Neonatal outcomes of maternal SARS-CoV-2 infection in the UK: a prospective cohort study using active surveillance.

BACKGROUND: Newborns may be affected by maternal SARS-CoV-2 infection during pregnancy. We aimed to describe the epidemiology, clinical course and short-term outcomes of babies admitted to a neonatal unit (NNU) following birth to a mother with confirmed SARS-CoV-2 infection within 7 days of birth. METHODS: This is a UK prospective cohort study; all NHS NNUs, 1 March 2020 to 31 August 2020. Cases were identified via British Paediatric Surveillance Unit with linkage to national obstetric surveillance data. Reporting clinicians completed data forms. Population data were extracted from the National Neonatal Research Database. RESULTS: A total of 111 NNU admissions (1.98 per 1000 of all NNU admissions) involved 2456 days of neonatal care (median 13 [IQR 5, 34] care days per admission). A total of 74 (67%) babies were preterm. In all, 76 (68%) received respiratory support; 30 were mechanically ventilated. Four term babies received therapeutic hypothermia for hypoxic ischaemic encephalopathy. Twenty-eight mothers received intensive care, with four dying of COVID-19. Eleven (10%) babies were SARS-CoV-2 positive. A total of 105 (95%) babies were discharged home; none of the three deaths before discharge was attributed to SARS-CoV-2. CONCLUSION: Babies born to mothers with SARS-CoV-2 infection around the time of birth accounted for a low proportion of total NNU admissions over the first 6 months of the UK pandemic. Neonatal SARS-CoV-2 was uncommon. STUDY REGISTRATION: ISRCTN60033461; protocol available at http://www.npeu.ox.ac.uk/pru-mnhc/research-themes/theme-4/covid-19 . IMPACT: Neonatal unit admissions of babies born to mothers with SARS-CoV-2 infection comprised only a small proportion of total neonatal admissions in the first 6 months of the pandemic. A high proportion of babies requiring neonatal admission who were born to mothers with confirmed SARS-CoV-2 infection were preterm and had neonatal SARS-CoV-2 infection and/or other conditions associated with long-term sequelae. Adverse neonatal conditions were more common in babies whose SARS-CoV-2-positive mothers required intensive care compared to those whose SARS-CoV-2-positive mothers who did not.

Childhood neurodevelopment after prescription of maintenance methadone for opioid dependency in pregnancy: a systematic review and meta-analysis.

AIM: To systematically review and meta-analyse studies of neurodevelopmental outcome of children born to mothers prescribed methadone in pregnancy. METHOD: MEDLINE, Embase, and PsycINFO were searched for studies published from 1975 to 2017 reporting neurodevelopmental outcomes in children with prenatal methadone exposure. RESULTS: Forty-one studies were identified (2283 participants). Eight studies were amenable to meta-analysis: at 2 years the Mental Development Index weighted mean difference of children with prenatal methadone exposure compared with unexposed infants was -4.3 (95% confidence interval [CI] -7.24 to -1.63), and the Psychomotor Development Index weighted mean difference was -5.42 (95% CI -10.55 to -0.28). Seven studies reported behavioural scores and six found scores to be lower among methadone-exposed children. Twelve studies reported visual outcomes: nystagmus and strabismus were common; five studies reported visual evoked potentials of which four described abnormalities. Factors that limited the quality of some studies, and introduced risk of bias, included absence of blinding, small sample size, high attrition, uncertainty about polydrug exposure, and lack of comparison group validity. INTERPRETATION: Children born to mothers prescribed methadone in pregnancy are at risk of neurodevelopmental problems but risk of bias limits inference about harm. Research into management of opioid use disorder in pregnancy should include evaluation of childhood neurodevelopmental outcome. WHAT THIS PAPER ADDS: Children born to opioid-dependent mothers prescribed methadone are at risk of neurodevelopmental impairment. Exposed infants have lower Mental Development Index and Psychomotor Development Index scores than unexposed children. Atypical visual evoked potentials, strabismus, and nystagmus have increased prevalence. Estimates of impairment may be biased by intermediate to poor quality evidence.

