Infant Formula with Added Bovine Milk Fat Globule Membrane and Modified Iron Supports Growth and Normal Iron Status at One Year of Age: A Randomized Controlled Trial.

Inclusion of bovine-derived milk fat globule membrane (bMFGM) or bMFGM components in infant formulas (IFs) may support healthy brain development. This double-blind, prospective trial evaluated growth, tolerance, and iron status in infants receiving added bMFGM and modified protein, iron, and arachidonic acid (ARA) concentrations in IF. Healthy term infants were randomized to: control (marketed, routine cow's milk-based IF/100 kcal: 2.1 g protein, 1.8 mg iron, 34 mg ARA) or INV-MFGM (investigational cow's milk-based IF/100 kcal: 1.9 g protein, 1.2 mg iron, 25 mg ARA and whey protein-lipid concentrate, 5 g/L (source of bMFGM)). Anthropometrics, stool characteristics, fussiness, and gassiness through day 365 and blood markers of iron status at day 365 were evaluated. The primary outcome was rate of weight gain from 14-120 days of age. Of 373 infants enrolled (control: 191, INV-MFGM: 182), 275 completed the study (control: 141; INV-MFGM: 134). No group differences in growth rate (g/day) from day 14-120 or study discontinuation were detected. Few group differences in growth or parent-reported fussiness, gassiness, or stool characteristics were detected. No group differences were detected in hemoglobin, hematocrit, or incidence of anemia. In healthy term infants, bMFGM and modified protein, iron, and ARA concentrations in a cow's milk-based IF were well-tolerated, associated with adequate growth throughout the first year of life, and supported normal iron status at one year of age.

Growth and tolerance of healthy, term infants fed lower protein extensively hydrolyzed or amino acid-based formula: double-blind, randomized, controlled trial.

BACKGROUND: Optimal protein level in hypoallergenic infant formulas is an area of ongoing investigation. The aim was to evaluate growth of healthy term infants who received extensively hydrolyzed (EH) or amino acid (AA)-based formulas with reduced protein. METHODS: In this prospective, multi-center, double-blind, controlled, parallel group study, infants were randomized to receive a marketed EH casein infant formula at 2.8 g protein/100 kcal (Control) or one of two investigational formulas: EH casein formula at 2.4 g protein/100 kcal (EHF) or AA-based formula at 2.4 g total protein equivalents/100 kcal (AAF). Control and EHF each had 2 × 107 CFU Lactobacillus rhamnosus GG/100 kcal. Anthropometrics were measured and recall of formula intake, tolerance, and stool characteristics was collected at 14, 30, 60, 90, 120 days of age. Primary outcome was weight growth rate (g/day) between 14 and 120 days of age (analyzed by ANOVA). Medically confirmed adverse events were recorded throughout the study. RESULTS: No group differences in weight or length growth rate from 14 to 120 days were detected. With the exception of significant differences at several study time points for males, no group differences were detected in mean head circumference growth rates. However, mean achieved weight, length, and head circumference demonstrated normal growth throughout the study period. No group differences in achieved weight or length (males and females) and head circumference (females) were detected and means were within the WHO growth 25th and 75th percentiles from 14 to 120 days of age. With the exception of Day 90, there were no statistically significant group differences in achieved head circumference for males; means remained between the WHO 50th and 75th percentiles for growth at Days 14, 30, and 60 and continued along the 75th percentile through Day 120. No differences in study discontinuation due to formula were detected. The number of participants for whom at least one adverse event was reported was similar among groups. CONCLUSIONS: This study demonstrated hypoallergenic infant formulas at 2.4 g protein/100 kcal were safe, well-tolerated, and associated with appropriate growth in healthy term infants from 14 to 120 days of age. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT01354366 . Registered 13 May 2011.

Stool microbiome, pH and short/branched chain fatty acids in infants receiving extensively hydrolyzed formula, amino acid formula, or human milk through two months of age.

