Early-life nutrition is associated with processing speed at age 5 in children born preterm with very low birth weight.

OBJECTIVE: Processing speed is suboptimal among preterm-born children which is of concern as it is a foundational skill supporting higher-level cognitive functions. The study objective was to evaluate associations between early-life nutrition and processing speed in childhood. METHODS: Macronutrient and human milk (mother's own, donor) intakes from 137 children born preterm with very low birth weight enrolled in a nutrition feeding trial were included. Processing speed was evaluated at age 5 using the Wechsler Preschool and Primary Scale of Intelligence-fourth edition Processing Speed Index. Associations between early-life nutrition and processing speed were explored through linear regression. RESULTS: Children had a mean (standard deviation [SD]) birth gestational age of 28.1 (2.5) weeks, weight of 1036 (260) g and 52% were male. The mean (SD) assessment age was 5.7 (0.2) years. Sex-dependent relationships were identified between first postnatal month protein, lipid and energy intakes and processing speed at 5 years. For females, lower protein (per 0.1 g/kg/d: -0.88, 95% confidence interval [CI]: -1.53, -0.23; p = 0.01) and energy (per 10 kcal/kg/d: -2.38, 95% CI: -4.70, -0.05; p = 0.03) intakes were related to higher processing speed scores. Mother's milk provision was positively associated (per 10% increase: 0.80, 95% CI: 0.22, 1.37; p = 0.01) and donor milk was negatively associated (per 10% increase: -1.15, 95% CI: -2.22, -0.08; p = 0.04) with processing speed scores; no sex differences were observed. CONCLUSIONS: First postnatal month nutrition was related to processing speed at age 5 in children born preterm with very low birth weight. Early-life nutrition that supports processing speed may be leveraged to improve later cognitive outcomes for this vulnerable population.

Review of current best practices for human milk banking.

Mother's/parent milk is the optimal way to feed infants and when unavailable, supplemental donor human milk is preferred. A safe supply of donor human milk should be available for all low birthweight infants for whom it has been shown to reduce morbidity. Human milk banking has been in existence for more than a century, although largely shut down during the 1980s, primarily due to fears of human immunodeficiency virus transmission. With renewed security in milk banking, has come an exponential growth in human donor milk use. Guidelines for milk banking have been published in many countries including Australia, France, India, Italy, Spain, Switzerland, the United Kingdom and the nonprofit organization PATH. The European Milk Bank Association and the Human Milk Banking Association of North America have also published recommendations for milk banks throughout Europe and North America, respectively. Although there is variability among these guidelines, there is general consensus on quality control measures required to provide a supply of safe donor milk. These measures include effective donor screening, safe collection, transport and storage of milk, standardized pasteurization and bacteriological testing. Operational considerations are also critical, such as appropriate training for staff, equipment maintenance and cleaning, protocol and record keeping and inspection and accreditation. Clearly delineating these key quality control measures provides an excellent foundation for establishing international guidelines. Acceptable modifications must be established for low- and middle-income countries that do not have sufficient resources; overly burdensome guidelines may make establishing a milk bank unnecessarily prohibitive. This review presents a summary of current best practices for human milk banking.

Association of Postnatal Growth Changes and Neurodevelopmental Outcomes in Preterm Neonates of <29 Weeks' Gestation.

OBJECTIVE: To examine associations between weight and head circumference (HC) changes and neurodevelopment in preterm infants. STUDY DESIGN: This retrospective cohort study of Canadian Neonatal Network and Canadian Neonatal Follow-Up Network sites included preterm infants born 2010-2018. Logistic regression and model diagnostics evaluated relationships between changes in z score and velocity of weight and HC from birth to discharge from a tertiary neonatal intensive care unit, discharge to 18-24 months corrected age (CA), and birth to 18-24 months CA and significant cognitive/motor impairment at 18-24 months CA classified using a Bayley Scales of Infant and Toddler Development-Third Edition cognitive or motor composite score <70. RESULTS: In total, 4530 infants (53.0% male) with a mean (SD) gestational age of 26.3 (1.4) weeks and birth weight of 920 (227) g were included. Weight and HC changes were associated with lower odds of significant cognitive/motor impairment including an OR of 0.87 (95% CI: 0.83, 0.91; P < .001) for a 1-g/d increase in weight from discharge to 18-24 months CA and 0.81 (95% CI: 0.75, 0.88; P < .001) for a 1-unit increase in HC z score from birth to 18-24 months CA. Associations were not statistically significant in morbidity-free neonates. Weight and HC gains poorly discriminated between infants with and without significant cognitive/motor impairment (areas under the receiver operating characteristic curve of <0.64). No growth measure had a clinically useful balance of sensitivity and specificity. CONCLUSIONS: Weight and HC changes were associated with significant cognitive/motor impairment but had poor discriminatory capability. Neonatal morbidities may make a larger contribution than postnatal growth to neurodevelopment.

