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The use of acidified milk for feeding infants has a long, interesting history that appears to have developed from the use of buttermilk in Holland as early as the late 19th century for feeding infants with diarrhea. Physicians in the early 20th century assumed that the observed benefits were from buttermilk's acidity leading to the practice of acidifying infant formula. The historical and physiological perspective on the use of acidified infant formula is now especially relevant with the emergence of an acidified liquid human milk fortifier for preterm infants. Here, we review that history, with a deeper dive into the contemporary research on the use of acidified human milk fortifiers, the consequences for preterm infants, and the underlying physiological mechanisms. KEY POINTS: · In the late 19th and early 20th century acidified feedings were in common use for sick infants.. · By the mid-20th century, acidified feedings tested in preterm infants resulted in acidic physiology and poor growth.. · The current practice of acidifying feedings in preterm infants has been associated with metabolic acidosis, poor tolerance, and delayed growth.., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.B.R. and G.E.B. are employees of Abbott Nutrition, Abbott Laboratories.M.L.M. is a paid consultant and national speaker for Abbott Nutrition., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Relatively high amounts of protein are required to achieve normal fractional protein synthetic rates during the late second through early third trimester of fetal growth. Once preterm infants achieve higher protein intakes for sustained periods, growth begins to approximate that of the normally growing fetus and long-term neurodevelopmental outcomes are improved. Preterm formulas have been developed that are enriched in protein. This review discusses several factors when using standard preterm formulas and high-protein preterm formulas in the neonatal intensive care unit, with an emphasis on quantity and quality of enteral protein delivery and risks to insufficient and/or excess protein administration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare the effects of an infant formula fortified with nucleotides (NF) with those of a control formula (CF) on the incidence of diarrhea, respiratory tract infections (RTIs), and immune responses in healthy term infants., Methods: This 12-month, double-blind study was conducted on 1- to 7-day-old infants randomized to receive NF or CF exclusively until 12 weeks of age, and fed the assigned formula with solid food until 12 months. NF was supplemented with 72 mg/L of nucleotides, based on the total potentially available nucleotide content of human milk. Subjects were evaluated within 1 week of birth, at 4 weeks, and every 4 weeks thereafter until 48 weeks of age. The primary outcome variable was the incidence of diarrhea. Secondary variables included RTIs, serum immunoglobulin concentrations, and response to hepatitis B vaccine., Results: Compared with subjects fed CF (n = 170), those fed NF (n = 166) had a trend toward reduced risk of diarrhea from 8 to 48 weeks of age and a significantly lower risk of 25.4% (P = 0.05) between 8 and 28 weeks. NF subjects had significantly higher serum immunoglobulin A concentrations ( P < 0.05) throughout the 48-week study. The NF group had an increased risk of upper RTIs, the same incidence of lower RTIs, and the same antibody response to hepatitis B vaccination as the CF group, based on one-sided tests. Growth was normal in both groups, and no adverse events were considered to be formula-related., Conclusions: Healthy term infants from 8 to 28 weeks of life are less likely to experience diarrhea and have higher serum immunoglobulin A concentrations with NF compared with formula without added nucleotides.

Objective: The objective was to measure the total potentially available nucleosides (TPAN) in breast milk from Asian women., Methods: One hundred sixty milk samples were collected from 135 healthy, lactating women in Hong Kong, the Philippines, and Singapore at four stages of lactation: colostrum (1 to 3 days postpartum), transitional (7 to 10 days postpartum), early mature (28 to 35 days postpartum), and late mature (90 to 100 days postpartum). Samples were pooled by site and stage of lactation before analysis., Results: The mean TPAN concentration was 203 microM/L (69.4 mg/L corrected for recovery). Average TPAN concentrations were 171.9 microM/L in colostrum, 208.1 microM/L in transitional milk, 221.6 microM/L in early mature milk, and 210.6 microM/L in late mature milk, with no notable differences between countries. The major sources of nucleosides were RNA (43.3% of TPAN) and free nucleotides (39.9% of TPAN). The average percentages of cytidine, uridine, guanosine, and adenosine monophosphates were 44.5%, 23.1%, 16.5%, and 16.1% of TPAN, respectively. The sources of nucleosides and percentages of nucleotide bases were similar for all stages of lactation. Over 91% of the TPAN was present in the non-cellular component except in colostrum., Conclusions: The average TPAN level in Asian women is similar to that in European and American women, and free nucleotides in human milk represent less than half of the TPAN.

