A comparative analyses of lipid ratios representing desaturase enzyme activity between preterm and term infants within the first ten weeks of life.

BACKGROUND: Desaturase enzymes play a key role in several pathways including biosynthesis of poly- and mono- unsaturated fatty acids (PUFAs, MUFA). In preterm infants, desaturase enzyme activity (DA) may be a rate-limiting step in maintaining PUFAs levels during this critical developmental window and impact on long term metabolic health. The study tested the hypothesis that DA is altered in preterm infants compared to term infants in early life and may be a marker of risk or contribute to later alterations in metabolic health. METHODS: Lipidomic analyses were conducted using blood samples from two established UK-based cohorts, involving very preterm (n = 105) and term (n = 259) infants. Blood samples were taken from term infants at birth, two and six weeks and from preterm infants when established on enteral feeds and at term corrected age. DA of the 2 groups of infants were estimated indirectly from product/precursor lipids ratios of phosphatidylcholine (PC) and triglycerides (TG) species and reported according to their postmenstrual and postnatal ages. RESULTS: There were changes in lipid ratios representing desaturase enzyme activity in preterm infants in the first weeks of life with higher delta 6 desaturases (D6D) triglyceride (TG) indices but significantly lower delta 9 desaturase (D9D) and D6D(PC) indices. In comparison to term infants, preterm have lower delta 5 desaturase (D5D) but higher D6D indices at all postnatal ages. Although point levels of desaturase indices were different, trajectories of changes in these indices over time were similar in preterm and term infants. CONCLUSIONS: This study findings suggest the patterns of desaturase indices in preterm infants differ from that of term infants but their trajectories of change in the first 10 weeks of life were similar. These differences of DA if they persist in later life could contribute to the mechanism of diseases in preterm adulthood and warrant further investigations.

Should continuous glucose monitoring be used to manage neonates at risk of hypoglycaemia?

The National Institute for Clinical Excellence (NICE) now recommends that continuous glucose monitoring (CGM) be offered to adults and children with diabetes who are at risk from hypoglycaemia. Hypoglycaemia is common in the neonatal period, and is a preventable cause of poor neurodevelopmental outcome, but is CGM helpful in the management of neonates at risk of hypoglycaemia? Neonatal studies have shown that CGM can detect clinically silent hypoglycaemia, which has been associated with reduced executive and visual function in early childhood. Intervention trials have further shown CGM can support the targeting of glucose levels in high-risk extremely preterm neonates. In spite of significant advances in technology, including smaller sensors, better accuracy and factory calibration, further progress and adoption into clinical practice has been limited as current devices are not designed nor have regulatory approval for the specific needs of the newborn. The use of CGM has the potential to support clinical management, and prevention of hypoglycaemia but must be set within its current limitations. The data CGM provides however also provides an important opportunity to improve our understanding of potential risks of hypoglycaemia and the impact of clinical interventions to prevent it.

Continuous glucose monitoring during therapeutic hypothermia for hypoxic ischaemic encephalopathy: a feasibility study.

OBJECTIVES: Glucose dysregulation is common in infants with hypoxic ischaemic encephalopathy (HIE) and is likely to exacerbate cerebral injury. Infrequent measurement of glucose concentrations makes both identification and prevention of this risk challenging. Continuous glucose monitoring (CGM) has the potential to address both these challenges, but has not been explored in these infants. We aimed to evaluate the feasibility and potential impact of real-time CGM in term infants with HIE being treated with therapeutic hypothermia (TH). DESIGN: Feasibility study. SETTING: Tertiary-level neonatal unit, UK. PATIENTS: Term infants with HIE undergoing TH. INTERVENTION: A CGM sensor was inserted within 48 hours of birth and kept in situ for the first week of life. Clinical staff were blinded to the CGM recordings and clinical decisions were based on blood glucose assays. MAIN OUTCOME MEASURES: (1) Accuracy of CGM values during and post TH, (2) Per cent of time spent outside the clinical range (2.6-10 mmol/L), (3) Episodes of hypoglycaemia and hyperglycaemia, (4) Adverse effects. RESULTS: The accuracy of CGM values during TH were comparable to those when infants were normothermic. There was wide variation in per cent time outside the target range (2.6-10 mmol/L) between infants (median 5%, range 0%-34%). CGM identified 44% of infants with ≥1 episode of hypoglycaemia (<2.6 mmol/L) and 50% with ≥1 episode of hyperglycaemia (>10 mmol/L). No adverse events were observed. CONCLUSIONS: This study demonstrates that CGM could be a useful adjunct for glucose monitoring in babies undergoing TH who are at risk of both hypoglycaemia and hyperglycaemia.

