New alternatives to holder pasteurization in processing donor milk in human milk banks.

Infectious and toxicological risks are the main potential hazards that operators of Human Milk Banks (HMBs) encounter and must eliminate. HMBs are trying to implement procedures that allow to manage and sanitize human milk without altering significantly its nutritional and biologically protective components, obtaining a product characterized by a valid balance between safety and biological quality. The history of human milk processing is linked to the origins of HMBs themselves. And although other forms of sterilization were used originally, pasteurization soon became the recognized most effective means for sanitizing milk: all the milk that arrives at the HMB must be pasteurized. Holder pasteurization (HoP) is the most used methodology, and it is performed using low temperature and long time (+62.5°C for 30 min). With HoP some bioactive milk components are lost to varying degrees, but many other precious bioactive compounds are completely or partially preserved. To improve the quality of human milk processed by HMBs, maintaining in the meantime the same microbiological safety offered by HoP, new technologies are under evaluation. At present, High-Temperature Short-Time pasteurization (HTST) and High-Pressure Processing are the most studied methodologies. HTST is already utilized in some HMBs for daily practical activity and for research purposes. They seem to be superior to HoP for a better preservation of some nutritional and biologically protective components. Freeze-drying or lyophilization may have advantages for room temperature storage and transportation. The aim of this study is to evaluate the advancement regarding the processing of DHM with a literature search from 2019 to 2022. The effects of the new technologies on safety and quality of human milk are presented and discussed. The new technologies should assure microbiological safety of the final product at least at the same level as optimized HoP, with an improved preservation of the nutritional and bioactive components of raw human milk.

Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Growth charts for use at birth and in the neonatal period: Recommendations of the French Neonatal Society.

INTRODUCTION: The use of different growth charts can lead to confusion in discussions between professionals. There are obstetric charts (of fetal growth) and neonatal charts (of measurements at birth and of postnatal growth). These charts can be descriptive (derived from an unselected population) or prescriptive (derived from of a population at low risk and with optimal conditions for growth). OBJECTIVES: (1) To describe available charts for infants at birth and in the neonatal period and compare them, and (2) to recommend one or more charts for use in neonatology in France. METHODS: Bibliographic research was conducted on MEDLINE and completed by the guidelines of professional societies. RESULTS: Antenatal information about fetal growth restriction (FGR) or fetuses identified as small-for-gestational-age using Intrauterine charts must be integrated into the identification of newborns at risk, but the use of Intrauterine charts to evaluate birthweight is not recommended to allow consistency with postnatal charts used in neonatal practice. Z-score variations using the updated Fenton postnatal charts are the most appropriate for the assessment of birthweight and postnatal growth for infants born preterm. These charts are sex-specific, include the three measurements (length, weight, and head circumference) and enable longitudinal follow-up of growth up to 50 weeks of corrected age and are linked to the WHO charts at term. The French Audipog charts, although are individualized, accessible online and can be used in maternity units to evaluate birthweight for term infants, but do not allow the follow-up of postnatal growth, while Fenton charts may be used to evaluate birthweight and postnatal growth in the first month for hospitalized term infants. CONCLUSION: The updated Fenton charts are the neonatal charts that best suit the objectives of pediatricians in France for monitoring the growth of preterm newborns. The use of the Audipog charts at term remains an alternative in maternity wards, while Fenton charts can be used for hospitalized term newborns.

Neurodevelopment at 24 months corrected age in extremely preterm infants treated with dexamethasone alternatives during the late postnatal period: a cohort study.

