Inflammation induces stunting by lowering bone mass via GH/IGF-1 inhibition in very preterm infants.

BACKGROUND: Sustained systemic inflammatory response (SIR) was associated with poor postnatal growth in very preterm infants (VPI). We hypothesize that VPI with sustained SIR will exhibit linear growth retardation related to lower bone mass accrual mediated by GH/IGF-1 axis inhibition at term corrected age (CA). METHODS: C-reactive protein (CRP), procalcitonin (PCT), growth hormone (GH), insulin-like growth factor 1 (IGF-1), calcium, phosphorus, alkaline phosphatase, anthropometric, nutritional, neonatal and maternal data were collected prospectively in 23 infants <32 weeks gestational age. Body composition using dual-energy X-ray absorptiometry was performed at term CA. Analysis was undertaken with multiple linear regression models. RESULTS: At term CA 11 infants with sustained SIR compared with 12 infants without sustained SIR present significantly lower IGF-1, length z-score (LZS), bone mineral content (BMC) and lean mass (LM), and higher GH and fat mass (FM). LZS was associated significantly with PCT, BMC with IGF-1, FM and LM with CRP, GH with bronchopulmonary dysplasia and CRP, and IGF-1 with invasive mechanical ventilation, CRP and PCT. CONCLUSIONS: In addition to the known effect on linear growth failure, sustained SIR induces lower bone mass accrual related to higher GH and lower IGF-1 levels in VPI. IMPACT: Very preterm infants (VPI) with sustained systemic inflammatory response (SIR) compared with VPI without SIR present stunting, lower bone mass, higher GH and lower IGF-1 levels at term corrected age. SIR may help to explain the influence of non-nutritional factors on growth and body composition in VPI. SIR induces postnatal stunting related to lower bone mass accrual via GH/IGF-1 axis inhibition in VPI. VPI with SIR need special attention to minimize inflammatory stress, which could result in improved postnatal growth. Research on inflammatory-endocrine interactions involved in the pathophysiology of postnatal stunting is needed as a basis for new interventional approaches.

Socioeconomic inequalities in low birth weight risk before and during the COVID-19 pandemic in Argentina: A cross-sectional study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have exacerbated existing socioeconomic inequalities in health. In Argentina, public hospitals serve the poorest uninsured segment of the population, while private hospitals serve patients with health insurance. This study aimed to assess whether socioeconomic inequalities in low birth weight (LBW) risk changed during the first wave of the COVID-19 pandemic. METHODS: This multicenter cross-sectional study included 15929 infants. A difference-in-difference (DID) analysis of socioeconomic inequalities between public and private hospitals in LBW risk in a pandemic cohort (March 20 to July 19, 2020) was compared with a prepandemic cohort (March 20 to July 19, 2019) by using medical records obtained from ten hospitals. Infants were categorized by weight as LBW < 2500 g, very low birth weight (VLBW) < 1500 g and extremely low birth weight (ELBW) < 1000 g. Log binomial regression was performed to estimate risk differences with an interaction term representing the DID estimator. Covariate-adjusted models included potential perinatal confounders. FINDINGS: Of the 8437 infants in the prepandemic cohort, 4887 (57•9%) were born in public hospitals. The pandemic cohort comprised 7492 infants, 4402 (58•7%) of whom were born in public hospitals. The DID estimators indicated no differences between public versus private hospitals for LBW risk (-1•8% [95% CI -3•6, 0•0]) and for ELBW risk (-0•1% [95% CI -0•6, 0•3]). Significant differences were found between public versus private hospitals in the DID estimators (-1•2% [95% CI, -2•1, -0•3]) for VLBW risk. The results were comparable in covariate-adjusted models. INTERPRETATION: In this study, we found evidence of decreased disparities between public and private hospitals in VLBW risk. Our findings suggest that measures that prioritize social spending to protect the most vulnerable pregnant women during the pandemic contributed to better birth outcomes. FUNDING: No funding was secured for this study.

Sustained Neonatal Inflammation Is Associated with Poor Growth in Infants Born Very Preterm during the First Year of Life.