Examination of school readiness and factors related to developmental vulnerability in children born very low birth weight.

BACKGROUND: Many children born very low birth weight (VLBW) experience school struggles with preparedness requiring adequate physical, social, behavioural, cognitive and communication skills. A global assessment of proficiency is necessary to identify those at risk in any such area and direct early intervention accordingly. Study objectives were to characterize developmental vulnerability and school readiness scores in these key domains in a sample of children born VLBW versus their provincial public school system peers and identify early-life infant and parent factors related to suboptimal school readiness. METHODS: The Early Development Instrument teacher assessments of school readiness were collected for a Canadian VLBW sample (NCT02759809). Comparisons between children born VLBW and peers were made. Group differences between children born VLBW considered vulnerable (<10th percentile, not developmentally ready for learning) and not vulnerable were tested and linear regression explored associations between early-life factors and domain scores. RESULTS: Of 77 available Early Development Instrument assessments, median (interquartile range) assessment age was 6.0 (5.7, 6.2) years, birth weight 950 (793, 1250) grammes and birth gestation 27.4 (25.6, 29.7) weeks. A higher proportion of children born VLBW versus peers exhibited vulnerability in Physical Health and Well-being (24.7% vs. 16.1%, p = 0.04), Communication Skills and General Knowledge (23.4% vs. 10.2%, p = 0.0001) and vulnerability in ≥2 domains (26.0% vs. 14.4%, p = 0.004). Children born VLBW classified as vulnerable versus not vulnerable had lower birth gestation and 5-min Apgar. Adjusted regression models found Apgar <7 associated with lower scores for Physical Health and Well-being (-0.86; 95%CI: -1.71, -0.00; p = 0.049), Social Competence (-1.77; 95%CI: -2.92, -0.62; p = 0.003), Emotional Maturity (-1.55; 95%CI: -2.43, -0.66; p = 0.0009) and Communication Skills and General Knowledge (-1.63; 95%CI: -3.19, -0.06; p = 0.04). CONCLUSIONS: This VLBW sample exhibited poor school readiness in multiple domains. Identification of lower birth gestation and Apgar may assist targeted early interventions to mitigate vulnerability.

State of the evidence from clinical trials on human milk fortification for preterm infants.

Infants born preterm or low birth weight are at risk for morbidity, mortality and later neuroimpairment. Appropriate early post-natal growth is associated with better outcomes in-hospital and post-discharge. Therefore, nutritional strategies that support growth may improve the long-term health of this population. Mother's milk with donor milk as a supplement are preferred sources of nutrition for these infants but may not always support growth, especially amongst infants born of very low birth weight (<1500 g) and or those with a major morbidity. Systematic reviews of randomised controlled trials to date demonstrate that multi-nutrient fortification of human milk improves in-hospital growth of preterm infants although data on long-term neurodevelopment are lacking. Further, individualised approaches to fortification based on milk analysis or the infant's metabolic response may improve growth over standard fortification. The evidence is insufficient to inform the timing of introducing fortifier, routine fortification of feeds post-discharge or routine use of fortifiers made from human instead of bovine milk. Importantly, there is insufficient data to determine if these fortification practices improve relevant clinical or neurodevelopmental outcomes. In sum, there is an urgent need for well-designed clinical trials to assess potential benefits and risks of fortification practices and at what cost.

Developing global guidance on human milk banking.

Donor human milk is recommended by the World Health Organization both for its advantageous nutritional and biological properties when mother's own milk is not available and for its recognized support for lactation and breastfeeding when used appropriately. An increasing number of human milk banks are being established around the world, especially in low- and middle-income countries, to facilitate the collection, processing and distribution of donor human milk. In contrast to other medical products of human origin, however, there are no minimum quality, safety and ethical standards for donor human milk and no coordinating global body to inform national policies. We present the key issues impeding progress in human milk banking, including the lack of clear definitions or registries of products; issues around regulation, quality and safety; and ethical concerns about commercialization and potential exploitation of women. Recognizing that progress in human milk banking is limited by a lack of comparable evidence, we recommend further research in this field to fill the knowledge gaps and provide evidence-based guidance. We also highlight the need for optimal support for mothers to provide their own breastmilk and establish breastfeeding as soon as and wherever possible after birth.