The administration of dexamethasone has been associated with suboptimal neurodevelopment. We aimed to compare the development of extremely premature infants treated or not with alternatives to dexamethasone: betamethasone, hydrocortisone hemisuccinate. This retrospective cohort study included infants born before 29 weeks of gestational age, treated or not with late (day ≥ 7) postnatal steroids (betamethasone, hydrocortisone hemisuccinate). The neurodevelopment outcome was evaluated at 24 months corrected age, after adjustment on comorbidities of extreme prematurity. In order to analyse their overall development, data about growth and respiratory outcomes were collected. Among the 192 infants included, 59 (30.7%) received postnatal steroids. Suboptimal neurodevelopment concerned 37/59 (62.7%) postnatal steroid-treated and 43/133 (38.1%; p = 0.002) untreated infants. However, in multivariable analysis, only severe neonatal morbidity (p = 0.007) and male gender (p = 0.027) were associated with suboptimal neurodevelopment outcome at 24 months.  Conclusions: Betamethasone or hydrocortisone hemisuccinate treatment was not an independent risk for suboptimal neurological development, growth and respiratory outcomes assessed at 24 months corrected age in extremely premature infants.  Registration number: The study was registered on the ClinicalTrials.gov register: NCT05055193. What is Known: • Late postnatal steroids are used to treat bronchopulmonary dysplasia • Meta-analyses warned against the neurological risk of dexamethasone use during neonatal period. Early or late hydrocortisone hemisuccinate has been evaluated in multiple studies, none of which have reported an adverse effect on neurodevelopment at least to 2 years. Data about the use of betamethasone are scarce. What is New: • The risk of suboptimal neurodevelopment was higher among extremely premature infants who received postnatal steroids when compared to those who did not. • Betamethasone and hydrocortisone hemisuccinate treatment was not an independent risk factor for suboptimal neurodevelopment at 24 months corrected age.

Vegan/vegetarian diet and human milk donation: An EMBA survey across European milk banks.

The nutritional adequacy of human milk (HM) from vegan/vegetarian mothers has been a matter of debate, and a variety of recommendations regarding the eligibility of these mothers as human milk donors exists. According to the latest evidence, HM from vegans/vegetarians is similar in its composition to that from omnivores, however, some differences may be observed regarding vitamin B12 and omega-3 fatty acids concentrations. Maternal supplementation of these compounds has been proven effective in increasing their HM concentration. With this survey, we aimed to explore the practices currently in use in European human milk banks (HMBs) regarding potential donors following vegan/vegetarian diets. The online survey was distributed to European HMBs between January and July 2022. A total of 188 HMBs were contacted, and 118 replied (response rate 63%). Vegan and vegetarian mothers were recommended supplements of vitamin B12 to be accepted as donors in 27% and 26% of HMBs, respectively. Additional omega-3 fatty acid supplementation was required in 8% HMBs. In the remaining HMBs, these mothers were either systematically excluded or included regardless of supplementation. The dosage of the recommended supplements was extremely variable. Fifty-one percent of HMBs were following recommendations to guide their practice, national or local recommendations mainly. Great variability in European HMBs practices towards potential donors following vegan/vegetarian diets exists. Some of these practices can result in loss of donors and/or in potential nutritional deficiencies. Standardised evidence-based recommendations on this issue and their implementation in daily HMB practice are needed.

High Amino Acid Intake in Early Life Is Associated With Systolic but Not Diastolic Arterial Hypertension at 5 Years of Age in Children Born Very Preterm.

BACKGROUND: The life course of individuals born very premature is a topic of increasing concern. The association between high early amino acid intake and later high blood pressure (HBP) in preterm neonates is debated. METHODS AND RESULTS: In a national, prospective, population-based birth cohort, EPIPAGE-2 (Etude Epidémiologique sur Petits Ages Gestationnels), we assessed blood pressure at 5 years. Eligible infants were those born between 24 and 29 weeks of gestation. Infants were distributed in 2 groups of 717 infants matched on propensity score on whether or not they were exposed to high amino acid intake (>3.5 g/kg per day at day 7); 455 control term infants were also enrolled. A value ≥95th percentile of reference values for age and height defined systolic or diastolic HBP. Blood pressure at 5 years of age was assessed for 389 and 385 children in the exposed and nonexposed groups, respectively. Rates (in percent) of systolic and diastolic HBP were 18.0% (95% CI, 14.5%-22.2%), 13.3% (95% CI, 10.3%-17.0%), 8.5% (95% CI, 6.5%-11.1%), and 9.0% (95% CI, 6.6%-12.3%), 10.2% (95% CI, 7.5%-13.6%), and 5.4% (95% CI, 3.8%-7.6%) in exposed, nonexposed, and term-born groups, respectively. Exposure to high early amino acid intake and maximal serum creatinine (by 50 µmol/L) between day 3 and day 7 were 2 independent risk factors for systolic HBP (adjusted odds ratio [aOR], 1.60 [95% CI, 1.05-2.43] and aOR, 1.59 [95% CI, 1.12-2.26], respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50-1.39] and aOR, 1.09 [95% CI, 0.71-1.67], respectively). After adjustment for 5-year weight Z score, the aOR between high early amino acid intake and systolic HBP was 1.50 [95% CI, 0.98-2.30]. CONCLUSIONS: These results suggest that mechanisms of childhood systolic HBP involve neonatal renal challenge by high amino acid intake or dysfunction.

