Feeding in Preterm Infants

Background: Infants have three options for feeding: their own mother’s breast milk, donor milk, or infant formula. Insulin, testosterone, total protein, and albumin levels were measured in breast milk samples from the first 6 months of lactation, in donor milk samples, and in different infant formulas. Methods: Mothers who gave birth to term (n = 19) or preterm (n = 19) infants were recruited to collect breast milk samples during the first 6 months of lactation. The Breast Milk Collection Center (Unified Health Institution, Pécs, Hungary) provided 96 donor milk (DM) samples for analysis in our study. Insulin, testosterone, total protein, and albumin levels were measured in breast milk, donor milk, and infant formulas. Results: During the first 2 months of lactation, the concentration of insulin was lower (−27.4%) while the testosterone concentration was higher (+20.8%) compared to the period between the 3rd and 6th months only in the preterm breast milk samples. The infant formulas examined did not contain insulin or testosterone. Holder pasteurization (HoP) did not influence the level of testosterone in human milk, although HoP decreased the insulin (−53.6%) and albumin (−38.6%) concentrations. Conclusions: Diet impacts the hormone intake of infants, underlining the importance of breastfeeding and the possible supplementation of formula-fed infants. Full article

Hyperglycemia (HG) is an independent risk factor of mortality and morbidity in very low birth weight newborns (VLBW). Achievement of high nutritional intakes in the first days of life (DoL) by parenteral nutrition (PN) increases the risk of HG. We aim to assess if a delayed achievement of the PN macronutrient target dose could reduce the occurrence of HG in VLBW. We enrolled 353 VLBW neonates in a randomized controlled clinical trial comparing two PN protocols that differed in the timing of energy and amino acid target dose achievement: (1) early target dose achievement (energy within 4–5 DoL; amino acids within 3–4 DoL) vs. (2) late target dose achievement (energy within 10–12 DoL; amino acids within 5–7 DoL). The primary outcome was the occurrence of HG during the first week of life. An additional endpoint was long-term body growth. We observed a significant difference in the rate of HG between the two groups (30.7% vs. 12.2%, p = 0.003). Significant differences were observed in terms of body growth at 12 months of life between the two groups (weight Z-Score: −0.86 vs. 0.22, p = 0.025; length: −1.29 vs. 0.55, p < 0.001). Delayed achievement of energy and amino acid intake may be useful to reduce the risk of HG along with an increase of growth parameters in VLBW neonates. Full article

Background: Microbiological quality is one of the key safety standards in human milk bank (HMB) operations. We describe the profiles of bacteria in donor human milk (DHM) before and after the pasteurization of samples collected from breastfeeding women in the hospital and from the community in the first HMB in Vietnam. Methods: Data were collected between February 2017 and January 2022 from an online HMB monitoring system. First, DHM samples were cultured, and the number of colony-forming units (CFU) were counted before (n = 708) and after pasteurization (n = 1146). The gram-staining method combined with the Vitek 2 Compact system were used to identify types of organisms at the Da Nang Hospital for Women and Children’s Laboratory. Passing criteria for DHM included pre-pasteurization samples had a total colony count <10⁵ CFU/mL and post-pasteurization was <10 CFU/mL. Results: During five years of operation, Da Nang HMB had 491 donors (48.7% were hospital and the rest community donors) who donated an average amount of 14.2 L over 45 days. Of this DHM volume, 84.9% of donor samples passed the pre- and post-pasteurization microbiological tests. DHM from community donors had a higher pass rate (87.8%) compared to that from hospital donors (79.5%). Before pasteurization, 15.4% of DHM samples had a bacteria count <10³ CFU/mL, 63.0% had 10³-<10⁵ CFU/mL, and 21.6% had ≥10⁵ CFU/mL. Most of the unpasteurized DHM samples (93.0%) had microorganism growth: with one organism (16.4%), two (33.9%), three or more (43.6%). After pasteurization, 17.9% samples had a bacteria count of 1–9 CFU/mL and 7.2% had ≥10 CFU/mL. DHM samples from community donors had a lower bacterial count and number of organisms than those from hospital donors both before and after pasteurization. The highest microorganisms from unpasteurized DHM samples were Staphylococcus epidermidis (74.2%), Acinetobacter sp. (52.1%), gram-positive bacillus (51.7%), Staphylococcus coagulase-negative (15.8%), and Staphylococcus aureus (10.5%). Common microorganisms from pasteurized DHM were gram-positive bacillus (21.0%), Staphylococcus epidermidis (3.9%), and Acinetobacter sp. (0.9%). Samples from the hospital tended to have a higher contamination with those microorganisms than those from community donors. Conclusions: The majority of DHM samples in Da Nang passed microbiological testing criteria. DHM from community donors had higher pass rates than hospital donors. Corrective actions are needed to improve HMB operations and hospital microbiological quality standards, as well as general improvements in water and sanitation. Full article

