Aspects of renal function in infants between 25-34 weeks gestation

This thesis describes an observational study of renal function in preterm babies. During the course of the study no attempt was made to manipulate clinical conditions. The study was performed in three parts.The principal portion of the work was an observation of renal function during the first week of life, in a group of infants between 25 -34 weeks gestation, who required intensive care; the influence of gestational age, postnatal age, birth weight and respiratory adaptation were explored. Comparison is made with published parameters of renal function derived from healthy preterm neonates.Glomerular filtration rate was assessed as endogenous creatinine clearance during prolonged urine collection. No increase in glomerular filtration rate was shown between days 2 -7 of life. The population of infants studied here, who required intensive care, showed little difference from published parameters of glomerular filtration rate measured in healthy preterms.Creatinine excretion rate was used to derive a regression equation predicting muscle mass from weight and gestational age. Muscle mass was found to increase from 12% of birth weight at 25 weeks gestation to 19% at 34 weeks 5 and 24% at 40 weeks. This is in agreement with classic dissection studies which have shown muscle mass to be 25% of body weight at term.Changes in urine flow rate, urine osmolality and sodium balance were studied. The influence of respiratory adaptation on various parameters of renal function and particularly on sodium handling was investigated. Positive sodium retention was seen in babies with respiratory disease; sodium retention changed to sodium loss at a point coinciding with improvement in respiratory function. The diuresis that accompanied the improvement in respiratory function, in infants with hyaline membrane disease, was characterised as a natriuresis, with increased creatinine clearance and osmolar clearance but unchanged free water clearance.Renal function was compared during periods of hyperglycaemia and normoglycaemia. The degree of hyperglycaemia observed did not result in an osmotic diuresis but was associated with a significant decrease in fractional sodium excretion and urinary sodium loss.The second part of the study determined the incidence, aetiology, diagnostic indices and outcome of acute renal failure in a series of 388 consecutive admissions. The incidence in this tertiary referral centre was found to be 6 6.2 %. The difficulties involved in making an accurate diagnosis of acute renal failure are examined.In the third part of this work serum beta -2- microglobulin was studied in a group of 'well' preterm babies and its value as an index of glomerular filtration rate assessed

Multiplatform characterization of dynamic changes in breast milk during lactation

The multicomponent analysis of human breast milk (BM) by metabolic profiling is a new area of study applied to determining milk composition, and is capable of associating BM composition with maternal characteristics, and subsequent infant health outcomes. A multiplatform approach combining HPLC‐MS and ultra‐performance LC‐MS, GC‐MS, CE‐MS, and 1H NMR spectroscopy was used to comprehensively characterize metabolic profiles from seventy BM samples. A total of 710 metabolites spanning multiple molecular classes were defined. The utility of the individual and combined analytical platforms was explored in relation to numbers of metabolites identified, as well as the reproducibility of the methods. The greatest number of metabolites was identified by the single phase HPLC‐MS method, while CE‐MS uniquely profiled amino acids in detail and NMR was the most reproducible, whereas GC‐MS targeted volatile compounds and short chain fatty acids. Dynamic changes in BM composition were characterized over the first 3 months of lactation. Metabolites identified as altering in abundance over lactation included fucose, di‐ and triacylglycerols, and short chain fatty acids, known to be important for infant immunological, neurological, and gastrointestinal development, as well as being an important source of energy. This extensive metabolic coverage of the dynamic BM metabolome provides a baseline for investigating the impact of maternal characteristics, as well as establishing the impact of environmental and dietary factors on the composition of BM, with a focus on the downstream health consequences this may have for infants

How to reach agreement: the impact of different analytical approaches to Delphi process results in core outcomes set development

