Randomized Controlled Trial of Early Docosahexaenoic Acid and Arachidonic Acid Enteral Supplementation in Very Low Birth Weight Infants.

OBJECTIVE: To determine feasibility of providing a concentrated emulsified long-chain polyunsaturated fatty acids (LCPUFA) supplement to very low birth weight infants, and to evaluate blood LCPUFA concentrations at 2 and 8 weeks of study supplementation. STUDY DESIGN: This prospective, randomized, double-blind, placebo-controlled trial randomized infants to receive (1) LCPUFA-120 (a supplement of 40 mg/kg/day docosahexaenoic acid [DHA] and 80 mg/kg/day arachidonic acid [ARA]; DHA:ARA at 1:2 ratio), (2) LCPUFA-360 (a supplement of 120 mg/kg/day DHA and 240 mg/kg/day ARA), or (3) sunflower oil (placebo control). Infants received supplement daily for 8 weeks or until discharge, whichever came first. Whole blood LCPUFA levels (wt%; g/100 g) were measured at baseline, 2 weeks, and 8 weeks. RESULTS: Infants were 28 weeks of gestation (IQR, 27-30 weeks of gestation) and weighed 1040 g (IQR, 910-1245 g). At 2 weeks, the change in blood DHA (wt%) from baseline differed significantly among groups (sunflower oil, n = 6; -0.63 [IQR, -0.96 to -0.55]; LCPUFA-120: n = 12; -0.14 [IQR, -0.72 to -0.26]; LCPUFA-360, n = 12; 0.46 [IQR, 0.17-0.81]; P = .002 across groups). Change in blood ARA (wt%) also differed by group (sunflower oil: -2.2 [IQR, -3.9 to -1.7]; LCPUFA-120: 0.1 [IQR, -2.1 to 1.1] vs LCPUFA-360: 2.9 IQR, 1.5 to 4.5]; P = .0002). Change from baseline to 8 weeks significantly differed between groups for DHA (P = .02) and ARA (P = .003). CONCLUSIONS: Enteral LCPUFA supplementation supported higher blood DHA by 2 weeks. LCPUFA supplementation at 360 mg of combined DHA and ARA is likely necessary to reduce declines as well as allow increases in whole blood concentrations in the first 8 weeks of life. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03192839.

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.

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.

Use of vitamin D supplements during infancy in an international feeding trial.

OBJECTIVE: To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial. DESIGN: Longitudinal study. SETTING: Information about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months. SUBJECTS: Infants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia. RESULTS: Daily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80% of the infants), with somewhat lower rates observed in Southern Europe (> 60%). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g., 71% v. 44% at 6 months of age). Less than 2% of infants in the U.S.A. and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements. CONCLUSIONS: Most of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the U.S.A. and Australia very few were given supplementation.

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.

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.

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.

Fortifying fresh human milk with commercial powdered human milk fortifiers does not affect bacterial growth during 6 hours at room temperature.

OBJECTIVE: To evaluate the growth of resident aerobic mesophilic flora and added Enterobacter sakazakii in fresh, unfortified human milk; fresh human milk fortified with two commercial powdered fortifiers differing in iron content; and infant formula prepared from powder. SUBJECTS: Eight mothers provided preterm breast milk samples. METHODS: Breast milk samples were divided into three aliquots: unfortified, fortified with fortifier containing 1.44 mg iron/14 kcal, and fortified with fortifier containing 0.4 mg iron/14 kcal. Aliquots of formula were prepared. Breast milk and formula aliquots were divided into two test samples. Half were inoculated with low amounts of E sakazakii; half were not. All test samples were maintained at room temperature (22 degrees C), serially diluted, and plated onto agars after 0, 2, 4, and 6 hours. Plates were incubated at 35 degrees C and enumerated. STATISTICAL ANALYSES: Data were analyzed using repeated measures analysis of variance. P<.05 was considered significant. RESULTS: There were no differences in colony counts of aerobic bacteria among uninoculated or among inoculated human milk samples at any time; counts did not increase significantly over 6 hours. There were no differences in colony counts of E sakazakii among inoculated human milk samples at any time; counts did not increase significantly over 6 hours. Aerobic bacteria and E sakazakii colony counts from infant formula did not increase significantly over 6 hours. CONCLUSIONS: During 6 hours at 22 degrees C, fresh human milk and formula had negligible bacterial growth; fortifying human milk with powdered fortifiers did not affect bacterial growth.

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.

Whose child is it anyway? Resolving parent-physician conflict in the NICU setting.

Much has been written on parental involvement in decision making when dealing with critically ill children, but few articles have touched upon parental refusal of treatment in noncritically ill children. What steps should be taken when a parent refuses what is generally considered "standard of care" medicine for their hospitalized child? Does medical advice outweigh parental views or wishes, and what does one do when our role as physician turns from medical expert into one of medical negotiator? The following case and discussion deal with parental refusal of conventional medical care, and how one may find peaceful resolutions to challenging situations for the ultimate good of the child.