Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

High protein intake on later outcomes in preterm children: a systematic review and meta-analysis.

BACKGROUND: Appropriate protein intake is crucial for growth and development in children born preterm. We assessed the effects of high (HP) versus low protein (LP) intake on neurodevelopment, growth, and biochemical anomalies in these children. METHODS: Randomised and quasi-randomised trials providing protein to children born preterm (<37 completed weeks of gestation) were searched following PRISMA guideline in three databases and four registers (PROSPERO registration CRD42022325659). Random-effects model was used for assessing the effects of HP (≥3.5 g/kg/d) vs. LP (<3.5 g/kg/d). RESULTS: Data from forty-four studies (n = 5338) showed HP might slightly reduce the chance of survival without neurodisability at ≥12 months (four studies, 1109 children, relative risk [RR] 0.95 [95% CI 0.90, 1.01]; P = 0.13; low certainty evidence) and might increase risk of cognitive impairment at toddler age (two studies; 436 children; RR 1.36 [0.89, 2.09]; P = 0.16; low certainty evidence). At discharge or 36 weeks, HP intake might result in higher weight and greater head circumference z-scores. HP intake probably increased the risk of hypophosphatemia, hypercalcemia, refeeding syndrome and high blood urea, but reduced risk of hyperglycaemia. CONCLUSIONS: HP intake for children born preterm may be harmful for neonatal metabolism and later neurodisability and has few short-term benefits for growth. IMPACT STATEMENT: Planned high protein intake after birth for infants born preterm might be harmful for survival, neurodisability and metabolism during infancy and did not improve growth after the neonatal period. Protein intake ≥3.5 g/kg/d should not be recommended for children born preterm.

Donor human milk versus infant formula for low-risk infants: a systematic review.

BACKGROUND: There is an increasing acceptance and use of donor human milk (DHM) in healthy infants. This review investigates the benefits and risks of mothers' own milk (MOM) supplementation with DHM compared to infant formula (IF) in moderate-late preterm (MLP) and early term (ET) infants. METHODS: MEDLINE, EMBASE, CINAHL, Scopus, Cochrane CENTRAL and clinical trial registries were searched for studies published up to September 2023. The primary outcome was rates of exclusive breastfeeding (EBF). Certainty of evidence was assessed using GRADE framework. RoB1 and EPHPP were used to assess risk of bias for controlled trials and observational studies, respectively. RESULTS: Eleven studies involving total of 10,147 infants and six ongoing trials were identified. Studies were of low quality, and the certainty of evidence was assessed as very low. Three studies suggested benefits of DHM compared to IF on EBF at discharge, while two suggested no difference. No clear effect was observed on EBF duration, any breastfeeding, hypoglycemia and morbidity. No health risks were reported. CONCLUSION: The effect of supplementing MOM with DHM instead of IF on EBF and other health outcomes is unclear. High-quality studies are required to determine the potential benefits or risks of DHM supplementation in this population. IMPACT: We identified 11 relevant studies reporting on supplementation of mothers' own milk (MOM) with donor human milk (DHM) compared to infant formula (IF). Studies were of low quality, had heterogeneous outcome definitions and were geographically limited; all except two were observational studies. Limited evidence showed no clear difference on rates of exclusive breastfeeding and other health outcomes. No potential risks were reported. The increasing acceptance and use of DHM in healthy infants highlights the need for future high-quality studies.

Exposure to the smell and taste of milk to accelerate feeding in preterm infants.