Outcomes at 7 Years of Age of Former Very Preterm Neonates with Repeated Surfactant Treatment for Prolonged Respiratory Distress in the Neonatal Period.

This study aimed at evaluating the 7-year outcomes of 118 very preterm newborns (VPNs, gestational age = 26 ± 1.4 w) involved in a randomized controlled trial. They presented neonatal respiratory distress (RDS), requiring ventilation for 14 ± 2 days post-natal age (PNA). A repeated instillation of 200 mg/kg poractant alfa (SURF) did not improve early bronchopulmonary dysplasia, but the SURF infants needed less re-hospitalization than the controls for respiratory problems at 1- and 2-year PNA. There was no growth difference at 7.1 ± 0.3 years between 41 SURF infants and 36 controls (80% of the eligible children), and 7.9% SURF infants vs. 28.6% controls presented asthma (p = 0.021). The children underwent cognitive assessment (WISC IV) and pulmonary function testing (PFT), measuring their spirometry, lung volume, and airway resistance. The spirometry measures showed differences (p < 0.05) between the SURF infants and the controls (mean ± standard deviation (median z-score)) for FEV1 (L/s) (1.188 ± 0.690(-0.803) vs. 1.080 ± 0.243 (-1.446)); FEV1 after betamimetics (1.244 ± 0.183(-0.525) vs. 1.091 ± 0.20(-1.342)); FVC (L) (1.402 ± 0.217 (-0.406) vs. 1.265 ± 0.267 (-1.141)), and FVC after betamimetics (1.452 ± 0.237 (-0.241) vs. 1.279 ± 0.264 (-1.020)). PFT showed no differences in the volumes or airway resistance. The global IQ median (interquartile range) was 89 (82:99) vs. 89 (76:98), with 61% of the children >85 in both groups. Repeated surfactant treatment in VPNs presenting severe RDS led to the attenuation of early lung injuries, with an impact on long-term pulmonary sequelae, without differences in neurodevelopmental outcomes.

Postnatal growth and body composition in extremely low birth weight infants fed with individually adjusted fortified human milk: a cohort study.

This cohort study aimed to evaluate the impact of an individualised nutritional care approach combining standardised fortification with adjustable fortification on postnatal growth and body composition in extremely low birth weight (ELBW) infants. We included ELBW infants admitted to a neonatal intensive care unit and still hospitalised at 35 weeks postmenstrual age (PMA). The fortification of human milk was standardised (multicomponent fortifier) between 70 mL/kg/day and full enteral feeding, and then individualised using adjustable fortification. When weight gain was below 20 g/kg/day, protein or energy was added when serum urea was below or above 3.5 mmol/L, respectively. Postnatal growth failure (PNGF) was defined as being small for gestational age at discharge and/or when the Z-score loss between birth and discharge was higher than 1. Body composition was assessed between 35 and 41 weeks of PMA. Among the 310 ELBW infants included, the gestational age of birth was 26.7 ± 1.8 weeks, and the birth weight was 800 ± 128 g. The mean Z-score difference between birth and discharge was moderately negative for the weight (-0.32), more strongly negative for length (-1.21), and almost nil for head circumference (+ 0.03). Only 27% of infants presented PNGF. At discharge, fat mass was 19.8 ± 3.6%. Multivariable analysis showed that the proportion of preterm formula received and gestational age at birth were independently associated with the percentage of fat mass.  Conclusion: The individualised nutritional care approach applied herein prevented postnatal weight loss in most infants, limited length growth deficit, and supported excellent head circumference growth. What is Known: • At least half of extremely low birth weight infants are small for gestational age at discharge and postnatal growth deficit has been associated with impaired neurocognitive and renal development. • Human milk is the main milk used in neonatology and, although fortification of human milk is a standard of care, there is no consensus regarding the optimal fortification strategy to be adopted. What is New: • Using an approach combining standardised fortification followed by individualised adjustable fortification limited postnatal growth deficit for body weight and head circumference. Postnatal growth failure is not a fatality in extremely low birth weight infants. • Each additional gestational age week at birth resulted in a decrease in fat mass percentage at discharge, which was higher than in foetuses of the same gestational age, likely representing a necessary adaptation to extra-uterine life.