Antenatal Doppler disturbances are associated with fetal hypoxia and may induce a brain-sparing vascular redistribution at the expense of splanchnic circulation, possibly predisposing to gut complications. We aimed to compare several gastrointestinal outcomes among very-low-birthweight (VLBW) preterm infants with different antenatal Doppler features. VLBW infants born between 2010–2022 were retrospectively included and stratified into the following clusters based on antenatal Doppler characteristics: normal Doppler (controls); absent or reversed end-diastolic flow in the umbilical artery (UA-AREDF) alone or also in the ductus venosus (UA+DV-AREDF); and abnormal Doppler with or without brain-sparing redistribution. The following outcomes were evaluated: time to reach full enteral feeds (FEF), feeding intolerance (FI), necrotizing enterocolitis (NEC), and spontaneous intestinal perforation (SIP). Overall, 570 infants were included. Infants born following UA+DV-AREDF had significantly higher FI, NEC, and SIP rates and achieved FEF later compared to controls. Increased FI prevalence and a longer time to FEF compared to controls were also observed among UA-AREDF infants and in the presence of brain-sparing redistribution, which also increased NEC rates. Antenatal Doppler abnormalities exacerbate the gastrointestinal risks of preterm infants. Detailed knowledge of Doppler features can aid in identifying those at highest risk of intestinal complications who may benefit from tailored enteral feeding management. Full article

Background: The present strategy of administering human milk fortifier (HMF) in southwest China (swC) is mainly based on European and American populations’ guidelines. Additionally, some southwest Chinese preterm infants have been observed to develop feeding intolerance (FI) after administration of HMF. In order to develop adapted southwest Chinese guidelines for the administration of HMF to preterm infants and improve fortification strategies, a retrospective cohort study was performed to explore the association of the use of HMF and FI. Objective: To explore the association between HMF and FI in preterm infants and provide recommendations for its use in swC. Methods: This cohort study included 298 preterm infants from West China Second University Hospital. Maternal and infant clinical data were collected from electronic patient records. The infant cohort was divided into two groups based on the use/nonuse of HMF. The association between HMF and FI was evaluated using multivariate analysis. Nonlinear relationships and threshold effects were evaluated using generalized additive models and two-piecewise linear regression models. Results: The multivariate analysis confirmed that there is no significant association between HMF use and FI, but significant risk factors for FI include early HMF initiation (p = 0.02), full-strength HMF initiation (p = 0.04), and fast HMF supplementation rates (p = 0.004). Through smooth curve fitting and threshold effect analysis, we found that two inflection points, an initial concentration of HMF > 24 mg/mL and a HMF supplementation rate > 12.5 mg/mL/d, significantly increased FI risk. Conclusions: Routine HMF fortification can be safely used in preterm infants with gestational age < 32 wk or birth weight < 1500 g in swC, and we advise initiating fortification when enteral milk intake reaches 100 mL/kg/day, with an HMF concentration of 1:50 and if tolerated, increase to 1:25 more than 38 h. The recommended HMF supplementation rate differs from current guidelines and provides evidence for developing southwest Chinese guidelines. A prospective trial is needed in order to validate this proposal. Full article