BACKGROUND: Preterm infants (born before 37 weeks' gestation) are often unable to co-ordinate sucking, swallowing, and breathing for oral feeding because of their immaturity. In such cases, initial nutrition is provided by orogastric or nasogastric tube feeding. Feeding intolerance is common and can delay attainment of full enteral and sucking feeds, prolonging the need for nutritional support and the hospital stay. Smell and taste play an important role in the activation of physiological pre-absorptive processes that contribute to food digestion and absorption. However, during tube feeding, milk bypasses the nasal and oral cavities, limiting exposure to the smell and taste of milk. Provision of the smell and taste of milk with tube feeds offers a non-invasive and low-cost intervention that, if effective in accelerating the transition to enteral feeds and subsequently to sucking feeds, would bring considerable advantages to infants, their families, and healthcare systems. OBJECTIVES: To assess whether exposure to the smell or taste (or both) of breastmilk or formula administered with tube feeds can accelerate the transition to full sucking feeds without adverse effects in preterm infants. SEARCH METHODS: We conducted searches in CENTRAL, MEDLINE, Embase, CINAHL, and Epistemonikos to 26 April 2023. We also searched clinical trial databases and conference proceedings. SELECTION CRITERIA: We included randomised and quasi-randomised studies that evaluated exposure versus no exposure to the smell or taste of milk (or both) immediately before or at the time of tube feeds. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data according to Cochrane Neonatal methodology. We performed meta-analyses using risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, with their respective 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included eight studies (1277 preterm infants). Seven studies (1244 infants) contributed data for meta-analysis. The evidence suggests that exposure to the smell and taste of milk with tube feeds has little to no effect on time taken to reach full sucking feeds (MD -1.07 days, 95% CI -2.63 to 0.50; 3 studies, 662 infants; very low-certainty evidence). Two studies reported no adverse effects related to the intervention. The intervention may have little to no effect on duration of parenteral nutrition (MD 0.23 days, 95% CI -0.24 to 0.71; 3 studies, 977 infants; low-certainty evidence), time to reach full enteral feeds (MD -0.16 days, 95% CI -0.45 to 0.12; 1 study, 736 infants; very low-certainty evidence) or risk of necrotising enterocolitis (RR 0.93, 95% CI 0.47 to 1.84; 2 studies, 435 infants; low-certainty evidence), although the evidence for time to reach full enteral feeds is very uncertain. Exposure to the smell and taste of milk with tube feeds probably has little to no effect on risk of late infection (RR 1.14, 95% CI 0.74 to 1.75; 2 studies, 436 infants; moderate-certainty evidence). There were no data available to assess feeding intolerance. The included studies had small sample sizes and methodological limitations, including unclear or lack of randomisation (four studies), lack of blinding of participants and personnel (five studies), unclear or lack of blinding of the outcome assessor (all eight studies), and different inclusion criteria and methods of administering the interventions. AUTHORS' CONCLUSIONS: The results of our meta-analyses suggest that exposure to the smell and taste of milk with tube feeds may have little to no effect on time to reach full sucking feeds and time to reach full enteral feeds. We found no clear difference between exposure and no exposure to the smell or taste of milk on safety outcomes (adverse effects, necrotising enterocolitis, and late infection). Results from one ongoing study and two studies awaiting classification may alter the conclusions of this review. Future research should examine the effect of exposing preterm infants to the smell and taste of milk with tube feeds on health outcomes during hospitalisation, such as attainment of feeding skills, safety, feed tolerance, infection, and growth. Future studies should be powered to detect the effect of the intervention in infants of different gestational ages and on each sex separately. It is also important to determine the optimal method, frequency, and duration of exposure.

Nutritional Support for Moderate-to-Late-Preterm Infants - A Randomized Trial.

