Gender and sex hormone effects on neonatal innate immune function.

OBJECTIVES: Scientific evidence provides a widened view of differences in immune response between male and female neonates. The X-chromosome codes for several genes important in the innate immune response and neonatal innate immune cells express receptors for, and are inhibited by, maternal sex hormones. We hypothesized that sex differences in innate immune responses may be present in the neonatal population which may contribute to the increased susceptibility of premature males to sepsis. We aimed to examine the in vitro effect of pro-inflammatory stimuli and hormones in neutrophils and monocytes of male and female neonates, to examine the expression of X-linked genes involved in innate immunity and the miRNA profiles in these populations. METHODS: Preterm infants (n = 21) and term control (n = 19) infants were recruited from the Coombe Women and Infants University Hospital Dublin with ethical approval and explicit consent. The preterm neonates (eight female, 13 male) were recruited with a mean gestation at birth (mean ± SD) of 28 ± 2 weeks and corrected gestation at the time of sampling was 30 + 2.6 weeks. The mean birth weight of preterm neonates was 1084 ± 246 g. Peripheral blood samples were used to analyze immune cell phenotypes, miRNA human panel, and RNA profiles for inflammasome and inflammatory genes. RESULTS: Dividing neutrophil results by sex showed no differences in baseline CD11b between sexes among either term or preterm neonates. Examining monocyte CD11b by sex shows, that at baseline, total and classical monocytes have higher CD11b in preterm females than preterm males. Neutrophil TLR2 did not differ between sexes at baseline or following lipopolysaccharide (LPS) exposure. CD11b expression was higher in preterm male non-classical monocytes following Pam3CSK treatment when compared to females, a finding which is unique to our study. Preterm neonates had higher TLR2 expression at baseline in total monocytes, classical monocytes and non-classical monocytes than term. A sex difference was evident between preterm females and term females in TLR2 expression only. Hormone treatment showed no sex differences and there was no detectable difference between males and females in X-linked gene expression. Two miRNAs, miR-212-3p and miR-218-2-3p had significantly higher expression in preterm female than preterm male neonates. CONCLUSIONS: This study examined immune cell phenotypes and x-linked gene expression in preterm neonates and stratified according to gender. Our findings suggest that the responses of females mature with advancing gestation, whereas male term and preterm neonates have very similar responses. Female preterm neonates have improved monocyte activation than males, which likely reflects improved innate immune function as reflected clinically by their lower risk of sepsis. Dividing results by sex showed changes in preterm and term infants at baseline and following LPS stimulation, a difference which is reflected clinically by infection susceptibility. The sex difference noted is novel and may be limited to the preterm or early neonatal population as TLR2 expression on monocytes of older children does not differ between males and females. The differences shown in female and male innate immune cells likely reflect a superior innate immune defense system in females with sex differences in immune cell maturation. Existing human studies on sex differences in miRNA expression do not include preterm patients, and most frequently use either adult blood or cord blood. Our findings suggest that miRNA profiles are similar in neonates of opposite sexes at term but require further investigation in the preterm population. Our findings, while novel, provide only very limited insights into sex differences in infection susceptibility in the preterm population leaving many areas that require further study. These represent important areas for ongoing clinical and laboratory study and our findings represent an important contribution to exiting literature.

Guidelines and Recommendations for Targeted Neonatal Echocardiography and Cardiac Point-of-Care Ultrasound in the Neonatal Intensive Care Unit: An Update from the American Society of Echocardiography.