Very preterm infants are at high risk for suboptimal nutrition in the first weeks of life leading to insufficient weight gain and complications arising from metabolic imbalances such as insufficient bone mineral accretion. We investigated the use of a novel set of standardized parenteral nutrition (PN; MUC PREPARE) solutions regarding improving nutritional intake, accelerating termination of parenteral feeding, and positively affecting growth in comparison to individually prescribed and compounded PN solutions. We studied the effect of MUC PREPARE on macro- and micronutrient intake, metabolism, and growth in 58 very preterm infants and compared results to a historic reference group of 58 very preterm infants matched for clinical characteristics. Infants receiving MUC PREPARE demonstrated improved macro- and micronutrient intake resulting in balanced electrolyte levels and stable metabolomic profiles. Subsequently, improved energy supply was associated with up to 1.5 weeks earlier termination of parenteral feeding, while simultaneously reaching up to 1.9 times higher weight gain at day 28 in extremely immature infants (<27 GA weeks) as well as overall improved growth at 2 years of age for all infants. The use of the new standardized PN solution MUC PREPARE improved nutritional supply and short- and long-term growth and reduced PN duration in very preterm infants and is considered a superior therapeutic strategy. Full article

Human milk (HM) is the best feeding option for preterm infants; however, when mother’s own milk (MOM) is not available, pasteurized donor human milk (DHM) is the best alternative. In this study, we profiled DHM microbiota (19 samples) using 16S rRNA amplicon sequencing and compared its compositional features with the MOM microbiota (14 samples) from mothers who delivered prematurely (PT-MOM). As a secondary study aim, we assessed the specific effect of pasteurization on the characteristics of the DHM microbiota. DHM showed significantly higher alpha diversity and significant segregation from PT-MOM. Compositionally, the PT-MOM microbiota had a significantly higher proportion of Staphylococcus than DHM, with Streptococcus tending to be and Pseudomonas being significantly overrepresented in DHM compared with the PT-MOM samples. Furthermore, pasteurization affected the HM microbiota structure, with a trend towards greater biodiversity and some compositional differences following pasteurization. This pilot study provided further evidence on the HM microbial ecosystem, demonstrating that the DHM microbiota differs from the PT-MOM microbiota, possibly due to inherent differences between HM donors and mothers delivering prematurely, and that pasteurization per se impacts the HM microbiota. Knowledge about HM microbiota needs to be acquired by investigating the effect of DHM processing to develop strategies aimed at improving DHM quality while guaranteeing its microbiological safety. Full article

Thyroxine (T4) importantly regulates the growth of newborns. Compared to fetuses with equivalent gestational ages, very preterm infants (VPIs) often experience relatively low thyroxinemia, with a normal thyroid-stimulating hormone (TSH) concentration < 10 μIU/mL. However, there is continued debate regarding postnatal thyroxine supplementation for VPIs with normal TSH and transitionally low thyroxinemia. Little research has explored the role of the postnatal total T4 (TT4) serum concentration on the growth of VPIs. In this study, we aim to clarify whether the postnatal thyroxine concentration is associated with the short- and long-term growth outcomes of VPIs. A total of 334 surviving VPIs in our previously reported cohort, born in the period August 2007–July 2016, were enrolled. The exposure variable was the postnatal TT4 concentration at 1 month old. The primary outcomes were body weight increments over 28 days after the screening and anthropometric outcomes at the corrected age of 24 months old. Infants with any hormonal replacement, severe brain injury, congenital anomaly, or cerebral palsy were excluded. In total, 290 (86.8%) VPIs were included for analysis. In the 28 days after thyroid function screening, the TT4 concentration was found to have a significant association with positive increments in body weight (mean increment: 25.7 g per 1 μg/dL; p < 0.001) and a positive body weight z-score (mean increment: 0.039 per 1 μg/dL; p = 0.037), determined by generalized estimating equation analysis. At the corrected age of 24 months old, a higher postnatal TT4 concentration was associated with a lower body mass index (mean coefficient: −0.136; 95% CI: −0.231 to −0.041, p = 0.005) and lower body mass index z-score (mean coefficient: −0.097; 95% CI: −0.170 to −0.024, p = 0.009). Infants with a TT4 concentration > 6.4 ug/dL had significantly lower odds of overweight status (odds ratio: 0.365; 95% CI: 0.177 to 0.754, p = 0.006). We conclude that the postnatal TT4 concentration is associated with a positive increment in body weight in the short term. At the same time, the postnatal TT4 concentration is associated with lower odds of overweight status after long-term follow-up. Full article