BACKGROUND: Most moderate-to-late-preterm infants need nutritional support until they are feeding exclusively on their mother's breast milk. Evidence to guide nutrition strategies for these infants is lacking. METHODS: We conducted a multicenter, factorial, randomized trial involving infants born at 32 weeks 0 days' to 35 weeks 6 days' gestation who had intravenous access and whose mothers intended to breast-feed. Each infant was assigned to three interventions or their comparators: intravenous amino acid solution (parenteral nutrition) or dextrose solution until full feeding with milk was established; milk supplement given when maternal milk was insufficient or mother's breast milk exclusively with no supplementation; and taste and smell exposure before gastric-tube feeding or no taste and smell exposure. The primary outcome for the parenteral nutrition and the milk supplement interventions was the body-fat percentage at 4 months of corrected gestational age, and the primary outcome for the taste and smell intervention was the time to full enteral feeding (150 ml per kilogram of body weight per day or exclusive breast-feeding). RESULTS: A total of 532 infants (291 boys [55%]) were included in the trial. The mean (±SD) body-fat percentage at 4 months was similar among the infants who received parenteral nutrition and those who received dextrose solution (26.0±5.4% vs. 26.2±5.2%; adjusted mean difference, -0.20; 95% confidence interval [CI], -1.32 to 0.92; P = 0.72) and among the infants who received milk supplement and those who received mother's breast milk exclusively (26.3±5.3% vs. 25.8±5.4%; adjusted mean difference, 0.65; 95% CI, -0.45 to 1.74; P = 0.25). The time to full enteral feeding was similar among the infants who were exposed to taste and smell and those who were not (5.8±1.5 vs. 5.7±1.9 days; P = 0.59). Secondary outcomes were similar across interventions. Serious adverse events occurred in one infant. CONCLUSIONS: This trial of routine nutrition interventions to support moderate-to-late-preterm infants until full nutrition with mother's breast milk was possible did not show any effects on the time to full enteral feeding or on body composition at 4 months of corrected gestational age. (Funded by the Health Research Council of New Zealand and others; DIAMOND Australian New Zealand Clinical Trials Registry number, ACTRN12616001199404.).

Postnatal growth and neurodevelopment at 2 years' corrected age in extremely low birthweight infants.

BACKGROUND: Faltering postnatal growth in preterm babies is associated with adverse neurodevelopment. However, which growth reference is most helpful for predicting neurodevelopment is unknown. We examined associations between faltering growth and developmental delay in extremely low birthweight (ELBW) infants. METHODS: We categorized faltering growth (z-score decrease ≥0.8 for weight/length, >1 for head circumference) between birth, 4 weeks, 36 weeks' postmenstrual age and 2 years' corrected age using fetal (Fenton, UK-WHO and Olsen) and healthy preterm (INTERGROWTH-21st) references. Associations between faltering growth and developmental delay were examined using binary logistic regression and area under the receiver operating curve (AUC). RESULTS: In 327 infants, Olsen charts identified the highest prevalence of faltering growth (weight 37%, length 63%, head 45%). Agreement in classification was higher amongst fetal references (kappa coefficient, ĸ = 0.46-0.94) than between INTERGROWTH-21st and fetal references (ĸ = 0.10-0.81). Faltering growth in all measures between 4-36 weeks (odds ratio, OR 2.0-4.7) compared with other time intervals (OR 1.7-2.7) were more strongly associated with developmental delay, particularly motor delay (OR 2.0-4.7). All growth references were poorly predictive of developmental delay at 2 years (AUC ≤ 0.62). CONCLUSIONS: Faltering postnatal growth in ELBW infants is associated with, but is poorly predictive of, developmental delay at 2 years. IMPACT: In babies born preterm, different growth references result in wide variation in categorization of faltering postnatal growth. Faltering growth in weight, length, and head circumference from 4 weeks to 36 weeks' postmenstrual age are associated with developmental delay at 2 years' corrected age, particularly motor delay. However, postnatal growth is a poor predictor of later developmental delay in extremely low birthweight infants irrespective of the growth reference used.

Associations between neonatal nutrition and visual outcomes in 7-year-old children born very preterm.

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm. METHODS: The study cohort comprised children (n = 128) with birthweight <1500 g or gestational age < 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years' corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models. RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02). CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.

Nutrition guidelines for preterm infants: A systematic review.