Targeted neonatal echocardiography (TNE) involves the use of comprehensive echocardiography to appraise cardiovascular physiology and neonatal hemodynamics to enhance diagnostic and therapeutic precision in the neonatal intensive care unit. Since the last publication of guidelines for TNE in 2011, the field has matured through the development of formalized neonatal hemodynamics fellowships, clinical programs, and the expansion of scientific knowledge to further enhance clinical care. The most common indications for TNE include adjudication of hemodynamic significance of a patent ductus arteriosus, evaluation of acute and chronic pulmonary hypertension, evaluation of right and left ventricular systolic and/or diastolic function, and screening for pericardial effusions and/or malpositioned central catheters. Neonatal cardiac point-of-care ultrasound (cPOCUS) is a limited cardiovascular evaluation which may include line tip evaluation, identification of pericardial effusion and differentiation of hypovolemia from severe impairment in myocardial contractility in the hemodynamically unstable neonate. This document is the product of an American Society of Echocardiography task force composed of representatives from neonatology-hemodynamics, pediatric cardiology, pediatric cardiac sonography, and neonatology-cPOCUS. This document provides (1) guidance on the purpose and rationale for both TNE and cPOCUS, (2) an overview of the components of a standard TNE and cPOCUS evaluation, (3) disease and/or clinical scenario-based indications for TNE, (4) training and competency-based evaluative requirements for both TNE and cPOCUS, and (5) components of quality assurance. The writing group would like to acknowledge the contributions of Dr. Regan Giesinger who sadly passed during the final revisions phase of these guidelines. Her contributions to the field of neonatal hemodynamics were immense.

Haemodynamic assessment and management of hypotension in the preterm.

The management of low blood flow states in premature neonates is fraught with many challenges. We remain over-reliant on regimented stepwise protocols that use mean blood pressure as a threshold for intervention to guide treatment, without giving due consideration to the underlying pathophysiology. The current available evidence does not reflect the need to concentrate on the unique pathophysiology of the preterm infant and thus leads to widespread misuse of vasoactive agents that often do not provide the desired clinical effect. Therefore, understanding the underlying pathophysiological underpinnings of haemodynamic compromise may better guide choice of agent and assess physiological response to the selected intervention.

Neonatal sepsis and cardiovascular dysfunction I: mechanisms and pathophysiology.

The highest incidence of sepsis across all age groups occurs in neonates leading to substantial mortality and morbidity. Cardiovascular dysfunction frequently complicates neonatal sepsis including biventricular systolic and/or diastolic dysfunction, vasoregulatory failure, and pulmonary arterial hypertension. The haemodynamic response in neonatal sepsis can be hyperdynamic or hypodynamic and the underlying pathophysiological mechanisms are heterogeneous. The diagnosis and definition of both neonatal sepsis and cardiovascular dysfunction complicating neonatal sepsis are challenging and not consensus-based. Future developments in neonatal sepsis management will be facilitated by common definitions and datasets especially in neonatal cardiovascular optimisation. IMPACT: Cardiovascular dysfunction is common in neonatal sepsis but there is no consensus-based definition, making calculating the incidence and designing clinical trials challenging. Neonatal cardiovascular dysfunction is related to the inflammatory response, which can directly target myocyte function and systemic haemodynamics.

Nutrition of the preterm infant with persistent ductus arteriosus: existing evidence and practical implications.

The persistence of a patent ductus arteriosus (PDA) is a common condition in preterm infants with a prevalence inversely proportional to gestational age. PDA is associated with mild-to-severe gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which represent a major challenge for the nutritional management in preterm infants. In this context, the Section on Nutrition, Gastroenterology and Metabolism and the Circulation Section of the European Society for Pediatric Research have joined forces to review the current knowledge on nutritional issues related to PDA in preterm infants. The aim of the narrative review is to discuss the clinical implications for nutritional practice. Because there is little literature on postnatal nutrition and PDA in preterm infants, further research with well-designed studies on this topic is urgently needed. Guidelines should also be developed to clearly define the implementation and course of enteral nutrition and the target nutritional intake before, during, and after pharmacologic or surgical treatment of PDA, when indicated. IMPACT: Persistent ductus arteriosus (PDA) is associated with gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which pose a major challenge to the nutritional management of preterm infants. In PDA infants, fluid restriction may lead to inadequate nutrient intake, which may negatively affect postnatal growth and long-term health. The presence of PDA does not appear to significantly affect mesenteric blood flow and splanchnic oxygenation after enteral feedings. Initiation or maintenance of enteral nutrition can be recommended in infants with PDA.

