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Human milk oligosaccharides (HMOs) are the third most abundant solid component in human milk after lactose and lipids. Preclinical research has demonstrated that HMOs and specifically 2'-fucosyllactose (2'-FL) are more than a prebiotic and have multiple functions, including immune, gut, and cognition benefits. Previously, human milk has been the only source for significant levels of HMOs. The most abundant HMO in most mothers' breast milk is 2'-FL. Recently, 2'-FL has been synthesized and shown to be structurally identical to the 2'-FL found in human milk. 2'-FL HMO is now available in some commercial infant formulas. The purpose of this narrative review was to summarize the clinical experiences of feeding infant formula supplemented with the HMO, 2'-FL. Most of these studies investigated standard intact milk protein-based infant formulas containing 2'-FL, and one evaluated a partially hydrolyzed whey-based formula. Collectively, these clinical experiences demonstrated that 2'-FL being added to infant formula was safe, well-tolerated, and absorbed and excreted with similar efficiency to 2'-FL in human milk. Further, infants that were fed formula with 2'-FL had immune benefits, fewer parent-reported respiratory infections, and improved symptoms of formula intolerance. Ultimately, infant formula with 2'-FL supports immune and gut health and is closer compositionally and functionally to human milk.

The aim of this narrative review was to assess published growth data for healthy, term, infants consuming extensively hydrolyzed protein-based (EHF), or amino acid-based formulas (AAF). These data may be of use to clinicians managing infants with medical conditions consuming these products. A search was conducted using key terms: amino acid-based, hydrolysate, hydrolyzed, hydrolysed, infant formula, infant formulae or formulas, baby formula, or formulae or formulas, infant, infants, infantile, and growth. Seven controlled, randomized, prospective growth trials of healthy term infants fed EHFs or AAFs at similar time points during the first four months of age met these and other criteria, including that the trial was published in a peer-reviewed journal, subjects were enrolled by ≤14 days of age and were exclusively formula-fed at entry and throughout the duration of the trial, and infants were assessed at regular intervals with weight measures available ideally at 14 days, one, two, three, and four months of age. Results suggested that healthy infants receiving commonly available EHFs and AAFs do not appear to experience accelerated growth as reported for infants fed many standard formulas. Differences in growth patterns were observed with some formulas supporting normative growth patterns during the first four months but others appearing to support markedly lower growth patterns. These observations should be confirmed in well-designed prospective randomized trials. Until that time, it is recommended that EHFs and AAFs be chosen carefully with individual patient needs considered., Competing Interests: M.W.B., G.E.B. and J.S.O. are employees of Abbott Nutrition, Abbott Laboratories, the manufacturer of two of the formulas included in this review.

Partially hydrolyzed formulas (pHF) represent a significant percentage of the infant formula market. A new whey-based, palm olein oil (PO)-free pHF was developed and a masked, randomized, parallel growth study was conducted in infants fed this formula or a commercially available whey-based pHF with PO. Infants between 0 and 8 days were to be enrolled and studied to 119 days of age. Growth and tolerance of infants were evaluated. Mean weight gain from 14 to 119 days of age was similar between groups. There were no significant differences between groups in weight, length, head circumference (HC), or length or HC gains. Infants fed the new PO-free pHF had significantly softer stools than those fed the PO-containing formula except at 119 days of age. This study demonstrates that whereas growth of infants fed different formulas during the first 4 months of life may be similar, infants may tolerate individual formulas differently., (© The Author(s) 2014.)

Objective: Food protein-induced proctocolitis usually occurs early in life and is characterized by blood-streaked stools and pain during defecation in an otherwise healthy infant. While many infants with food protein-induced proctocolitis respond well to a casein hydrolysate formula, some require an amino acid-based formula. The objective of the study was to measure the change in physician-rated symptom score from enrollment to study completion in infants with presumptive food protein-induced proctocolitis fed with a specific amino acid-based formula., Methods: In this study, infants ≤6 months of age diagnosed with presumptive food protein-induced proctocolitis received an amino acid-based formula for 42 days. Intake, stool patterns, weight, stool occult blood, and questionnaires assessing infant feeding and stool patterns and parental formula satisfaction were collected., Results: The full analysis set included 43 infants. The mean age at enrollment was 59 ± 5 days. A significant improvement was observed from enrollment to exit in physician-rated symptom score (9.1 ± 0.5 to 4.8 ± 0.5, p < 0.0001), the number of infants with occult blood in stool, and weight-for-age Z-scores during the study. Parental satisfaction with the formula was high., Conclusion: The results confirm that the amino acid-based formula studied is efficacious for managing symptoms of presumptive food protein-induced proctocolitis.

Extensively hydrolyzed formulas present a complex matrix subject to adverse conditions during manufacture that could influence growth and tolerance of infants fed these formulas. A masked, randomized, parallel growth study was conducted in infants fed a ready-to-feed (RTF) or powdered (PWD) form of an extensively hydrolyzed casein-based formula. Infants were enrolled between 0 and 9 days and studied to 112 days of age. Growth, formula intake, and stool patterns were assessed. There were no significant differences between groups in weight, length, head circumference, or their respective gains. Tolerance was similar between groups except that the RTF group had greater formula intakes and passed more stools/day compared to the PWD group. This study demonstrates that the PWD formulation of this RTF formula supports similar growth and tolerance in infants during the first 4 months of life.

