Improved Neurodevelopmental Outcomes at 5.5 Years of Age in Children Who Received Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula Through 12 Months: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the neurodevelopmental outcomes at 5.5 years of age in children who were previously randomized to cow milk-based infant formula (control) or similar formula (milk fat globule membrane + lactoferrin) with added sources of bovine milk fat globule membrane and bovine lactoferrin through 12 months of age. DESIGN: Children who completed study feeding were invited to participate in follow-up assessments: cognitive development across multiple domains (primary outcome; Wechsler Preschool & Primary Scale of Intelligence, 4th Edition), inhibitory control/rule learning (Stroop Task), flexibility/rule learning (Dimensional Change Card Sort), and behavior/emotion (Child Behavior Checklist). RESULTS: Of 292 eligible participants (control: 148, milk fat globule membrane + lactoferrin: 144), 116 enrolled and completed assessments (control: 59, milk fat globule membrane + LF: 57). There were no group demographic differences except family income (milk fat globule membrane + lactoferrin significantly higher). Wechsler Preschool & Primary Scale of Intelligence, 4th Edition composite scores (mean ± standard error) for Visual Spatial (100.6 ± 1.7 vs 95.3 ± 1.7; P = .027), Processing Speed (107.1 ± 1.4 vs 100.0 ± 1.4; P < .001), and Full-Scale IQ (98.7 ± 1.4 vs 93.5 ± 1.5; P = .012) were significantly higher for milk fat globule membrane + lactoferrin versus control, even after controlling for demographic/socioeconomic factors. Stroop Task scores were significantly higher in milk fat globule membrane + lactoferrin versus control (P < .001). Higher Dimensional Change Card Sort scores (P = .013) in the border phase (most complex/challenging) were detected, and more children passed the border phase (32% vs 12%; P = .039) for milk fat globule membrane versus control. No group differences in Child Behavior Checklist score were detected. CONCLUSIONS: Children who received infant formula to 12 months of age with added bovine milk fat globule membrane and bovine lactoferrin versus standard formula demonstrated improved cognitive outcomes in multiple domains at 5.5 years of age, including measures of intelligence and executive function. TRIAL REGISTRATION: Clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT04442477.

Missed Cystic Fibrosis Newborn Screening Cases due to Immunoreactive Trypsinogen Levels below Program Cutoffs: A National Survey of Risk Factors.

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above ("high") and below ("low") the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with "high" CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with "low" CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce "high" IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce "low" IRT CFFNs.

Infant behavioral state and stool microbiome in infants receiving Lactocaseibacillus rhamnosus GG in formula: randomized controlled trial.

BACKGROUND: Our aim was to evaluate infant behavioral state, stool microbiome profile and calprotectin in infants with infantile colic receiving a partially hydrolyzed protein formula with or without added Lacticaseibacillus (formerly Lactobacillus) rhamnosus GG (LGG). METHODS: In this single-center, double-blind, controlled, parallel, prospective study, term infants (14-28 days of age) identified with colic (using modified Wessel's criteria: cried and/or fussed ≥ 3 h/day for ≥ 3 days/week, in a one-week period) were randomized to receive one of two formulas over a three-week feeding period: marketed partially hydrolyzed cow's milk-based infant formula (PHF, n = 35) or a similar formula with added LGG (PHF-LGG, n = 36). Parent-reported infant behavior was recorded at three time points (Study Days 2-4, 10-12, and 18-20). Duration (hours/day) of crying/fussing (averaged over each three-day period) was the primary outcome. Stool samples were collected at Baseline and Study End (Days 19-21) to determine stool LGG colonization (by qPCR) and microbial abundance (using 16S rRNA gene sequencing) and calprotectin (µg/g). RESULTS: Duration of crying/fussing (mean ± SE) decreased and awake/content behavior increased over time with no significant group differences over the course of the study. There were no group differences in the percentage of infants who experienced colic by study end. Colic decreased by Study End vs Baseline in both groups. Change in fecal calprotectin also was similar between groups. Comparing Study End vs Baseline, LGG abundance was greater in the PHF-LGG group (P < 0.001) whereas alpha diversity was greater in the PHF group (P = 0.022). Beta diversity was significantly different between PHF and PHF-LGG at Study End (P = 0.05). By study end, relative abundance of L. rhamnosus was higher in the PHF-LGG vs PHF group and vs Baseline. CONCLUSIONS: In this pilot study of infants with colic, both study formulas were well tolerated. Crying/fussing decreased and awake/content behavior increased in both study groups over the course of the study. Study results demonstrate a successful introduction of the probiotic to the microbiome. The partially hydrolyzed protein formula with added LGG was associated with significant changes in the gut microbiome. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT02340143 . Registered 16/01/2015.