BACKGROUND: There is no consensus on optimal nutrition for preterm infants, leading to substantial practice variation. We aimed to assess the quality of nutrition guidelines for preterm infants, the consistency of recommendations, and the gaps in recommendations. METHODS: We searched databases and websites for nutrition guidelines for preterm infants before first hospital discharge, which were endorsed, prepared, or authorized by a regional, national, or international body, written in English, and published between 2012 and 2023. Two reviewers independently screened articles and extracted the recommendations. Four reviewers appraised the included guidelines using Appraisal of Guidelines, Research, and Evaluation II. RESULTS: A total of 7051 were identified, with 27 guidelines included, 26% of which were high in quality. Most guidelines lacked stakeholder involvement and rigor of development. We found considerable variation in recommendations, many of which lacked details on certainty of evidence and strength of recommendation. Recommendations for type of feed and breastmilk fortification were consistent among high-quality guidelines, but recommendations varied for intakes of almost all nutrients and monitoring of nutrition adequacy. Different guidelines gave different certainty of evidence for the same recommendations. Most gaps in recommendations were due to very low certainty of evidence. CONCLUSION: Future development of nutrition guidelines for preterm infants should follow the standard guideline development method and ensure the rigorous process, including stakeholders' involvement, to improve the reporting of strength of recommendation, certainty of evidence, and gaps in recommendation. Evidence is needed to support recommendations about macro and micronutrient intakes, breastmilk fortification, and markers on adequacy of intake of different nutrients.

COHESION: a core outcome set for the treatment of neonatal encephalopathy.

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE. METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics. RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment. CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS. IMPACT: We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Multi-Round versus Real-Time Delphi survey approach for achieving consensus in the COHESION core outcome set: a randomised trial.

BACKGROUND: Delphi surveys are commonly used to prioritise critical outcomes in core outcome set (COS) development. This trial aims to compare a three-round (Multi-Round) Delphi (MRD) with a Real-Time Delphi (RTD) in the prioritisation of outcomes for inclusion in a COS for neonatal encephalopathy treatments and explore whether 'feedback', 'iteration', and 'initial condition' effects may occur in the two survey methods. METHODS: We recruited 269 participants (parents/caregivers, healthcare providers and researchers/academics) of which 222 were randomised to either the MRD or the RTD. We investigated the outcomes prioritised in each survey and the 'feedback', 'iteration', and 'initial condition' effects to identify differences between the two survey methods. RESULTS: In the RTD, n = 92 participants (83%) fully completed the survey. In the MRD, n = 60 participants (54%) completed all three rounds. Of the 92 outcomes presented, 26 (28%) were prioritised differently between the RTD and MRD. Significantly fewer participants amended their scores when shown stakeholder responses in the RTD compared to the MRD ('feedback effect'). The 'iteration effect' analysis found most experts appeared satisfied with their initial ratings in the RTD and did not amend their scores following stakeholder response feedback. Where they did amend their scores, ratings were amended substantially, suggesting greater convergence. Variance in scores reduced with subsequent rounds of the MRD ('iteration effect'). Whilst most participants did not change their initial scores in the RTD, of those that did, later recruits tended to align their final score more closely to the group mean final score than earlier recruits (an 'initial condition' effect). CONCLUSION: The feedback effect differed between the two Delphi methods but the magnitude of this difference was small and likely due to the large number of observations rather than because of a meaningfully large difference. It did not appear to be advantageous to require participants to engage in three rounds of a survey due to the low change in scores. Larger drop-out through successive rounds in the MRD, together with a lesser convergence of scores and longer time to completion, indicate considerable benefits of the RTD approach. TRIAL REGISTRATION: NCT04471103. Registered on 14 July 2020.

Determinants of handgrip strength at age 2 years in children born moderate and late preterm and associations with neurodevelopmental outcomes.

BACKGROUND: Handgrip strength (HGS) indicates current and future health. Although preterm infants have an increased risk of poor grip strength in later life, its determinants and relationship with neurodevelopment are not well understood. AIMS: To determine HGS in children born preterm and explore the relationship of HGS with demography, anthropometry, nutritional factors, and neurodevelopmental outcomes. STUDY DESIGN: A prospective cohort study of moderate-late preterm babies enrolled in a randomised trial of nutritional support strategies, the DIAMOND trial. SUBJECTS: A total of 116 children born between 32 and 35 weeks' gestation, whose HGS was measured at 2 years' corrected age. OUTCOME MEASURES: HGS was measured using a dynamometer, and neurodevelopment was assessed using the Bayley Scales of Infant Development-III. Anthropometry and body composition were assessed at birth, discharge, and at 4 months' and 2 years' corrected age. Information on demographics and breastfeeding practices, including type of milk at discharge and duration of exclusive breastfeeding, was collected using questionnaires. RESULTS: The mean (standard deviation) HGS was 2.26 (1.07) kg. The Bayley scores were < 85 (-1 standard deviation) in 6 %, 20 %, and 1 % for the cognitive, language, and motor scales, respectively. Multiple regression analysis revealed that HGS was positively associated with language and motor scores (p < .05) after adjusting for confounding factors. HGS was not associated with sex, anthropometry, body composition, or breastfeeding practices. Maternal education was independently associated with HGS (p < .01). CONCLUSIONS: HGS at age 2 years in children born moderate-late preterm is associated with language and motor development and maternal education level.