DESARROLLO NEUROLÓGICO INFANTIL TRAS LA PRESCRIPCIÓN DE METADONA DE MANTENIMIENTO PARA EL TRATAMIENTO DE LA DEPENDENCIA DE OPIOIDES DURANTE EL EMBARAZO: REVISIÓN SISTEMÁTICA Y META-ANÁLISIS: OBJETIVO: Revisar sistemáticamente y realizar un meta-análisis de estudios sobre el resultado del desarrollo neurológico de los niños nacidos de madres a quienes se les recetó metadona durante el embarazo. METODOLOGÍA: Se realizó una búsqueda en MEDLINE, Embase, y PsycINFO de estudios publicados desde el año 1975 al 2017 que informaran sobre el resultado del desarrollo neurológico de niños que hubieran tenido exposición prenatal a la metadona. RESULTADOS: Se identificaron 41 estudios (2283 participantes). Ocho estudios se pudieron someter al meta-análisis: a los dos años de edad los niños con exposición prenatal a la metadona mostraron una diferencia de medias ponderada de -4,3 (95% intervalo de confianza [IC] −7,24 to −1,63) en el Índice de Desarrollo Mental (Mental Development Index) en comparación con los niños no expuestos. En el Índice de Desarrollo Psicomotor (Psychomotor Development Index) la diferencia de medias ponderada fue −5,42 (95% CI −10,55 to −0,28). 7 estudios mostraron las puntuaciones comportamentales y 6 de ellos encontraron puntuaciones más bajas entre los niños expuestos a la metadona. Doce estudios informaron sobre los resultados a nivel visual: el nistagmo y el estrabismo fueron comunes; 5 estudios informaron sobre los potenciales evocados visuales, de los cuáles cuatro describieron anormalidades. Los factores que limitaron la calidad de algunos estudios e introdujeron el riesgo de sesgo, incluyeron la ausencia de cegamiento, el pequeño tamaño de la muestra, el alto desgaste, la incertidumbre acerca de la exposición a varias drogas y la falta de validez del grupo de comparación. INTERPRETACIÓN: Los niños nacidos de madres a quienes se les recetó metadona durante el embarazo se encuentran en riesgo de sufrir problemas de desarrollo neurológico, pero el riesgo de sesgo limita la inferencia sobre el daño. La investigación sobre el manejo del trastorno por uso de opioides en el embarazo debe incluir la evaluación del resultado del desarrollo neurológico infantil.

NEURODESENVOLVIMENTO INFANTIL APÓS PRESCRIÇÃO DE METADONA DE MANUTENÇÃO PARA DEPENDÊNCIA DE OPIÓIDES NA GESTAÇÃO: UMA REVISÃO SISTEMÁTICA E METANÁLISE: OBJETIVO: Revisar sistematicamente e metanalisar os estudos com resultados do neurodesenvolvimento de crianças nascidas de mães que tiveram prescrição de metadona na gestação. MÉTODO: MEDLINE, Embase, e PsycINFO foram pesquisadas por estudos publicados de 1974 a 2017 relatando resultados do neurodesenvolvimento em crianças expostas a metadona no período pré-natal. RESULTADOS: Quarenta e um estudos foram identificados (2.283 participantes). Oito estudos foram possíveis de incluir na metanálise: aos 2 anos a diferença na média ponderada do Índice de Desenvolvimento Mental de crianças expostas a metadona pré-natal comparadas com as não expostas foi −4,3 (intervalo de confiança [IC a 95%] −7,24 a −1,63), e a diferença na média ponderada do Índice de Desenvolvimento Psicomotor foi −5,42 (IC 95% −10,55 a −0,28). Sete estudos relataram escores comportamentais e seis encontraram escores menores entre crianças expostas a metadona. Doze estudos relataram resultados visuais: nistagmo e estrabismo foram comuns; cinco estudos reportaram potenciais evocados visuais, dos quais quatro descreveram anormalidades. Fatores que limitaram a qualidade de alguns estudos e introduziram risco de viéis incluíram falta de cegamento, reduzido tamanho amostral, desgaste alto, incerteza sobre exposição a outras drogas, e falta de validade por grupo de comparação. INTERPRETAÇÃO: Crianças nascidas de mães que receberam prescrição de metadona na gestação apresentam risco para problemas neurodesenvolvimentais, mas o risco de viés limita as inferências sobre o dano. Pesquisas sobre o manejo do uso de opióides na gestação devem incluir a avaliação do resultado do neurodesenvolvimento na infância.