Assessment of Myocardial Function in Infants of Mothers with Gestational Diabetes Mellitus Using Deformation Imaging over the First Year of Age.

OBJECTIVE: To assess serial myocardial performance and pulmonary vascular resistance (PVR) in infants of mothers with gestational diabetes mellitus (GDM) over the first year of life. STUDY DESIGN: This was a prospective, observational study. Echocardiography was performed at birth, 6 months, and 1 year of age. Pulmonary artery acceleration time and left ventricular (LV) eccentricity index provided surrogate measurements of PVR. Biventricular function was assessed by tissue Doppler imaging and deformation analysis. RESULTS: Fifty infants of mothers with GDM were compared with 50 controls with no difference in gestation (38.9 ± 0.8 weeks vs 39.3 ± 0.9 weeks; P = .05) or birthweight (3.55 ± 0.49 kg vs 3.56 ± 0.41 kg; P = .95). At 1 year of age, the pulmonary artery acceleration time was lower (70 ± 11 vs 79 ± 10; P = .01) in the GDM group. LV global longitudinal strain (24.7 ± 1.9 vs 28.8 ± 1.8 %; P < .01), LV systolic strain rate (1.8 ± 0.2 vs 2.1 ± 0.3 1/s; P < .01), and RV free wall strain (31.1 ± 4.8 vs 34.6 ± 3.9 %; P < .01) were lower in the GDM cohort at 1 year of age (all P values adjusted for gestation, mode of delivery, and maternal body mass index). CONCLUSIONS: Our findings demonstrate higher indices of PVR and lower biventricular function in infants of mothers with GDM compared with controls at each time point assessed in this study over the first year of life.

Reproducibility of the EL-Khuffash PDA severity score and PDA diameter measurements in extremely preterm infants.

BACKGROUND & AIM: Almost all randomised controlled trials use a Patent Ductus Arteriosus (PDA) diameter ≥ 1.5 mm as the primary criterion to ascribe haemodynamic significance to the PDA. The aim of this study was to evaluate if calculation of a PDA Severity Score (PDAsc) possessed superior intra- and inter-rater reproducibility when compared with the measurement of PDA diameter alone. METHODS: This cross-sectional study assessed echocardiograms performed on infants <30 weeks gestation at 36 to 72 h of age between July 2020 and December 2022 to calculate the PDAsc. Intra-observer reproducibility of the PDA diameter and PDAsc were assessed by blinded repeated measurements performed by one investigator (AS) 4 weeks apart. One set of those measurements was compared with blinded measurements by another investigator (RM) to assess inter-rater reliability. RESULTS: Echocardiograms from 150 infants with mean ± SD gestation and birthweights of 26.5 ± 1.7 weeks and 903 ± 249 g respectively were examined. The PDAsc demonstrated near perfect agreement both within raters (Cohen's Kappa 0.97, p < 0.01) and between raters (Cohen's Kappa 0.94, p < 0.01) with regards to the threshold for treatment (a cut off ≥5.0). The PDA diameter threshold only demonstrated moderate agreement within raters (Kappa 0.57, p < 0.01) and between raters (Kappa 0.54, p < 0.01). In this cohort, 31 % of infants with a low risk PDAsc (< 5.0) also had a PDA diameter >1.5 mm. CONCLUSION: Future RCTs for PDA treatment should strongly consider abandoning the use of PDA diameter in isolation as a criterion for recruitment into clinical trials.

Noise exposure exceeded safe limits during neonatal care and road transport but was reduced by active noise cancelling.