From fetus to neonate: A review of cardiovascular modeling in early life.

Computational modeling has well-established utility in the study of cardiovascular hemodynamics, with applications in medical research and, increasingly, in clinical settings to improve the diagnosis and treatment of cardiovascular diseases. Most cardiovascular models developed to date have been of the adult circulatory system; however, the perinatal period is unique as cardiovascular physiology undergoes drastic changes from the fetal circulation, during the birth transition, and into neonatal life. There may also be further complications in this period: for example, preterm birth (defined as birth before 37 completed weeks of gestation) carries risks of short-term cardiovascular instability and is associated with increased lifetime cardiovascular risk. Here, we review computational models of the cardiovascular system in early life, their applications to date and potential improvements and enhancements of these models. We propose a roadmap for developing an open-source cardiovascular model that spans the fetal, perinatal, and postnatal periods. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Congenital Diseases > Computational Models.

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood.

Introduction: Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring. Methods: Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11ßHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11ßHSD1, 11ßHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 µg/kg) and corticotropin-releasing hormone (CRH, 0.5 µg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals. Results: Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN. Conclusions: We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

Nitrate contamination in drinking water and adverse reproductive and birth outcomes: a systematic review and meta-analysis.

Exposure to low levels of nitrate in drinking water may have adverse reproductive effects. We reviewed evidence about the association between nitrate in drinking water and adverse reproductive outcomes published to November 2022. Randomized trials, cohort or case-control studies published in English that reported the relationship between nitrate intake from drinking water and the risk of perinatal outcomes were included. Random-effect models were used to pool data. Three cohort studies showed nitrate in drinking water is associated with an increased risk of preterm birth (odds ratio for 1 mg/L NO3-N increased (OR1) = 1.01, 95% CI 1.00, 1.01, I2 = 23.9%, 5,014,487 participants; comparing the highest versus the lowest nitrate exposure groups pooled OR (ORp) = 1.05, 95% CI 1.01, 1.10, I2 = 0%, 4,152,348 participants). Case-control studies showed nitrate in drinking water may be associated with the increased risk of neural tube defects OR1 = 1.06, 95% CI 1.02, 1.10; 2 studies, 2196 participants; I2 = 0%; and ORp = 1.51, 95% CI 1.12, 2.05; 3 studies, 1501 participants; I2 = 0%). The evidence for an association between nitrate in drinking water and risk of small for gestational age infants, any birth defects, or any congenital heart defects was inconsistent. Increased nitrate in drinking water may be associated with an increased risk of preterm birth and some specific congenital anomalies. These findings warrant regular review as new evidence becomes available.

Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years.