Softer More Frequent Stools in Infants With Difficult Stooling Fed Hydrolyzed Protein Formula With Added Prebiotics: Randomized Controlled Trial.

Objective: To evaluate stool consistency in infants with reported hard or infrequent stools fed hydrolyzed protein formula with added prebiotics designed to promote stool softening. Methods: In this multi-center, double-blind, controlled study, eligible infants (28-300 days of age at enrollment) were randomized to: partially hydrolyzed cow's milk protein formula (PHF, 75% carbohydrate as lactose; 12 mg Mg/100 kcal; n = 49) or routine intact protein cow's milk-based infant formula (Control, 92% carbohydrate as lactose; 8 mg Mg/100 kcal; n = 51) over a 14-day period. Both formulas had a prebiotic blend (polydextrose and galactooligosaccharides, 4 g/L; 1:1 ratio). Parent-reported stool consistency (hard = 1 through watery = 5) and other daily outcomes were collected by diary. Endpoint stool consistency (mean score over last 3 days of study feeding) was the primary outcome. Adverse events were recorded. Results: Baseline stool consistency (Control: 1.4 ± 0.1, PHF: 1.4 ± 0.1) and frequency were similar between groups; the majority had hard (n = 61, 64%) or formed (n = 30, 32%) stools. Stool consistency became softer over Day 1-3 (Control: 2.5 ± 0.1, PHF: 2.6 ± 0.1) and remained similar from Day 4 to 6 through study end (post hoc analysis). For PHF vs Control, endpoint stool consistency was significantly softer (3.4 ± 0.1 vs 3.0 ± 0.1; P = 0.019) and frequency significantly higher (1.5 ± 0.1 vs 1.0 ± 0.1; P = 0.002). Crying, fussing, and appearance of pain during stooling decreased from baseline to study end in both groups. Formula intake, infant fussiness and incidence of adverse events were similar between groups. Conclusion: An infant formula designed to promote stool softening was well-tolerated and associated with softer, more frequent stools in infants with reported hard or infrequent stools.

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.

Effect of Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula on Gut Microbiome and Metabolome at 4 Months of Age.

BACKGROUND: Milk fat globule membrane (MFGM) and lactoferrin (LF) are human-milk bioactive components demonstrated to support gastrointestinal and immune development. Significantly fewer diarrhea and respiratory-associated adverse events through 18 mo of age were previously reported in healthy term infants fed a cow-milk-based infant formula with an added source of bovine MFGM and bovine LF through 12 mo of age. OBJECTIVES: The aim was to compare microbiota and metabolite profiles in a subset of study participants. METHODS: Stool samples were collected at baseline (10-14 d of age) and day 120. Bacterial community profiling was performed via 16S rRNA gene sequencing and alpha and beta diversity were analyzed (QIIME 2). Differentially abundant taxa were determined using linear discriminant analysis effect size (LefSE) and visualized (Metacoder). Untargeted stool metabolites were analyzed (HPLC/MS) and expressed as the fold-change between group means (control to MFGM+LF ratio). RESULTS: Alpha diversity increased significantly in both groups from baseline to 4 mo. Subtle group differences in beta diversity were demonstrated at 4 mo (Jaccard distance; R 2 = 0.01, P = 0.042). Specifically, Bacteroides uniformis and Bacteroides plebeius were more abundant in the MFGM+LF group at 4 mo. Metabolite profile differences for MFGM+LF versus control included lower fecal medium-chain fatty acids, deoxycarnitine, and glycochenodeoxycholate, and some higher fecal carbohydrates and steroids (P < 0.05). After applying multiple test correction, the differences in stool metabolomics were not significant. CONCLUSIONS: Addition of bovine MFGM and LF in infant formula was associated with subtle differences in stool microbiome and metabolome by 4 mo of age, including increased prevalence of Bacteroides species. Stool metabolite profiles may be consistent with altered microbial metabolism. This trial was registered at https://clinicaltrials.gov as NCT02274883.