Background: Preterm birth is associated with an increased risk of many complications, which is a main public health problem worldwide with social and economic consequences. Human milk from breast feeding has been proved to be the optimal nutrition strategy for preterm infants when available. However, the lack of human milk from mothers makes formula widely used in clinical practice. In recent years, donated breast milk has gained popularity as an alternative choice which can provide human milk oligosaccharides and other bioactive substances. Objective: We aimed to conduct a systematic review and meta-analysis to evaluate the nutritional effects of donated breast milk on preterm infants compared with formula. Method: In the present study, we searched Medline, Web of Science, Embase, clinicaltrials.gov, the China national knowledge infrastructure, and the Cochrane central register of controlled trials for candidate randomized controlled trials (RCTs). Results: A total of 1390 patients were enrolled in 11 RCTs and meta-analysis results showed that donated breast milk is also more advantageous in reducing the incidence of necrotizing enterocolitis (NEC, RR = 0.67, 95% CI = 0.48 to 0.93, p = 0.02), reducing the duration of parenteral nutrition (MD = −2.39, 95% CI = −3.66 to −1.13, p = 0.0002) and the time of full enteral feeding (MD = −0.33, 95% CI = −3.23 to 2.57, p = 0.0002). In comparison, formula significantly promotes the growth of premature infants, including their weight gain (MD = −3.45, 95% CI = −3.68 to −3.21, p < 0.00001), head growth (MD = −0.07, 95% CI = −0.08 to −0.06, p < 0.00001) and body length (MD = −0.13, 95% CI = −0.15 to −0.11, p < 0.00001), and reduces the time it takes for premature infants to regain birth weight (MD = 6.60, 95% CI = 6.11 to 7.08, p < 0.00001. Conclusion: Compared with formula, donated breast milk could significantly reduce the incidence of NEC, the duration of parenteral nutrition, and the time of full enteral feeding. Adding fortifiers in donated milk could make it as effective as formula in promoting the physical growth of premature infants. Full article

Early nutrition is one of the most modifiable factors influencing postnatal growth. Optimal nutrient intakes for very preterm infants remain unknown, and poor postnatal growth is common in this population. The aim of this study was to assess nutrient intake during the first 4 weeks of life with early progressive enteral feeding and its impact on the in-hospital growth of very low-birth-weight (VLBW) infants. In total, 120 infants with birth weights below 1500 g and gestational ages below 35 weeks were included in the study. Nutrient intakes were assessed daily for the first 28 days. Growth was measured weekly until discharge. Median time of parenteral nutrition support was 6 days. Target enteral nutrient and energy intake were reached at day 10 of life, and remained stable until day 28, with slowly declining protein intake. Median z-scores at discharge were −0.73, −0.49, and −0.31 for weight, length, and head circumference, respectively. Extrauterine growth restriction was observed in 30.3% of the whole cohort. Protein, carbohydrates, and energy intakes correlated positively with weight gain and head circumference growth. Early progressive enteral feeding with human milk is well tolerated in VLBW infants. Target enteral nutrient intake may be reached early and improve in-hospital growth. Full article

