Is maternal body weight or composition associated with onset of lactogenesis II, human milk production or infant consumption of mother's own milk? A systematic review and meta-analysis.

Maternal adiposity impacts lactation performance, but the pathways are unclear. We conducted a systematic review to understand whether maternal adiposity (body mass index [BMI] or % fat mass) is associated with onset of lactogenesis II (copious milk; hours), human milk production (expressed volume/24hrs), and infant consumption of mother's own milk (volume/24hrs). We used random-effects standard meta-analyses to compare the relative risk (RR) of delayed lactogenesis II (>72 hours) between mothers classified as underweight (BMI <18.5kg/m2), healthy weight (BMI 18.5-24.9 kg/m2), and overweight/obese (BMI >25kg/m2) and random-effects meta-regressions to examine associations with hours to lactogenesis II and infant milk consumption. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. We included 122 articles. Mothers with underweight (RR: 0.61; 95% CI: 0.46, 0.83; I2= 46.27%; 8 articles/datapoints) or healthy weight status (RR: 0.72; 95% CI: 0.61, 0.84; I2= 64.41%; 15 articles/datapoints) were less likely to experience delayed lactogenesis II than mothers with overweight/obesity. We found no association between maternal BMI and time onset of lactogenesis II (ß= 1.45 hours; 95% CI: -3.19, 6.09; p= 0.52, I2= 0.00%; 8 articles, 15 datapoints). Due to limited data, we narratively reviewed articles examining BMI or % fat mass and milk production (n=6); half reported an inverse association, and half no association. We found no association between maternal BMI (ß= 5.84mL; 95% CI: -11.92, 23.60; p= 0.51, I2= 44.18 %; 58 articles, 75 datapoints) nor % fat mass (ß= 6.54mL; 95% CI: -3.60, 16.68; p= 0.20, I2= 21.40%; 30 articles, 32 datapoints) and infant milk consumption. Certainty of evidence for all outcomes was very low. In conclusion, mothers with overweight/obesity may be at risk of delayed lactogenesis II. Available data do not support an association with infant milk consumption but included studies do not adequately represent mothers with obesity. PROSPERO REGISTRATION #: 285344 STATEMENT OF SIGNIFICANCE: While results suggest mothers with overweight/obesity may be at risk of delayed lactogenesis II, it is important to note that available data do not adequately represent mothers at the higher end of the BMI and % fat mass spectrum (BMI >30 kg/m2, % fat mass >40%). Future research should explore the association between maternal body weight or composition and lactation outcomes including onset of lactogenesis II, human milk production and infant consumption of mother's own milk among mothers with greater variability in weight status. Understanding these relationships may help guide the creation of more specialized lactation care for mothers of all body sizes.

SARS-CoV-2 antibodies and their neutralizing capacity against live virus in human milk after COVID-19 infection and vaccination: prospective cohort studies.