Developmental effects on sleep-wake patterns in infants receiving a cow's milk-based infant formula with an added prebiotic blend: a Randomized Controlled Trial.

BACKGROUND: Few studies have evaluated nutritive effects of prebiotics on infant behavior state, physiology, or metabolic status. METHODS: In this double-blind randomized study, infants (n = 161) received cow's milk-based infant formula (Control) or similar formula with an added prebiotic blend (polydextrose and galactooligosaccharides [PDX/GOS]) from 14-35 to 112 days of age. Infant wake behavior (crying/fussing, awake/content) and 24-h sleep-wake actograms were analyzed (Baseline, Days 70 and 112). Salivary cortisol was immunoassayed (Days 70 and 112). In a subset, exploratory stool 16S ribosomal RNA-sequencing was analyzed (Baseline, Day 112). RESULTS: One hundred and thirty-one infants completed the study. Average duration of crying/fussing episodes was similar at Baseline, significantly shorter for PDX/GOS vs. Control at Day 70, and the trajectory continued at Day 112. Latency to first and second nap was significantly longer for PDX/GOS vs. Control at Day 112. Cortisol awakening response was demonstrated at Days 70 and 112. Significant stool microbiome beta-diversity and individual taxa abundance differences were observed in the PDX/GOS group. CONCLUSIONS: Results indicate faster consolidation of daytime waking state in infants receiving prebiotics and support home-based actigraphy to assess early sleep-wake patterns. A prebiotic effect on wake organization is consistent with influence on the gut-brain axis and warrants further investigation. IMPACT: Few studies have evaluated nutritive effects of prebiotics on infant behavior state, cortisol awakening response, sleep-wake entrainment, and gut microbiome. Faster consolidation of daytime waking state was demonstrated in infants receiving a prebiotic blend in infant formula through ~4 months of age. Shorter episodes of crying were demonstrated at ~2 months of age (time point corresponding to age/developmental range associated with peak crying) in infants receiving formula with added prebiotics. Results support home-based actigraphy as a suitable method to assess early sleep-wake patterns. Prebiotic effect on wake organization is consistent with influence on the gut-brain axis and warrants further investigation.

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.

Improved Neurodevelopmental Outcomes Associated with Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula: A Randomized, Controlled Trial.

OBJECTIVE: To evaluate neurodevelopment, growth, and health outcomes in infants receiving bovine milk fat globule membrane (MFGM) and lactoferrin in infant formula. STUDY DESIGN: Healthy term infants were randomized to a cow's milk-based infant formula or MFGM + LF (a similar infant formula, with an added source of bovine milk fat globule membrane [bMFGM; whey protein-lipid concentrate, 5 g/L] and bovine lactoferrin [0.6 g/L]) through 365 days of age. The Bayley Scales of Infant Development, 3rd edition cognitive composite score at day 365 was the primary outcome. Secondary outcomes included tolerance measures through day 365, additional neurodevelopmental and language outcomes, growth, and medically confirmed adverse events through day 545. RESULTS: Of 451 infants enrolled (control, 228; MFGM + LF, 223), 291 completed study feeding and Bayley-III testing at day 365 (control, 148; MFGM + LF, 143). The mean cognitive (+8.7), language (+12.3), and motor (+12.6) scores were higher (P < .001) for the MFGM + LF group; no differences were observed at day 545. Global development scores from day 120 to day 275 and attention at day 365 were significantly improved. Few group differences in day 545 neurodevelopmental outcomes were detected, however scores of some subcategories of the MacArthur-Bates Communicative Development Inventories were higher (P < .05) in the MFGM + LF group. The overall incidence of respiratory-associated adverse events and diarrhea were significantly lower for the MFGM + LF group through day 545. CONCLUSIONS: Infants receiving formula with added bovine MFGM and bovine lactoferrin had an accelerated neurodevelopmental profile at day 365 and improved language subcategories at day 545. Formulas were associated with age-appropriate growth and significantly fewer diarrhea and respiratory-associated adverse events through 545 days of age. TRIAL REGISTRATION CLINICALTRIALS.GOV:: NCT02274883.