Lorsque la mère est dans l'impossibilité d'allaiter, l'Organisation mondiale de la Santé recommande d'opter pour le lait humain provenant de donneuses, tant pour ses propriétés nutritionnelles et biologiques que pour la contribution avérée qu'il apporte à la lactation et à l'allaitement quand il est utilisé à bon escient. Un nombre croissant de banques de lait humain s'établissent dans le monde entier, en particulier dans les pays à faible et moyen revenu, afin de faciliter la collecte, le traitement et la distribution de lait humain provenant de donneuses. Cependant, contrairement à d'autres produits médicaux d'origine humaine, il n'existe aucune norme minimale de qualité, de sécurité et d'éthique en la matière, et aucun organe de coordination global n'a été créé pour guider les politiques nationales. Dans le présent document, nous évoquons les principaux obstacles à la progression des banques de lait humain, notamment l'absence de définition claire ou de registre de produits; les problèmes relatifs à la réglementation, la qualité et la sécurité; ainsi que les questions éthiques entourant la commercialisation et l'exploitation potentielle des femmes. Jugeant cette progression limitée par le manque de données comparables, nous encourageons à mener d'autres recherches dans ce domaine pour combler les lacunes et fournir des orientations fondées sur des preuves. Nous soulignons également la nécessité d'offrir un soutien optimal aux mères afin qu'elles puissent produire leur propre lait et allaiter autant que possible immédiatement après la naissance.

La Organización Mundial de la Salud recomienda la leche humana donada tanto por sus ventajosas propiedades nutricionales y biológicas cuando no se dispone de la propia leche materna como por su reconocido apoyo a la lactancia y al amamantamiento cuando se utiliza de manera adecuada. Cada vez se crean más bancos de leche humana en todo el mundo, sobre todo en los países de ingresos bajos y medios, para facilitar la recogida, el procesamiento y la distribución de leche humana donada. Sin embargo, a diferencia de lo que ocurre con otros productos médicos de origen humano, no existen estándares mínimos de calidad, seguridad y ética para la leche humana donada ni un organismo mundial de coordinación que sirva de base a las políticas nacionales. En este documento se exponen los principales problemas que impiden el progreso de los bancos de leche humana, como la falta de definiciones claras o de registros de productos; los problemas relacionados con la regulación, la calidad y la seguridad; y las preocupaciones éticas sobre la comercialización y la posible explotación de las mujeres. Dado que el progreso de los bancos de leche humana se ve limitado por la falta de evidencias comparables, se recomienda seguir investigando en este campo para compensar los vacíos de conocimiento y proporcionar una guía asistencial. Asimismo, se destaca la necesidad de apoyar al máximo a las madres para que se provean de su propia leche materna y establezcan la lactancia materna tan pronto y siempre que sea posible después del nacimiento.

Predicting Protein and Fat Content in Human Donor Milk Using Machine Learning.

BACKGROUND: Donor milk is the standard of care for hospitalized very low birth weight (VLBW) infants when mother's milk is unavailable; however, growth of donor milk-fed infants is frequently suboptimal. Variability in nutrient composition of donated milk complicates the production of a uniform pooled product and, subsequently, the provision of adequate nutrition to promote optimal growth and development of VLBW infants. We reasoned a machine learning approach to construct batches using characteristics of the milk donation might be an effective strategy in reducing the variability in donor milk product composition. OBJECTIVE: The objective of this study was to identify whether machine learning models can accurately predict donor milk macronutrient content. We focused on predicting fat and protein, given their well-established importance in VLBW infant growth outcomes. METHODS: Samples of donor milk, consisting of 272 individual donations and 61 pool samples, were collected from the Rogers Hixon Ontario Human Milk Bank and analyzed for macronutrient content. Four different machine learning models were constructed using independent variable groups associated with donations, donors, and donor-pumping practices. A baseline model was established using lactation stage and infant gestational status. Predictions were made for individual donations and resultant pools. RESULTS: Machine learning models predicted protein of individual donations and pools with a mean absolute error (MAE) of 0.16 g/dL and 0.10 g/dL, respectively. Individual donation and pooled fat predictions had an MAE of 0.91 g/dL and 0.42 g/dL, respectively. At both the individual donation and pool levels, protein predictions were significantly more accurate than baseline, whereas fat predictions were competitive with baseline. CONCLUSIONS: Machine learning models can provide accurate predictions of macronutrient content in donor milk. The macronutrient content of pooled milk had a lower prediction error, reinforcing the value of pooling practices. Future research should examine how macronutrient content predictions can be used to facilitate milk bank pooling strategies.

Maternal Diet and Infant Feeding Practices Are Associated with Variation in the Human Milk Microbiota at 3 Months Postpartum in a Cohort of Women with High Rates of Gestational Glucose Intolerance.