BACKGROUND: Early infant feeding with intact or extensively hydrolyzed (EH) proteins or free amino acids (AA) may differentially affect intestinal microbiota composition and immune reactivity. This multicenter, double-blind, controlled, parallel-group, pilot study compared stool microbiota from Baseline (1-7 days of age) up to 60 days of age in healthy term infants who received mother's own milk (assigned to human milk [HM] reference group) (n = 25) or were randomized to receive one of two infant formulas: AA-based (AAF; n = 25) or EH cow's milk protein (EHF; n = 28). Stool samples were collected (Baseline, Day 30, Day 60) and 16S rRNA genes were sequenced. Alpha (Shannon, Simpson, Chao1) and beta diversity (Bray Curtis) were analyzed. Relative taxonomic enrichment and fold changes were analyzed (Wilcoxon, DESEq2). Short/branched chain fatty acids (S/BCFA) were quantified by gas chromatography. Mean S/BCFA and pH were analyzed (repeated measures ANOVA). RESULTS: At baseline, alpha diversity measures were similar among all groups; however, both study formula groups were significantly higher versus the HM group by Day 60. Significant group differences in beta diversity at Day 60 were also detected, and study formula groups were compositionally more similar compared to HM. The relative abundance of Bifidobacterium increased over time and was significantly enriched at Day 60 in the HM group. In contrast, a significant increase in members of Firmicutes for study formula groups were detected at Day 60 along with butyrate-producing species in the EHF group. Stool pH was significantly higher in the AAF group at Days 30 and 60. Butyrate increased significantly from Baseline to Day 60 in the EHF group and was significantly higher in study formula groups vs HM at Day 60. Propionate was also significantly higher for EHF and AAF at Day 30 and AAF at Day 60 vs HM. Total and individual BCFA were higher for AAF and EHF groups vs HM through Day 60. CONCLUSIONS: Distinct patterns of early neonatal microbiome, pH, and microbial metabolites were demonstrated for infants receiving mother's own milk compared to AA-based or extensively hydrolyzed protein formula. Providing different sources of dietary protein early in life may influence gut microbiota and metabolites. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02500563 . Registered July 28, 2015.

Effectiveness of Implemented Interventions on Pathologic Nodal Staging of Non-Small Cell Lung Cancer.

BACKGROUND: Accurate pathologic nodal staging improves early stage non-small cell lung cancer survival. In an ongoing implementation study, we measured the impact of a surgical lymph node specimen collection kit and a more thorough pathologic gross dissection method on attainment of guideline-recommended pathologic nodal staging quality. METHODS: We prospectively collected data on curative intent non-small cell lung cancer resections from 2009 to 2016 from 11 hospitals in four contiguous Dartmouth Hospital referral regions. We categorized patients into four groups based on exposure to the two interventions in our staggered implementation study design. We used χ2 tests to examine the differences in demographic and disease characteristics and surgical quality criteria across implementation groups. RESULTS: Of 2,469 patients, 1,615 (65%) received neither intervention; 167 (7%) received only the pathology intervention; 264 (11%) received only the surgery intervention; and 423 (17%) had both. Rates of nonexamination of lymph nodes reduced sequentially in the order of no intervention, novel dissection, kit, and combined interventions, including nonexamination of any lymph nodes and hilar/intrapulmonary and mediastinal nodes (p < 0.001 for all comparisons). The rates of attainment of National Comprehensive Cancer Network, Commission on Cancer, American Joint Committee on Cancer, and American College of Surgeons Oncology Group guidelines increased significantly in the same sequential order (p < 0.001 for all comparisons). CONCLUSIONS: The combined effect of two interventions to improve pathologic lymph node examination has a greater effect on attainment of a range of surgical quality criteria than either intervention alone.

Prognostic Value of National Comprehensive Cancer Network Lung Cancer Resection Quality Criteria.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) surgical resection guidelines for non-small cell lung cancer recommend anatomic resection, negative margins, examination of hilar/intrapulmonary lymph nodes, and examination of three or more mediastinal nodal stations. We examined the survival impact of these criteria. METHODS: A population-based observational study was done using patient-level data from all curative-intent, non-small cell lung cancer resections from 2004 to 2013 at 11 institutions in four contiguous Dartmouth Hospital referral regions in three US states. We used an adjusted Cox proportional hazards model to assess the overall survival impact of attaining NCCN guidelines. RESULTS: Of 2,429 eligible resections, 91% were anatomic, 94% had negative margins, 51% sampled hilar nodes, and 26% examined three or more mediastinal nodal stations. Only 17% of resections met all four criteria; however, there was a significant increasing trend from 2% in 2004 to 39% in 2013 (p < 0.001). Compared with patients whose surgery missed one or more criteria, the hazard ratio for patients whose surgery met all four criteria was 0.71 (95% confidence interval: 0.59 to 0.86, p < 0.001). Margin status and the nodal staging criteria were most strongly linked with survival. CONCLUSIONS: Attainment of NCCN surgical quality guidelines was low, but improving, over the past decade in this cohort from a high lung cancer mortality region of the United States. The NCCN quality criteria, especially the nodal examination criteria, were strongly associated with survival. The quality of nodal examination should be a focus of quality improvement in non-small cell lung cancer care.