Drug delivery from a solid formulation during breastfeeding-A feasibility study with mothers and infants.

BACKGROUND: Breastfeeding is critical to health outcomes, particularly in low-resource settings where there is little access to clean water. For infants in their first twelve months of life, the delivery of medications is challenging, and use of oral syringes to deliver liquid formulations can pose both practical and emotional challenges. OBJECTIVE: To explore the potential to deliver medicine to infants via a solid formulation during breastfeeding. METHODS: Single center feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. A solid formulation of Vitamin B12 was delivered to infants during breastfeeding. Outcomes included the quantitative change in serum vitamin B12 and assessment of maternal expectations and experiences. RESULTS: Delivery of Vitamin B12 through a solid formulation that dissolved in human milk did not impair breastfeeding, and Vitamin B12 levels rose in all infants from a mean baseline (range) 533 pg/mL (236-925 pg/mL) to 1871 pg/mL (610-4981 pg/mL) at 6-8 hours post-delivery. Mothers described the surprising ease of 'drug' delivery, with 85% reporting a preference over the use of syringes. CONCLUSIONS: Solid drug formulations can be delivered during breastfeeding and were preferred by mothers over the delivery of liquid formulations via a syringe.

Continuous Glucose Monitoring in the Management of Neonates With Persistent Hypoglycemia and Congenital Hyperinsulinism.

BACKGROUND: Persistent hypoglycemia is common in the newborn and is associated with poor neurodevelopmental outcome. Adequate monitoring is critical in prevention, but is dependent on frequent, often hourly blood sampling. Continuous glucose monitoring (CGM) is increasingly being used in children with type 1 diabetes mellitus, but use in neonatology remains limited. We aimed to introduce real-time CGM to provide insights into patterns of dysglycemia and to support the management of persistent neonatal hypoglycemia. METHODS: This is a single-center retrospective study of real-time CGM use over a 4-year period in babies with persistent hypoglycemia. RESULTS: CGMs were inserted in 14 babies: 8 term and 6 preterm infants, 9 with evidence of congenital hyperinsulinism (CHI). A total of 224 days of data was collected demonstrating marked fluctuations in glucose levels in babies with CHI, with a higher sensor glucose SD (1.52 ±â€…0.79 mmol/L vs 0.77 ±â€…0.22 mmol/L) in infants with CHI compared with preterm infants. A total of 1254 paired glucose values (CGM and blood) were compared and gave a mean absolute relative difference of 11%. CONCLUSION: CGM highlighted the challenges of preventing hypoglycemia in these babies when using intermittent blood glucose levels alone, and the potential application of CGM as an adjunct to clinical care.

Hyperglycaemia in the Newborn Infant. Physiology Verses Pathology.

Hyperglycemia is common in newborns requiring intensive care, particularly in preterm infants, in sepsis and following perinatal hypoxia. The clinical significance, and optimal intervention strategy varies with context, but hyperglycaemia is associated with increased mortality and morbidity. The limited evidence for optimal clinical targets mean controversy remains regarding thresholds for intervention, and management strategies. The first consideration in the management of hyperglycaemia must be to ascertain potentially treatable causes. Calculation of the glucose infusion rate (GIR) to insure this is not excessive, is critical but the use of insulin is often helpful in the extremely preterm infant, but is associated with an increased risk of hypoglycaemia. The use of continuous glucose monitoring (CGM) has recently been demonstrated to be helpful in targeting glucose control, and reducing the risk from hypoglycaemia in the preterm infant. Its use in other at risk infants remains to be explored, and further studies are needed to provide a better understanding of the optimal glucose targets for different clinical conditions. In the future the combination of CGM and advances in computer algorithms, to provide intelligent closed loop systems, could allow a safer and more personalized approached to management.

Antenatal Determinants of Childhood Obesity in High-Risk Offspring: Protocol for the DiGest Follow-Up Study.