Evolution in the Surgical Care of Patients With Non-Small Cell Lung Cancer in the Mid-South Quality of Surgical Resection Cohort.

Surgery is the most important curative treatment modality for patients with early-stage non-small cell lung cancer (NSCLC). We examined the pattern of surgical resection for NSCLC in a high incidence and mortality region of the United States over a 10-year period (2004-2013) in the context of a regional surgical quality improvement initiative. We abstracted patient-level data on all resections at 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in North Mississippi, East Arkansas, and West Tennessee. Surgical quality measures focused on intraoperative practice, with emphasis on pathologic nodal staging. We used descriptive statistics and trend analyses to assess changes in practice over time. To measure the effect of an ongoing regional quality improvement intervention with a lymph node specimen collection kit, we used period effect analysis to compare trends between the preintervention and postintervention periods. Of 2566 patients, 18% had no preoperative biopsy, only 15% had a preoperative invasive staging test, and 11% underwent mediastinoscopy. The rate of resections with no mediastinal lymph nodes examined decreased from 48%-32% (P < 0.0001), whereas the rate of resections examining 3 or more mediastinal stations increased from 5%-49% (P < 0.0001). There was a significant period effect in the increase in the number of N1, mediastinal, and total lymph nodes examined (all P < 0.0001). A quality improvement intervention including a lymph node specimen collection kit shows early signs of having a significant positive effect on pathologic nodal examination in this population-based cohort. However, gaps in surgical quality remain.

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.

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.

New prebiotic blend of polydextrose and galacto-oligosaccharides has a bifidogenic effect in young infants.

OBJECTIVE: The aim of the study was to evaluate the effect of infant formula with polydextrose (PDX) and galacto-oligosaccharides (GOS) on fecal microbiota and secretory IgA (sIgA). MATERIALS AND METHODS: In the present double-blind, randomized study, term infants received control (Enfamil Lipil) or the same formula with PDX/GOS (4 g/L, 1:1 ratio; PDX/GOS) for 60 days; a reference breast-fed group was included. Formula intake, tolerance, and stool characteristics were collected via electronic diary and analyzed by repeated measures analysis of variance. Anthropometric measurements and stool samples were obtained at baseline and after 30 and 60 days of feeding. Fecal sIgA was measured by enzyme-linked immunosorbent assay and fecal bacteria by fluorescent in situ hybridization and quantitative real-time polymerase chain reaction (qPCR); both were analyzed by Wilcoxon rank sum test. RESULTS: Two hundred thirty infants completed the study. Infants consuming PDX/GOS had softer stools than control at all times (P < 0.001). Using qPCR, counts in PDX/GOS were closer to the breast-fed group, tended to be higher than control for total bifidobacteria (P = 0.069) and Bifidobacterium longum (P = 0.057) at 30 days, and were significantly higher for total bifidobacteria and B longum at 60 days and B infantis at 30 days (P = 0.002). No significant differences were detected between PDX/GOS and control in changes from baseline to 30 or 60 days for sIgA or total bifidobacteria by fluorescent in situ hybridization or qPCR; however, significantly higher changes from baseline were detected between PDX/GOS and control for B infantis at 30 days and B longum at 60 days (P ≤ 0.035). CONCLUSIONS: Infant formula with PDX/GOS produces soft stools and a bifidogenic effect closer to breast milk than formula without PDX/GOS.

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.

Clinical response to 2 commonly used switch formulas occurs within 1 day.

Very fussy or extremely fussy infants were randomized to receive: soy-based formula (Soy: n = 82) or a partially hydrolyzed cow's milk protein (CMP), low-lactose formula (PHF: n = 77) in a multicenter, double-blind, randomized, parallel, prospective 28-day feeding trial. Body weight and infant formula tolerance were reported. Adverse events were recorded throughout the study. A significant reduction in mean scores of fussiness, gas, spit-up, and crying compared with baseline measures was observed in infants who received either Soy or PHF within 1 day of formula intake; improvement in symptoms was sustained by study end. Stool consistency remained constant through day 28 in the PHF group, whereas stools in the Soy group became more firm by day 2 and did not return to prestudy consistency. PHF, with a protein profile patterned more closely on human breast milk, improved symptoms of formula intolerance as well as soy-based formula.