Background: Infants and children with chronic diarrhea (CD) often require specialized foods or parenteral nutrition (PN) to achieve adequate nutrient intakes to support growth and development. We assessed the efficacy of an amino acid-based formula (AAF) in supporting growth and improving symptoms in infants and children with CD from multiple etiologies., Methods: Two studies were conducted: CD study in children (CD-C) and CD study in infants (CD-I). Each was a single group, baseline-controlled study in which each subject served as his/her own control. At enrollment, all subjects had CD lasting > 2 weeks and had ≥ 4 stools/day. Subjects were fed an AAF for 80 days starting at SD5, and were assessed at SD 28 and 84., Results Cd-C: 18 of 19 subjects completed the study. At enrollment, the mean age was 5.6 ± 0.7 years, the most common diagnosis was short bowel syndrome (SBS) (n = 13), and 5 subjects with SBS were on PN. Subjects achieved significant increases in weight-for-age z-scores (p = 0.026). Over 50% of subjects achieved improvements in clinical outcomes targeted most frequently by their physicians. Of the five subjects on PN at enrollment, four had substantial weight gain and four had their PN requirements decreased. CD-I: 22 of 27 subjects completed the study. At enrollment, the mean age was 3.3 ± 0.3 months, the most common diagnosis was food allergy (n = 20), and no subjects were on PN. Subjects achieved significant increases in weight-for-age z-scores (p = 0.0023), significant decreases in the number of stools/day (p = 0.0012), and improvements in stool consistency (p = 0.0024). Over 80% of subjects achieved improvements in the clinical outcomes targeted most frequently by their physicians., Conclusions: Infants and children with CD fed an AAF for three months displayed significant improvements in weight-for-age z-scores and clinical symptoms. Children dependent on PN also grew well and four of five decreased their dependence on PN., Trial Registration: Both trials were registered on ClinTrials.gov (CD-C, NCT01812629; CD-I, NCT01820494).

A masked, randomized, parallel growth study was conducted in infants fed an amino acid-based formula (AF) or an extensively hydrolyzed casein-based formula (HF). Infants were enrolled between 0 and 9 days and studied to 112 days of age. Growth, formula intake, stool patterns, and serum albumin concentrations were assessed. There were no significant differences between groups in weight, length, or head circumference, gains in weight or length, or study formula intake. The number of stools parents rated as being formed, and the mean daily number of stools were greater in the HF than in the AF group at 14 and 28 days of age. Mean serum albumin concentrations were not significantly different between groups and were within the normal range. This study demonstrates that AF supports normal growth of infants comparable to that of infants fed HF during the critical first 4 months of life.

Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine beta-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na(+),K(+)-ATPase is inhibited by methionine and related metabolites.

Objective: Quantitative balance studies were performed to compare fat and calcium absorption in healthy, full term infants fed casein hydrolysate-based (CHF) and soy protein-based (SPF) infant formulas with or without palm olein (PO). Previous studies have reported that PO significantly reduced absorption of both fat and calcium in cow's milk-based formulas in which most of the calcium is inherent in the milk protein. In both SPF and CHF virtually all calcium is added as calcium salts., Methods: Two randomized, blinded, crossover balance studies were conducted in normal term infants using a three-day home balance method. One study evaluated 10 infants fed commercially available CHF with or without PO, and the other study evaluated 12 infants fed commercially available SPF with or without PO. Fat and calcium absorption were determined based on the weight of formula intake, weight of stools, and measured calcium and fat in formula and stools., Results: Fat and calcium intake did not differ between the groups fed CHF. However, infant's calcium and fat absorption was less, 41 +/- 6% (Mean +/- SEM) and 92.0 +/- 0.8%, respectively, when fed CHF with PO compared to 66 +/- 5% and 96.6 +/- 1.1%, respectively, when fed CHF without PO, (p < 0.01). For infants fed SPF, fat and calcium intake did not differ between the feeding groups. Mean calcium absorption was also significantly less when infants were fed SPF with PO, 22 +/- 3%, than when fed SPF with no PO, 37 +/- 4% (p < 0.05). Fat absorption did not differ between the two SPFs., Conclusion: This study demonstrates that PO, as the predominant fat, is associated with significantly lower absorption of calcium from infant formulas in which calcium salts are the source of calcium. These findings corroborate previous reports of this negative effect of PO in cow milk-based infant formulas in which most of the calcium is a component of the cow milk protein source.