The Dietary Inflammatory Index Is Associated with Subclinical Mastitis in Lactating European Women.

Subclinical mastitis (SCM) is an inflammatory state of the lactating mammary gland, which is asymptomatic and may have negative consequences for child growth. The objectives of this study were to: (1) test the association between the dietary inflammatory index (DII®) and SCM and (2) assess the differences in nutrient intakes between women without SCM and those with SCM. One hundred and seventy-seven women with available data on human milk (HM) sodium potassium ratio (Na:K) and dietary intake data were included for analysis. Multivariable logistic regression was used to examine the association between nutrient intake and the DII score in relation to SCM. Women without SCM had a lower median DII score (0.60) than women with moderate (1.12) or severe (1.74) SCM (p < 0.01). A one-unit increase in DII was associated with about 41% increased odds of having SCM, adjusting for country and mode of delivery, p = 0.001. Women with SCM had lower mean intakes of several anti-inflammatory nutrients. We show for the first time exploratory evidence that SCM may be associated with a pro-inflammatory diet and women with SCM have lower intakes of several antioxidant and anti-inflammatory nutrients.

Birth during on-call period: Impact of care organization on mortality and morbidity of very premature neonates.

Objectives: The evidence that risks of morbidity and mortality are higher when very premature newborns are born during the on-call period is inconsistent. This study aimed to assess the impact of this situation among other determinants of outcomes, particularly newborn characteristics and care organization. Methods: Observational study including all infants born < 30 weeks' gestation in a French tertiary perinatal center between 2007 and 2020. On-call period corresponded to weekdays between 6:30 p.m. and 8:30 a.m., weekends, and public holidays. The primary endpoint was survival without severe morbidity, including grade 3-4 intraventricular hemorrhage (IVH), cystic periventricular leukomalacia, necrotizing enterocolitis, severe bronchopulmonary dysplasia (BPD), and severe retinopathy of prematurity. The relationship between admission and outcome was assessed by an adjusted odds ratio (aOR) on the propensity of being born during on-call period and expressed vs. weekday. Secondary analyses were carried out in extremely preterm newborns (<27 weeks' gestation), in cases of early death (within 7 days), and before (2007-2013, 51.5% of the cohort) vs. after (2014-2020, 48.5% of the cohort) the implementation of a pediatrician-nurse team dedicated to newborn care in the delivery room. Results: A total of 1,064 infants [27.9 (26.3; 28.9) weeks, 947 (760; 1,147) g] were included: 668 during the on-call period (63%) and 396 (37%) on weekdays. For infants born on weekdays, survival without severe morbidity was 54.5% and mortality 19.2%. During on-call, these rates were 57.3% [aOR 1.08 (0.84-1.40)] and 18.4% [aOR 0.93 (0.67-1.29)]. Comparable rates of survival without severe morbidity [aOR 1.42 (0.87-2.34)] or mortality [aOR 0.76 (0.47-1.22)] were observed in extremely preterm infants. The early death rate was 6.4% on weekdays vs. 8.2% during on-call [aOR 1.44 (0.84-2.48)]. Implementation of the dedicated team was associated with decreased rates of mortality [aOR 0.57 (0.38, 0.85)] and grade 3-4 IVH [aOR 0.48 (0.30, 0.75)], and an increased rate of severe BPD [aOR 2.16 (1.37, 3.41)], for infants born during on-call. Conclusion: In this cohort, most births of very premature neonates occurred during the on-call period. A team dedicated to newborn care in the delivery room may have a favorable effect on the outcome of infants born in this situation.

