The electroretinogram and vitamin A in preterm infants

The electroretinogram (ERG) records an electrical potential arising from cells within the retina in response to stimulation by light. As an objective measure of retinal function, electroretinography has potential clinical application in neonates. However, technical difficulties inherent in recording low amplitude responses from unco-operative subjects have limited work in this field, and to date little is known about the normal development of the ERG during the early weeks of life. Plasma concentrations of retinol in the majority of preterm infants are marginal or deficient by adult standards, and there is indirect evidence that this reflects depleted liver stores of vitamin A. At present the functional significance of these observations is unclear. The earliest sign of vitamin A deficiency in adults and older children is impaired dark adaptation, and this is associated with changes in the ERG prior to the onset of subjective nightblindness. Thus, it was anticipated that the development of a reliable method for recording the ERG in the neonatal period might help to determine vitamin A requirements in preterm infants. A technique is described by which the ERG could be studied soon after birth in extremely low birthweight infants. The success rate in recording an interpretable averaged ERG was 96% in term infants and 92% in preterm infants. Results with this method in adult controls were comparable to results obtained by standard techniques. Continuous observation of the infant and assessment of the degree of eye opening was achieved by video monitoring. Minimal restraint was necessary, and no major incidents or complications were encountered. Electroretinograms were recorded successfully in 50 term infants aged between 7 and 148 hours. The amplitude of the ERG was less and the a- and b-wave latencies were longer than in adult controls. Eyelid closure during recording of the ERG significantly increased the a-wave latency and diminished the amplitude of the response. Both the a- and b-wave latencies shortened with advancing postnatal age. Fifty-nine preterm infants were studied at ages ranging from 7 hours to 87 days. The amplitude of the ERG was less and the a-wave latency was longer than in term infants of comparable postnatal age. The ERG was absent initially in two of the most immature infants although each subsequently demonstrated a clearly defined response. Eyelid closure did not have a significant effect upon any of the ERG parameters in preterm infants. The b-wave latency decreased after 48 hours' exposure to light (p < 0. 01) and subsequently was related inversely to postconceptional age. Longitudinal and cross-sectional observations both showed a reduction in the a-and b-wave latencies and an increase in the amplitude of the ERG over time. Maturation of the ERG in preterm infants appears to be mediated, at least in part, by exposure to light. The preterm infants had significantly lower plasma levels of retinol, retinol-binding protein, prealbumin and a-tocopherol than term infants of comparable postnatal age. Plasma concentrations of retinol were below accepted normal levels for older children in all but three preterm infants, and did not change over time. The rise in plasma retinol concentration following an oral dose of 5000 IU retinol (the retinol dose response) suggested that low circulating levels of retinol in preterm infants reflect reduced hepatic reserves of vitamin A. Tocopherol levels were adequate in the majority of preterm infants after the fifth day of life and were higher in infants of all gestational ages fed with own mother's milk. Standard oral vitamin supplementation did not affect plasma levels of either retinol or alpha-tocopherol. A relationship was not demonstrated between any of the averaged ERG parameters and either the plasma concentration of retinol or the retinol dose response. The electroretinographic threshold was measured in 12 preterm infants. Allowing for eye opening, there was a significant reduction in the threshold over time. The logarithm of the electroretinographic threshold correlated with the retinol dose response, but was not related significantly to the predose plasma concentration of retinol. This work suggests that retinal stores of vitamin A in apparently healthy preterm infants are reduced in conjunction with depletion of hepatic reserves. Current recommendations for vitamin A supplementation of preterm infants may be inadequate and require review subsequent to further studies of vitamin A tissue function

Executive functioning, behavioural, emotional, and cognitive difficulties in school-aged children prenatally exposed to methadone