Increased DNA Methylation of ABCB1, CYP2D6, and OPRM1 Genes in Newborn Infants of Methadone-Maintained Opioid-Dependent Mothers.

OBJECTIVE: To investigate whether in utero opioid exposure, which has been linked to adverse neurodevelopmental and social outcomes, is associated with altered DNA methylation of opioid-related genes at birth. STUDY DESIGN: Observational cohort study of 21 healthy methadone-maintained opioid-dependent mother-infant dyads consecutively delivered at >36 weeks of gestation, and 2 comparator groups: smoking, "deprived" opioid-naïve mother-infant dyads (n = 17) and nonsmoking, "affluent" opioid-naïve mother-infant dyads (n = 15). DNA methylation of ABCB1, CYP2D6, and OPRM1 genes for mothers and babies was determined from buccal swabs. Plasma methadone concentrations were additionally measured for methadone-maintained opioid-dependent mothers. RESULTS: DNA methylation for ABCB1 and CYP2D6 was similar in opioid-naïve infants compared with their mothers, but was less for OPRM1 (3 ± 1.6% vs 8 ± 1%, P < .0005). Opioid-exposed newborns had similar DNA methylation to their mothers for all genes studied and greater methylation of ABCB1 (18 ± 4.8% vs 3 ± 0.5%), CYP2D6 (92 ± 1.2% vs 89 ± 2.4%), and OPRM1 (8 ± 0.3% vs 3 ± 1.6%) compared with opioid-naïve newborns (P < .0005 for all 3 genes). Infant DNA methylation was not related to birth weight, length of hospital stay, maternal smoking, dose or plasma concentration of methadone at delivery, or postcode of residence. CONCLUSIONS: In utero exposure to opioids is associated with increased methylation of opioid-related genes in the newborn infant. It is not clear whether these findings are due to opioid exposure per se or other associated lifestyle factors.

Variations in Infant CYP2B6 Genotype Associated with the Need for Pharmacological Treatment for Neonatal Abstinence Syndrome in Infants of Methadone-Maintained Opioid-Dependent Mothers.

Background Neonatal abstinence syndrome (NAS) in infants of methadone-maintained opioid-dependent (MMOD) mothers cannot be predicted in individual cases. We investigated whether variation in infant genotype is associated with severity of NAS. Methods This is a pilot observational cohort study of 21 MMOD mothers and their newborns. Infant buccal swabs were obtained soon after delivery, together with a maternal blood sample for the determination of maternal plasma methadone concentration. Genomic variation in five opioid-related genes (ABCB1, COMT, CYP2B6, CYP2D6, and OPRM1) was ascertained from infant buccal swabs and related to need for pharmacological treatment of NAS. Results Out of 21 infants, 11 (52%) required treatment for NAS. Mothers of treated infants tended to have been prescribed higher doses of methadone, but plasma methadone concentrations did not differ between mothers of treated or untreated babies. Treated and untreated babies did not differ in terms of method of feeding. Treated infants were more likely to carry the normal (homozygous) allele at 516 and 785 regions of CYP2B6 gene (p = 0.015 and 0.023, respectively). There were no differences in any other genes between infants who did or did not require treatment for NAS. Conclusion Genomic variation in CYP2B6 may explain, at least in part, severity of NAS.

A novel, simultaneous extraction of FAEE and EtG from meconium and analysis by LC-MS/MS.