BACKGROUND: There is limited understanding of the impact of coronavirus disease 2019 (COVID-19) infection and vaccination type and interval on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human milk antibodies and their neutralizing capacity. OBJECTIVES: These cohort studies aimed to determine the presence of antibodies and live virus neutralizing capacity in milk from females infected with COVID-19, unexposed milk bank donors, and vaccinated females and examine impacts of vaccine interval and type. METHODS: Milk was collected from participants infected with COVID-19 during pregnancy or lactation (Cohort-1) and milk bank donors (Cohort-2) from March 2020-July 2021 at 3 sequential 4-wk intervals and COVID-19 vaccinated participants with varying dose intervals (Cohort-3) (January-October 2021). Cohort-1 and Cohort-3 were recruited from Sinai Health (patients) and through social media. Cohort-2 included Ontario Milk Bank donors. Milk was examined for SARS-CoV-2 antibodies and live virus neutralization. RESULTS: Of females with COVID-19, 53% (Cohort-1, n = 55) had anti-SARS-CoV-2 IgA antibodies in ≥1 milk sample. IgA+ samples (40%) were more likely neutralizing than IgA- samples (odds ratio [OR]: 2.18; 95% confidence interval [CI]: 1.03, 4.60; P = 0.04); however, 25% of IgA- samples were neutralizing. Both IgA positivity and neutralization decreased ∼6 mo after symptom onset (0-100 compared with 201+ d: IgA OR: 14.30; 95% CI: 1.08, 189.89; P = 0.04; neutralizing OR: 4.30; 95% CI: 1.55, 11.89; P = 0.005). Among milk bank donors (Cohort-2, n = 373), 4.3% had IgA antibodies; 23% of IgA+ samples were neutralizing. Vaccination (Cohort-3, n = 60) with mRNA-1273 and shorter vaccine intervals (3 to <6 wk) resulted in higher IgA and IgG than BNT162b2 (P < 0.04) and longer intervals (6 to <16 wk) (P≤0.02), respectively. Neutralizing capacity increased postvaccination (P = 0.04) but was not associated with antibody positivity. CONCLUSIONS: SARS-CoV-2 infection and vaccination (type and interval) impacted milk antibodies; however, antibody presence did not consistently predict live virus neutralization. Although human milk is unequivocally the best way to nourish infants, guidance on protection to infants following maternal infection/vaccination may require more nuanced messaging. This study was registered at clinicaltrials.gov as NCT04453969 and NCT04453982.

Inflammatory Markers in Mother's Own Milk and Infant Stool of Very Low Birthweight Infants.

BACKGROUND: Mother's breastmilk is the gold standard for feeding preterm infants. Preterm delivery may be precipitated by inflammatory maternal states, but little is known about milk cytokine profiles and how they correlate with markers of infant gut inflammation (i.e., stool calprotectin) in this vulnerable population. RESEARCH AIM: To assess cytokines and inflammatory markers in milk from parents of very preterm infants over time as well as correlations between milk and infant's stool calprotectin. METHOD: This is a secondary analysis of milk samples collected during OptiMoM, a triple-blind randomized clinical trial of infants born < 1250 g (NCT02137473). Longitudinally collected samples were analyzed for cytokines, choline, and inflammatory markers (C-reactive protein [CRP], IFN-γ, IL-10, IL-1ß, IL-1ra, IL-6, IL-8, TNF-α). Infant stools were collected for longitudinal calprotectin analysis. Generalized estimating equations quantified longitudinal profiles of milk markers and stool calprotectin, their associations, and the correlation between free choline and C-reactive protein over follow-up. RESULT: Participants included 92 parents and infants (median weeks of gestation 27.3, median birth weight 845 g, and prevalence of male infants 45%). In all, 212 milk samples and 94 corresponding stool calprotectin levels were collected 1-11 weeks postpartum. C-reactive protein was present in much higher concentrations than other markers, and was highest in Week 1 postpartum. It decreased over time. IL-8 and free choline also changed over time while other markers did not. There was no correlation between any milk markers and stool calprotectin. CONCLUSION: Milk from mothers of very preterm infants has detectable inflammatory markers, some of which change over time. Research is needed to determine if infant outcomes are associated with these markers.

Characterization of protein aggregates in cream and skimmed human milk after heat and high-pressure pasteurization treatments.

Preservation processes applied to ensure microbial safety of human milk (HM) can modify the native structure of proteins and their bioactivities. Consequently, this study evaluated the effect of pasteurization methods (Holder pasteurization, high-temperature short-time (HTST), and high hydrostatic pressure (HHP)) of whole human milk (HM) on protein aggregates in skim milk and cream fractions. For heat-treated whole milk, insoluble protein aggregates at milk fat globule membrane (MFGM) were formed by disulfide and non-covalent bonds, but insoluble skim milk protein aggregates were only stabilized by non-covalent interactions. Contrary to heat treatment, the insolubilization of main proteins at the MFGM of HHP-treated HM was only through non-covalent interactions rather than disulfide bonds. Moreover, only heat treatment induced the insoluble aggregation of ⍺-lactalbumin. Overall, compared to heat treatment, HHP produced a milder effect on protein aggregation, validating the use of this process to better preserve the native state of HM bioactive proteins.