Establishing the different feeding trajectories based on daily enteral feeding data in preterm infants at different gestational ages (GAs), may help to identify the risks and extrauterine growth restriction (EUGR) outcomes associated with the adverse feeding pattern. In a single center, we retrospectively included 625 infants born at 23–30 weeks of gestation who survived to term-equivalent age (TEA) from 2009 to 2020. The infants were designated into three GA groups: 23–26, 27–28, and 29–30 weeks. The daily enteral feeding amounts in the first 56 postnatal days were analyzed to determine the feeding trajectories. The primary outcomes were EUGR in body weight and head circumference calculated, respectively, by the changes between birth and TEA. Clustering analysis identified two feeding trajectories, namely the improving and adverse patterns in each GA group. The adverse feeding pattern that occurred in 49%, 20%, and 17% of GA 23–26, 27–28, and 29–30 weeks, respectively, was differentiated from the improving feeding pattern as early as day 7 in infants at GA 23–26 and 27–28 weeks, in contrast to day 21 in infants at GA 29–30 weeks. The adverse feeding patterns were associated with sepsis, respiratory, and gastrointestinal morbidities at GA 23–26 weeks; sepsis, hemodynamic and gastrointestinal morbidities at GA 27–28 weeks; and preeclampsia, respiratory, and gastrointestinal morbidities at GA 29–30 weeks. Using the improving feeding group as a reference, the adverse feeding group showed significantly higher adjusted odds ratios of EUGR in body weight and head circumference in infants at GA 23–26 and 27–28 weeks. Identifying the early-life adverse feeding trajectories may help recognize the related EUGR outcomes of preterm infants in a GA-related manner. Full article

Background: High hydrostatic pressure (HHP) processing is a non-thermal method proposed as an alternative to Holder pasteurization (HoP) for the sterilization of human breast milk (BM). HHP preserves numerous milk bioactive factors that are degraded by HoP, but no data are available for milk apelin and glucagon-like peptide 1 (GLP-1), two hormones implicated in the control of glucose metabolism directly and via the gut–brain axis. This study aims to determine the effects of HoP and HHP processing on apelin and GLP-1 concentrations in BM and to test the effect of oral treatments with HoP- and HHP-BM on intestinal contractions and glucose metabolism in adult mice. Methods: Mice were treated by daily oral gavages with HoP- or HHP-BM during one week before intestinal contractions, and glucose tolerance was assessed. mRNA expression of enteric neuronal enzymes known to control intestinal contraction was measured. Results: HoP-BM displayed a reduced concentration of apelin and GLP-1, whereas HHP processing preserved these hormones close to their initial levels in raw milk. Chronic HHP-BM administration to mice increased ileal mRNA nNos expression level leading to a decrease in gut contraction associated with improved glucose tolerance. Conclusion: In comparison to HoP, HPP processing of BM preserves both apelin and GLP-1 and improves glucose tolerance by acting on gut contractions. This study reinforces previous findings demonstrating that HHP processing provides BM with a higher biological value than BM treated by HoP. Full article

Supplementation of infant and follow-up formula with probiotics or synbiotics has become a common practice. In 2011 and 2017, the evidence regarding the impact of these interventions was analysed systematically. Recently new evidence was published. To evaluate through a systematic review with network meta-analysis the evidence on the impact of infant formula supplemented with probiotics or synbiotics for healthy infants and 36-month-old toddlers. RCTs published between 1999–2019 for infant formulas supplemented with probiotics alone or synbiotics in healthy infants and toddlers were identified. Data analysis included clinical (gastrointestinal symptoms, risk reduction of infectious diseases, use of antibiotics, weight/height gain and frequency of adverse events) and non-clinical outcomes (changes in faecal microbiota and immune parameters). A random effect model was used. Hedges’ standard mean difference (SMD) and risk ratio (RR) were calculated. Rank analysis was performed to evaluate the superiority of each intervention. Twenty-six randomised controlled trials with 35 direct comparisons involving 1957 children receiving probiotic-supplemented formula and 1898 receiving control formula were reviewed. The mean duration of intervention was 5.6 ± 2.84 months. Certain strains demonstrated a reduction in episodes of colic, number of days with fever and use of antibiotics; however, there was considerable heterogeneity which reduced the level of certainty of effect. No significant effects were observed on weight, height or changes in faecal proportions of Bifidobacteria, Lactobacillus, Bacteroides or Clostridia. Although there is some evidence that may support a potential benefit of probiotic or synbiotic supplementation of infant formulas, variation in the quality of existing trials and the heterogeneity of the data preclude the establishment of robust recommendations. Full article

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. Full article

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. Full article