Growth and tolerance of infants fed formula with a new algal source of docosahexaenoic acid: Double-blind, randomized, controlled trial.

Docosahexaenoic acid (DHA) in infant formula at concentrations based on worldwide human milk has resulted in circulating red blood cell (RBC) lipids related to visual and cognitive development. In this study, infants received study formula (17mg DHA/100kcal) with a commercially-available (Control: n=140; DHASCO®) or alternative (DHASCO®-B: n=127) DHA single cell oil from 14 to 120 days of age. No significant group differences were detected for growth rates by gender through 120 days of age. Blood fatty acids at 120 days of age were assessed by capillary column gas chromatography in a participant subset (Control: n=34; DHASCO-B: n=27). The 90% confidence interval (91-104%) for the group mean (geometric) total RBC DHA (µg/mL) ratio fell within the pre-specified equivalence limit (80-125%), establishing study formula equivalence with respect to DHA. This study demonstrated infant formula with DHASCO-B was safe, well-tolerated, and associated with normal growth. Furthermore, DHASCO and DHASCO-B represented equivalent sources of DHA as measured by circulating RBC DHA.

The relationship between mindfulness, pain intensity, pain catastrophizing, depression, and quality of life among cancer survivors living with chronic neuropathic pain.

PURPOSE: This study aims to examine if mindfulness is associated with pain catastrophizing, depression, disability, and health-related quality of life (HRQOL) in cancer survivors with chronic neuropathic pain (CNP). METHOD: We conducted a cross-sectional survey with cancer survivors experiencing CNP. Participants (n = 76) were men (24 %) and women (76 %) with an average age of 56.5 years (SD = 9.4). Participants were at least 1 year post-treatment, with no evidence of cancer, and with symptoms of neuropathic pain for more than three months. Participants completed the Five Facets Mindfulness Questionnaire (FFMQ), along with measures of pain intensity, pain catastrophizing, pain interference, depression, and HRQOL. RESULTS: Mindfulness was negatively correlated with pain intensity, pain catastrophizing, pain interference, and depression, and it was positively correlated with mental health-related HRQOL. Regression analyses demonstrated that mindfulness was a negative predictor of pain intensity and depression and a positive predictor of mental HRQOL after controlling for pain catastrophizing, age, and gender. The two mindfulness facets that were most consistently associated with better outcomes were non-judging and acting with awareness. Mindfulness significantly moderated the relationships between pain intensity and pain catastrophizing and between pain intensity and pain interference. CONCLUSION: It appears that mindfulness mitigates the impact of pain experiences in cancer survivors experiencing CNP post-treatment. IMPLICATIONS FOR CANCER SURVIVORS: This study suggests that mindfulness is associated with better adjustment to CNP. This provides the foundation to explore whether mindfulness-based interventions improve quality of life among cancer survivors living with CNP.

Growth and tolerance of formula with lactoferrin in infants through one year of age: double-blind, randomized, controlled trial.