BACKGROUND: Human milk contains a diverse community of bacteria believed to play a role in breast health and inoculation of the infant's gastrointestinal tract. The role of maternal nutrition and infant feeding practices on the human milk microbiota remains poorly understood. OBJECTIVE: Our aim was to explore the associations between maternal diet (delivery to 3 mo postpartum), infant feeding practices, and the microbial composition and predicted function in milk from women with varied metabolic status. METHODS: This was an exploratory analysis of a previously completed prospective cohort study of women with varying degrees of gestational glucose intolerance (NCT01405547). Milk samples (n = 93 mothers) were collected at 3 mo postpartum. Maternal dietary information (validated food-frequency questionnaire) and infant feeding practices (human milk exclusivity, frequency of direct breastfeeding per day) were collected. V4-16S ribosomal RNA gene sequencing (Illumina MiSeq) was conducted to determine microbiota composition. RESULTS: Intake of polyunsaturated fat [ß estimate (SE): 0.036 (0.018), P = 0.047] and fiber from grains [0.027 (0.013), P = 0.048] were positively associated with ɑ-diversity (Shannon index) of human milk. Overall microbial composition of human milk clustered based on human milk exclusivity (weighted UniFrac R2 = 0.034, P = 0.015; Bray-Curtis R2 = 0.041, P = 0.007), frequency of direct breastfeeding per day (Bray-Curtis R2 = 0.057, P = 0.026), and maternal fiber intake from grains (Bray-Curtis R2 = 0.055, P = 0.040). Total fiber, fiber from grains, dietary fat, and infant feeding practices were also associated with a number of differentially abundant taxa. The overall composition of predicted microbial functions was associated with total fiber consumption (Bray-Curtis R2 = 0.067, P = 0.036) and human milk exclusivity (Bray-Curtis R2 = 0.041, P = 0.013). CONCLUSIONS: Maternal consumption of fiber and fat, as well as mother's infant feeding practices, are important determinants of the human milk microbiota. Understanding whether these microbial changes impact an infant's overall health and development requires future study.

A Human Milk-Based Protein Concentrate Developed for Preterm Infants Retains Bioactive Proteins and Supports Growth of Weanling Rats.

BACKGROUND: Bovine milk-based protein modulars are currently available to nutrient-enrich enteral feedings; however, they have limitations for use in very-low-birth-weight infants. OBJECTIVES: Our objectives were to develop a human milk-based protein (HMP) concentrate and to conduct a preclinical assessment of the HMP concentrate in weanling rats. METHODS: An HMP concentrate was produced from donor milk using pressure-driven membrane filtration processes and high hydrostatic pressure processing. Protein and lactoferrin concentrations and lysozyme activity were determined by Kjeldahl, HPLC, and turbidimetric assay, respectively. Male Sprague Dawley rats 24 d old (n = 30) were randomly assigned to 1 of 3 isocaloric AIN-93G diets for 4 wk containing 100% casein (control) or with 50% of the casein replaced with the HMP concentrate (treatment) or a bovine whey protein isolate (treatment). Body weight, food intake, fat mass, plasma amino acid profiles, and organ weights were measured. Data were analyzed using linear regression models. RESULTS: Raw donor milk contained (mean ± SD) 101 ± 6 g protein/kg and 5 ± 1 g lactoferrin/kg of milk solids. Postprocessing, protein and lactoferrin concentrations were 589 ± 3 g/kg and 29 ± 10 g/kg, respectively. Lysozyme activity was initially 209 ± 4 U/kg and increased to 959 ± 39 U/kg in the HMP concentrate. There were no statistically significant differences in body weight, food intake, fat mass, or plasma amino acid profiles between rats fed diets containing the HMP concentrate and the control diet. Full cecum weights were higher in rats fed the HMP concentrate than in those fed control diets (mean difference: 5.59 g; 95% CI: 4.50, 6.68 g; P < 0.0001), likely reflecting the concentration of human milk oligosaccharides. No differences were found for other organ weights. CONCLUSIONS: The HMP concentrate retained important bioactive proteins and supported normal rat growth in the preclinical assessment.

Oligosaccharides and Microbiota in Human Milk Are Interrelated at 3 Months Postpartum in a Cohort of Women with a High Prevalence of Gestational Impaired Glucose Tolerance.