Risk Factors of Very Severe RSV Infections in a Multicenter Cohort of Very Preterm and Extreme Preterm Babies Receiving or Not Palivizumab.

Introduction: Preterm infants are at risk of lower respiratory tract infections (LRTI), including Respiratory Syncytial Virus (RSV) associated bronchiolitis, for which palivizumab prophylaxis can be proposed. Our aim was to determine risk factors of very severe RSV disease in children born before 34 weeks of gestation. Methods: Among 2,101 infants born before 34 weeks of gestation in 3 maternity wards between 2012 and 2017, the laboratory confirmed RSV-infected patients requiring hospitalization before 12 months of corrected age were retrospectively included. We collected data about the neonatal period, the palivizumab prophylaxis and the hospitalization for a RSV-related LRTI. LRTI was considered as very severe (VS-LRTI) when patients required invasive or non-invasive positive pressure ventilation. Results: Among 86 included patients, 31 met the criteria of VS-LRTI. The VS-LRTI patients had a higher birth gestational age and weight but less heart disease and bronchopulmonary dysplasia. They received palivizumab prophylaxis less frequently than the other patients but the difference was not significant. At the onset of infection, VS-LRTI patients had a younger corrected age for prematurity and presented more frequently with apnea, bradycardia, life-threatening event, hemodynamic failure, hypercapnia. Using logistic regression, the main factor associated with VS-LRTI was a younger corrected age for prematurity at the onset of infection [Odd ratio for each month of corrected age = 0.77 (0.62; 0.93), p = 0.012]. Conclusion: Infants at the highest risk of VS-LRTI were infants with a younger corrected age for prematurity. Therefore, a better targeting of infants requiring palivizumab prophylaxis and early interventions at hospital discharge could limit VS-LRTI in these infants.

Partial Hydrolyzed Protein as a Protein Source for Infant Feeding: Do or Don't?

Exclusive breastfeeding until the age of six months is the recommended feeding method for all infants. However, this is not possible for every infant. Therefore, a second choice of feeding, as close as possible to the gold standard, is needed. For historical reasons, this has been cow's-milk-based feeding. This paper discusses if this second-choice feeding method should contain intact protein or partially hydrolyzed proteins. The limited data available indicates that mother's milk is relatively rich in bioactive peptides. Whether partially hydrolyzed protein might be a protein source closer to human milk protein content than intact cow's milk needs further research. However, more research on protein and bioactive peptides in mother's milk should be a priority for future scientific development in this field. Results of such research will also provide an answer to the question of which option would be the best second choice for infant feeding if sufficient breast milk is not available.

Mode of Neonatal Delivery Influences the Nutrient Composition of Human Milk: Results From a Multicenter European Cohort of Lactating Women.

