Digital fetal scalp stimulation (dFSS) versus fetal blood sampling (FBS) to assess fetal wellbeing in labour-a multi-centre randomised controlled trial: Fetal Intrapartum Randomised Scalp Stimulation Trial (FIRSST NCT05306756).

BACKGROUND: Cardiotocography (CTG) is a screening test used to detect fetal hypoxia in labour. It has a high false positive rate resulting in many potentially unnecessary caesarean sections. Fetal blood sampling (FBS) is a second-line test of the acid-base status of the fetus. It is used to provide either reassurance that it is safe for labour to continue or objective evidence of compromise so that delivery can be expedited. Digital fetal scalp stimulation (dFSS) to elicit a fetal heart rate acceleration is an alternative less invasive second-line test of fetal wellbeing. This study aims to provide robust evidence on the role of these two second-line tests in assessing fetal wellbeing and potentially preventing operative delivery. METHODS: A multi-centre parallel group randomised controlled trial (RCT) is planned in four maternity centres in Ireland. The study aims to recruit 2500 nulliparous women with a term (≥37+0 weeks) singleton pregnancy who require a second-line test of fetal wellbeing in labour due to an abnormal CTG. Women will be allocated randomly to dFSS or FBS on a 1:1 ratio. The primary outcome is caesarean section. With 1250 women in each arm, the study will have 90% power to detect a difference of 5-6%, at a two-sided alpha significance level of 5%, assuming a caesarean section rate of at least 20% in the dFSS group. DISCUSSION: If the proposed study shows evidence that dFSS is a safe, reliable and effective alternative to FBS, this would have ground-breaking implications for labour management worldwide. It could potentially lead to a reduction in invasive procedures and emergency caesarean sections. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306756. Registered on 31 March 2022. The trial commenced enrolment on 10 May 2022. Ethical committee approval has been granted by the Research Ethics Committee (REC) of each hospital: Dublin/CWIUH REC: 12.06.2019; Cork/UCC REC: 29.11.2019; Galway/NUIG REC: 06.09.2019; Limerick/UL REC: 30.09.2019.

Paediatric and neonatal sepsis and inflammation.

Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

Carbon dioxide levels in neonates: what are safe parameters?

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.

Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy.

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.

Altered inflammasome activation in neonatal encephalopathy persists in childhood.

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1ß, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1ß and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1ß gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.

Paediatric Head Injury and Traumatic Brain Injury.

Aim To determine prevalence of head injury presenting to paediatric emergency departments (PEDs) and characterise by demographics, triage category, disposition neuroimaging or re-attendance. Methods Presentations in 2014 and 2015, with diagnoses of head injury, intracranial bleed, skull fracture including single or re-attendances within 28 days post head injury to all national PEDs, were analysed. Demographics, triage score, imaging rate, admission, mechanisms and representation rate were recorded. Results Head injury was diagnosed in 13,392 of 224,860 (5.9%), median (IQR) age 3.9 (1.4 - 8.3) years. Regionally 3% of children <5 years attend each year. The total admitted/transferred was 10.8% (n=1460). Neuroimaging rate was 4.3% (n= 570). Falls predominated. Sport accounted for 12.2%. Conclusion One in twenty children PED presentations are head injury, over half in preschool children. A sizeable number were symptomatic reflected by admission, transfer, imaging or re-attendance. Observational management was favoured over imaging reflected in the higher admission versus imaging rate.

Children's Palliative Care; the identified Learning Needs of Paediatricians.

Aim To determine baseline learning needs of Paediatricians in Ireland when caring for children with palliative care needs. Methods A questionnaire based online survey was conducted. Results One hundred and fourteen paediatricians responded to the survey, the majority were Specialist Registrars but almost half were consultant paediatricians (46% n=52). Most had never had formal education in the paediatric palliative care (57% n=48). Areas of future training that were ranked as important or highly important (percentage of respondents) included: pain management (98% n=81), management of the dying child (96% n=80), palliative care resources (95%n=79), advanced care planning (95% n=79) and communication skills (86% n=71). Those surveyed were asked to comment on the challenges of recent clinical interactions, on analysis three overarching themes emerged; best interests of the child, inadequate training and confidence and co-ordinating care. Conclusion This survey highlights the learning needs of paediatricians and will inform the development of meaningful education sessions for doctors.

