Maternal and infant outcomes in women with sickle cell disease: a matched cohort study.

OBJECTIVE: Women with sickle cell disease (SCD) have adverse maternal and infant outcomes. Our aim was to determine whether the outcomes of SCD mothers and their infants differed from African or Caribbean women not affected by SCD and whether there were differences between SCD individuals with the haemoglobin SS (HbSS) or haemoglobin SC (HbSC) genotypes. Furthermore, we wished to determine if any differences related to deprivation. DESIGN: A matched cohort study. SETTING: Tertiary perinatal centre in London PATIENTS: 4964 African or Caribbean women without SCD and 148 with SCD. MAIN OUTCOME MEASURES: Mode of delivery, maternal exchange transfusion, birthweight, neonatal unit admission, neonatal death and deprivation indices RESULTS: SCD women were more likely to be delivered by caesarean section (p<0.001) and had babies of lower birthweight (p<0.001). Their infants were no more likely to be admitted to neonatal intensive care unit or suffer a neonatal death. There were no significant differences between the SCD women and those without SCD in their deprivation index or deprivation decile. The women with the HbSS genotype compared to those with the HbSC genotype were more anaemic (p<0.02), required more exchange transfusions (p<0.001) and were more likely to be delivered by caesarean section (p=0.008). The infant outcomes did not differ significantly between the genotypes. CONCLUSIONS: Although, the SCD women, particularly those with the HbSS genotype, had greater morbidity, infant morbidity, and mortality was similar in mothers with the HbSS or HbSC genotypes and those without SCD.

Chest radiographic thoracic areas and respiratory outcomes in infants with anterior abdominal wall defects.

OBJECTIVES: Infants with anterior abdominal wall defects (AWD) can suffer from pulmonary complications. Our aims were to determine if the chest radiographic thoracic areas (CRTAs) on day one differed between infants with exomphalos or gastroschisis, whether this related to differing severity of outcomes and if they were lower than those of controls indicating abnormal antenatal lung growth. METHODS: A review of infants with exomphalos or gastroschisis born between January 2004 and January 2023 was conducted. The control group was term, newborn infants ventilated for poor respiratory drive at birth. Chest radiographs on day one were analysed and the highest CRTA in the first 24 h after birth for each infant included in the analysis. RESULTS: The 127 infants with gastroschisis had a lower gestational age and birthweight than the 62 exomphalos infants and 130 controls (all p<0.001) The CRTAs of the controls were greater than the CRTAs of the exomphalos and the gastroschisis infants (p = 0.001). The median CRTA corrected for birthweight was lower in the exomphalos infants [688, IQR 568-875 mm2/kg] than the gastroschisis infants [813, IQE 695-915 mm2/kg] No gastroschisis infant developed bronchopulmonary dysplasia (BPD). A CRTA of 1759 mm2 had a sensitivity of 81 % and specificity of 71 % in predicting BPD in infants with exomphalos. CONCLUSIONS: Infants with gastroschisis or exomphalos had lower CRTAs than controls suggesting both groups had abnormal antenatal lung development. The CRTA was lower in the exomphalos infants who also had worse respiratory outcomes, hence CRTA assessment may a useful prognostic aid.

Study protocol for a randomised cross-over trial of Neurally adjusted ventilatory Assist for Neonates with Congenital diaphragmatic hernias: the NAN-C study.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a mode of mechanical ventilation that delivers oxygen pressures in proportion to electrical signals of the diaphragm. The proportional assistance can be adjusted by the clinician to reduce the patient's work of breathing. Several case series of infants with congenital diaphragmatic hernias (CDH) have shown that NAVA may reduce oxygenation index and mean airway pressures. To date, no clinical trial has compared NAVA to standard methods of mechanical ventilation for babies with CDH. METHODS: The aim of this dual-centre randomised cross-over trial is to compare post-operative NAVA with assist control ventilation (ACV) for infants with CDH. If eligible, infants will be enrolled for a ventilatory support tolerance trial (VSTT) to assess their suitability for randomisation. If clinically stable during the VSTT, infants will be randomised to receive either NAVA or ACV first in a 1:1 ratio for a 4-h period. The oxygenation index, respiratory severity score and cumulative sedative medication use will be measured. DISCUSSION: Retrospective studies comparing NAVA to ACV in neonates with congenital diaphragmatic hernia have shown the ventilatory mode may improve respiratory parameters and benefit neonates. To our knowledge, this is the first prospective cross-over trial comparing NAVA to ACV. TRIAL REGISTRATION: NAN-C was prospectively registered on ClinicalTrials.gov NCT05839340  Registered on May 2023.