BACKGROUND: Human milk is a rich source of human milk oligosaccharides (HMOs) and bacteria. It is unclear how these components interact within the breast microenvironment. OBJECTIVES: The objectives were first, to investigate the association between maternal characteristics and HMOs, and second, to assess the association between HMOs and microbial community composition and predicted function in milk from women with high rates of gestational glucose intolerance. METHODS: This was an exploratory analysis of a previously completed prospective cohort study (NCT01405547) where milk samples (n = 107) were collected at 3 mo postpartum. Milk microbiota composition was analyzed by V4-16S ribosomal RNA gene sequencing and HMOs by rapid high-throughput HPLC. Data were stratified and analyzed by maternal secretor status phenotype and associations between HMOs and microbiota were determined using linear regression models (ɑ-diversity), Adonis (B-diversity), Poisson regression models (differential abundance), and general linear models (predicted microbial function). RESULTS: Prepregnancy BMI, race, and frequency of direct breastfeeding, but not gestational glucose intolerance, were found to be significantly associated with a number of HMOs among secretors and non-secretors. Fucosyllacto-N-hexaose was negatively associated with microbial richness (Chao1) among secretors [B-estimate (SE): -9.3 × 102 (3.4 × 102); P = 0.0082] and difucosyllacto-N-hexaose was negatively associated with microbiota diversity (Shannon index) [-1.7 (0.78); P = 0.029] among secretors. Lacto-N-neotetraose (LNnT) was associated with both microbial B-diversity (weighted UniFrac R2 = 0.040, P = 0.036) and KEGG ortholog B-diversity (Bray-Curtis R2 = 0.039, P = 0.043) in secretors. Additionally, difucosyllactose in secretors and disialyllacto-N-hexaose and LNnT in non-secretors were associated with enrichment of predicted microbial genes encoding for metabolism- and infection-related pathways (P-false discovery rate < 0.1). CONCLUSIONS: HMOs are associated with the microbial composition and predicted microbial functions in human milk at 3 mo postpartum. Further research is needed to investigate the role these relations play in maternal and infant health.

Regional variation in cost of neonatal intensive care for extremely preterm infants.

BACKGROUND: Regional variation in cost of neonatal intensive care for extremely preterm infant is not documented. We sought to evaluate regional variation that may lead to benchmarking and cost saving. METHODS: An analysis of a Canadian national costing data from the payor perspective. We included all liveborn 23-28-week preterm infants in 2011-2015. We calculated variation in costs between provinces using non-parametric tests and a generalized linear model to evaluate cost variation after adjustment for gestational age, survival, and length of stay. RESULTS: We analysed 6932 infant records. The median total cost for all infants was $66,668 (Inter-Quartile Range (IQR): $4920-$125,551). Medians for the regions varied more than two-fold and ranged from $48,144 in Ontario to $122,526 in Saskatchewan. Median cost for infants who survived the first 3 days of life was $91,000 (IQR: $56,500-$188,757). Median daily cost for all infants was $1940 (IQR: $1518-$2619). Regional variation was significant after adjusting for survival more than 3 days, length of stay, gestational age, and year (pseudo-R2 = 0.9, p < 0.01). Applying the model on the second lowest-cost region to the rest of the regions resulted in a total savings of $71,768,361(95%CI: $65,527,634-$81,129,451) over the 5-year period ($14,353,672 annually), or over 11% savings for the total program cost of $643,837,303 over the study period. CONCLUSION: Costs of neonatal intensive care are high. There is large regional variation that persists after adjustment for length of stay and survival. Our results can be used for benchmarking and as a target for focused cost optimization, savings, and investment in healthcare.

The ultrafiltration molecular weight cut-off has a limited effect on the concentration and protein profile during preparation of human milk protein concentrates.

Optimizing protein intake for very low birth weight (<1,500 g) infants is fundamental to prevent faltering postnatal growth with the potential association of impaired neurodevelopment. The protein content of human milk is not sufficient to support the growth of very low birth weight infants. To meet their elevated protein requirements, human milk is currently fortified using typically bovine milk-based protein isolates (>85% on a dry basis). However, these products have several limitations for use in this vulnerable population. To overcome the shortcomings of bovine milk-based protein supplement, a human milk protein concentrate (HMPC) was developed. In preliminary attempts using 10 kDa ultrafiltration (UF) membranes, it was not possible to reach the protein content of commercial protein isolates, presumably due to the retention of human milk oligosaccharides (HMO). Consequently, it was hypothesized that the use of a UF membrane with a higher molecular weight cut-off (50 kDa rather than 10 kDa) could improve the transmission of carbohydrates, including HMO, in the permeate, thus increasing the protein purity of the subsequent HMPC. The results showed that permeate fluxes during the concentration step were similar to either UF molecular weight cut-off, but the 50-kDa membrane had a higher permeate flux during the diafiltration sequence. However, it was not sufficient to increase the protein purity of the human milk retentate, as both membranes generated HMPC with similar protein contents of 48.8% (10 kDa) and 50% (50 kDa) on a dry basis. This result was related to the high retention of HMO, mainly during the concentration step, although the diafiltration step was efficient to decrease their content in the HMPC. As the major bioactive proteins (lactoferrin, lysozyme, bile salt stimulated lipase, and α1-antitrypsin) in human milk were detected in both HMPC, the 50-kDa membrane seems the most appropriate to the preparation of HMPC in terms of permeation flux values. However, improving the separation of HMO from proteins is essential to increase the protein purity of HMPC.

Examining the relationship between maternal body size, gestational glucose tolerance status, mode of delivery and ethnicity on human milk microbiota at three months post-partum.