Fatty acid ethyl esters (FAEEs) and ethyl-glucuronide (EtG) in meconium have been widely studied as biomarkers of maternal alcohol consumption during pregnancy. Many analytical approaches have been proposed for their analysis, mostly consisting of separated extraction procedures requiring the use of two meconium aliquots. This study aimed to validate a new analytical procedure for the simultaneous extraction of FAEEs and EtG from a meconium aliquot through a single solid-phase extraction (SPE) applied to 242 anonymized samples of meconium. Targeted FAEEs were: ethyl-myristate (Myr), ethyl-palmitate (Pal), ethyl-oleate (Ole) and ethyl-stearate (Ste). Two hundred milligrams of meconium was sonicated with acetonitrile, and a single SPE performed by means of aminopropyl columns. FAEEs were eluted with hexane, followed by EtG elution with water. Both the mixtures were dried, recovered, and analyzed by liquid chromatography-tandem mass spectrometry using C8 (FAEEs) and C18 (EtG) columns. Transitions were: m/z 257 → 57,88, Myr; m/z 262 → 57,88, Myr-d5; m/z 285 → 57, 72, Pal; m/z 290 → 57,258, Pal-d5; m/z 311 → 72,114, Ole; m/z 316 → 72,265, Ole-d5; m/z 257 → 57,72 Ste; m/z 318 → 57,286, Ste-d5; m/z 221 → 75,85, EtG; m/z 226 → 75,85, EtG-d5. Lower limit of quantification range was 10-15 ng/g for FAEEs and 10 ng/g for EtG. Linearity was evaluated for different concentration ranges; the mean coefficients of determination (R (2)) were above 0.9961. Precision and accuracy for FAEEs and EtG were consistently ≤20 % and ±20 %, respectively. Ion suppression was observed for all the analytes. Matrix effect did not significantly affect the analyses. Recovery efficiency was 93 % for EtG and 75-85 % for FAEEs.

Can transcutaneous bilirubinometry safely be used to monitor rebound hyperbilirubinaemia after phototherapy in neonates ≥35 weeks' gestation? A prospective, comparative study.

INTRODUCTION: There is insufficient evidence to determine if non-invasive transcutaneous bilirubin (TcB) measurement can replace serum bilirubin (SBR) in assessing rebound hyperbilirubinaemia after phototherapy. OBJECTIVE: To investigate if TcB can safely guide management of neonates after phototherapy. SUBJECTS: 100 well neonates ≥35 weeks' gestation who had received inpatient phototherapy. METHOD: Measurement of both helix (manufacturer's recommendation) and earlobe TcB coincidentally with routine SBR 12 hours after cessation of phototherapy. All mothers gave written informed consent. RESULTS: Gestation ranged from 35+0 to 41+5 (median 37+6) weeks; birth weight 2018-4566 (median 3230) g; age 55-222 (median 109) hours at testing. 86% neonates were Caucasian. Outcomes determined by SBR included restarting phototherapy (n=0), repeat SBR next day (n=29), no further routine follow-up (n=71).TcB and SBR measurements were unpredictably inconsistent. Helix TcB tended to underestimate SBR (mean difference 50.1 (95% CI 113.9 to -13.7) µmols/L); for earlobe TcB mean difference was -13.4 (95% CI 46.3 to -73.2) µmols/L (overestimate), but bias was greater over the range of mean differences. No demographic factor predicted consistency between TcB and SBR. TcB was 25% (helix) and 76% (earlobe) sensitive in predicting repeat phototherapy and/or repeat SBR; specificities were 92% and 58%, respectively. Adding a safety margin of 120 µmols/L to helix TcB value could have safely avoided invasive SBR measurement in 50/98 (51%) babies. CONCLUSIONS: Consistency between TcB and rebound SBR is unpredictable in well neonates >35 weeks' gestation but adopting a wide safety margin has potential to reduce blood sampling. Recommencement of phototherapy is uncommon in this population.

Tear Proteomics in Infants at Risk of Retinopathy of Prematurity: A Feasibility Study.