Pancreatic Insufficiency, Digestive Enzyme Supplementation, and Postnatal Growth in Preterm Babies.

BACKGROUND: Optimising postnatal growth facilitates better long-term neonatal neurodevelopmental outcomes. Early postnatal growth is often hindered by a variety of factors unique to the extrauterine environment and digestive immaturity both contributing to reduced enteral feed tolerance during the first few days and weeks after birth. Preterm infants display varying levels of pancreatic insufficiency that are related to gestational age and providing digestive enzyme supplementation, may be one way in which to improve postnatal growth in enterally fed preterm babies. SUMMARY: In this review, we explore which exocrine pancreatic enzymes are deficient in preterm babies, the methods by which exocrine pancreatic function is measured, potential avenues by which digestive enzyme replacement might improve postnatal growth failure, and which babies might benefit most from this intervention. KEY MESSAGES: Pancreatic exocrine function exhibits developmental immaturity in extremely preterm infants and may contribute to postnatal growth failure. Stool elastase is a simple, non-invasive method of assessing pancreatic function in preterm infants. Available evidence does not currently support routine use of digestive enzyme supplementation in preterm infants.

Artificial intelligence in the NICU to predict extubation success in prematurely born infants.

OBJECTIVES: Mechanical ventilation in prematurely born infants, particularly if prolonged, can cause long term complications including bronchopulmonary dysplasia. Timely extubation then is essential, yet predicting its success remains challenging. Artificial intelligence (AI) may provide a potential solution. CONTENT: A narrative review was undertaken to explore AI's role in predicting extubation success in prematurely born infants. Across the 11 studies analysed, the range of reported area under the receiver operator characteristic curve (AUC) for the selected prediction models was between 0.7 and 0.87. Only two studies implemented an external validation procedure. Comparison to the results of clinical predictors was made in two studies. One group reported a logistic regression model that outperformed clinical predictors on decision tree analysis, while another group reported clinical predictors outperformed their artificial neural network model (AUCs: ANN 0.68 vs. clinical predictors 0.86). Amongst the studies there was an heterogenous selection of variables for inclusion in prediction models, as well as variations in definitions of extubation failure. SUMMARY: Although there is potential for AI to enhance extubation success, no model's performance has yet surpassed that of clinical predictors. OUTLOOK: Future studies should incorporate external validation to increase the applicability of the models to clinical settings.

Postnatal corticosteroid usage in United Kingdom and Ireland neonatal units.

AIM: To perform a survey on postnatal corticosteroids usage in neonatal units in the United Kingdom and Ireland. METHODS: An 18-item structured questionnaire was created asking for the level of neonatal care and corticosteroid prescribing practices. A consultant neonatologist or senor specialty training registrar/advanced neonatal nurse practitioner was contacted in every neonatal unit in the UK and Ireland between September and December 2022. RESULTS: The response rate to the survey was 96% (203 of 211 units). Postnatal corticosteroids were prescribed in 48% of units: 5% of special care units, 43% of local neonatal units and 100% of neonatal intensive care units. Most units (90%) prescribed dexamethasone, which was prescribed to infants born at gestational ages less than 30 weeks in all those units prescribing postnatal corticosteroids, however, eight units also reported use in infants greater than 30 weeks of gestation. Dexamethasone regimens varied with starting doses from 50 to 500 µg/kg/day. Most tertiary units (97%) prescribed repeated courses of dexamethasone. In all levels of neonatal care, postnatal corticosteroids were prescribed to ventilated infants as well as those receiving non-invasive respiratory support. CONCLUSION: There is use of postnatal corticosteroids in all levels of neonatal care and much of the practice is not evidence based.

Carboxyhaemoglobin levels in infants with hypoxic ischaemic encephalopathy.