OBJECTIVE: To determine whether a sustained neonatal systemic inflammatory response was associated with poor postnatal growth among infants born very preterm during the first year of life. STUDY DESIGN: We studied prospectively 192 infants born preterm (birth weight ≤1.5 kg and gestational age ≤31 weeks). Weight, length, and head circumference were measured at birth, term, 4, and 12 months of corrected age. Serial C-reactive protein and procalcitonin were measured at 1, 3, 7, 14, and 28 days of age and averaged for each infant. A sustained neonatal systemic inflammatory response was defined as an average C-reactive protein level greater than the median for the group. Analysis was undertaken with linear mixed models. RESULTS: Decreases in mean z scores for weight, length, and head circumference were associated with the presence of a sustained neonatal systemic inflammatory response from birth to 12 months of corrected age (ß [95% CI] = -0.282 [-0.306 to -0.258]; -1.899 [-2.028,-1.769]; -0.806 [-0.910, to -0.701], P < .001, respectively) in main effect models. This association remained significant after including interaction terms for bronchopulmonary dysplasia, neonatal sepsis, and necrotizing enterocolitis (ß [95% CI] = -0.393 [-0.520 to -0.265]; -2.128 [-2.754, -1.503]; -1.102 [-1.604, -0.600]; P < .001; respectively) in interaction models. CONCLUSIONS: A sustained neonatal systemic inflammatory response was associated with poor postnatal growth, particularly poor linear growth. Serial C-reactive protein and procalcitonin may be useful markers for identifying infants at risk for postnatal growth failure.

C-reactive protein, platelets, and patent ductus arteriosus.

The association between inflammation, platelets, and patent ductus arteriosus (PDA) has not been studied so far. The purpose of this study was to evaluate whether C-reactive protein (CRP) is related to low platelet count and PDA. This was a retrospective study of 88 infants with a birth weight ≤1500 g and a gestational age ≤30 weeks. Platelet count, CRP, and an echocardiogram were assessed in all infants. The subjects were matched by sex, gestational age, and birth weight. Differences were compared using the χ2, t-test, or Mann-Whitney U-test, as appropriate. Significant variables were entered into a logistic regression model. The association between CRP and platelets was evaluated by correlation and regression analysis. Platelet count (167 000 vs. 213 000 µl-1, p = 0.015) was lower and the CRP (0.45 vs. 0.20 mg/dl, p = 0.002) was higher, and the platelet count correlated inversely with CRP (r = -0.145, p = 0.049) in the infants with vs. without PDA. Only CRP was independently associated with PDA in a logistic regression model (OR 64.1, 95% confidence interval 1.4-2941, p = 0.033).

[Heart rate variability analysis: a new approach in clinical research methodology for neonatal sepsis]. / Análisis sobre la variabilidad de la frecuencia cardíaca: un nuevo enfoque en la metodología de la investigación clínica de la sepsis neonatal.

The knowledge on neonatal sepsis has increase significantly, but a clinical or biochemical marker is not available for an early and appropriate diagnosis. This fact results of an inadequate analysis which might be missing important quantum of biological information. A new method of nonlinear analysis have been proposed to investigate time series of physiological data, particularly heart rate variability analysis, that apparently would detect abnormal changes which precedes clinical or biochemical signs of infection by as much as 12-24 hours.

Análisis sobre la variabilidad de la frecuencia cardíaca: un nuevo enfoque en la metodología de la investigación clínica de la sepsis neonatal / Heart rate variability analysis: a new approach in clinical research methodology for neonatal sepsis

Los conocimientos sobre sepsis neonatal se han incrementado notablemente, pero aún no se dispone de ninguna prueba clínica o bioquímica lo sufcientemente sensible y específca para el diagnóstico temprano y oportuno de la enfermedad. Esta situación sería consecuencia de la utilización de procedimientos analíticos que podrían perder elementos importantes de información biológica. Se han propuesto nuevos métodos de análisis no-lineal para series temporales de datos fsiológicos; de particular interés resulta el estudio de la variabilidad de la frecuencia cardíaca, que aparentemente permitiría detectar anormalidades con una antelación de 12-24 h a las manifestaciones clínicas o bioquímicas de la infección.

The knowledge on neonatal sepsis has increase signifcantly, but a clinical or biochemical marker is not available for an early and appropriate diagnosis. This fact results of an inadequate analysis which might be missing important quantum of biological information. A new method of nonlinear analysis have been proposed to investigate time series of physiological data, particularly heart rate variability analysis, that apparently would detect abnormal changes which precedes clinical or biochemical signs of infection by as much as 12-24 hours.

[Brain signaling mechanisms during neonatal sepsis]. / Mecanismos de señalizacion cerebral durante la sepsis neonatal.

The brain and the immune system are the two major adaptive systems of the body. During an immune response the developing neonatal brain and the immune system "cross-talk" and this course of action is essential for maintaining homeostasis. Two pathway are involved in this intercommunication: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence suggests that norepinephrine (NE) is a neurotransmitter/neuromodulator in different organs and tissues. Under stimulation, NE is released from the sympathetic nerve terminals in these organs and tissues .Through stimulation of specific receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response.