AIM: Noise levels above 45 dB in a neonatal intensive care unit (NICU) and 60 dB during neonatal transport are recognised hazards, but protective equipment is not standard. We measured noise levels in both settings, with and without noise protection. METHODS: Peak sound and equivalent continuous sound levels were measured in a NICU and during road transport, at a mannequin's ear and inside and outside the incubator. Recordings were made without protective earwear, with noise protecting earmuffs and with active noise cancelling headphones. RESULTS: In the NICU, the peak levels at the ear, and inside and outside the incubator, were 61, 68 and 76 dB. The equivalent continuous sound levels were 45, 54 and 59 dB. During road transport, the respective levels were 70, 77 and 83 dB and 54, 62 and 68 dB. In the NICU, 80% of environmental peak noise reached the ear and this was reduced to 78% with earmuffs and 75% with active noise cancelling. The respective figures during transport were 87% without protection and 72% with active noise cancelling, with an unexpected increase for ear muffs. CONCLUSION: Noise levels exceeded safe limits in the NICU and during transport, but active noise cancelling reduced exposure.

Machine Learning Detects Intraventricular Haemorrhage in Extremely Preterm Infants.

OBJECTIVE: To test the potential utility of applying machine learning methods to regional cerebral (rcSO2) and peripheral oxygen saturation (SpO2) signals to detect brain injury in extremely preterm infants. STUDY DESIGN: A subset of infants enrolled in the Management of Hypotension in Preterm infants (HIP) trial were analysed (n = 46). All eligible infants were <28 weeks' gestational age and had continuous rcSO2 measurements performed over the first 72 h and cranial ultrasounds performed during the first week after birth. SpO2 data were available for 32 infants. The rcSO2 and SpO2 signals were preprocessed, and prolonged relative desaturations (PRDs; data-driven desaturation in the 2-to-15-min range) were extracted. Numerous quantitative features were extracted from the biosignals before and after the exclusion of the PRDs within the signals. PRDs were also evaluated as a stand-alone feature. A machine learning model was used to detect brain injury (intraventricular haemorrhage-IVH grade II-IV) using a leave-one-out cross-validation approach. RESULTS: The area under the receiver operating characteristic curve (AUC) for the PRD rcSO2 was 0.846 (95% CI: 0.720-0.948), outperforming the rcSO2 threshold approach (AUC 0.593 95% CI 0.399-0.775). Neither the clinical model nor any of the SpO2 models were significantly associated with brain injury. CONCLUSION: There was a significant association between the data-driven definition of PRDs in rcSO2 and brain injury. Automated analysis of PRDs of the cerebral NIRS signal in extremely preterm infants may aid in better prediction of IVH compared with a threshold-based approach. Further investigation of the definition of the extracted PRDs and an understanding of the physiology underlying these events are required.

Assessment of myocardial function in infants conceived by assisted reproductive technologies using deformation imaging over the first year of age: A cohort study.

BACKGROUND AND AIM: There is emerging evidence of cardiovascular remodeling and functional impairment in individuals conceived via Assisted Reproductive Technologies (ART). The aim of this study was to serially assess myocardial function and pulmonary hemodynamic measurements in infants conceived via ART over the first year of age and to compare them to a cohort of spontaneously conceived controls. METHODS: This was a prospective, observational study. Echocardiography was performed at Day 2, 6 months and 1 year of age. Biventricular function was assessed by deformation analysis. Pulmonary artery acceleration time (PAAT) and left ventricular (LV) eccentricity index (LVEI) provided surrogate measures of pulmonary vascular resistance (PVR). RESULTS: Fifty infants conceived via ART were compared to 50 spontaneously conceived controls. There were no differences in baseline infant demographics between the two groups. At 1 year of age right ventricular (RV) basal and RV mid cavity diameters were higher in the ART group. PAATi was lower and LVEI higher in the ART group at 6 months and 1 year. In the ART group, LV global longitudinal strain, LV systolic strain rate, LV early diastolic strain rate and RV free wall strain were lower on Day 2, 6 months, and 1 year of age in comparison to the control group (all p < .05). Within the ART group, on linear regression, maternal age, the type of ART treatment or egg characteristics did not influence PAAT or deformation measurements. CONCLUSION: Our findings suggest that greater cardiovascular surveillance of ART conceived infants may be warranted.