A comparison of tertiary level NICU costs for infants born <1250 g supplemented with human versus bovine milk-based fortifiers.

BACKGROUND: Human milk-based fortifiers (HMBF) are more costly than bovine milk-based fortifiers (BMBF); but, the efficacy of human or bovine fortification for infants born <1250 g has yet to be fully elucidated. Our objective was to determine the effect of fortifier source on tertiary neonatal costs. METHODS: Costs associated with tertiary neonatal care, including direct and indirect hospital expenditures, feed-related costs and physician billing were analysed retrospectively for participants of OptiMoM (NCT02137473), a blinded RCT comparing fortifier type for babies born <1250 g. A generalized linear model of cost according to fortifier type was created. RESULTS: Mean [95% confidence interval] daily costs per patient, adjusted for birth gestation and weight, was significantly greater in the human than the BMBF group ($3,452 [$3,186 - $3,740] Canadian dollars (CAD) versus $2,451 [$2,257 - $2,662] CAD) respectively, p < 0.0001). CONCLUSION: HMBF usage entails additional costs on NICU stay that should be considered with implementation.

Development of a human milk protein concentrate from donor milk: Impact of the pasteurization method on static in vitro digestion in a preterm newborn model.

The impact of high temperature short time (HTST, 72 °C, 15 s), Holder pasteurization- (63 °C, 30 min) and high hydrostatic pressure (HHP, 600 MPa-10 min) was evaluated on the digestibility of human milk protein concentrate (HMPC) by using a static in vitro gastrointestinal digestion system. The results showed that the processing steps used to produce the HMPC induced a decrease in readily available nitrogen (non-protein nitrogen and peptides). Overall, digestibility was similar between pasteurized and raw HMPC (degree of hydrolysis ranged from 26 to 34 %). Lactoferrin was more susceptible to gastric and intestinal digestion after thermal pasteurization. Additionally, the resistance of ß-casein to digestion increased after HHP and Holder pasteurization due to aggregation and changes in protein structure. During intestinal digestion, Holder pasteurization induced a higher release of arginine, phenylalanine and tyrosine from HMPC compared to raw and HHP-treated HMPC. Overall, protein structural changes induced by human milk (HM) processing (freeze-thawing and filtration) and pasteurization treatments affected HMPC proteolysis during in vitro digestion. However, protein digestion behaviors were quite similar for raw and HHP-treated HMPC compared to the thermal-treated HMPC, with no effect on lactoferrin digestion. Consequently, pasteurization of HMPC by HHP represents an interesting non-thermal process that preserves the HM bioactive proteins during digestion.

The price of neonatal intensive care outcomes - in-hospital costs of morbidities related to preterm birth.

Background: Neonatal care for preterm babies is prolonged and expensive. Our aim was to analyze and report costs associated with common preterm diagnoses during NICU stay. Methods: We analyzed data from the Ontario healthcare data service. Diagnoses were collated by discharge ICD codes, and categorized by gestational age. We calculated typical non parametric statistics, and for each diagnosis we calculated median shifts and generalized linear mode. Results: We included data on 12,660 infants between 23 and 30 weeks gestation in 2005-2017. Calculated cost increment with diagnosis were: Intestinal obstruction: $94,738.08 (95%CI: $70,093.3, $117,294.2), Ventriculoperitoneal shunt: $86,456.60 (95%CI: $60,773.7, $111,552.2), Chronic Lung Disease $77,497.70 (95%CI: $74,937.2, $80,012.8), Intestinal perforation $57,997.15 (95%CI:$45,324.7, $70,652.6), Retinopathy of Prematurity: $55,761.80 (95%CI: $53,916.2, $57,620.1), Patent Ductus Arteriosus $53,453.70 (95%CI: $51,206.9, $55692.7, Post-haemorrhagic ventriculomegaly $41,822.50 (95%CI: $34,590.4, $48,872.4), Necrotizing Enterocolitis $39,785 (95%CI: $35,728.9, $43,879), Meningitis $38,871.85 (95%CI: $25,272.7, $52,224.4), Late onset sepsis $32,954.20 (95%CI: $30,403.7, 35.515), Feeding difficulties $24,820.90 (95%CI: $22,553.3, $27,064.7), Pneumonia $23,781.70 (95%CI: $18,623.8, $28,881.6), Grade >2 Intraventricular Haemorrhage $14,777.38 (95%CI: $9,821.7, $20,085.2). Adjusted generalized linear model of diagnoses as coefficients for cost confirmed significance and robustness of the model. Conclusion: Cost of care for preterm infant is expensive, and significantly increases with prematurity complication. Interventions to reduce those complications may enable resource allocation and better understanding of the needs of the neonatal health services.