OBJECTIVES: Hypoxic ischaemic encephalopathy (HIE) is associated with oxidative stress. A potential marker of oxidative damage is carboxyhaemoglobin (COHb) which is the product of the reaction between carbon monoxide and haemoglobin and is routinely assessed on blood gas analysis. Our objective was to test the hypothesis that higher COHb levels would be associated with worse outcomes in infants treated for HIE. METHODS: A retrospective, observational study was performed of all infants who received whole body hypothermia for HIE at a tertiary neonatal intensive care unit between January 2018 and August 2021. For each participating infant, the highest COHb level per day was recorded for days one, three and five after birth. RESULTS: During the study period, 67 infants with a median (IQR) gestational age of 40 (38-41) weeks underwent therapeutic hypothermia for HIE. The median (IQR) COHb level on day three was higher in infants without electroencephalographic seizures (1.4 [1.1-1.4] %) compared with infants with seizures (1.1 [0.9-1.3] %, p=0.024). The median (IQR) COHb on day five was higher in infants without MRI brain abnormalities (1.4 [1.2-1.7] %) compared with infants with MRI abnormalities (1.2 [1.0-1.4] %, p=0.032). The COHb level was not significantly different between the nine infants who died compared to the infants who survived. CONCLUSIONS: COHb levels were higher in infants with HIE without seizures and in those with normal MRI brain examinations. We suggest that carbon monoxide has a potential protective role in HIE.

Systematic review of the long-term effects of postnatal corticosteroids.

BACKGROUND: Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects. CONTENT: A systematic review was performed to determine the childhood and adolescent cardiopulmonary and cognitive effects of dexamethasone systemically administered to preterm infants during neonatal intensive care. Relevant studies were identified by searching two electronic health databases and the grey literature. Spirometry assessments were used as respiratory outcomes, blood pressure and echocardiography assessments as cardiovascular outcomes and cognitive and motor function as cognitive outcomes. From 1,479 articles initially identified, 18 studies (overall 1,609 patients) were included (respiratory n=8, cardiovascular n=2, cognitive n=10); all were observational cohort studies. Dexamethasone exposure was associated with worse pulmonary outcomes in children and adolescents (more abnormal FVC and FEV1:FVC z scores). Dexamethasone exposure was associated in one study with lower IQ scores compared to preterm controls (mean 78.2 [SD 15.0] vs. 84.4 [12.6], [p=0.008]) and in two others was associated with lower total and performance IQ when compared to term controls (p<0.001). SUMMARY AND OUTLOOK: Postnatal dexamethasone exposure has a negative influence on pulmonary and cognitive outcomes in childhood and adolescence. Medications with a better benefit to risk profile need to be identified.

Does closed-loop automated oxygen control reduce the duration of supplementary oxygen treatment and the amount of time spent in hyperoxia? A randomised controlled trial in ventilated infants born at or near term.

BACKGROUND: Ventilated infants frequently require supplemental oxygen, but its use should be monitored carefully due to associated complications. The achievement of oxygen saturation (SpO2) targets can be challenging as neonates experience frequent fluctuations of their oxygen levels that further increase the risk of complications. Closed-loop automated oxygen control systems (CLAC) improve achievement of oxygen saturation targets, reduce hyperoxaemic episodes and facilitate weaning of the inspired oxygen concentration in ventilated infants born at or near term. This study investigates whether CLAC compared with manual oxygen control reduces the time spent in hyperoxia and the overall duration of supplemental oxygen treatment in ventilated infants born at or above 34 weeks gestation. METHODS: This randomised controlled trial performed at a single tertiary neonatal unit is recruiting 40 infants born at or above 34 weeks of gestation and within 24 h of initiation of mechanical ventilation. Infants are randomised to CLAC or manual oxygen control from recruitment till successful extubation. The primary outcome is the percentage of time spent in hyperoxia (SpO2 > 96%). The secondary outcomes are the overall duration of supplementary oxygen treatment, the percentage of time spent with an oxygen requirement above thirty per cent, the number of days on mechanical ventilation and the length of neonatal unit stay. The study is performed following informed parental consent and was approved by the West Midlands-Edgbaston Research Ethics Committee (Protocol version 1.2, 10/11/2022). DISCUSSION: This trial will investigate the effect of CLAC on the overall duration of oxygen therapy and the time spent in hyperoxia. These are important clinical outcomes as hyperoxic injury is related to oxidative stress that can adversely affect multiple organ systems. TRIAL REGISTRATION: ClinicalTrials.Gov NCT05657795. Registered on 12/12/2022.

Ventilatory response to added dead space in infants exposed to second-hand smoke in pregnancy.