Cerebral Oximetry Monitoring in Extremely Preterm Infants.

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

The impact of a PDA on tissue oxygenation and haemodynamics following a blood transfusion in preterm infants.

BACKGROUND: To examine the impact of PRBC transfusion on pulmonary vascular resistance (PVR), systemic vascular resistance and myocardial function using echocardiography and cerebral and splanchnic tissue oxygenation using near-infrared spectroscopy (NIRS) in premature babies with and without a PDA. METHODS: A prospective observational study of premature infants born <1500 g in receipt of PRBC transfusions beyond 10 days of age. Echocardiography and NIRS monitoring were performed at baseline, during the transfusion and 24 h after transfusion. RESULTS: Thirty infants with a median gestation of 26.4 [24.8-28.0] weeks were enrolled. Ten infants had a PDA. Following transfusion, a significant decrease in PVR markers occurred in all infants. Right ventricular (RV) function increased following transfusion in the PDA closed group only. Cerebral oxygen saturation increased following transfusion in all infants. Babies in the PDA open group had significantly lower splanchnic oxygen saturations at baseline compared to the PDA closed group which persisted over the study period and were unaltered by transfusion. CONCLUSIONS: PRBC transfusion lowers PVR irrespective of PDA status. Those with a PDA demonstrated a lack of improvement in RV function and splanchnic oxygenation highlighting the impact a PDA has on the neonatal circulation. IMPACT: The presence or absence of the PDA imposes differential effects on splanchnic oxygenation during red blood cell (PRBC) transfusion in the premature population. This is the first study to assess the impact of the PDA on splanchnic oxygenation via near-infrared spectroscopy (NIRS) during red blood cell transfusion in premature neonates. New insights have been found into the impact of PRBC transfusion on pulmonary vascular resistance, right ventricular function, cerebral and splanchnic oxygenation in the presence and absence of a PDA and emphasises the ongoing impact of ductal patency on gut oxygenation.

Inhaled nitric oxide in preterm neonates with preterm prelabour rupture of membranes, a systematic review.

AIM: To perform a systematic literature review to determine the effect of inhaled nitric oxide (iNO) on oxygenation, mortality and morbidity in preterm neonates with preterm prelabour rupture of membranes (PPROM) and early hypoxaemic respiratory failure (HRF). METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Zetoc and ProQuest were searched. Studies including neonates <34 weeks' gestation with PPROM, oligohydramnios or pulmonary hypoplasia and HRF in the first 28 days of life treated with iNO were included. Studies were critically appraised and assessed for potential risk of bias using standardised checklists. RESULTS: Six hundred and two records remained after duplicates were removed. Seven studies were included in the critical appraisal process. Quality of available evidence was very low to low. Six studies described an improvement in oxygenation after commencement of iNO. One hundred and three of 284 (36%) neonates exposed to iNO died. Seventy-seven of 92 (84%) neonates that had an echocardiogram performed before commencement of iNO had pulmonary hypertension (PH) present. CONCLUSION: iNO may improve oxygenation when standard care fails. Improvement in oxygenation is likely associated with increase in survival. Survival may lead to an increase in morbidity. Efficacy of iNO in this cohort is likely secondary to relatively high prevalence of PH.

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1).