Donor human milk processing and its impact on infant digestion: A systematic scoping review of in vitro and in vivo studies.

When there is an inadequate supply of mother's milk, pasteurized donor human milk is preferred over formula to supplement feeds for preterm infants. Although providing donor milk helps to improve feeding tolerance and reduce necrotizing enterocolitis, changes to its composition and reductions in bioactivity during processing, are thought to contribute to the slower growth often exhibited by these infants. To improve the clinical outcomes of recipient infants by maximizing the quality of donor milk, research is currently investigating strategies to optimize all aspects of processing, including pooling, pasteurization, and freezing; however, reviews of this literature typically only summarize the impact of a processing technique on composition or bioactivity. Reviews of published research investigating the impact of donor milk processing on infant digestion/absorption are lacking and thus, was the objective for this systematic scoping review, Open Science Framework (https://doi.org/10.17605/OSF.IO/PJTMW). Databases were searched for primary research studies evaluating donor milk processing for pathogen inactivation or other rationale and subsequent effect on infant digestion/absorption. Non-human milk studies or those assessing other outcomes were excluded. Overall, 24 articles from 12,985 records screened were included. Most studied thermal methods to inactivate pathogens, predominantly Holder pasteurization (HoP) (62.5°C, 30 min) and high-temperature short-time. Heating consistently decreased lipolysis and increased proteolysis of lactoferrin and caseins; however, protein hydrolysis was unaffected from in vitro studies. The abundance and diversity of released peptides remain unclear and should be further explored. Greater investigation into less-harsh methods for pasteurization, such as high-pressure processing, is warranted. Only 1 study assessed the impact of this technique and found minimal impact on digestion outcomes compared with HoP. Fat homogenization appeared to positively impact fat digestion (n = 3 studies), and only 1 eligible study investigated freeze-thawing. Identified knowledge gaps regarding optimal methods of processing should be further explored to improve the quality and nutrition of donor milk.

Digestion of human milk processed by high pressure processing and Holder pasteurization using a dynamic in vitro model of the preterm infant.

Holder pasteurization (HoP) (62.5 °C, 30 min) of donor human milk is widely used to inactivate potential pathogens but may lead to denaturation and aggregation of bioactive proteins, reducing their functionality. In contrast, high pressure processing (HPP) is a non-thermal technique that minimally affects assessed bioactive components; however, it is unclear how HPP affects protein digestion, and retention of functional bioactive proteins. Raw or processed (HoP; HPP[500 MPa,10 min]) pools of milk (N = 3, from 9 donors) were subjected in triplicate to in vitro digestion simulating the preterm infant gastrointestinal tract. Compared to raw or HPP, HoP increased intestinal proteolysis of lactoferrin and bioactive milk fat globule membrane proteins. Lysozyme activity was impacted by digestion following HoP (72 % to 7 %)-significantly more than HPP (75 % to 34 %) or raw (100 % to 39 %), which did not differ. Proteins in HPP-treated donor milk are digested no different than raw milk, while preserved bioactivity remains functional upon digestion.

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.

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.

Associations of maternal inflammatory states with human milk composition in mothers of preterm infants.