Background: The effect of the mode of neonatal delivery (cesarean or vaginal) on the nutrient composition of human milk (HM) has rarely been studied. Given the increasing prevalence of cesarean section (C-section) globally, understanding the impact of C-section vs. vaginal delivery on the nutrient composition of HM is fundamental when HM is the preferred source of infant food during the first 4 postnatal months. Objective: This study aimed to evaluate the association between mode of delivery and nutrient composition of HM in the first 4 months of life. Design: Milk samples were obtained from 317 healthy lactating mothers as part of an exploratory analyses within a multicenter European longitudinal cohort (ATLAS cohort) to study the HM composition, and its potential association with the mode of delivery. We employed traditional mixed models to study individual nutrient associations adjusted for mother's country, infant birth weight, parity, and gestational age, and complemented it, for the first time, with a multidimensional data analyses approach (non-negative tensor factorization, NTF) to examine holistically how patterns of multiple nutrients and changes over time are associated with the delivery mode. Results: Over the first 4 months, nutrient profiles in the milk of mothers who delivered vaginally (n = 237) showed significantly higher levels of palmitoleic acid (16:1n-7), stearic acid (18:0), oleic acid (18:1n-9), arachidic acid (20:0), alpha-linolenic acid (18:3n-3), eicosapentaenoic acid (20:5n-3), docosahexenoic acid (22:6n-3), erucic acid (22:1n-9), monounsaturated fatty acids (MUFA)%, calcium, and phosphorus, whereas the ratios of arachidonic acid/docosahexaenoic acid (ARA/DHA) and n-6/n-3, as well as polyunsaturated fatty acids (PUFA)% were higher in milk from women who had C-sections, in the unadjusted analyses (p < 0.05 for all), but did not retain significance when adjusted for confounders in the mixed models. Using a complementary multidimension data analyses approach (NTF), we show few similar patterns wherein a group of mothers with a high density of C-sections showed increased values for PUFA%, n-6/n-3, and ARA/DHA ratios, but decreased values of MUFA%, 20:1n-9, iodine, and fucosyl-sialyl-lacto-N-tetraose 2 during the first 4 months of lactation. Conclusion: Our data provide preliminary insights on differences in concentrations of several HM nutrients (predominantly fatty acids) among women who delivered via C-section. Although these effects tend to disappear after adjustment for confounders, given the similar patterns observed using two different data analytical approaches, these preliminary findings warrant further confirmation and additional insight on the biological and clinical effects related to such differences early in life.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Nephrocalcinosis in very low birth weight infants: incidence, associated factors, and natural course.

BACKGROUND: Preterm kidney is exposed to various exogenous factors that may impact its function such as nephrotoxic drugs or nephrocalcinosis. We investigated prevalence and risk factors of nephrocalcinosis (NC) in recently born very low birth weight (VLBW) infants submitted to improved biological monitoring. METHODS: Retrospective, case-control study in very preterm infants (< 32 + 6 weeks, ≤ 1500 g) admitted to a tertiary care unit during a 6-year period. Each case (ultrasound-diagnosed NC) was matched with two controls (no NC). Data were collected at days 15 and 30 of life and 35 weeks corrected age, with follow-up at 18 months and 3 years. RESULTS: Of 525 eligible infants, overall prevalence of NC was 17.1% at 35 weeks corrected age. Prevalence was halved between 2012 (26.1%) and 2017 (11.8%). We included 265 infants, more than half being born before 28 weeks. Cases presented with more severe morbidity than controls, but reached statistical significance only in infants born < 28 weeks (88.2% vs. 68.3%, P = 0.01). Protein, energy, calcium, phosphorus, and vitamin D intakes were similar in the two groups and did not change significantly over the study period. Weight gain was similar in the two groups. Exposure to furosemide (OR [IC95%]: 1.26 [1.02; 1.57]) and postnatal growth (1.65 [1.04; 2.67]) were independent risk factors of NC. NC resolved 12-18 months after diagnosis in 61% of infants. CONCLUSION: Prevalence of NC is significant but can be reduced. Furosemide should be cautiously prescribed in VLBW infants, and nutritional support must be well monitored to support postnatal growth and limit risk of nephrocalcinosis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT 04,860,583. A higher resolution version of the Graphical abstract is available as Supplementary information.

Review highlights the importance of donor human milk being available for very low birth weight infants.

AIM: The aim of this paper was to review the role that donor human milk plays in caring for very low birth weight (VLBW) infants. METHODS: This review focussed on academic papers and background information published in English and French up to 8 August 2021. RESULTS: Donor human milk provides a useful bridge to successful breastfeeding in hospitalised neonates and does not have a negative impact on the use of mother's own milk and breastfeeding rates at discharge. It helps to prevent key complications of prematurity, particularly necrotising enterocolitis up to 36 weeks of postmenstrual age, which is more common in infants fed formulas based on cows' milk. When it is carefully fortified, it supports the postnatal growth of the majority of very preterm infants. Well-organised, accessible human milk banks are required to cover the needs of hospitalised infants, and donor human milk must be prioritised for patients who derive the greatest health benefit from it. These include very preterm infants and those born at term, or near term, with surgical digestive malformations or congenital heart disease. CONCLUSION: Safe, high-quality donor human milk, which is distributed by well-organised human milk banks, is essential for the most vulnerable hospitalised neonates.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.