelet transfusion practice has been limited. In pediatrics, much of the evidence has been inferred from studies in adult patients, although neonatologists have generally applied more cautious and liberal platelet transfusion thresholds to mitigate the complications of intraventricular hemorrhage. A total of three randomized controlled trials have now been published comparing different platelet transfusion strategies in neonates.

Cardiovagal baroreflex sensitivity, blood pressure and blood pressure variability - the Maastricht study.

OBJECTIVE: Low baroreflex sensitivity (BRS) has been hypothesized to underlie high blood pressure (BP) and greater BP variability on the longer term, but evidence is scarce. In addition, these associations may differ by sex and (pre)diabetes. Therefore, we investigated whether cardiovagal BRS is associated with short- to mid-term mean BP and BP variability, and differs according to sex and (pre)diabetes. METHODS: Cross-sectional data from the population-based Maastricht study (age 60 ±â€Š8 years, 52% men), where office ( n  = 2846), 24-h ( n  = 2404) and 7-day BP measurements ( n  = 2006) were performed. Spontaneous BRS was assessed by cross-correlating systolic BP and instantaneous heart rate. We used linear regression with adjustments for age, sex, BP or BP variability, and cardiovascular risk factors. RESULTS: With regard to BP, 1-SD (standard deviation) lower BRS (-5.75 ms/mmHg) was associated with higher office, 24-h and 7-day systolic BP (2.22 mmHg [95% confidence interval [CI]: 1.59; 2.80], 0.95 mmHg [0.54; 1.36], and 1.48 mmHg [0.99; 1.97], respectively) and diastolic BP (1.31 mmHg [0.97; 1.66], 0.57 mmHg [0.30; 0.84], and 0.86 mmHg [0.54; 1.17], respectively). Per 1-SD lower BRS, these associations were stronger in women (0.5-1.5 mmHg higher compared to men), and weaker in those with type 2 diabetes (1-1.5 mmHg lower compared to normal glucose metabolism). With regard to BP variability, BRS was not consistently associated with lower BP variability. CONCLUSIONS: Lower cardiovagal BRS is associated with higher mean BP from the short- to mid-term range, and not consistently with BP variability. The associations with mean BP are stronger in women and weaker in those with type 2 diabetes.

The critical roles of iron during the journey from fetus to adolescent: Developmental aspects of iron homeostasis.

Iron is indispensable for human life. However, it is also potentially toxic, since it catalyzes the formation of harmful oxidative radicals in unbound form and may facilitate pathogen growth. Therefore, iron homeostasis needs to be tightly regulated. Rapid growth and development require large amounts of iron, while (especially young) children are vulnerable to infections with iron-dependent pathogens due to an immature immune system. Moreover, unbalanced iron status early in life may have effects on the nervous system, immune system and gut microbiota that persist into adulthood. In this narrative review, we assess the critical roles of iron for growth and development and elaborate how the body adapts to physiologically high iron demands during the journey from fetus to adolescent. As a first step towards the development of clinical guidelines for the management of iron disorders in children, we summarize the unmet needs regarding the developmental aspects of iron homeostasis.