Childhood obesity is an area of intense concern internationally and is influenced by events during antenatal and postnatal life. Although pregnancy complications, such as gestational diabetes and large-for-gestational-age birthweight have been associated with increased obesity risk in offspring, very few successful interventions in pregnancy have been identified. We describe a study protocol to identify if a reduced calorie diet in pregnancy can reduce adiposity in children to 3 years of age. The dietary intervention in gestational diabetes (DiGest) study is a randomised, controlled trial of a reduced calorie diet provided by a whole-diet replacement in pregnant women with gestational diabetes. Women receive a weekly dietbox intervention from enrolment until delivery and are blinded to calorie allocation. This follow-up study will assess associations between a reduced calorie diet in pregnancy with offspring adiposity and maternal weight and glycaemia. Anthropometry will be performed in infants and mothers at 3 months, 1, 2 and 3 years post-birth. Glycaemia will be assessed using bloodspot C-peptide in infants and continuous glucose monitoring with HbA1c in mothers. Data regarding maternal glycaemia in pregnancy, maternal nutrition, infant birthweight, offspring feeding behaviour and milk composition will also be collected. The DiGest follow-up study is expected to take 5 years, with recruitment finishing in 2026.

Real-time continuous glucose monitoring in preterm infants (REACT): an international, open-label, randomised controlled trial.

BACKGROUND: Hyperglycaemia and hypoglycaemia are common in preterm infants and have been associated with increased risk of mortality and morbidity. Interventions to reduce risk associated with these exposures are particularly challenging due to the infrequent measurement of blood glucose concentrations, with the potential of causing more harm instead of improving outcomes for these infants. Continuous glucose monitoring (CGM) is widely used in adults and children with diabetes to improve glucose control, but has not been approved for use in neonates. The REACT trial aimed to evaluate the efficacy and safety of CGM in preterm infants requiring intensive care. METHODS: This international, open-label, randomised controlled trial was done in 13 neonatal intensive care units in the UK, Spain, and the Netherlands. Infants were included if they were within 24 h of birth, had a birthweight of 1200 g or less, had a gestational age up to 33 weeks plus 6 days, and had parental written informed consent. Infants were randomly assigned (1:1) to real-time CGM or standard care (with masked CGM for comparison) using a central web randomisation system, stratified by recruiting centre and gestational age (<26 or ≥26 weeks). The primary efficacy outcome was the proportion of time sensor glucose concentration was 2·6-10 mmol/L for the first week of life. Safety outcomes related to hypoglycaemia (glucose concentrations <2·6 mmol/L) in the first 7 days of life. All outcomes were assessed on the basis of intention to treat in the full analysis set with available data. The study is registered with the International Standard Randomised Control Trials Registry, ISRCTN12793535. FINDINGS: Between July 4, 2016, and Jan 27, 2019, 182 infants were enrolled, 180 of whom were randomly assigned (85 to real-time CGM, 95 to standard care). 70 infants in the real-time CGM intervention group and 85 in the standard care group had CGM data and were included in the primary analysis. Compared with infants in the standard care group, infants managed using CGM had more time in the 2·6-10 mmol/L glucose concentration target range (mean proportion of time 84% [SD 22] vs 94% [11]; adjusted mean difference 8·9% [95% CI 3·4-14·4]), equivalent to 13 h (95% CI 5-21). More infants in the standard care group were exposed to at least one episode of sensor glucose concentration of less than 2·6 mmol/L for more than 1 h than those in the intervention group (13 [15%] of 85 vs four [6%] of 70). There were no serious adverse events related to the use of the device or episodes of infection. INTERPRETATION: Real-time CGM can reduce exposure to prolonged or severe hyperglycaemia and hypoglycaemia. Further studies using CGM are required to determine optimal glucose targets, strategies to obtain them, and the potential effect on long-term health outcomes. FUNDING: National Institute for Health Research Efficacy and Mechanisms Evaluation Programme.

Cost-effectiveness of real time continuous glucose monitoring to target glucose control in preterm infants.

The optimal management of glucose levels in critical care remains an area for research due to the problems of balancing the risks of hyperglycemia versus hypoglycemia. This paper reports the first economic evaluation of real time continuous glucose monitoring to guide the clinical management of preterm infants, based on evidence from the REACT trial. Bivariate regression of costs (£, 2016-17 prices) and cases of adequate glucose control, with multiple imputation of missing data, was conducted. When the economic evaluation was restricted to the first week of life, real time continuous glucose monitoring was associated with increased costs and a statistically significant increase in adequate glucose control. When the assessment was performed over a time horizon extending to 36 weeks' corrected gestational age, real time CGM was dominant in health economic terms, i.e. associated with lower costs and better outcomes. These results largely remained robust to a range of sensitivity analyses and sub-group analyses designed to address uncertainty and heterogeneity surrounding the cost-effectiveness outcomes. This study suggests that the use of real time continuous glucose monitoring in preterm infants is associated with a high probability of cost-effectiveness.