Dynamic platelet function on von Willebrand factor is different in preterm neonates and full-term neonates: changes in neonatal platelet function.

Essentials It is unclear if platelet function differs between preterm and full-term neonates. Platelet behavior was characterized using a flow-based assay on von Willebrand Factor (VWF). Preterms had increased platelet interaction with VWF and glycoprotein Ibα expression. Platelets from preterm neonates behave differently on VWF compared to full-term neonates. SUMMARY: Background Very low birth weight (VLBW) preterm neonates have an increased risk of hemorrhage-related morbidity and mortality as compared with their full-term counterparts. It is unclear whether platelet function differs between preterm and full-term neonates. This is partly because of the large volumes of blood required to perform standard platelet function tests, and the difficulty in obtaining such samples in neonates. Objectives This study was designed to characterize platelet behavior in neonates with a physiologic flow-based assay that quantifies platelet function in microliter volumes of blood under arterial shear. Methods Blood from VLBW preterm neonates of ≤ 32 weeks' gestation (n = 15) and full-term neonates (n = 13) was perfused under arterial shear over surface-immobilized von Willebrand factor (VWF). Platelet behavior was recorded by digital-image microscopy and analyzed. Surface expression of platelet glycoprotein (GP) Ibα and GPIIIa of VLBW preterm and full-term neonates was also measured. Results VLBW preterm neonates had increased numbers of platelets interacting with VWF, and increased GPIbα expression on the platelet surface. Despite the increased numbers of VWF interactions as reflected by flow-driven platelet translocation along the protein surface, no significant differences were observed in the numbers of platelets that adhered in a stationary fashion to VWF. Platelets from VLBW preterm neonates and those from full-term neonates behaved differently on VWF. Conclusions These differences in platelet function may contribute to the higher incidence of bleeding observed in VLBW preterm neonatal populations, or may represent a compensatory mechanism to counteract this risk of bleeding.

Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy.

AIM: Circulating immune cell activation is associated with worse outcome in adult and animal models of brain injury. Our aim was to profile the systemic inflammatory response over the first week of life in infants at risk of neonatal encephalopathy and correlate early neutrophil and monocyte endotoxin and activation responses with outcome. METHODS: Prospective observational study in a tertiary referral university hospital including 22 infants requiring resuscitation at birth who had serial (five time points) neutrophil and monocyte CD11b (marker of cell adhesion) (intracellular Reactive oxygen intermediates) ROI (cell activation), and Toll-like receptor (endotoxin recognition) before and after endotoxin stimulation ex vivo compared to neonatal controls. RESULTS: All neonates requiring resuscitation at delivery (n = 122 samples) had higher neutrophil and monocyte CD11b and TLR-4 expressions compared with adults and neonatal controls. Neonates with abnormal neuroimaging and/or severe neonatal encephalopathy had increased CD11b, ROI and TLR-4. Increased PMN TLR-4 expression was associated with increased mortality in infants with neonatal encephalopathy (NE). CONCLUSION: Innate immune dysregulation in the first week of life is associated with severity of outcome in neonatal brain injury in this cohort and may be amenable to immunomodulation.

Correction of vitamin D deficiency in a cohort of newborn infants using daily 200 IU vitamin D supplementation.

INTRODUCTION: Although the role of vitamin D in the prevention of rickets has long been well established, controversies still exist on the ideal dose of vitamin D supplementation in infants. OBJECTIVE: We assessed serum 25-hydroxyvitamin D (25OHD) status simultaneously in maternal and cord samples and the response to vitamin D3 supplementation in neonates. METHODS: Serum 25OHD levels were evaluated from maternal, and umbilical cord samples from term normal pregnancies. Repeat 25OHD levels were assessed in neonates with 25OHD below 30 nmol/L following vitamin D3 200 IU daily after 6 weeks. RESULTS: Blood samples were taken including 57 cord samples and 16 follow-up neonatal samples. Maternal and cord serum 25OHD were 43 ± 21 and 29 ± 15 nmol/L, respectively. Infants with 25OHD < 30 nmol/L (19.8 ± 4.7 nmol/L) had a significant increase in serum 25OHD (63.3 ± 14.5 nmol/L) following vitamin D3 200 IU daily after 6 weeks. CONCLUSION: Healthy Irish infants born at term are at high risk of vitamin D deficiency, but vitamin D3 200 IU daily, rapidly corrects poor vitamin D status.