BACKGROUND: Human milk provides necessary macronutrients (protein, carbohydrate, fat) required for infant nutrition. Lactoferrin (Lf), a multifunctional iron-binding protein predominant in human milk, shares similar protein sequence, structure, and bioactivity with bovine Lf (bLf). This large-scale pediatric nutrition study was designed to evaluate growth and tolerance in healthy infants who received study formulas with bLf at concentrations within the range of mature human milk. METHODS: In this multi-center, double-blind, parallel-designed, gender-stratified prospective study 480 infants were randomized to receive a marketed routine cow's milk-based infant formula (Control; n = 155) or one of two investigational formulas with bLf at 0.6 g/L (LF-0.6; n = 165) or 1.0 g/L (LF-1.0; n = 160) from 14-365 days of age. Investigational formulas also had a prebiotic blend of polydextrose (PDX) and galactooligosaccharides (GOS) and adjusted arachidonic acid (ARA). The primary outcome was weight growth rate from 14-120 days of age. Anthropometric measurements were taken at 14, 30, 60, 90, 120, 180, 275, and 365 days of age. Parental recall of formula intake, tolerance, and stool characteristics was collected at each time point. Medically-confirmed adverse events were collected throughout the study period. RESULTS: There were no group differences in growth rate (g/day) from 14-120 days of age; 353 infants completed the study through 365 days of age ( CONTROL: 110; LF-0.6: 127; LF-1.0: 116). Few differences in growth, formula intake, and infant fussiness or gassiness were observed through 365 day of age. Group discontinuation rates and the overall group incidence of medically-confirmed adverse events were not significantly different. From 30 through 180 days of age, group differences in stool consistency (P < 0.005) were detected with softer stools for infants in the LF-0.6 and LF-1.0 groups versus CONTROL. CONCLUSION: Compared to the Control, infants who received investigational formulas with bLf and the prebiotic blend of PDX and GOS experienced a softer stooling pattern similar to that reported in breastfed infants. This study demonstrated routine infant formulas with bLf, a blend of PDX and GOS, and adjusted ARA were safe, well-tolerated, and associated with normal growth when fed to healthy term infants through 365 days of age. TRIAL REGISTRATION: ClinicalTrials.gov NCT01122654 . Registered 10 May 2010.

Higher protein intake improves length, not weight, z scores in preterm infants.

OBJECTIVE: The aim of the study was to evaluate the relation between nutritional intake (kilocalories, protein) and weight and length growth in preterm infants, and to describe their metabolic tolerance with a focus on those with high protein intake (≥ 4.6 g · kg(-1) · day(-1)). METHODS: Secondary analysis of data from appropriate-for-gestational age preterm infants in a 28-day randomized clinical trial that evaluated growth, tolerance, and safety of a new ultraconcentrated liquid human milk fortifier (original study n = 150). This subset of 56 infants had complete growth and nutrition data and met criteria for the original study's "efficacy analysis" (eg, >80% of kilocalorie intake from study diet). Nutritional intake was estimated, not actual. Regressions were used to test cumulative kilocalories and protein as the predictors of 28-day change in weight and length z scores (growth status), and to evaluate protein tolerance. RESULTS: Average intake was 118 ± 8 kcal · kg(-1) · day(-1) and 4.3 ± 0.4 g protein · kg(-1) · day(-1), with 16 ± 3 g · kg(-1) · day(-1) and 1.1 ± 0.2 cm/week growth for 28 days. Cumulative total kilocalories and protein were significant predictors of improved length z score (P = 0.0054, 0.0005) but not weight z score change. Regression models indicated that protein not kilocalories explained the improvement in length z score, with protein explaining 19% of the variability. The high protein group averaged 4.6 to 5.5 g · kg(-1) · day(-1) (n = 16). Protein tolerance was adequate for all of the study infants based on metabolic measures (blood urea nitrogen, serum carbon dioxide, pH). CONCLUSIONS: Higher cumulative protein intake was tolerated and overall lessened the commonly occurring decline in the length but not weight growth status in a 28-day study of preterm infants.

Growth and tolerance of infants fed formula supplemented with polydextrose (PDX) and/or galactooligosaccharides (GOS): double-blind, randomized, controlled trial.

BACKGROUND: To ensure the suitability of an infant formula as the sole source of nutrition or provide benefits similar to outcomes in breastfed infants, advancements in formula composition are warranted as more research detailing the nutrient composition of human milk becomes available. This study was designed to evaluate growth and tolerance in healthy infants who received one of two investigational cow's milk-based formulas with adjustments in carbohydrate, fat, and calcium content and supplemented with a prebiotic blend of polydextrose (PDX) and galactooligosaccharides (GOS) or GOS alone. METHODS: In this multi-center, double-blind, parallel-designed, gender-stratified prospective study 419 infants were randomized and consumed either a marketed routine cow's milk-based infant formula (Control; Enfamil® LIPIL®, Mead Johnson Nutrition, Evansville, IN) (n = 142) or one of two investigational formulas from 14 to 120 days of age. Investigational formulas were supplemented with 4 g/L (1:1 ratio) of a prebiotic blend of PDX and GOS (PDX/GOS; n = 139) or 4 g/L of GOS alone (GOS; n = 138). Anthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age. Daily recall of formula intake, tolerance, and stool characteristics was collected during study weeks 1 and 2 and 24-h recall was collected at 60, 90, and 120 days of age. Medically-confirmed adverse events were recorded throughout the study. RESULTS: There were no group differences in growth rate from 14 to 120 days of age. Discontinuation rates were not significantly different among study groups. No differences in formula intake or infant fussiness or gassiness were observed. During study weeks 1 and 2 and at 60 days of age stool consistency ratings were higher (i.e. softer stools) for infants in the PDX/GOS and GOS groups versus Control and remained higher at 120 days for the PDX/GOS group (all P < 0.05). The overall incidence of medically-confirmed adverse events was similar among groups. CONCLUSIONS: Investigational routine infant formulas supplemented with 4 g/L of either a prebiotic blend of PDX and GOS or GOS alone were well-tolerated and supported normal growth. Compared to infants who received the unsupplemented control formula, infants who received prebiotic supplementation experienced a softer stooling pattern similar to that reported in breastfed infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00712608.