OBJECTIVE: To assess the impact of milrinone administration on time spent on nitric oxide (iNO) in infants with acute pulmonary hypertension (aPH). We hypothesized that intravenous milrinone used in conjunction with iNO would reduce the time on iNO therapy and the time spent on invasive ventilation in infants ≥34 weeks gestation with a diagnosis of aPH. We aimed to assess the practicality of instituting the protocol and contributing to a sample size calculation for a definitive multicentre study. STUDY DESIGN: This was a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation. Infants with a gestation ≥34 weeks and a birth weight ≥2000 grams aPH, an oxygenation index of ≥10, and commenced on iNO were eligible. Participants on iNO were assigned to either a milrinone infusion (intervention) or a normal saline infusion (placebo) for up to 35 h. The primary outcome was time on iNO and feasibility of conducting the protocol. RESULTS: The trial was terminated early after 4 years of enrollment due to poor recruitment. Four infants were allocated to the intervention arm and 5 to the placebo arm. The groups were well matched for baseline variables. No differences were seen in any of the primary or secondary outcomes. CONCLUSION: Conducting an interventional trial in the setting of acute pulmonary hypertension in infants is not feasible using our current approach. Future studies in this area require alternative trial design to improve recruitment as this topic remains understudied in the neonatal field. TRIAL REGISTRATION: www.isrctn.com ; ISRCTN:12949496; EudraCT Number:2014-002988-16.

Serial Assessment of Cardiac Function and Pulmonary Hemodynamics in Infants With Down Syndrome.

BACKGROUND: There is a dearth of longitudinal data describing the evolution of cardiopulmonary hemodynamics in infants with Down syndrome (DS) beyond infancy. We hypothesized that babies with DS, independent of the presence of congenital heart disease (CHD), demonstrate biventricular systolic and diastolic impairment and sustained elevation of pulmonary pressures compared with controls over the first 2 years of age. METHODS: This was a prospective observational cohort study of 70 infants with DS (48 with CHD and 22 without CHD) and 60 controls carried out in 3 tertiary neonatal intensive care units in Dublin, Ireland. Infants with DS with and without CHD and non-DS controls underwent serial echocardiograms at birth, 6 months, 1 year, and 2 years of age to assess biventricular systolic and diastolic function using deformation analysis. Pulmonary vascular resistance was assessed using pulmonary artery acceleration time and left ventricular (LV) eccentricity index. RESULTS: Infants with DS exhibited smaller LV (birth: 27 ± 4 vs 31 ± 2 mm, P < .01; 2 years: 43 ± 5 vs 48 ± 4 mm, P < .01) and right ventricular (birth: 28 ± 3 vs 31 ± 2 mm, P < .01; 2 years: 40 ± 4 vs 44 ± 3 mm, P < .01) lengths and lower LV (birth: -19% ± 3% vs -22% ± 2%, P < .01; 2 years: -24% ± 2% vs -26% ± 2%, P < .01) and right ventricular (birth: -19% ± 4% vs -22% ± 3%, P < .01; 2 years: -29% ± 6% vs -33% ± 4%, P < .01) systolic strain over the 2-year period. Pulmonary artery acceleration time was lower in the DS group throughout the study period (birth: 44 ± 10 vs 62 ± 14 ms, P < .01; 2 years 71 ± 12 vs 83 ± 11 ms, P < .01). No differences were observed between DS infants with and without CHD (all P > .05). CONCLUSIONS: Infants with DS exhibit impaired maturational changes in myocardial function and pulmonary vascular resistance. Such novel findings provide valuable insights into the pathophysiology affecting cardiorespiratory morbidity in this population.

The role of furosemide and fluid management for a hemodynamically significant patent ductus arteriosus in premature infants.

A patent ductus arteriosus (PDA) in infants born premature can present significant management challenges for neonatal providers. Quantifying a hemodynamically significant PDA (hsPDA) represents the first hurdle, however, identifying the best evidence-based approach amongst conservative, pharmacologic, and/or interventional management options has proven to be even more complicated. Within the conservative arm, furosemide to reduce pulmonary edema and improve lung function has spawned several discussions given the concerns for its upregulation of prostaglandin E2 in the kidneys and conflicting outcomes data. There remains no consensus regarding furosemide use in hsPDAs. In this perspective article, we summarize the approach to defining a hsPDA, review the current practice of furosemide use in the management of hsPDA, and suggest an approach to fluid management and diuresis to address the question: is the routine use of furosemide in hsPDA merited in current practice?