Comparación de la morbimortalidad entre recién nacidos prematuros pequeños y adecuados para la edad gestacional de acuerdo a estándares de crecimiento neonatales y fraccionales / Comparison of the morbimortality between small premature newborns and adequate for gestational age in agreement to standards of neonatal and fractional growth

Objetivo: Evaluar eventos neonatales adversos en recién nacidos prematuros ≤ 34 semanas pequeños y adecuados para su edad gestacional de acuerdo a estándares de crecimiento neonatales y fraccionales. Material y métodos: Estudio de una cohorte hospitalaria de recién nacidos prematuros con una edad gestacional ≤ 34 semanas, admitidos a la unidad de cuidados intensivos neonatales, desde el 1/1/98 hasta el 31/12/08. Las variables estudiadas fueron: mortalidad, enfermedad de membrana hialina, displasia broncopulmonar, hemorragia intraventricular (todos los grados), enterocolitis necrotizante y retinopatía del prematuro (todos los estadios). Las mismas se analizaron en un modelo de riesgo estimado mediante el cálculo del OR con IC95 por ciento. Resultados: La prevalencia de recién nacidos pequeños para la edad gestacional de acuerdo a los estándares de crecimiento neonatales fue de 56/218 (25,7 por ciento IC95 por ciento 19,6 a 31,7), mientras que de acuerdo a los estándares fraccionales fue de 78/218 (35,8 por ciento IC95 por ciento 29,2 - 42,4, p = 0,029). Cuando los recién nacidos prematuros pequeños para la edad gestacional fueron comparados a los adecuados para la edad gestacional de acuerdo a los estándares fraccionales presentaron un riesgo significativamente aumentado para mortalidad (OR 3 IC95 por ciento 1,2-7,7); enfermedad de membrana hialina (OR 2,7 IC95 por ciento 1,1-6,9), displasia broncopulmonar (OR 1,9 IC95 por ciento 1,1-3,7) y hemorragia intraventricular (OR 3,8 IC95 por ciento 2-6,9), mientras que el cotejo con estándares neonatales no arrojó diferencias. Conclusión: Las curvas fraccionales identificaron un aumento significativo en el riesgo de eventos adversos en prematuros pequeños para la edad gestacional, en comparación con las curvas neonatales.

Objective: To evaluate neonatal and fractional growth standards in determining charges of mortality and morbidity between premature small for gestational age infants. Material and methods: Hospital-based cohort study of singleton newborns of ≤ 34 weeks gestational age admitted to neonatal intensive care unit between January 1, 1998 and December 31, 2008. Outcome variables include: mortality, hyaline membrane disease, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis and retinopathy of prematurity. For each variable bivariate analysis were performed (OR CI95 per cent). Results: The prevalence of small for gestational age according to neonatal growth standards was 56/218 (25.7 per cent, CI95 per cent 19.6-31.7) and according to fractional standards was 78/218 (35.8 per cent CI95 per cent 29.2-42.4, p= 0.029). According to fractional growth standards, when small for gestational age was compared with adequate for gestational age, it was associated with an increased risk of mortality (OR 3 CI95 per cent 1.2-7.7), hyaline membrane disease (OR 2, 7, CI95 per cent 1.1-6.9), bronchopulmonary dysplasia (OR 1.9 CI 95 per cent 1.1-3.7) and intraventricular hemorrhage (OR 3.8 CI95 per cent 2-6.9). Neonatal growth standard was not associated with an increased risk of mortality or morbidity. Conclusions: Fractional growth standards identifying an increased risk of adverse neonatal outcomes between preterm SGA infants, than neonatal standards.

Fetal and neonatal consequences of antenatal exposure to type 1 angiotensin II receptor-antagonists.

Sartans are selective type 1 angiotensin II receptor-antagonists that are used in the treatment of arterial hypertension. Few reports are available concerning the use of sartans during pregnancy. We report two cases of adverse fetal outcome in hypertensive pregnancies exposed to sartans. In the first case, anamnios and fetal renal failure due to severe tubular dysgenesia led to termination of pregnancy in the 27th week. The second patient presented with hypocalvaria and developed fetal renal failure. The use of sartans during the two last trimesters of pregnancy should be strictly avoided.

Ethical dilemmas in extreme prematurity: recent answers; more questions.

Advances in perinatal care allow survival of more extremely premature infants, but the implementation and continuation of intensive care may itself constitute an ethical dilemma, given the limited chances of intact survival among the patients most at risk. This paper discusses several key issues raised by the options that are under general consideration with reference to births of infants at the threshold of viability, in particular: the implications of making a distinction between extreme prematurity and other general medical situations that may involve decisions on ending support; the concrete nature of the restrictions on therapy in such patients interactions and the need for feedback between parents, medical staff and society.