Introduction: Overweight/obesity (ow/ob) is increasing in prevalence in pregnant women, and it is associated with other pro-inflammatory states, such as pre-eclampsia, gestational diabetes, and preterm labor. Data are lacking if mothers experiencing inflammatory states who deliver preterm have mother's own milk (MOM) with differing inflammatory markers or pro-inflammatory fatty acid (FA) profiles. Methods: The aim was to explore associations of maternal pre- and perinatal inflammatory states with levels of inflammatory markers and/or FAs in longitudinal samples of MOM from mothers of preterm infants born <1,250 g. Inflammatory states included pre-pregnancy ow/ob, diabetes, chorioamnionitis (chorio), preterm labor (PTL), premature rupture of membranes (PROM), pre-eclampsia, and cesarian delivery. In MOM, inflammatory markers studied included c-reactive protein (CRP), free choline, IFN-Ɣ, IL-10, IL-1ß, IL-1ra, IL-6, IL-8, and TNF-α, and FAs included omega-6:omega-3 ratio, arachidonic acid, docosahexaenoic acid, linoleic acid, monounsaturated FAs, and saturated FAs. The above inflammatory states were assessed individually, and the healthiest mothers (normal BMI, no chorio, and ± no pre-eclampsia) were grouped. Regression analysis tested associations at baseline (day 5) and over time using generalized estimating equations. Results: A total of 92 infants were included who were delivered to mothers (42% ow/ob) at a median gestational age of 27.7 weeks and birth weight of 850 g. MOM CRP was 116% higher (relative change 2.16) in mothers with ow/ob at baseline than others (p = 0.01), and lower (relative change 0.46, 0.33, respectively) in mothers in the two "healthy groups" at baseline (both p < 0.05) than others. MOM IL-8 levels were lower with chorio and PTL at baseline. No significant associations were found for other individual or grouped inflammatory states nor for other MOM inflammatory markers nor FA profiles at baseline. Discussion: In conclusion, MOM CRP levels are positively associated with inflammatory states, such as ow/ob. Reassuringly, there was no association between FA profiles or most other inflammatory markers and maternal inflammatory states. Further studies are needed to determine potential associations or ramifications of MOM CRP in vulnerable preterm infants.

Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.

BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

Diet Quality and Cognitive Performance in Children Born Very Low Birth Weight.

Children born very low birth weight (VLBW, <1,500 g) are at high risk for cognitive and academic difficulties later in life. Although early nutrition (e.g., breastfeeding) is positively correlated with IQ in children born VLBW, the association between dietary intake in childhood and cognitive performance is unknown. Thus, our study is the first to investigate the relationship between diet quality, as measured by the Healthy Eating Index-2010 (HEI-2010) and cognitive performance in a Canadian cohort of 5-year-old children born VLBW (n = 158; 47% female). Diet quality was measured using two 24-h diet recalls obtained from parents and cognitive performance was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). To account for additional sociodemographic factors that could influence neurodevelopment, linear regression analyses were adjusted for sex, household income above/below the poverty line, maternal education, birth weight and breastfeeding duration. Mean ± SD HEI-2010 score was 58.2 ± 12.4, with most children (67%) having diets in "need of improvement" (scores 51-80). HEI-2010 scores were not significantly associated with IQ or any other WPPSI-IV composite score. Significant predictors of IQ in our model were birth weight, sex, and maternal education. Our findings emphasize the important role of maternal education and other sociodemographic factors on neurodevelopment in children born VLBW. Further, despite not finding any significant association between HEI-2010 scores and IQ, our results highlight the need to improve diet quality in young children born VLBW. Further research is needed to confirm the impact of diet quality on cognitive performance in this vulnerable population.

Human milk nutrient fortifiers alter the developing gastrointestinal microbiota of very-low-birth-weight infants.