Purpose: This feasibility study investigated the practicability of collecting and analyzing tear proteins from preterm infants at risk of retinopathy of prematurity (ROP). We sought to identify any tear proteins which might be implicated in the pathophysiology of ROP as well as prognostic markers. Methods: Schirmer's test was used to obtain tear samples from premature babies, scheduled for ROP screening, after parental informed consent. Mass spectrometry was used for proteomic analysis. Results: Samples were collected from 12 infants, which were all adequate for protein analysis. Gestational age ranged from 25 + 6 to 31 + 1 weeks. Postnatal age at sampling ranged from 19 to 66 days. One infant developed self-limiting ROP. Seven hundred one proteins were identified; 261 proteins identified in the majority of tear samples, including several common tear proteins, were used for analyses. Increased risk of ROP as determined by the postnatal growth ROP (G-ROP) criteria was associated with an increase in lactate dehydrogenase B chain in tears. Older infants demonstrated increased concentration of immunoglobulin complexes within their tear samples and two sets of twins in the cohort showed exceptionally similar proteomes, supporting validity of the analysis. Conclusions: Tear sampling by Schirmer test strips and subsequent proteomic analysis by mass spectrometry in preterm infants is feasible. A larger study is required to investigate the potential use of tear proteomics in identification of ROP. Translational Relevance: Tear sampling and subsequent mass spectrometry in preterm infants is feasible. Investigation of the premature tear proteome may increase our understanding of retinal development and provide noninvasive biomarkers for identification of treatment-warranted ROP.

Characteristics and outcomes of neonates hospitalised with SARS-CoV-2 infection in the UK by variant: a prospective national cohort study.

OBJECTIVE: Neonatal infection with wildtype SARS-CoV-2 is rare and good outcomes predominate. We investigated neonatal outcomes using national population-level data to describe the impact of different SARS-CoV-2 variants. DESIGN: Prospective population-based cohort study. SETTING: Neonatal, paediatric and paediatric intensive care inpatient care settings in the UK. PATIENTS: Neonates (first 28 days after birth) with confirmed SARS-CoV-2 infection who received inpatient care, March 2020 to April 2022. Neonates were identified through active national surveillance with linkage to national SARS-CoV-2 testing data, routinely recorded neonatal data, paediatric intensive care data and obstetric and perinatal mortality surveillance data. OUTCOMES: Presenting signs, clinical course, severe disease requiring respiratory support are presented by the dominant SARS-CoV-2 variant in circulation at the time. RESULTS: 344 neonates with SARS-CoV-2 infection received inpatient care; breakdown by dominant variant: 146 wildtype, 123 alpha, 57 delta and 18 omicron. Overall, 44.7% (153/342) neonates required respiratory support; short-term outcomes were good with 93.6% (322/344) of neonates discharged home. Eleven neonates died: seven unrelated to SARS-CoV-2 infection, four were attributed to neonatal SARS-CoV-2 infection (case fatality 4/344, 1.2% 95% CI 0.3% to 3.0%) of which three were born preterm due to maternal COVID-19. More neonates were born very preterm (23/54) and required invasive ventilation (27/57) when delta variant was predominant, and all four SARS-CoV-2-related deaths occurred in this period. CONCLUSIONS: Inpatient care for neonates with SARS-CoV-2 was uncommon. Although rare, severe neonatal illness was more common during the delta variant period, potentially reflecting more severe maternal disease and associated preterm birth. TRIAL REGISTRATION NUMBER: ISRCTN60033461.

Dark-adapted oscillatory potentials in preterm infants with and without retinopathy of prematurity.

PURPOSE: To describe the appearance and maturation of dark-adapted oscillatory potentials (OPs) in electroretinograms (ERGs) recorded from preterm infants, and to determine any effect of retinopathy of prematurity (ROP). METHODS: Dark-adapted ERGs were recorded in conjunction with screening for ROP and at outpatient follow-up, using a flash luminance of 11.3 scot cd s m(-2) (4.06 phot cd s m(-2)). Eligible infants were born before 31 weeks' gestation and/or weighed ≤1,250 grams at birth. RESULTS: Presence or absence of OPs was established for 68 ERG recordings from 38 infants at maturities ranging from 30 weeks' postmenstrual age (PMA) to 28 weeks' post-term corrected age. 20 infants did not develop ROP, eight developed stage 1, one stage 2 and one stage 3 disease which regressed spontaneously. Eight infants received treatment for threshold ROP. OPs were present in 50 % of infants at 36 weeks' PMA and in all by 50 weeks' PMA. The earliest appearance of OPs was at 30+5 weeks' PMA. Individual OP amplitudes increased and peak time of individual OPs decreased with increasing maturity. For infants with threshold ROP summed OP amplitudes tended to be smaller prior to treatment (6.5 vs 9.9µV, P = 0.09) and were significantly smaller by 50 weeks' PMA (14 vs 30µV, P = 0.007). OP1 was less likely to be present in infants who developed stage 3 or worse ROP (P = 0.000). CONCLUSIONS: Dark-adapted OPs are recordable in some preterm infants from 30 weeks' PMA. Relative suppression of early OPs is a potential marker for developing ROP.