Aim: The aim of this study was to examine executive function and emotional and behavioural difficulties of children aged between 8 and 10 years who had been prenatally exposed to methadone, compared to non-exposed peers. Methods: Prospective study: third follow-up of an original cohort of 153 children born to methadone-maintained opioid-dependent mothers 2008–2010: previous investigations were at 1–3 days and at 6–7 months of age. Carers completed the Strength and Difficulties Questionnaire (SDQ) and the Behaviour Rating Inventory of Executive Function, Second Edition (BRIEF®2). Results were compared between exposed and non-exposed groups. Results: Carers of 33 of 144 traceable children completed the measures. SDQ responses showed no group differences on subscales of emotional symptoms, conduct problems, or peer relationship problems. A marginally higher proportion of exposed children had a high or very high hyperactivity subscale score. Exposed children scored significantly higher on BRIEF®2 behavioural, emotional, and cognitive regulation indices, and on the global executive composite. After controlling for potentially confounding higher reported maternal tobacco use in the exposed group via regression modelling, the effect of methadone exposure reduced. Interpretation: This study supports evidence that methadone exposure in utero is associated with adverse neurodevelopmental outcomes in childhood. Challenges in studying this population include difficulties with long-term follow-up and controlling for potentially confounding factors. Further investigation of the safety of methadone and other opioids in pregnancy must include consideration of maternal tobacco use

Assessing maternal alcohol consumption in pregnancy : comparison of confidential postnatal maternal interview and measurement of alcohol biomarkers in meconium

Knowledge of alcohol consumption in pregnancy is important for early identification of children with fetal alcohol spectrum disorder. We investigated whether alcohol biomarkers fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG) in meconium are predicted by maternal or newborn demographics and/or correlate with confidential early postnatal self-report of alcohol consumption in pregnancy. Anonymised, observational population-based study. Inner-city maternity unit, Glasgow, UK. Singleton mother/infant dyads delivering every fourth day. Mother: confidential postnatal interview. Baby: meconium sample for FAEEs and EtG. 840/908 mothers consented. 370 (46.4%) reported alcohol consumption in pregnancy, generally of modest amount; for 114 (13.6%) this was after 20 weeks' gestation. Alcohol consumption in later pregnancy was more commonly reported by older (31.3 vs 29.5 years) women of white British ethnicity (

Assessing maternal alcohol consumption in pregnancy : does phosphatidylethanol measured from day 5 newborn blood spot cards have any value? An observational, population-based study

Objective Prenatal alcohol exposure (PAE) places children at risk of fetal alcohol spectrum disorder (FASD) but ascertainment of PAE is problematic. Early intervention for children at risk of FASD may help mitigate long-term difficulties. Phosphatidylethanol (PEth), a metabolite of alcohol, is incorporated into red cell membranes and can be measured in dried blood spot (DBS) cards. In the UK, DBS samples are collected on day 5 for routine newborn screening. We sought to examine if PEth measured from DBS correlates with postnatal maternal self-report of alcohol consumption in pregnancy. Design Observational population-based study. Comparison of infant PEth concentration and self-report of maternal alcohol use during pregnancy.Setting Large maternity unit in Glasgow, Scotland. Participants All singleton mother–infant dyads delivered during each fourth consecutive 24-hour period.Interventions Mother: direct, confidential, immediate postnatal interview by a single researcher examining alcohol use during pregnancy. Infant: one extra DBS collected coincident with routine newborn screening if bleeding continued. Results 92.5% of eligible mothers agreed to participate. 510 DBS were obtained of which 502 were successfully analysed. 216 (43%) samples contained PEth at a concentration of ≥8 ng/mL and 148 (29.5%) at ≥20 ng/mL. The sensitivity of PEth ≥8 ng/mL and ≥20 ng/mL in identifying women who self-reported modest alcohol use after 36 weeks’ gestation was 50% and 36.4%, respectively. Conclusion PEth measured from DBS obtained on day 5 of life does not reliably identify modest PAE after 36 weeks’ gestation from maternal self-report. Data are available upon reasonable request

Early versus delayed fortification of human milk in preterm infants: a systematic review