Toddler formula supplemented with docosahexaenoic acid (DHA) improves DHA status and respiratory health in a randomized, double-blind, controlled trial of US children less than 3 years of age.

Studies of docosahexaenoic acid (DHA) intake and status in US toddlers are lacking. One national survey found low DHA intakes. The objectives of this double-blind, randomized study were to (a) determine usual DHA intakes, (b) measure the effect of consuming formulas with DHA on red blood cell (RBC) and plasma DHA and (c) record adverse events in US children between 18 and 36 months of age. Children aged 18-36 months were provided 237-ml formula with 0, 43, or 130 mg DHA per day for 60 days. Blood was obtained at 0 and 60 days and 24-hour dietary recalls at 0, 30 and 60 days. Usual median daily DHA intake was 13.3 mg. RBC DHA increased in a dose-dependent manner with increasing DHA intake (p<0.05). Toddlers consuming the formula with 130 mg DHA per day have fewer adverse events (p=0.007) and a lower incidence of respiratory illness (p=0.024), compared to the formula without DHA. US toddlers have low DHA intake and status. Modest increases in DHA intake in toddlers might improve development, including respiratory health.

The impact of early nutrition on incidence of allergic manifestations and common respiratory illnesses in children.

OBJECTIVE: To investigate the incidence of allergic and respiratory diseases through age 3 years in children fed docosahexaenoic acid (DHA)- and arachidonic acid (ARA)-supplemented formula during infancy. STUDY DESIGN: Children who completed randomized, double-blind studies of DHA/ARA-supplemented (0.32%-0.36%/0.64%-0.72% of total fatty acids, respectively) versus nonsupplemented (control) formulas, fed during the first year of life, were eligible. Blinded study nurses reviewed medical charts for upper respiratory infection (URI), wheezing, asthma, bronchiolitis, bronchitis, allergic rhinitis, allergic conjunctivitis, otitis media, sinusitis, atopic dermatitis (AD), and urticaria. RESULTS: From the 2 original cohorts, 89/179 children participated; 38/89 were fed DHA/ARA formula. The DHA/ARA group had significantly lower odds for developing URI (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.08-0.58), wheezing/asthma (OR, 0.32; 95% CI, 0.11-0.97), wheezing/asthma/AD (OR, 0.25; 95% CI, 0.09-0.67), or any allergy (OR, 0.28; 95% CI, 0.10-0.72). The control group had significantly shorter time to first diagnosis of URI (P = .006), wheezing/asthma (P = .03), or any allergy (P = .006). CONCLUSIONS: DHA/ARA supplementation was associated with delayed onset and reduced incidence of URIs and common allergic diseases up to 3 years of age.

Growth and tolerance of healthy term infants receiving hydrolyzed infant formulas supplemented with Lactobacillus rhamnosus GG: randomized, double-blind, controlled trial.

Healthy, term infants received extensively hydrolyzed casein formula (EHF; control), the same formula supplemented with Lactobacillus rhamnosus GG (EHF-LGG), or partially hydrolyzed whey:casein (60:40) formula supplemented with LGG (PHF-LGG), in this double-blind, randomized, controlled, parallel, prospective study. Anthropometric measures and 24-hour dietary and tolerance recalls were obtained at 30, 60, 90, 120, and 150 days of age. Blood collected in a subset of infants was analyzed for fatty acid profiles in plasma and red blood cells and for markers of allergic sensitization. Adverse events were recorded throughout the study. Growth rates were not statistically different between EHF and PHF-LGG and between EHF and EHF-LGG from day 14 to day 30, 120, or 150. No relevant differences in formula tolerance, adverse events, or allergic and immune markers were demonstrated between groups. The extensively and partially hydrolyzed formulas supplemented with LGG support normal growth in healthy, term infants and are well tolerated and safe.