Background: Core outcomes sets are increasingly used to define research outcomes that are most important for a condition. Different consensus methods are used in the development of core outcomes sets; the most common is the Delphi process. Delphi methodology is increasingly standardised for core outcomes set development, but uncertainties remain. We aimed to empirically test how the use of different summary statistics and consensus criteria impact Delphi process results. Methods: Results from two unrelated child health Delphi processes were analysed. Outcomes were ranked by mean, median, or rate of exceedance, and then pairwise comparisons were undertaken to analyse whether the rankings were similar. The correlation coefficient for each comparison was calculated, and Bland-Altman plots produced. Youden’s index was used to assess how well the outcomes ranked highest by each summary statistic matched the final core outcomes sets. Consensus criteria identified in a review of published Delphi processes were applied to the results of the two child-health Delphi processes. The size of the consensus sets produced by different criteria was compared, and Youden’s index was used to assess how well the outcomes that met different criteria matched the final core outcomes sets. Results: Pairwise comparisons of different summary statistics produced similar correlation coefficients. Bland–Altman plots showed that comparisons involving ranked medians had wider variation in the ranking. No difference in Youden’s index for the summary statistics was found. Different consensus criteria produced widely different sets of consensus outcomes (range: 5–44 included outcomes). They also showed differing abilities to identify core outcomes (Youden’s index range: 0.32–0.92). The choice of consensus criteria had a large impact on Delphi results. Discussion: The use of different summary statistics is unlikely to affect how outcomes are ranked during a Delphi process: mean, median, and rates of exceedance produce similar results. Different consensus criteria have a large impact on resultant consensus outcomes and potentially on subsequent core outcomes sets: our results confirm the importance of adhering to pre-specified consensus criteria

Recent advances in the genetics of preterm birth

Preterm birth is associated with short‐ and long‐term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene–environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing

Development of a pipeline for exploratory metabolic profiling of infant urine

Numerous metabolic profiling pipelines have been developed to characterize the composition of human biofluids and tissues, the vast majority of these being for studies in adults. To accommodate limited sample volume and to take into account the compositional differences between adult and infant biofluids, we developed and optimized sample handling and analytical procedures for studying urine from newborns. A robust pipeline for metabolic profiling using NMR spectroscopy was established, encompassing sample collection, preparation, spectroscopic measurement, and computational analysis. Longitudinal samples were collected from five infants from birth until 14 months of age. Methods of extraction and effects of freezing and sample dilution were assessed, and urinary contaminants from breakdown of polymers in a range of diapers and cotton wool balls were identified and compared, including propylene glycol, acrylic acid, and tert-butanol. Finally, assessment of urinary profiles obtained over the first few weeks of life revealed a dramatic change in composition, with concentrations of phenols, amino acids, and betaine altering systematically over the first few months of life. Therefore, neonatal samples require more stringent standardization of experimental design, sample handling, and analysis compared to that of adult samples to accommodate the variability and limited sample volume

Public and patient involvement in child health research and service improvements

Objectives To determine whether paediatricians are supported by their organisations to encourage patient and public involvement (PPI) in research activities and clinical improvement work, the challenges they face and how they think these could be addressed by the Royal College of Paediatrics and Child Health (RCPCH).Design A survey.Setting UK consultant paediatricians and staff associate specialist and specialty (SAS) doctors who are members of RCPCH.Main outcome measures The proportion of respondents who said that PPI was central to research and service improvements in their organisation, the type of local support for PPI activity, challenges in undertaking PPI and the support members wanted from RCPCH.Results There was a response rate of 44.4% (n=1924). In their organisation, 29.1% of respondents stated PPI was central to research and 36.1% to service improvement; 46% were unaware of support for PPI and 15% said there was no support. The main challenges for PPI activity were a lack of clinician time, local support and funding. Respondents wanted RCPCH to advocate for protected time for PPI, provide access to PPI groups and deliver guidance and training.Conclusions The majority of paediatricians feel unsupported to undertake PPI activity by their local organisation. The RCPCH has a key role to enable all paediatricians to work with children, young people and their carers to improve the quality of research and clinical services as demonstrated by RCPCH’s ongoing activity in these crucial and important areas

Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study.

OBJECTIVE: To examine the timing and duration of RSV bronchiolitis hospital admission among term and preterm infants in England and to identify risk factors for bronchiolitis admission. DESIGN: A population-based birth cohort with follow-up to age 1 year, using the Hospital Episode Statistics database. SETTING: 71 hospitals across England. PARTICIPANTS: We identified 296618 individual birth records from 2007/08 and linked to subsequent hospital admission records during the first year of life. RESULTS: In our cohort there were 7189 hospital admissions with a diagnosis of bronchiolitis, 24.2 admissions per 1000 infants under 1 year (95%CI 23.7-24.8), of which 15% (1050/7189) were born preterm (47.3 bronchiolitis admissions per 1000 preterm infants (95% CI 44.4-50.2)). The peak age group for bronchiolitis admissions was infants aged 1 month and the median was age 120 days (IQR = 61-209 days). The median length of stay was 1 day (IQR = 0-3). The relative risk (RR) of a bronchiolitis admission was higher among infants with known risk factors for severe RSV infection, including those born preterm (RR = 1.9, 95% CI 1.8-2.0) compared with infants born at term. Other conditions also significantly increased risk of bronchiolitis admission, including Down's syndrome (RR = 2.5, 95% CI 1.7-3.7) and cerebral palsy (RR = 2.4, 95% CI 1.5-4.0). CONCLUSIONS: Most (85%) of the infants who are admitted to hospital with bronchiolitis in England are born at term, with no known predisposing risk factors for severe RSV infection, although risk of admission is higher in known risk groups. The early age of bronchiolitis admissions has important implications for the potential impact and timing of future active and passive immunisations. More research is needed to explain why babies born with Down's syndrome and cerebral palsy are also at higher risk of hospital admission with RSV bronchiolitis