Maternal cigarette smoking in pregnancy can adversely affect infant respiratory control. In utero nicotine exposure has been shown to blunt the infant ventilatory response to hypercapnia, which could increase the risk of sudden infant death syndrome. The potential impact of maternal second-hand smoke exposure, however, has not yet been determined. The aim of this study was to assess ventilatory response to added dead-space (inducing hypercapnia) in infants with second-hand smoke exposure during pregnancy, in infants whose mothers smoked and in controls (non-smoke exposed). Infants breathed through a face mask and specialised "tube-breathing" circuit, incorporating a dead space of 4.4 ml/kg body weight. The maximum minute ventilation (MMV) during added dead space breathing was determined and the time taken to achieve 63% of the MMV calculated (the time constant (TC) of the response). Infants were studied on the postnatal ward prior to discharge home. Thirty infants (ten in each group) were studied with a median gestational age of 39 [range 37-41] weeks, birthweight of 3.1 [2.2-4.0] kg, and postnatal age of 33 (21-62) h. The infants whose mothers had second-hand smoke exposure (median TC 42 s, p = 0.001), and the infants of cigarette smoking mothers (median TC 37 s, p = 0.002) had longer time constants than the controls (median TC 29 s). There was no significant difference between the TC of the infants whose mothers had second-hand smoke exposure and those whose mothers smoked (p = 0.112).    Conclusion: Second-hand smoke exposure during pregnancy was associated with a delayed newborn ventilatory response. What is Known: • Maternal cigarette smoking in pregnancy can adversely affect infant respiratory control. • The potential impact of maternal second-hand smoke exposure, however, has not yet been determined. What is New: • We have assessed the ventilatory response to added dead-space (inducing hypercapnia) in newborns with second-hand smoke exposure during pregnancy, in infants whose mothers smoked, and in controls (non-smoke exposed). • Maternal second-hand smoke exposure, as well as maternal smoking, during pregnancy was associated with a delayed newborn ventilatory response.

Closed-loop oxygen system in late preterm/term, ventilated infants with different severities of respiratory disease.

AIM: To evaluate closed-loop automated oxygen control (CLAC) in ventilated infants >33 weeks of gestation with different respiratory disease severities. METHODS: Infants were studied on two consecutive days for 6 h each day. They were randomised to receive standard care or standard care with CLAC (Oxygenie) first. Analyses were performed of the results of infants with or without an FiO2 ≥ 0.3 and infants with congenital diaphragmatic hernia (CDH). RESULTS: Thirty-one infants with a median (IQR) gestational age of 37.9 (37.1-38.9) weeks were studied at a median postmenstrual age (IQR) of 38.9 (37.4-39.8) weeks. In infants with an FiO2 ≥ 0.3 (n = 8), CLAC increased the time spent in target oxygen range (92-96%) by 61.6% (p = 0.018), whereas in infants with an FiO2 < 0.3, the time in target was increased by 3.8% (p = 0.019). During CLAC, only infants with an FiO2 ≥ 0.3 spent less time in hyperoxemia (SpO2 > 96%) (p = 0.012) and hyperoxemic episodes were shorter (p = 0.012). In both groups, CLAC reduced the duration of desaturations (SpO2 < 92%, p < 0.001). In CDH infants, CLAC increased the time spent in target oxygen range by 34% (p = 0.036) and the median duration of desaturations was reduced (p = 0.028). CONCLUSION: CLAC may be more useful in infants with more severe respiratory distress.

Randomised study of heart rate measurement in preterm newborns with ECG plus pulse oximetry versus oximetry alone.

AIM: To determine whether the IntelliVue monitor (ECG plus Masimo pulse oximeter (PO)) displays heart rate (HR) at birth more quickly than Nellcor PO (PO alone) among infants of 29-35 weeks' gestational age. METHODS: Unmasked parallel group randomised (1:1) study. RESULTS: We planned to enrol 100 infants; however, the study was terminated due to the COVID-19 pandemic when 39 infants had been enrolled (17 randomised to IntelliVue, 22 to Nellcor). We found no differences between the groups in the time to first HR display (median (IQR) IntelliVue ECG 49 (33, 71) vs Nellcor 47 (37, 86) s, p>0.999), in the proportion who had a face mask applied for breathing support, or in the time at which it was applied. Infants monitored with IntelliVue were handled more frequently and for longer. CONCLUSION: IntelliVue ECG did not display HR more quickly than Nellcor PO in preterm infants. We found no differences in the rate of or time to intervention between groups. Our study was terminated early so these findings should be interpreted with caution. TRIAL REGISTRATION NUMBER: ISRCTN16473881.

Clinical Heterogeneity in Familial IgA Nephropathy.