Generation COVID-19 - Should the foetus be worried?

AIM: The aim of this narrative review was to evaluate the risks, both direct and indirect, to the foetus from the COVID-19 pandemic. METHODS: Direct and indirect risks were defined as (a) vertical infection (congenital or intrapartum), (b) maternal infection and its sequelae, and (c) sources of maternal stress during lockdown, including social isolation and altered healthcare provision. RESULTS: Early studies suggest that vertical viral transmission is low; however, there may be an important effect of maternal infection on foetal growth and development. The impact of various degrees of lockdown on prospective mothers' health, habits and healthcare provision is of concern. In particular, increased maternal stress has been shown to have a significant effect on foetal brain development increasing the risk of mental health, and cognitive and behavioural disorders in later life. CONCLUSION: From the evidence available to date, direct risks to the foetus from the SARS-CoV-2 virus are low. Indirect effects of the pandemic, particularly resulting from the effect of maternal stress on the developing brain, can have lifelong detrimental impacts for this generation of children.

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK.

OBJECTIVES: To determine differences in body composition and glucose metabolism according to childhood growth outcomes in a population-based sample of children born small for gestational age (SGA). METHODS: A single-centre study of 259 children born SGA identified through hospital records and contacted when aged 4-7 years. Questionnaire data on pre/perinatal history and growth parameters during childhood was collected from the parents, and in a subgroup of 150 children face-to-face assessments were performed, including anthropometric parameters, lean and fat mass, blood pressure, fasting glucose, and C-peptide. RESULTS: Based on the questionnaires, few children had formal clinic follow-up of growth, but 7% of the cohort showed a height and weight of <-2SDS during childhood, and only 2 children met the criteria for growth hormone therapy. Out of the 150 children assessed at a mean age of 6.1 ± 0.8 years, 122 (81%) showed a catch-up growth in weight. Compared to those without weight catch-up, these children had a higher fat mass index (3.13 ± 1.36 vs. 2.56 ± 0.91 kg/m2, p = 0.04), trunk-to-limb fat mass ratio (0.63 ± 0.14 vs. 0.56 ± 0.08, p = 0.002), systolic blood pressure SDS (0.09 ± 0.71 vs. -0.32 ± 0.63, p = 0.008), fasting glucose (4.5 ± 0.5 vs. 4.3 ± 0.5 mmol/L, p = 0.03), and C-peptide (306 ± 116 vs. 256 ± 112 pmol/L, p = 0.08). Among children with weight catch-up growth, those with less height gain had a lower limb lean mass index (4.25 ± 0.48 vs. 4.48 ± 0.56 kg/m2, p = 0.02) and fat mass index (1.57 ± 0.59 vs. 1.83 ± 0.77 kg/m2, p = 0.04). CONCLUSIONS: Within this population-based sample of SGA children, catch-up growth in weight was associated with higher abdominal fat mass, blood pressure and glycemia; furthermore, in these children, less height gain was associated with reduced limb lean and fat mass.

Feasibility of automated insulin delivery guided by continuous glucose monitoring in preterm infants.

OBJECTIVE: Closed-loop systems have been used to optimise insulin delivery in children with diabetes, but they have not been tested in neonatal intensive care. Extremely preterm infants are prone to hyperglycaemia and hypoglycaemia; both of which have been associated with adverse outcomes. Insulin sensitivity is notoriously variable in these babies and glucose control is time-consuming, with management requiring frequent changes of dextrose-containing fluids and careful monitoring of insulin treatment. We aimed to evaluate the feasibility of closed-loop management of glucose control in these infants. DESIGN AND SETTING: Single-centre feasibility study with a randomised parallel design in a neonatal intensive care unit. Eligibility criteria included birth weight <1200 g and <48 hours of age. All infants had subcutaneous continuous glucose monitoring for the first week of life, with those in the intervention group receiving closed-loop insulin delivery in a prespecified window, between 48 and 72 hours of age during which time the primary outcome was percentage of time in target (sensor glucose 4-8 mmol/L). RESULTS: The mean (SD) gestational age and birth weight of intervention and control study arms were 27.0 (2.4) weeks, 962 (164) g and 27.5 (2.8) weeks, 823 (282) g, respectively, and were not significantly different. The time in target was dramatically increased from median (IQR) 26% (6-64) with paper guidance to 91% (78-99) during closed loop (p<0.001). There were no serious adverse events and no difference in total insulin infused. CONCLUSIONS: Closed-loop glucose control based on subcutaneous glucose measurements appears feasible as a potential method of optimising glucose control in extremely preterm infants.