Expressed breast milk (EBM) is commonly supplemented with commercially prepared human milk fortifier to meet the additional nutritional needs of preterm infants. The optimal milk intake at which to introduce fortification is unknown. The objective of this systematic review was to compare the effect of early fortification (EF) versus that of delayed introduction of human milk fortifier (DF) on short-term outcomes including growth, feeding intolerance, length of hospital stay, and maturity at discharge in very-low-birth-weight infants. The search was carried out until March 2019 using 5 electronic databases (PubMed, Ovid Medline, Web of Science, Ovid Embase, and the Cochrane Library). The search was supplemented with a search of the clinical trial registry and reference lists. Eligible studies involved randomized controlled trials that had been designed to compare EF against DF using multi-nutrient fortifier for infants of a birth weight of &lt;1,500 g who were fed exclusively or predominantly EBM. Four authors independently screened the studies for eligibility. A total of 1,972 articles were screened; 2 studies met the inclusion criteria and were included with a total number of participants of 171. The definition of EF and DF was not consistent between the 2 studies. There was no significant impact of EF versus DF on all outcomes. In conclusion, current data are limited and do not provide evidence on the optimal time to start fortification. The definition of EF and DF needs to be agreed upon and further larger randomized controlled trials are required

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the UK

BACKGROUND: The provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials. OBJECTIVE: To involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK. DESIGN: Research questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups. PARTICIPANTS: One hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds. RESULTS: Two hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support. CONCLUSIONS: We have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care

Surfactant replacement therapy for respiratory distress syndrome in preterm infants: United Kingdom national consensus

Our aim was to develop consensus recommendations from United Kingdom (UK) neonatal specialists on the use of surfactant for the management of respiratory distress syndrome RDS in preterm infants. RDS due to surfactant deficiency is common in preterm infants. Signs, including tachypnoea, recessions, and grunting, usually commence shortly after birth, and increase in severity during the first 12–48 h of postnatal life. Significant RDS may require mechanical ventilation (MV) or noninvasive ventilatory support (NIV), both of which have potential to cause lung injury via a number of mechanisms.1 The aim of RDS management is to provide appropriate respiratory support whilst minimising complications and, ultimately, bronchopulmonary dysplasia (BPD). Treatment with exogenous surfactant reduces requirement for positive pressure ventilation, mitigates risk of pulmonary air leak, and improves survival.1 International consensus guidelines on management of RDS have been published;1 however, recent developments in the field of less invasive surfactant administration prompt the need for a UK national consensus on surfactant use in preterm infants with, or at risk of, RDS

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the United Kingdom

Introduction: Methodologically robust clinical trials are required to improve neonatal care and reduce unwanted variations in practice. Previous neonatal research prioritisation processes have identified important research themes rather than specific research questions amenable to clinical trials. Practice-changing trials require well-defined research questions, commonly organised using the Population, Intervention, Comparison, Outcome (PICO) structure. By narrowing the scope of research priorities to those which can be answered in clinical trials and by involving a wide range of different stakeholders, we aim to provide a robust and transparent process to identify and prioritise research questions answerable within the National Healthcare System to inform future practice-changing clinical trials. Methods and analysis: A steering group comprising parents, doctors, nurses, allied health professionals, researchers and representatives from key organisations (Neonatal Society, British Association of Perinatal Medicine, Neonatal Nurses Association and Royal College of Paediatrics and Child Health) was identified to oversee this project. We will invite submissions of research questions formatted using the PICO structure from the following stakeholder groups using an online questionnaire: parents, patients, healthcare professionals and academic researchers. Unanswered, non-duplicate research questions will be entered into a three-round eDelphi survey of all stakeholder groups. Research questions will be ranked by mean aggregate scores. Ethics and dissemination: The final list of prioritised research questions will be disseminated through traditional academic channels, directly to key stakeholder groups through representative organisations and on social media. The outcome of the project will be shared with key research organisations such as the National Institute for Health Research. Research ethics committee approval is not required

Enteral lactoferrin supplementation for very preterm infants : a randomised placebo-controlled trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) in 37 UK hospitals were allocated randomly (1:1) within 72 hours after birth to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected lateonset infection (occurring >72 hours after birth). The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.86, 1.04). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Funding: UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants : a randomised placebo-controlled trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) in 37 UK hospitals were allocated randomly (1:1) within 72 hours after birth to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected lateonset infection (occurring >72 hours after birth). The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.86, 1.04). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Funding: UK National Institute for Health Research Health Technology Assessment programme (10/57/49)