Molecular ecological analysis of fecal bacterial populations from term infants fed formula supplemented with selected blends of prebiotics.

Supplementation of infant formulas with prebiotic ingredients continues the effort to mimic functional properties of human milk. In this double-blind, controlled, 28-day study, healthy term infants received control formula (control group; n = 25) or control formula supplemented with polydextrose (PDX) and galactooligosaccharide (GOS) (4 g/liter) (PG4 group; n = 27) or with PDX, GOS, and lactulose (LOS) (either 4 g/liter [PGL4 group; n = 27] or 8 g/liter [PGL8 group; n = 25]). A parallel breast-fed group (BF group) (n = 30) was included. Stool characteristics, formula tolerance, and adverse events were monitored. Fecal bacterial subpopulations were evaluated by culture-based selective enumeration (Enterobacteriaceae), quantitative real-time PCR (Clostridium clusters I, XI, and XIV, Lactobacillus, and Bifidobacterium), and fluorescence in situ hybridization (FISH) (Bifidobacterium). Fecal bacterial community profiles were examined by using 16S rRNA gene PCR-denaturing gradient gel electrophoresis. The daily stool consistency was significantly softer or looser in the BF group than in all of the groups that received formula. The formulas were well tolerated, and the incidences of adverse events did not differ among feeding groups. Few significant changes in bacterial subpopulations were observed at any time point. The bacterial communities were stable; individual profiles tended to cluster by subject rather than by group. Post hoc analysis, however, demonstrated that the bacterial community profiles for subjects in the BF, PG4, PGL4, and PGL8 groups that first received formula at a younger age were less stable than the profiles for subjects in the same groups that received formula at an older age, but there was no difference for the control group. These data indicate that formulas containing PDX, GOS, and LOS blends are more likely to influence gut microbes when administration is begun in early infancy and justify further investigation of the age-related effects of these blends on fecal microbiota.

Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with docosahexaenoic acid and arachidonic acid.

OBJECTIVE: In study 1, to compare the effect on growth in healthy infants of a new amino acid-based formula (AAF) and a control extensively hydrolyzed formula (EHF), with both docosahexaenoic acid (DHA) and arachidonic acid (ARA) at levels similar to those in human milk worldwide. In study 2, to evaluate the hypoallergenicity of this new AAF in infants and children with confirmed cow's milk allergy (CMA). STUDY DESIGN: In study 1, a total of 165 healthy, full-term, formula-fed infants randomly received the new AAF or control formula. Anthropometric measurements, tolerance, and adverse events were recorded throughout the study. Plasma amino acid profiles were evaluated in a subset of the infants. In study 2, the hypoallergenicity of the new AAF was evaluated in 32 infants and children using a double-blind, placebo-controlled food challenge; an open challenge; and a 7-day feeding. RESULTS: In study 1, overall growth, tolerance, and safety outcomes were similar in both groups. In study 2, 29 of the 32 subjects completed both challenges; no allergic reaction was seen in any of the 32 subjects. CONCLUSIONS: The new AAF with DHA and ARA at levels similar to those in human milk worldwide is hypoallergenic. It also is safe and supports growth in healthy, term infants.

Soy-based infant formula supplemented with DHA and ARA supports growth and increases circulating levels of these fatty acids in infants.

Healthy term infants (n = 244) were randomized to receive: (1) control, soy-based formula without supplementation or (2) docosahexaenoic acid-arachidonic acid (DHA + ARA), soy-based formula supplemented with at least 17 mg DHA/100 kcal (from algal oil) and 34 mg ARA/100 kcal (from fungal oil) in a double-blind, parallel group trial to evaluate safety, benefits, and growth from 14 to 120 days of age. Anthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age and 24-h dietary and tolerance recall were recorded at 30, 60, 90, and 120 days of age. Adverse events were recorded throughout the study. Blood samples were drawn from subsets of 25 infants in each group. Capillary column gas chromatography was used to analyze the percentages of fatty acids in red blood cell (RBC) lipids and plasma phospholipids. Compared with the control group, percentages of fatty acids such as DHA and ARA in total RBC and plasma phospholipids were significantly higher in infants in the DHA + ARA group at 120 days of age (P < 0.001). Growth rates did not differ significantly between feeding groups at any assessed time point. Supplementation did not affect the tolerance of formula or the incidence of adverse events. Feeding healthy term infants soy-based formula supplemented with DHA and ARA from single cell oil sources at concentrations similar to human milk significantly increased circulating levels of DHA and ARA when compared with the control group. Both formulas supported normal growth and were well tolerated.