Real time continuous glucose monitoring in neonatal intensive care.

Hypoglycaemia and hyperglycaemia are common in infants requiring intensive care and are associated with worse clinical outcomes. However, glucose levels are taken infrequently, and there remains controversy regarding optimal management. In adults and children continuous glucose monitoring (CGM) is now established as an important adjunct to caring for patients at risk from dysglycaemia. This technology is also increasingly providing insights into glucose regulation in the newborn, demonstrating significant periods of clinically silent hypoglycaemia and hyperglycaemia. This baseline data will be important to allow the significance of glucose dysregulation on long-term outcomes to be assessed. Small studies have also shown the potential for CGM to safely support targeting of glucose control in preterm infants, and a large multicentre trial is ongoing. Current technology is not specifically designed for use in NICU, but with rapid technological developments, CGM holds promise for the future care of babies in NICU.

Rare case of congenital chylothorax and challenges in its management.

This case describes the difficulties faced in treating recurrent pleural effusions and diagnosing chylothorax in a preterm neonate. The mother of this case was one of the first neonates to undergo in utero pleural shunting for bilateral pleural effusions 30 years ago. She then presented with an antenatal diagnosis of fetal hydrops at 31+1 weeks gestation in her own pregnancy and her baby was delivered 3 days later due to concerns about fetal distress. The baby was clinically unstable with recurrent bilateral effusions which were extensively investigated and shown to be the result of congenital chylothorax of possible genetic origin. This case demonstrates the challenges of managing chylothorax in the newborn.

A Feasibility Study of Paired Continuous Glucose Monitoring Intrapartum and in the Newborn in Pregnancies Complicated by Type 1 Diabetes.

AIM: To describe the continuous glucose monitoring (CGM) profiles of type 1 diabetes (T1D) offspring in the early neonatal period and its association with maternal intrapartum glucose control. METHODS: A prospective observational study of T1D pregnant women and their neonatal offspring. Women had a CGM sensor inserted 2-3 days before delivery. Infants had a masked CGM sensor inserted as soon as possible after delivery. Maternal glycemic outcomes were time-in-target (70-140 mg/dL [3.9-7.8 mmol/L]), hyperglycemia >140 mg/dL (7.8 mmol/L), and mean CGM glucose during the 24 h preceding delivery. Neonatal outcomes included lowest recorded blood glucose concentration, and CGM measures (glucose <47 mg/dL [2.6 mmol/L], time-in-target (47-144 mg/dL [2.6-8.0 mmol/L]), glucose standard deviation [SD]) during the first 72 h of life. RESULTS: Data were available for 16 mother-infant pairs. Mothers had a mean age (SD) 32.3 (4.3) years, T1D duration 17.6 (6.8) years, first antenatal glycated hemoglobin 7.4 (0.8)% (57 [8.5] mmol/mol). In the 24 h preceding delivery, mothers spent mean (SD) 72 (20)% time-in-target (70-140 mg/dL [3.9-7.8 mmol/L]), 19 (15)% time >140 mg/dL (7.8 mmol/L), and 9 (9)% time <70 mg/dL (3.9 mmol/L) with mean (SD) CGM glucose 113 (9) mg/dL (6.3 [0.7] mmol/L). Fifteen infants (93.8%) had ≥1 blood glucose concentration <47 mg/dL (2.6 mmol/L), and five had ≥1 blood glucose concentration <18 mg/dL (1.0 mmol/L). The mean infant CGM glucose on days 1, 2, and 3 of life was 63 (14), 67 (13), 76 (11) mg/dL (3.5 [0.8], 3.7 [0.7], and 4.2 [0.6] mmol/L). Four infants (25%) spent >50% time with CGM glucose levels <47 mg/dL (2.6 mmol/L) on day 1. CONCLUSIONS: CGM detected widespread neonatal hypoglycemia, even among mothers with good intrapartum glucose control.