Adiposity and hepatic lipid in healthy full-term, breastfed, and formula-fed human infants: a prospective short-term longitudinal cohort study

Background: The effect of mode of infant feeding on adiposity deposition is not fully understood. Objective: The objective was to test the hypothesis that differences in total and regional adipose tissue content and intrahepatocellular lipid (IHCL) arise in early infancy between breast- and formula-fed infants and to describe longitudinal changes. Design: This prospective longitudinal cohort study was performed in 2 hospitals in the United Kingdom. Healthy, full-term, appropriate weight-for-gestational age infants were recruited; adipose tissue volume and distribution were directly quantified by using whole-body magnetic resonance imaging; IHCL was assessed by in vivo proton magnetic resonance spectroscopy. Measurements were performed after birth (median age: 13 d) and at 6–12 wk of age. Method of infant feeding was recorded prospectively by using maternally completed feeding diaries. Breastfed was defined as >80% of feeds consisting of breast milk at both points; formula-fed was defined as >80% of feeds consisting of formula milk at both points. Results: Longitudinal results were obtained from 70 infants (36 breastfed, 9 mixed-fed, and 25 formula-fed). No differences were found in total or regional adipose tissue or IHCL between breastfed and formula-fed infants. In pooled analyses including all feeding groups, IHCL and total adipose tissue approximately doubled between birth and 6–12 wk: IHCL after birth (median: 0.949; IQR: 0.521–1.711) and at 6–12 wk (1.828; 1.376–2.697; P < 0.001) and total adipose tissue after birth (0.749 L; 0.620–0.928 L) and at 6–12 wk (1.547 L; 1.332–1.790 L; P < 0.001). Increasing adiposity was characterized by greater relative increases in subcutaneous than in internal adipose tissue depots. Conclusions: No differences were detectable in adipose tissue or IHCL accretion between breastfed and formula-fed infants up to 2 mo. The substantial increase in IHCL seen over this period in both breastfed and formula-fed infants is a novel observation, which suggests that hepatic storage of lipids may be physiologic up to 2 mo. This trial was registered at www.clinicaltrials.gov as NCT02033005

Pilot study to establish a prospective neonatal cohort: Study of Preterm Infants and Neurodevelopmental Genes (SPRING).

BACKGROUND: Genetic risk variants and preterm birth are early and potent risk factors for later neuropsychiatric disorders. To understand the interrelationships between these factors, a large-scale genetic study of very preterm (VPT, <32 weeks gestation) infants with prospective follow-up is required. In this paper, we describe a streamlined study approach, using efficient processes for biological and clinical data collection, to feasibly establish such a cohort. METHODS: We sought to recruit 500 VPT families within a 1 year period from neonatal units. Treating clinical teams recruited eligible participants, obtained parent consent, collected blood samples and posted specimens to the research laboratory. We extracted all clinical data from the National Neonatal Research Database, an existing UK resource that captures daily patient-level data on all VPT infants. RESULTS: Between May 2017 and June 2018, we established a cohort of 848 VPT infants and their parents from 60 English neonatal units. The study population (median (IQR), gestation: 28.9 (26-30) weeks; birth weight: 1120 (886-1420) g) represented 18.9% of eligible infants born at the study sites during the recruitment period (n=4491). From the subset of 521 complete family trios, we successfully completed genotyping for 510 (97.9%) trios. Of the original 883 infants whose parents consented to participate, the parents of 796 (90.1%) infants agreed to future data linkage and 794 (89.9%) agreed to be recalled. CONCLUSION: We demonstrate the feasibility and acceptability of streamlined strategies for genetic, neonatal and longitudinal data collection and provide a template for future cost-effective and efficient cohort development