Nutrient fortifiers are added to human milk to support the development of very-low-birth-weight infants. Currently, bovine-milk-based fortifiers (BMBFs) are predominantly administered, with increasing interest in adopting human-milk-based fortifiers (HMBFs). Although beneficial for growth, their effects on the gastrointestinal microbiota are unclear. This triple-blind, randomized clinical trial (NCT02137473) tested how nutrient-enriching human milk with HMBF versus BMBF affects the gastrointestinal microbiota of infants born < 1,250 g during hospitalization. HMBF-fed infants (n = 63, n = 269 stools) showed lower microbial diversity, altered microbial community structure, and changes in predicted microbial functions compared with BMBF-fed infants (n = 56, n = 239 stools). HMBF-fed infants had higher relative and normalized abundances of unclassified Enterobacteriaceae and lower abundances of Clostridium sensu stricto. Post hoc analyses identified dose-dependent relationships between individual feed components (volumes of mother's milk, donor milk, and fortifiers) and the microbiota. These results highlight how nutrient fortifiers impact the microbiota of very-low-birth-weight infants during a critical developmental window.

Preservation of Anti-cytomegalovirus Activity in Human Milk Following High-Pressure Processing Compared to Holder Pasteurization.

Pasteurized donor human milk is recommended for hospitalized preterm infants when mother's own milk is unavailable. Our aim was to compare the antiviral activity of human milk processed by Holder pasteurization (HoP) or high-pressure processing (HPP) against representative enveloped and non-enveloped viruses including cytomegalovirus and hepatitis A virus. Expressed milk from 20 donors collected from the Ontario Milk Bank was combined into 10 pools, each from two unique donors. Each pool was processed by HoP (62.5°C, 30 min) or HPP (500 MPa, 8 min, 4°C) and subsequently inoculated with cytomegalovirus or hepatitis A virus to achieve a final concentration of 5-log plaque-forming units/mL. Plaque reduction assays were used to quantify detectable virus after 30 min incubation (room temperature). Post hoc experiments using a 4 h incubation time were conducted if reductions were detected at 30 min. Irrespective of processing, cytomegalovirus concentrations declined in all pools after 30 min incubation (P < 0.0001). Milk processed by HoP exhibited significantly less reduction compared to raw milk (P = 0.0069). In post hoc experiments, anti-cytomegalovirus activity was maintained at 4 h, with high inter-pool variability. Hepatitis A virus concentration remained unchanged after 30 min incubation in raw and processed milk. Anti-cytomegalovirus activity in human milk is preserved following HoP and HPP, persisting up to 4 h post-inoculation; anti-hepatitis A virus activity was not observed in raw or processed milk. Further research is needed to understand how HoP or promising alternative processing methods affect the antiviral activity of donated milk, given its potential importance to recipient infants.

Social-Cognitive Network Connectivity in Preterm Children and Relations With Early Nutrition and Developmental Outcomes.

Infants born very low birth weight (VLBW, < 1,500 g) are at a heightened risk for structural brain abnormalities and social-cognitive deficits, which can impair behavioural functioning. Resting-state fMRI, reflecting a baseline level of brain activity and underlying social-cognitive processes, has also been reported to be altered in children born VLBW. Yet very little is known about the functional networks underlying social cognition using magnetoencephalography (MEG) and how it relates to neonatal factors and developmental outcomes. Thus, we investigated functional connectivity at rest in VLBW children and the associations with early nutrition and IQ and behavioural problems. We collected resting-state MEG recordings and measures of IQ and social-cognitive behaviour, as well as macronutrient/energy intakes during initial hospitalisation in 5-year-old children born VLBW (n = 37) compared to full-term (FT; n = 27) controls. We examined resting-state network differences controlling for sex and age at scan. Functional connectivity was estimated using the weighted phase lag index. Associations between functional connectivity with outcome measures and postnatal nutrition were also assessed using regression analyses. We found increased resting-state functional connectivity in VLBW compared to FT children in the gamma frequency band (65-80 Hz). This hyper-connected network was primarily anchored in frontal regions known to underlie social-cognitive functions such as emotional processing. In VLBW children, increased functional connectivity was related to higher IQ scores, while reduced connectivity was related to increased behavioural problems at 5 years of age. These within-group associations were found in the slower frequency bands of theta (4-7 Hz) and alpha (8-12 Hz), frequently linked to higher-order cognitive functions. We also found significant associations between macronutrient (protein and lipid) and energy intakes during the first postnatal month with functional connectivity at preschool-age, highlighting the long-term impacts of postnatal nutrition on preterm brain development. Our findings demonstrate that at preschool-age, VLBW children show altered resting-state connectivity despite IQ and behaviour being in the average range, possibly reflecting functional reorganisation of networks to support social-cognitive and behavioural functioning. Further, our results highlight an important role of early postnatal nutrition in the development of resting-state networks, which in turn may improve neurodevelopmental outcomes in this vulnerable population.