BACKGROUND: IgA nephropathy is the most common primary glomerulonephritis worldwide and a significant cause of end-stage renal disease (ESRD). While most cases of IgA nephropathy are considered sporadic, familial cases have been reported. METHODS: We performed a national audit of 1,809 patients attending renal clinics and dialysis units to identify a family history among patients with kidney disease. We reviewed all renal biopsies performed at our institution spanning a 30-year period. Paediatric cases were not included. RESULTS: We identified 14 families involving 41 affected individuals with biopsy-proven IgA nephropathy and at least one other member with either biopsy-proven IgA nephropathy or ESRD. Detailed family histories were obtained, medical records reviewed and family pedigrees constructed. Retrospective application of the MESTC criteria to all familial IgA biopsies was performed. Seven families had 2 or more members with biopsy-proven IgA nephropathy, equating to 23 (1.8%) of 1,283 biopsies with IgA nephropathy over the last 30 years. A complex inheritance pattern was observed, with autosomal dominant and autosomal recessive families identified with varying penetrance. There was a male preponderance (68%), and a complex heterogeneity in the clinical and histopathological features of familial IgA patients (age range 16-60 years; creatinine range 60-350 µmol/L). We observed a high rate (66%) of progression to ESRD, with a mean time to progression of 5.13 years (SD 1.8 years; range 2-8 years). Among those patients who had undergone transplantation, recurrence of disease was reported in 5 (50%) cases. CONCLUSION: These data suggests familial aggregation of IgA nephropathy, confirm the clinical and histopathological heterogeneity and raise the possibility of monogenic inheritance.

Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.

We report a female child from an Irish Traveller family presenting with severe intellectual disability, dysmorphic features, renal anomalies, dental caries and cyclical vomiting. Current health issues include global developmental delay, mild concentric left ventricular hypertrophy, dental malocclusion and caries and a single duplex left kidney. The proband and her mother also have multiple epiphyseal dysplasia. Whole-exome sequencing was performed to identify the underlying genetic cause. DNA from the proband was enriched with the Agilent Sure Select v5 Exon array and sequenced on an Illumina HiSeq. Rare homozygous variants were prioritized. Whole-exome sequencing identified three linked homozygous missense variants in THOC6 (c.298T>A, p.Trp100Arg; c.700G>C, p.Val234Leu; c.824G>A, p.Gly275Asp) as the likely cause of this child's intellectual disability syndrome, resulting in a molecular diagnosis of Beaulieu-Boycott-Innes syndrome (BBIS). This is the first report of BBIS in Europe. BBIS has been reported previously in two Hutterite families and one Saudi family. A review of all patients to date shows a relatively homogenous phenotype. Core clinical features include low birth weight with subsequent growth failure, short stature, intellectual disability with language delay, characteristic facies, renal anomalies and dental malocclusion with caries. Some patients also have cardiac defects. All patients show characteristic dysmorphic facial features including a tall forehead with high anterior hairline and deep-set eyes with upslanting palpebral fissures. The coexistence of intellectual disability together with these characteristic facies should provide a diagnostic clue for BBIS during patient evaluation.

Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment.

Bone is the most common site of metastasis for breast cancer, however the reasons for this remain unclear. We hypothesise that under certain conditions mammary cells possess osteomimetic capabilities that may allow them to adapt to, and flourish within, the bone microenvironment. Mammary cells are known to calcify within breast tissue and we have recently reported a novel in vitro model of mammary mineralization using murine mammary adenocarcinoma 4T1 cells. In this study, the osteomimetic properties of the mammary adenocarcinoma cell line and the conditions required to induce mineralization were characterized extensively. It was found that exogenous organic phosphate and inorganic phosphate induce mineralization in a dose dependent manner in 4T1 cells. Ascorbic acid and dexamethasone alone have no effect. 4T1 cells also show enhanced mineralization in response to bone morphogenetic protein 2 in the presence of phosphate supplemented media. The expression of several bone matrix proteins were monitored throughout the process of mineralization and increased expression of collagen type 1 and bone sialoprotein were detected, as determined by real-time RT-PCR. In addition, we have shown for the first time that 3D collagen glycosaminoglycan scaffolds, bioengineered to represent the bone microenvironment, are capable of supporting the growth and mineralization of 4T1 adenocarcinoma cells. These 3D scaffolds represent a novel model system for the study of mammary mineralization and bone metastasis. This work demonstrates that mammary cells are capable of osteomimicry, which may ultimately contribute to their ability to preferentially metastasize to, survive within and colonize the bone microenvironment.