Docosahexaenoic acid in red blood cells of term infants receiving two levels of long-chain polyunsaturated fatty acids.

OBJECTIVES: A randomized, double-blind, prospective trial assessed effects of different formula levels of polyunsaturated fatty acids on blood phospholipid docosahexaenoic (DHA; 22:6omega3) and arachidonic acids (ARA; 20:4omega6) in term infants at 120 days of age. METHODS: Healthy, formula-fed term infants (n = 78) were randomized to 1) routine milk-based formula with 8 mg DHA, 21 mg ARA, 110 mg alpha-linolenic (ALA; 18:3omega3), and 1,000 mg linoleic acids (LA; 18:2omega6) per 100 kcal (Lower-long-chain polyunsaturated fatty acids [LCPUFA]; n = 39) or 2) routine milk-based formula with 17 mg DHA, 34 mg ARA, 85 mg ALA, and 860 mg LA per 100 kcal (Higher-LCPUFA; n = 39). Fatty acid methyl esters from red blood cell (RBC) and plasma phospholipid fractions were assessed using capillary column gas chromatography. RESULTS: Compared with infants fed Lower-LCPUFA formula, the Higher-LCPUFA group had significantly greater percentages of fatty acids as DHA in RBC phosphatidylethanolamine (PE), RBC phosphatidylcholine (PC), total RBC, and plasma phospholipids (P < 0.001). Infants fed Lower-LCPUFA formula had higher percentages of precursor omega6 fatty acids in the desaturation/elongation pathway but lower percentages of ARA (RBC PE, RBC PC, and plasma phospholipid, P < 0.001; total RBC, P = 0.017) compared with the Higher-LCPUFA group. CONCLUSIONS: Greater amounts of dietary ALA do not produce as great an increase in DHA in blood lipids as preformed dietary DHA. Infants fed DHA at levels similar to human milk had significantly greater percentage of DHAat 120 days of age compared with the Lower-LCPUFA group despite higher precursor levels of ALA.

Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid.

OBJECTIVES: To evaluate safety and benefits of feeding preterm infants formulas containing docosahexaenoic acid (DHA) and arachidonic acid (ARA) until 92 weeks postmenstrual age (PMA), with follow-up to 118 weeks PMA. STUDY DESIGN: This double-blinded study of 361 preterm infants randomized across three formula groups: (1) control, no supplementation; (2) algal-DHA (DHA from algal oil, ARA from fungal oil); and (3) fish-DHA (DHA from fish oil, ARA from fungal oil). Term infants breast-fed > or =4 months (n = 105) were a reference group. Outcomes included growth, tolerance, adverse events, and Bayley development scores. RESULTS: Weight of the algal-DHA group was significantly greater than the control group from 66 to 118 weeks PMA and the fish-DHA group at 118 weeks PMA but did not differ from term infants at 118 weeks PMA. The algal-DHA group was significantly longer than the control group at 48, 79, and 92 weeks PMA and the fish-DHA group at 57, 79, and 92 weeks PMA but did not differ from term infants from 79 to 118 weeks PMA. Supplemented groups had higher Bayley mental and psychomotor development scores at 118 weeks PMA than did the control group. Supplementation did not increase morbidity or adverse events. CONCLUSIONS: Feeding formulas with DHA and ARA from algal and fungal oils resulted in enhanced growth. Both supplemented formulas provided better developmental outcomes than unsupplemented formulas.

Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier.