BACKGROUND: Few studies have examined how maternal body mass index (BMI), mode of delivery and ethnicity affect the microbial composition of human milk and none have examined associations with maternal metabolic status. Given the high prevalence of maternal adiposity and impaired glucose metabolism, we systematically investigated the associations between these maternal factors in women ≥20 years and milk microbial composition and predicted functionality by V4-16S ribosomal RNA gene sequencing (NCT01405547;  https://clinicaltrials.gov/ct2/show/NCT01405547 ). Demographic data, weight, height, and a 3-h oral glucose tolerance test were gathered at 30 (95% CI: 25-33) weeks gestation, and milk samples were collected at 3 months post-partum (n = 113). RESULTS: Multivariable linear regression analyses demonstrated no significant associations between maternal characteristics (maternal BMI [pre-pregnancy, 3 months post-partum], glucose tolerance, mode of delivery and ethnicity) and milk microbiota alpha-diversity; however, pre-pregnancy BMI was associated with human milk microbiota beta-diversity (Bray-Curtis R2 = 0.037). Women with a pre-pregnancy BMI > 30 kg/m2 (obese) had a greater incidence of Bacteroidetes (incidence rate ratio [IRR]: 3.70 [95% CI: 1.61-8.48]) and a reduced incidence of Proteobacteria (0.62 [0.43-0.90]) in their milk, compared to women with an overweight BMI (25.0-29.9 kg/m2) as assessed by multivariable Poisson regression. An increased incidence of Gemella was observed among mothers with gestational diabetes who had an overweight BMI versus healthy range BMI (5.96 [1.85-19.21]). An increased incidence of Gemella was also observed among mothers with impaired glucose tolerance with an obese BMI versus mothers with a healthy range BMI (4.04 [1.63-10.01]). An increased incidence of Brevundimonas (16.70 [5.99-46.57]) was found in the milk of women who underwent an unscheduled C-section versus vaginal delivery. Lastly, functional gene inference demonstrated that pre-pregnancy obesity was associated with an increased abundance of genes encoding for the biosynthesis of secondary metabolites pathway in milk (coefficient = 0.0024, PFDR < 0.1). CONCLUSIONS: Human milk has a diverse microbiota of which its diversity and differential abundance appear associated with maternal BMI, glucose tolerance status, mode of delivery, and ethnicity. Further research is warranted to determine whether this variability in the milk microbiota impacts colonization of the infant gut.

Associations between Diet Quality and Body Composition in Young Children Born with Very Low Body Weight.

BACKGROUND: Very low birth weight (VLBW; <1500 g) infants have increased adiposity and metabolic disease risk in adulthood. Limited evidence suggests low-quality childhood diets are a predisposing risk factor. Despite this, to our knowledge no study has yet examined associations between diet quality and body composition in VLBW individuals. OBJECTIVE: The objective of this study was to determine associations between Healthy Eating Index-2010 (HEI-2010) scores and consumption of fruits/vegetables, added sugars, and macronutrients with body composition in 5.5-y-old children born VLBW. We hypothesized HEI-2010 scores were inversely associated with adiposity. METHODS: This cohort study leveraged the 5.5-y follow-up to the Donor Milk for Improved Neurodevelopmental Outcomes randomized controlled trial. From June 2016 to July 2018, participants attended a follow-up visit at The Hospital for Sick Children, Canada, or were visited in their home. All 316 surviving infants from the trial were eligible, and the caregivers of 158 children (50%; 53% male) consented to follow-up. Diet quality (HEI-2010) and usual intake of fruits/vegetables, added sugars, and macronutrients were determined from two 24-h dietary recalls (ASA24). Linear regressions evaluated associations of diet with BMI (kg/m2) and waist circumference z-scores, total fat, fat-free mass (air displacement plethysmography), and skinfolds. RESULTS: Mean ± SD age at follow-up was 5.7 ± 0.2 y, birth weight was 1013 ± 264 g, and gestational age was 27.9 ± 2.5 wk. Dietary data and BMI z-scores were available for all children; 123 completed air displacement plethysmography. HEI-2010 score was 58.2 ± 12.4 out of 100, and 27% of children had poor quality diets (scores ≤50). HEI-2010 scores were inversely associated with BMI z-score, but only in children with obese mothers. A 10-point increase in HEI-2010 score was associated with reduced BMI (ß: -0.5 SD; 95% CI: -0.7, -0.2) and subscapular (-0.3 SD; 95% CI: -0.6, -0.06) z-scores. CONCLUSIONS: Improving diet quality in children born VLBW with obese mothers may be an important strategy to prevent excess adiposity. This trial was registered at clinicaltrials.gov as Optimizing Mothers' Milk for Preterm Infants (OptiMoM) Program of Research: Study 1-Impact of Donor Milk at Kindergarten, NCT02759809.