Neonatal brain injury and systemic inflammation: modulation by activated protein C ex vivo.

Infection and inflammation can be antecedents of neonatal encephalopathy (NE) and increase the risk of neurological sequelae. Activated protein C (APC) has anti-coagulant and anti-inflammatory effects and provides neuroprotection in brain and spinal cord injury. We examined neutrophil and monocyte responses to lipopolysaccharide (LPS) in infants with NE compared with healthy adult and neonatal controls, and also studied the effect of APC. Whole blood was incubated with LPS and APC and Toll-like receptor (TLR)-4 (LPS recognition), CD11b expression (activation) and intracellular reactive oxygen intermediate (ROI; function) release from neutrophils and monocytes was examined by flow cytometry serially from days 1 to 7. We found a significant increase in neutrophil ROI in infants with NE on day 3 following LPS compared to neonatal controls and this augmented response was reduced significantly by APC. Neutrophil and monocyte CD11b expression was increased significantly on day 1 in infants with NE compared to neonatal controls. LPS-induced neutrophil TLR-4 expression was increased significantly in infants with NE on days 3 and 7 and was reduced by APC. LPS-induced monocyte TLR-4 was increased significantly in infants with NE on day 7. Neutrophil and monocyte activation and production of ROIs may mediate tissue damage in infants with NE. APC modified LPS responses in infants with NE. APC may reduce the inflammatory responses in NE and may ameliorate multi-organ dysfunction. Further study of the immunomodulatory effects of protein C may be warranted using mutant forms with decreased bleeding potential.

Impact of maternal diet on neonatal anthropometry: a randomized controlled trial.

OBJECTIVE: Large for gestational age infants are at increased risk of childhood obesity and maternal nutrition impacts birthweight. The aim of this study was to assess the impact of a maternal low glycaemic index (GI) diet on neonatal anthropometry. METHODS: The ROLO (Randomised Control Trial of Low Glycaemic Index Diet in Pregnancy) study was a randomized controlled trial to assess the impact of a low GI diet versus usual diet on birthweight. It took place in a tertiary maternity hospital in Ireland and women were randomized to receive either a low GI diet or no dietary intervention from early pregnancy to term. Two hundred sixty-five neonates had anthropometric measurements on day 1-2 of life, 126 in the intervention group and 139 in the control group. Measurements included birthweight, length and circumferences of the head, chest, abdominal, thigh and mid-upper arm. A subgroup of 219 (82%) neonates also had skin-fold measurements. RESULTS: Neonates whose mothers had a low GI diet in pregnancy had lower thigh circumference (15.9 ± 1.7 cm vs. 16.6 ± 1.5 cm, P = 0.04). There was no difference between the intervention and control groups in head, chest abdominal or mid-upper arm circumferences. No difference was noted between the two groups for any skin-fold measurements (subscapular, thigh, biceps and triceps). CONCLUSION: Neonatal thigh circumference was altered by maternal low GI diet in pregnancy. These findings suggest that maternal low GI diet is safe in pregnancy and may positively impact infant adiposity.

Vitamin D and neonatal immune function.

Vitamin D deficiency is widespread in the neonatal and paediatric population of northern latitudes, particularly in children of African, Middle Eastern and Asian ethnicity. This is associated with diminished immune function and increases the risk of Th1 autoimmune diseases like type 1 diabetes. Epidermiological studies have also shown a link between vitamin D deficiency in children and a more severe course of illness with lower respiratory tract infection or Respiratory Syncitial Virus (RSV) bronchiolitis. The mechanism by which vitamin D enhances immunity is complex. It acts through the innate immune system by inducing antimicrobial peptides in epithelial cells, neutrophils and macrophages. The role of Vitamin D in neonatal and paediatric immunomodulation requires further study.