Background: The results of earlier, nonquantitative studies suggested that absorption of zinc from a semielemental (casein hydrolysate) formula was inferior to absorption from a cow's milk-based formula. The objective of this study was to compare fractional, total and net zinc absorption, and fecal excretion of endogenous zinc in the same healthy young infants when fed a casein hydrolysate versus cow's milk-based formula., Methods: Fractional absorption of zinc and fecal excretion of endogenous zinc were determined from measurement of cumulative fecal excretion of unabsorbed tracer and by an isotope dilution technique, respectively, after oral administration of a 70Zn tracer with all formula feedings for 1 day. Six infants were assigned randomly to receive the test or control formula, and the other formula was administered 2 to 5 weeks later., Results: Mean (+/-SD) fractional absorption of zinc from the casein hydrolysate formula (0.47 +/- 0.17) was double that from the cow's milk-based formula (0.22 +/- 0.04; P = 0.01) with a correspondingly greater total zinc absorption (3.23 +/- 1.67 mg Zn/day vs. 1.55 +/- 0.55 mg Zn/day; P = 0.05). Because the excretion of endogenous zinc in the feces did not differ between formulas (0.90 +/- 0.44 mg Zn/day vs. 0.91 +/- 0.29 mg Zn/day), net absorption of zinc was also higher with the casein hydrolysate formula (2.33 +/- 1.65 mg Zn/day vs. 0.81 +/- 0.67 mg Zn/day; P = 0.02)., Conclusions: Retention of zinc appeared to be adequate to meet the needs for growth during feeding with cow's milk-based formula and was more than adequate during short-term feeding with the casein hydrolysate formula.

Objective: The purpose of this study was to compare growth and protein status of healthy term infants from 2 to 112 days of age fed a commercially available soy-based formula (IS) and a similar formula (EF) containing less protein (2.91 vs 2.45 g/100 kcal)., Design: A controlled, randomized, blind parallel clinical trial was conducted in 32 male and 32 female infants. Infants were enrolled at 2 days of age, and their assigned formula was their only feeding to 112 days of age. At this time their weight, length, and head circumference were measured. Weight, length, and head circumference were measured and formula intake, formula intolerance and stool characteristics were recorded at 8, 28, 56, and 112 days of age. Plasma urea nitrogen (PUN), total protein, albumin, and transthyretin were determined at 56 and 112 days., Results: There were no statistically significant differences in weight, length, head circumference, or gains in these measures. PUN concentration was significantly lower in infants fed EF than IS at 56 and 112 days. Plasma total protein, albumin, and transthyretin concentrations were not different between the two feeding groups at the two testing periods. Tolerance to the two formulas was similar. Stool characteristics did not differ between the two groups., Conclusion: A soy-based formula containing 2.45 g protein/100 kcal and approximately 640 mumol of total sulfur containing amino acids/100 kcal adequately meets the protein needs of term infants from 2 to 112 days of age.

Because infants with colic appear to have abdominal pain similar to that of adults with irritable bowel syndrome, who may benefit from the addition of fiber to their diet, we tested whether fiber added to infant formula would alleviate colic. Twenty-seven normal, term infants (aged 2 to 8 weeks; 14 girls) with colic, defined as crying plus fussing for more than 3 hours a day for at least 3 days of a 6-day baseline period, were enrolled. Infants were randomly assigned in 9-day periods to a sequence of placebo (Isomil formula) followed by fiber-supplemented formula (Isomil plus soy polysaccharide) (n = 12) or the reverse (n = 15). Daily diaries of crying, fussing, sleeping, formula, intake, and stooling were kept. Twenty-two infants completed three lactulose breath hydrogen tests at the end of the baseline period and after each study period. The crossover trial was followed by 30 to 35 days of use of the study formula chosen by the parents as most beneficial but unknown to the investigators. Growth was monitored throughout. Serum cholesterol, calcium, phosphate, albumin, iron, and zinc concentrations were measured at the conclusion. There were no significant differences in average daily time spent by the infants in fussing and crying during ingestion of the fiber-supplemented formula. However, parents of 18 of 27 infants chose fiber-supplemented formula as most beneficial in ameliorating symptoms of colic. While the infants were consuming fiber-supplemented formula, stool frequency increased, and breath hydrogen excretion increased significantly, in response to lactulose. Growth and serum biochemical measurements were normal in all infants. Supplementation of infant formula with the level of soy polysaccharide used in this study may have reduced crying and fussing in some infants but did not affect colicky behavior in the majority of infants, who continued to cry and fuss excessively.

A widely used macromethod employing tyrosine apodecarboxylase for measurement of pyridoxal phosphate (PLP) concentration in 0.5-1.0-ml plasma was modified to a microscale utilizing 0.1-ml plasma. Mean PLP levels in 12 plasma samples were 160.6 +/- 32.8 pmol/ml (mean +/- SD) when analyzed by the macromethod, and were not significantly different compared to those obtained by the micromethod (158.4 +/- 28.2 pmol/ml). Results of the two methods were significantly correlated (r = +0.97, p less than 0.001). Plasma PLP concentrations of 11 samples determined by the micromethod (means = 151.8 +/- 30.0 pmol/ml) were similar and significantly correlated (r = +0.95, p less than 0.001) to levels measured in the same samples 1-2 years earlier (means = 145.1 +/- 26.2 pmol/ml). This suggests that plasma PLP content of the samples was stable for up to 2 years of storage when the micromethod was utilized for analysis. The strong significant correlation between macro- and micromethods attests that the micromethod is a reliable alternative to the macromethod. The micromethod is useful in instances where only small samples of plasma are available for measurement of PLP.