Adiposity and Fat-Free Mass of Children Born with Very Low Birth Weight Do Not Differ in Children Fed Supplemental Donor Milk Compared with Those Fed Preterm Formula.

BACKGROUND: Many mothers of very-low-birth-weight (VLBW) infants (<1500 g) are unable to provide sufficient breast milk, and supplemental pasteurized donor human milk (donor milk) or preterm formula is required. The composition of donor milk differs from that of mother's milk and infants fed with donor milk often exhibit slower growth during hospitalization. The long-term impact of nutrient-enriched donor milk on growth, body composition, or blood pressure is unknown. OBJECTIVE: We aimed to determine the effects of nutrient-enriched donor milk compared with preterm formula on growth, body composition, and blood pressure of children born preterm and with VLBW. Associations with in-hospital mother's milk intake were explored. METHODS: This study was a follow-up of children at 5.5-y of age who participated in a randomized controlled trial evaluating the effect of nutrient-enriched donor milk (commencing at ≥120 mL·kg-1·d-1) or preterm formula fed as a supplement when mother's milk was unavailable. The trial intervention lasted 90 d or until hospital discharge, whichever occurred first. In this follow-up investigation, differences in total body fat percentage determined by using air displacement plethysmography (primary outcome), fat-free mass, skinfold thickness, waist circumference, BMI z scores, and blood pressure] were evaluated using linear regressions. RESULTS: Of 316 surviving infants from the earlier trial, 158 (50%) participated in the current study (53% male). Mean ± SD birth weight and gestational age were 1013 ± 264 g and 27.9 ± 2.5 wk. The median (IQR) intervention period was 67.5 d (52.0-91.0 d). Mean ± SD age and BMI z score at follow-up were 5.7 ± 0.2 y and -0.3 ± 1.2. Supplemental nutrient-enriched donor milk, compared to preterm formula, was not associated with growth, body composition, or blood pressure. In-hospital mother's milk intake was positively associated with height z score at 5.5 y (ß: 0.07; 95% CI: 0.004, 0.1; P = 0.04). CONCLUSIONS: Supplemental nutrient-enriched donor milk and preterm formula during initial hospitalization results in comparable long-term growth and body composition in young children born VLBW. This trial was registered at clinicaltrials.gov as NCT02759809 and at isrctn.com as ISRCTN35317141.

Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants.

Our improved tools to identify the aetiologies in patients with multiple abnormalities resulted in the finding that some patients have more than a single genetic condition and that some of the diagnoses made in the past are acquired rather than inherited. However, limited knowledge has been accumulated regarding the phenotypic outcome of the interaction between different genetic conditions identified in the same patients. We report a newborn girl with brachytelephalangic chondrodysplasia punctata (BCDP) as well as frontonasal dysplasia, ptosis, bilateral hearing loss, vertebral anomalies, and pulmonary hypoplasia who was found, by whole exome sequencing, to have a de novo pathogenic variant in RAF1 (c.770C>T, [p.Ser257Leu]) and a likely pathogenic variant in SIX2 (c.760G>A [p.A254T]), as well as maternal systemic lupus erythematosus (SLE). This case shows that BCDP is most probably not a diagnostic entity and can be associated with various conditions associated with CDP including maternal SLE.

Holder pasteurization of donated human milk is effective in inactivating SARS-CoV-2.

BACKGROUND: Provision of pasteurized donor human milk, as a bridge to mother's own milk, is the standard of care for very low-birth-weight infants in hospital. The aim of this research was to confirm that Holder pasteurization (62.5°C for 30 min) would be sufficient to inactivate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in donated human milk samples. METHODS: We spiked frozen milk samples from 10 donors to the Rogers Hixon Ontario Human Milk Bank with SARS-CoV-2 to achieve a final concentration of 1 × 107 TCID50/mL (50% of the tissue culture infectivity dose per mL). We pasteurized samples using the Holder method or held them at room temperature for 30 minutes and plated serial dilutions on Vero E6 cells for 5 days. We included comparative controls in the study using milk samples from the same donors without addition of virus (pasteurized and unpasteurized) as well as replicates of Vero E6 cells directly inoculated with SARS-CoV-2. We reported cytopathic effects as TCID50/mL. RESULTS: We detected no cytopathic activity in any of the SARS-CoV-2-spiked milk samples that had been pasteurized using the Holder method. In the SARS-CoV-2-spiked milk samples that were not pasteurized but were kept at room temperature for 30 minutes, we observed a reduction in infectious viral titre of about 1 log. INTERPRETATION: Pasteurization of human milk by the Holder method (62.5°C for 30 min) inactivates SARS-CoV-2. Thus, in the event that donated human milk contains SARS-CoV-2 by transmission through the mammary gland or by contamination, this method of pasteurization renders milk safe for consumption and handling by care providers.