OBJECTIVE: Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time. In response to this continuing decrease in birth weight of surviving preterm infants, Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller, more rapidly growing infants. It now provides an increased protein level of 1.1 g/58 kJ, a decreased carbohydrate level of 0.2 g/58 kJ, and a combined linoleic and alpha-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron, the fortifier has been supplemented with 1.44 mg/58 kJ of iron, an amount of iron similar to that provided in a typical iron-fortified term infant formula. An iron-fortified product obviates the need for administration of an iron supplement, a hyperosmolar-inducing intervention. The purpose of this prospective, double-blind, randomized, controlled study was to evaluate growth, safety, and efficacy in a population of very low birth weight (VLBW) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product (HMF-T) or a powdered commercially available human milk fortifier control product (HMF-C). METHODS: Infants who weighed < or =1500 g, had a gestational age < or =33 weeks postmenstrual age, and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and randomized to receive HMF-T or HMF-C product from study day 1 to study day 28, hospital discharge, or the termination of human milk feedings, whichever came first. Unless medically indicated, investigators were not to administer iron supplements from study days 1 to 14. Infants were assessed serially for growth; enteral and parenteral intake; serum chemistry and hematologic values; clinical histories, including the administration of blood transfusions; feeding tolerance; respiratory outcomes; and morbidities, including adverse events. RESULTS: Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, there were no significant differences in infant characteristics between the fortifier groups. The percentage of participants who remained in the study for 28 days was similar between fortifier groups (57% HMF-T, 46% HMF-C). For both fortifier groups, the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge. Rate of weight gain was similar between the fortifier groups (17.5 +/- 0.53 g/kg per day for HMF-T and 17.3 +/- 0.59 g/kg per day for HMF-C). Mean achieved weight, length, and head circumference were comparable between groups across the 28-day study period. Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group; however, this difference did not result in any difference in growth between the 2 fortifier groups. An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population. There were no clinically significant differences in the results of laboratory studies between the groups at study days 0, 14, and 28. Anemia of prematurity was prevalent in both study groups; by study day 28, median hematocrit levels were 27.0% (interquartile range [IQR]: 24.0%-29.6%) for the HMF-T group and 26.0% (IQR: 24.0%-31.0%) for the HMF-C group. Median ferritin levels were 77.0 ng/mL (IQR: 37-155 ng/ml) for HMF-T and 92.0 ng/mL (IQR: 33-110 ng/mL) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14. However, from study day 15 to study day 28, fewer HMF-T infants (n = 12) required a blood transfusion than did HMF-C infants (n = 20). Although the higher levels of iron in the HMF-T fortifier (1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier) did not prevent anemia per se, it did reduce the frequency of one of the most serious outcomes of anemia: the need for a blood transfusion. There was no statistically significant difference between fortifier groups in regard to feeding tolerance. Rates of suspected sepsis (26% HMF-T vs 31% HMF-C) and confirmed sepsis (5% HMF-T, 7% HMF-C) were low as were the rates of suspected necrotizing enterocolitis (NEC; 6% HMF-T and 5% HMF-C) and confirmed Bell's stage 2 or more NEC (1% HMF-T and 1% HMF-C). There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC. CONCLUSION: Both human milk fortifiers studied are safe, are well tolerated, and facilitate comparable good growth; however, using the iron-fortified product may reduce the need for blood transfusions in VLBW infants. The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC. Indeed, the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk.

Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula.

OBJECTIVE: To determine if docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplementation influences growth or visual acuity of formula-fed premature infants. STUDY DESIGN: Double-blind, multi-center study of 194 premature infants given preterm formula with no DHA or ARA (control), 0.15% energy DHA, or 0.14% DHA + 0.27% ARA from single-cell triglycerides for at least 28 days and then fed term formula (no DHA or ARA) to 57 weeks postmenstrual age (PMA), with 90 breast-fed term infants as reference. RESULTS: Infants fed DHA+ARA formula gained weight significantly faster (post-hoc analysis) during preterm formula feeding than control infants (34.7 vs. 30.7 g/d) and had weights and weight:length ratios not different from term breast-fed infants at 48 and 57 weeks PMA. Infants fed control or DHA formula had lower body weights than term infants. Red blood cell phosphatidylethanolamine ARA was significantly correlated to weight gain during preterm formula feeding and to weight and length at 40, 48, and 57 weeks PMA (r = 0.19 to 0.24, P =.004-.02). Providing DHA or DHA+ARA during the preterm period had no effect on subsequent visual acuity or incidence of adverse events. CONCLUSIONS: Feeding DHA+ARA from single-cell triglycerides enhances weight gain in formula-fed premature infants with no evidence of adverse effects.