Is additional oral phosphate supplementation for preterm infants necessary: an assessment of clinical audit.

UNLABELLED: Adequate phosphate intake is important for the prevention of metabolic bone disease in preterm infants. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommends a daily phosphate intake of 184-230 mg/kg/day, which should be met by standard feed volumes of either commercially fortified breast milk or preterm formulae. We sought to investigate whether our local practise of providing supplemental oral phosphate for all infants born before 32 weeks' gestation continues to be necessary. Details of parenteral and milk feeding and both oral and parenteral phosphate supplementation from birth until 8 weeks of age were collected retrospectively from the case notes of 31 preterm infants. Routinely collected biochemical markers of bone mineral status were also recorded. Mean (SD) plasma phosphate concentration was higher when oral phosphate supplementation was given [2.10 (0.38) versus 1.92(0.50) mM/L without supplement (p < 0.001)]. A minimum average phosphate intake of 184 mg/kg/day was achieved by 47 and 77 % of babies in weeks 1 and 2, respectively, and by 84-100 % of infants from week 3. The percentage of plasma phosphate measurements below the minimum target of 1.8 mM/L was greater amongst unsupplemented babies (45 versus 18 %). CONCLUSION: A majority of infants <32 weeks' gestation did not achieve the recommended phosphate intake during the first week of life. Despite achieving the recommended phosphate intake from week 3, many infants did not have plasma phosphate concentrations within the accepted normal range. Additional oral supplementation may help to achieve blood phosphate concentrations within this target range.

Monitoring population levels of alcohol consumption in pregnant women: a case for using biomarkers.

A challenge to biochemically monitoring alcohol consumption in pregnancy is the prohibitive costs of collecting thousands of blood samples. This pilot study looks at the feasibility of using residual samples to monitor chronic and acute alcohol consumption in pregnancy. Residual anomalies screening samples (n = 150, 2006/7) were tested for carbohydrate-deficient transferrin (CDT, chronic marker) and ethyl glucuronide (EtG, acute marker). Valid readings were obtained for CDT but not EtG. These results pave the way for a larger representative study, to provide, for the first time, a national biochemical baseline estimate of chronic alcohol consumption in the pregnant population.

Variation in use of extended pulse oximetry testing to guide decisions around home oxygen provision for ex-preterm infants; A nationwide survey of UK neonatal units.

Differences in the diagnostic approach to bronchopulmonary dysplasia (BPD) may contribute to variation in reported BPD rates. We undertook a nationwide survey of UK neonatal units (NNUs) to describe criteria applied by neonatologists to conduct pulse oximetry studies in ex-preterm infants to assess their need for supplemental oxygen near discharge, as well as criteria applied to interpret saturation studies. Responses from 112 (64.7%) NNUs demonstrated wide variation in both criteria used to select infants for assessment and thresholds for interpretation. Neither demonstrated a clear relationship with reported BPD rates. Variation in clinical practice requires further scrutiny to inform and streamline management of ex-preterm infants at risk of BPD, and potentially improve outcomes.

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: 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.

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

OBJECTIVE: 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. DESIGN: Anonymised, observational population-based study. SETTING: Inner-city maternity unit, Glasgow, UK. PATIENTS: Singleton mother/infant dyads delivering every fourth day. INTERVENTIONS: Mother: confidential postnatal interview. Baby: meconium sample for FAEEs and EtG. RESULTS: 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 (p<0.05); their babies were on average 118 g heavier (p=0.032). FAEEs were identified in all meconium samples; concentration was ≥600 ng/g in 39.6%. EtG concentration was ≥30 ng/g in 14.5%. Neither biomarker was associated with maternal age, body mass index or socioeconomic status but when EtG was ≥30 ng/g, the mother was less likely to identify as white British (71.3% vs 81.8%, p=0.028). Sensitivities of FAEEs ≥600 ng/g and EtG ≥30 ng/g were 43.1% and 11.6%, respectively for postnatal self-report of alcohol use in later pregnancy (specificities 60.6% and 84.8%). CONCLUSIONS: FAEEs and EtG measured in meconium have low sensitivity and specificity for self-reported alcohol consumption after 20 weeks' gestation in an unselected Scottish population.