Les dons de lait humain pasteurisé et non pasteurisé.

Il est universellement reconnu que le lait humain est la source de nutrition exclusive optimale pour les nouveau-nés de 0 à six mois et qu'il peut faire partie du régime du nourrisson en santé jusqu'à l'âge de deux ans et même après. Malgré les avancées dans le secteur des préparations lactées pour nourrisson, le lait humain apporte tout un éventail d'avantages, en partie grâce à sa matrice bioactive qu'aucune autre source d'alimentation ne peut reproduire. Lorsque la mère produit une quantité de lait insuffisante pour son nouveau-né vulnérable, du lait pasteurisé de donneuses devrait être rendu disponible pour compléter le lait maternel et être le premier choix proposé, suivi des préparations lactées commerciales. La quantité de lait de ce type est limitée au Canada, et sa distribution est priorisée auprès des nouveau-nés malades et hospitalisés. Le partage informel de lait humain consiste à donner et recevoir du lait humain exprimé sans passer par une banque de lait humain. Il comporte un risque de transmission de bactéries et de virus en plus d'être lié à des irrégularités et des incertitudes à l'égard du dépistage des donneuses. Les pédiatres et les autres dispensateurs de soins doivent connaître les risques du partage informel de lait humain et être en mesure de proposer des possibilités plus sécuritaires aux familles.

Pasteurized and unpasteurized donor human milk.

It is universally accepted that human milk is the optimal, exclusive source of nutrition for infants 0 to 6 months of age, and may remain part of the healthy infant diet for the first 2 years of age and beyond. Despite advances in infant formulas, human milk provides a wide range of benefits, due in part to its bioactive matrix that cannot be replicated by any other source of nutrition. When there is an insufficient volume of mother's milk for the vulnerable newborn, pasteurized donor human milk should be made available, as a bridge to mother's milk and as the first alternative feeding choice, followed by commercial formula. There is a limited supply of donor milk in Canada and distribution is prioritized for sick, hospitalized neonates. Informal milk sharing is the practice of donating and receiving expressed human milk without going through a human milk bank. Informal milk sharing carries risk for bacterial and viral transmission as well as inconsistency and uncertainty regarding donor screening. Paediatricians and other health care providers need to be aware of the risks of informal milk sharing and be able to counsel families appropriately on safer alternatives.

High Hydrostatic Pressure Processing Better Preserves the Nutrient and Bioactive Compound Composition of Human Donor Milk.

BACKGROUND: When mother's milk is insufficient, pasteurized human donor milk (DM) is the recommended supplement for hospitalized very-low-birth-weight infants. The current method of pasteurization (Holder, 62.5°C, 30 min) negatively affects heat-sensitive nutrients and bioactive proteins. OBJECTIVES: Objectives of this study were to compare changes in DM composition after thermal pasteurization (Holder and flash-heating) and nonthermal methods [UV-C irradiation and high hydrostatic pressure (HHP)]. We hypothesized that nonthermal techniques would result in fewer changes to composition. METHODS: Holder, flash-heating (brought to boil), UV-C irradiation (250 nm, 25 min), and HHP (500 MPa, 8 min) were studied. Pools of milk from 17 women known to contain bacteria at >5 × 107 colony forming units (CFU)/L were collected from the Rogers Hixon Ontario Human Milk Bank and underwent each pasteurization technique. Macronutrients, heat-sensitive micronutrients (vitamin C, folate), and bioactive components [bile-salt-stimulated lipase (BSSL), lysozyme, lactoferrin] were measured in raw and pools of pasteurized milk. Milk was cultured to determine how well each technique produced a culture negative result (detection limit <1 × 103 CFU/L). RESULTS: Folate was reduced by 24-27% after Holder, flash-heating, and UV-C (P < 0.05); no reduction was observed after HHP. All pasteurization methods reduced vitamin C (60-75%, P < 0.001). BSSL was abolished after Holder and flash-heating (P < 0.001), reduced after UV-C (48%, P < 0.001), but unaffected by HHP. Lysozyme activity was reduced after flash-heating (44%) and UV-C (74%, P < 0.004) but unaffected by Holder or HHP. Lactoferrin was reduced by all methods (P < 0.02) but most severely by flash-heating (74%) and least severely by HHP (25%). Holder and UV-C reduced lactoferrin by ∼48%. All pasteurization methods reduced the number of culture positive DM samples (P < 0.001). CONCLUSIONS: HHP better preserves human milk composition than Holder pasteurization. Future research on the feasibility of HHP for pasteurizing human milk is warranted because its implementation may improve the nutritional status and health of DM-fed infants.