BACKGROUND: Whether higher parenteral amino acid intake improves outcomes in infants with extremely low birth weight is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned infants with birth weights of less than 1000 g at 8 neonatal intensive care units to receive amino acids at a dose of 1 g per day (intervention group) or placebo in addition to usual nutrition for the first 5 days after birth. The primary outcome was survival free from neurodisability as assessed with the Bayley Scales of Infant and Toddler Development and neurologic examination at 2 years, corrected for gestational age at birth. Secondary outcomes were the components of the primary outcome as well as the presence or absence of neonatal disorders, the rate of growth, and nutritional intake. RESULTS: We enrolled 434 infants (217 per group) in this trial. Survival free from neurodisability was observed in 97 of 203 children (47.8%) in the intervention group and in 102 of 205 (49.8%) in the placebo group (adjusted relative risk, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P = 0.56). Death before the age of 2 years occurred in 39 of 217 children (18.0%) in the intervention group and 42 of 217 (19.4%) in the placebo group (adjusted relative risk, 0.93; 95% CI, 0.63 to 1.36); neurodisability occurred in 67 of 164 children (40.9%) in the intervention group and 61 of 163 (37.4%) in the placebo group (adjusted relative risk, 1.16; 95% CI, 0.90 to 1.50). Neurodisability was moderate to severe in 27 children (16.5%) in the intervention group and 14 (8.6%) in the placebo group (adjusted relative risk, 1.95; 95% CI, 1.09 to 3.48). More children in the intervention group than in the placebo group had patent ductus arteriosus (adjusted relative risk, 1.65; 95% CI, 1.11 to 2.46). In a post hoc analysis, refeeding syndrome occurred in 42 of 172 children in the intervention group and 26 of 166 in the placebo group (adjusted relative risk, 1.64; 95% CI, 1.09 to 2.47). Eight serious adverse events occurred. CONCLUSIONS: In infants with extremely low birth weight, extra parenteral amino acids at a dose of 1 g per day for 5 days after birth did not increase the number who survived free from neurodisability at 2 years. (Funded by the New Zealand Health Research Council and others; ProVIDe Australian New Zealand Clinical Trials Registry number, ACTRN12612001084875.).

Glucocorticoids in preterm human milk.

Background: Glucocorticoids (GCs), cortisol and cortisone, are essential regulators of many physiological responses, including immunity, stress and mammary gland function. GCs are present in human milk (HM), but whether maternal and infant factors are associated with HM GC concentration following preterm birth is unclear. Materials and methods: HM samples were collected on postnatal day 5 and 10 and at 4 months' corrected age (4m CA) in a cohort of moderate- and late-preterm infants. GCs in HM were measured by liquid chromatography-tandem mass spectrometry. Relationships between GCs in HM and both maternal and infant characteristics were investigated using Spearman's correlations and linear mixed models. Results: 170 mothers of 191 infants provided 354 HM samples. Cortisol concentrations in HM increased from postnatal day 5-4m CA (mean difference [MD] 0.6 ± 0.1 ng/ml, p < 0.001). Cortisone concentration did not change across lactation but was higher than cortisol throughout. Compared to no antenatal corticosteroid (ANS), a complete course of ANS was associated with lower GC concentrations in HM through to 4m CA (cortisol: MD -0.3 ± 0.1 ng/ml, p < 0.01; cortisone MD -1.8 ± 0.4 ng/ml, p < 0.001). At 4m CA, higher maternal perceived stress was negatively associated with GC concentrations in HM (cortisol adjusted beta-coefficient [aß] -0.01 ± 0.01 ng/ml, p = 0.05; and cortisone aß -0.1 ± 0.03 ng/ml, p = 0.01), whereas higher postpartum depression and maternal obesity were associated with lower cortisone concentrations (aß -0.1 ± 0.04 ng/ml p < 0.05; MD [healthy versus obese] -0.1 ± 0.04 ng/ml p < 0.05, respectively). There was a weak positive correlation between GC concentrations in HM and gestational age at birth (r = 0.1, p < 0.05). Infant birth head circumference z-score was negatively associated with cortisol concentrations (aß -0.01 ± 0.04 ng/ml, p < 0.05). At hospital discharge, fat-free mass showed a weak positive correlation with cortisol concentrations (r = 0.2, p = 0.03), while fat mass showed a weak negative correlation with cortisone concentrations (r = -0.25, p < 0.001). Conclusion: The mammary gland appears to protect the infant from cortisol through inactivation into cortisone. Maternal and infant characteristics were associated with concentration of GCs in HM, including ANS, stress and depression scores, obesity, gestational age and infant size. The effects of HM glucocorticoids on long-term health outcomes requires further research.