Docosahexaenoic acid and arachidonic acid levels are correlated in human milk: Implications for new European infant formula regulations.

From February 2022, all infant formula sold in the European Union must contain docosahexaenoic acid (DHA) at ~0.33%-1.14% of total fat with no minimum requirement for arachidonic acid (ARA). This work examines the association between DHA and ARA levels in human milk, the gold standard for infant feeding. Human milk (n = 470) was collected over 12-weeks postpartum from lactating mothers (n = 100) of infants born weighing <1250 g (NCT02137473). Fatty acids were analyzed by gas chromatography. ARA and DHA concentrations were associated in human milk (ß = 0.47 [95% confidence interval 0.38-0.56] mol%), including transitional and mature milk, but not colostrum. This remained significant upon adjustment for percentages of other saturated, monounsaturated, n-3, or n-6 fatty acids, day of sample collection, or maternal characteristics (body mass index, ethnicity, education, and income). Infant formulas containing relatively high concentrations of DHA without ARA, as permitted by the new regulations, would not reflect the balance of these fatty acids in human milk.

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.

Eating Behaviors, Caregiver Feeding Interactions, and Dietary Patterns of Children Born Preterm: A Systematic Review and Meta-Analysis.

Infants born preterm (<37 weeks of gestation) often experience feeding problems during hospitalization. Whether difficulties persist or have long-term sequelae on childhood eating is unclear. We aimed to describe the oromotor eating skills (e.g., chewing/swallowing), eating behaviors (e.g., food neophobia), food parenting practices (e.g., pressure to eat), and dietary patterns of preterm children during late infancy (6-12 mo) and early childhood (>12 mo-7 y) and to determine whether these differed from those of term-born peers. We identified 67 articles (57 unique studies) for inclusion. We used random-effects meta-analysis of proportions to examine the prevalence of oromotor eating skill and eating behavior challenges among preterm children, standard meta-analysis for comparisons with term-born peers, and the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty of evidence. Forty-three percent (95% CI: 24%, 62%) of infants and 25% (95% CI: 17%, 33%) of children born preterm experienced oromotor eating difficulties and 16% (95% CI: 4%, 27%) and 20% (95% CI: 11%, 28%), respectively, exhibited challenging eating behaviors. During late infancy and early childhood, oromotor eating difficulties (OR: 2.86; 95% CI: 1.71, 4.77; I2 = 67.8%) and challenging eating behaviors (OR: 1.52; 95% CI: 1.11, 2.10; I2 = 0.0%) were more common in those born preterm than in those born term: however, the certainty of evidence was very low. Owing to the low number and heterogeneity of studies, we narratively reviewed literature on food parenting and dietary patterns. Mothers of preterm infants appeared to have heightened anxiety while feeding and utilized coercive food parenting practices; their infants reportedly received less human milk, started solid foods earlier, and had poorer diet quality than term-born peers. In conclusion, meta-analyses show preterm children experience frequent oromotor eating difficulties and challenging eating behaviors throughout the early years. Given preterm birth increases risk of later obesity and diet-related chronic disease, research examining the effects of caregiver-child interactions on subsequent diet is warranted. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42020176063.