Association between Early Feeding Patterns and Neonatal Outcomes in Very Preterm Infants: A Retrospective Cohort Study.

OBJECTIVE: Mother's own milk (MOM) is the optimal feed for premature infants but may not always be sufficiently available. Alternative feeding includes donor human milk (DONOR), with or without fortification and preterm formula. This study evaluated the association between early feeding with exclusively and predominantly MOM (MAINLY-MOM) versus MOM supplemented with fortified DONOR (MOM + DONOR) or preterm formula (MOM + FORMULA) and in-hospital growth and neonatal morbidities. METHOD: This was a multicentre (n = 13 units) cohort study of infants born at <32 weeks' gestation. Data captured at the point of care were extracted from the UK National Neonatal Research Database. The study groups were defined based on feeding patterns within the first 2 weeks of life using predefined cut-offs. The primary outcome was the in-hospital growth rate. RESULTS: Data from 1,272 infants were analysed. Infants fell into two groups: extremely preterm (EPT) infants and very preterm (VPT) infants, born after <28 weeks and 28 to <32 weeks of gestation, respectively. Only 11 of 365 EPT infants received formula supplements, precluding a useful comparison of MOM + DONOR and MOM + FORMULA. There was no difference in median (25th-75th centile) growth velocity over the first 30 days of life between the MAINLY-MOM (n = 248) and MOM + DONOR (n = 106) groups: 10 (8-13) versus 10 (7-13) g/kg/day. Similarly, for VPT infants, there was no difference in growth velocities between MAINLY-MOM (n = 407), MOM + DONOR (N = 196), and MOM + FORMULA (N = 304): 11 (8-14) versus 11 (8-14) versus 11 (8-14) g/kg/day. Head growth did not differ (p value = 0.670). Cox regression analysis showed no difference in time to discharge between feeding types or any difference in major neonatal morbidities. In both EPT and VPT infants, growth velocity from the time of regaining birth weight to discharge was significantly lower in the MAINLY-MOM group compared to the MOM-DONOR group (EPT: 12.5 [11-14.2] vs. 14 [12.3-15.9] p = 0.45, VPT 13.5 [11-15.7] vs. 14.5 [12.6-16.8] p = 0.015). CONCLUSION: Early feeding with fortified DONOR, in comparison to formula, to supplement MOM was not associated with any differences in short-term growth, length of stay, and neonatal morbidities. However, early feeding with mainly maternal milk, compared to maternal milk supplemented with DONOR, was associated with significantly lower overall weight gain.

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.

Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity.

OBJECTIVE: Preterm infants show reduced retinal sensitivity at term corrected age compared with newborn term infants. We tested the hypothesis that retinal sensitivity in preterm infants is improved by early, high-dose vitamin A. STUDY DESIGN: We report a double-blind, randomized controlled trial of infants <32 weeks' gestation and/or <1501 g birth weight. Supplemented infants received additional intramuscular vitamin A 10 000 IU 3 times weekly from day 2 for a minimum of 2 weeks or until establishment of oral feeding. Hepatic stores were assessed by relative dose response (RDR). The primary outcome measure was cone-corrected dark-adapted retinal rod sensitivity measured by electroretinogram at 36 weeks' postmenstrual age (PMA). RESULTS: Eighty-nine infants (42 supplemented and 47 controls) were recruited. Plasma retinol was higher in supplemented infants at 7 and 28 days (median, 1.0 vs 0.5 µmol/L and 0.7 vs 0.6 µmol/L; P < .001 and .03, respectively). Neither plasma retinol nor RDR differed between groups at 36 weeks' PMA. Retinal sensitivity was greater in supplemented infants (-0.81 vs -0.61 log cd • s • m(-2); P < .03) and was not related to RDR. CONCLUSIONS: Early high-dose intramuscular vitamin A supplementation for infants at risk of retinopathy of prematurity improves retinal function at 36 weeks' PMA.