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

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

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

Neonatal brain injuries in England:Population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database

Objective In 2015, the Department of Health in England announced an ambition to reduce’brain injuries occurring during or soon after birth’. We describe the development of a pragmatic case definition and present annual incidence rates. Design Retrospective cohort study using data held in the National Neonatal Research Database (NNRD) extracted from neonatal electronic patient records from all National Health Service (NHS) neonatal units in England, Wales and Scotland. In 2010–2011, population coverage in the NNRD was incomplete, hence rate estimates are presented as a range; from 2012, population coverage is complete, and rates (95% CIs) are presented. Rates are per 1000 live births. setting NHS neonatal units in England. Patients Infants admitted for neonatal care; denominator: live births in England. Main outcome measure ’Brain injuries occurring at or soon after birth’ defined as infants with seizures, hypoxic-ischaemic encephalopathy, stroke, intracranial haemorrhage, central nervous system infection and kernicterus and preterm infants with cystic periventricular leucomalacia. results In 2010, the lower estimate of the rate of’Brain injuries occurring at or soon after birth’ in England was 4.53 and the upper estimate was 5.19; in 2015, the rate was 5.14 (4.97, 5.32). For preterm infants, the population incidence in 2015 was 25.88 (24.51, 27.33) and 3.47 (3.33, 3.62) for term infants. Hypoxic-ischaemic encephalopathy was the largest contributor to term brain injury, and intraventricular/periventricular haemorrhage was the largest contributor to preterm brain injury. Conclusions Annual incidence rates for brain injuries can be estimated from data held in the NNRD; rates for individual conditions are consistent with published rates. Routinely recorded clinical data can be used for national surveillance, offering efficiencies over traditional approaches

Contribution of de novo and inherited rare copy number variants to very preterm birth

Background The genomic contribution to adverse health sequelae in babies born very preterm (<32 weeks’ gestation) is unknown. We conducted an investigation of rare CNVs in infants born very preterm as part of a study to determine the feasibility and acceptability of a larger, well-powered genome-wide investigation in the UK, with follow-up using linked National Health Service records and DNA storage for additional research. Methods We studied 488 parent–offspring trios. We performed genotyping using Illumina Infinium OmniExpress Arrays. CNV calling and quality control (QC) were undertaken using published protocols. We examined de novo CNVs in infants and the rate of known pathogenic variants in infants, mothers and fathers and compared these with published comparator data. We defined rare pathogenic CNVs as those consistently reported to be associated with clinical phenotypes. Results We identified 14 de novo CNVs, representing a mutation rate of 2.9%, compared with 2.1% reported in control populations. The median size of these CNV was much higher than in comparator data (717 kb vs 255 kb). The rate of pathogenic CNVs was 4.3% in infants, 2.7% in mothers and 2% in fathers, compared with 2.3% in UK Biobank participants. Conclusion Our findings suggest that the rate of de novo CNVs, especially rare pathogenic CNVs, could be elevated in those born very preterm. However, we will need to conduct a much larger study to corroborate this conclusion

Association of early postnatal transfer and birth outside a tertiary hospital with mortality and severe brain injury in extremely preterm infants: observational cohort study with propensity score matching

Objective To determine if postnatal transfer or birth in a non-tertiary hospital is associated with adverse outcomes.Design Observational cohort study with propensity score matching.Setting National health service neonatal care in England; population data held in the National Neonatal Research Database.Participants Extremely preterm infants born at less than 28 gestational weeks between 2008 and 2015 (n=17 577) grouped based on birth hospital and transfer within 48 hours of birth: upward transfer (non-tertiary to tertiary hospital, n=2158), non-tertiary care (born in non-tertiary hospital; not transferred, n=2668), and controls (born in tertiary hospital; not transferred, n=10 866). Infants were matched on propensity scores and predefined background variables to form subgroups with near identical distributions of confounders. Infants transferred between tertiary hospitals (horizontal transfer) were separately matched to controls in a 1:5 ratio.Main outcome measures Death, severe brain injury, and survival without severe brain injury.Results 2181 infants, 727 from each group (upward transfer, non-tertiary care, and control) were well matched. Compared with controls, infants in the upward transfer group had no significant difference in the odds of death before discharge (odds ratio 1.22, 95% confidence interval 0.92 to 1.61) but significantly higher odds of severe brain injury (2.32, 1.78 to 3.06; number needed to treat (NNT) 8) and significantly lower odds of survival without severe brain injury (0.60, 0.47 to 0.76; NNT 9). Compared with controls, infants in the non-tertiary care group had significantly higher odds of death (1.34, 1.02 to 1.77; NNT 20) but no significant difference in the odds of severe brain injury (0.95, 0.70 to 1.30) or survival without severe brain injury (0.82, 0.64 to 1.05). Compared with infants in the upward transfer group, infants in the non-tertiary care group had no significant difference in death before discharge (1.10, 0.84 to 1.44) but significantly lower odds of severe brain injury (0.41, 0.31 to 0.53; NNT 8) and significantly higher odds of survival without severe brain injury (1.37, 1.09 to 1.73; NNT 14). No significant differences were found in outcomes between the horizontal transfer group (n=305) and controls (n=1525).Conclusions In extremely preterm infants, birth in a non-tertiary hospital and transfer within 48 hours are associated with poor outcomes when compared with birth in a tertiary setting. We recommend perinatal services promote pathways that facilitate delivery of extremely preterm infants in tertiary hospitals in preference to postnatal transfer.</p