Objective: Perceived intolerance to infant formula is a frequently reported reason for formula switching. Formula intolerance may be related to perceived symptoms of constipation, fussiness, abdominal cramps, and excessive spit-up or vomit. Commercially available formulas differ from each other in processing and in sources and levels of protein, lipids, and micronutrients. These differences may affect tolerance. The objective of this article was to compare the tolerance of two commercially available powder infant formulas that differ in composition. Measures of tolerance in exclusively breastfed infants weaned to an infant formula and exclusively formula-fed infants were evaluated., Methods: Two clinical studies were conducted. In study 1, 82 healthy, full-term infants who were exclusively breastfed at the time of enrollment were randomized at weaning to formula A (commercially available Similac With Iron Powder) or formula B (previously available Enfamil With Iron Powder). Parents completed daily records of tolerance during exclusive breast milk feeding, during the weaning period, and for a 2-week exclusive formula-feeding period. In study 2, 87 healthy, full-term infants who were exclusively formula-fed at the time of study enrollment (by 2 weeks of age) were fed a standard cow milk-based formula (previously commercially available Similac With Iron Powder) and then randomized to receive formula A or B for a 2-week period. Parents completed daily records of tolerance throughout the study. Formula A was a cow milk-based formula with a whey:casein ratio of 48:52 and a fat blend of 42% high-oleic safflower, 30% coconut, and 28% soy oils. Formula B was a cow milk-based formula with a whey:casein ratio of 60:40 and a fat blend of 45% palm olein, 20% soy, 20% coconut, and 15% high-oleic sunflower oils. Both formulas had lactose as the source of carbohydrate and contained 12 mg of iron per liter. Only formula A contained nucleotides at the time of the study. Measures of tolerance included volume of each formula feeding, occurrences of spit-up and/or vomit, and the color (yellow, green, brown, or black) and consistency (water, loose/mushy, soft, formed, or hard) of each stool., Results: In both studies, volume of formula intake, weight gain, and incidence of spit-up or vomit did not differ between feeding groups. In study 1, stool frequency decreased significantly from the exclusive breast milk period to weaning. Stools also became firmer as infants moved from breast milk to weaning and to exclusive formula feeding. When formula was introduced into the diet, stools became less yellow and more green. Infants weaned to formula B had less frequent stools, fewer brown stools, and more yellow stools than did infants fed formula A. In both studies, infants fed formula B experienced significantly firmer stools than did those fed formula A., Conclusions: The present clinical studies indicate that the composition and/or processing of milk-based powder iron-fortified infant formulas affect stool characteristics experienced by infants. The inclusion of palm olein oil in formula B may be the reason for the observed differences in stool characteristics. Palm olein is used in infant formulas to provide palmitic acid at a level similar to that found in breast milk. However, palmitic acid from palm olein is arranged differently from that in breast milk triglyceride and is poorly absorbed. Unabsorbed palmitic acid tends to react with calcium to form insoluble soaps, and the level of these soaps is correlated with stool hardness. The pattern of softer stools and greater frequency of stooling associated with formula A is similar to the stool pattern in the exclusively breastfed infant. Thus, the use of formula A may ease the transition from breast milk to formula feeding and ameliorate parents' perception that constipation is associated with iron-fortified formula.

Objective: To determine whether human milk and nucleotides added to infant formula at levels present in human milk enhance development of the immune system during infancy., Methods: A 12-month, controlled, randomized and blinded, multisite feeding trial was conducted on two infant formulas: iron-fortified, milk-based control formula (Control) or the same formula fortified with nucleotides (Nucleotide). The level (72 mg/L) and ratio of individual nucleotides selected were patterned after those available in human milk. A third group fed human milk exclusively for 2 months and then human milk or Similac with iron until 12 months of age also was studied. Response to immunizations was chosen to assess development of the immune system. Infants followed the immunization schedule recommended by the American Academy of Pediatrics in 1991., Outcome Variables: Antibody responses were determined at 6, 7, and 12 months of age to Haemophilus influenzae type b polysaccharide (Hib), to diphtheria and tetanus toxoids, and to oral polio virus (OPV) immunizations., Results: Of 370 full-term, healthy infants enrolled, 311 completed the study (107 Control, 101 Nucleotide, 103 human milk/Similac with iron). Intake, tolerance, and growth of infants were similar in all three groups. Compared with the Control group 1 month after the third immunization (7 months of age), the Nucleotide group had a significantly higher Hib antibody concentration (geometric mean concentrations of 7.24 vs 4.05 micrograms/mL, respectively), and a significantly higher diphtheria antibody concentration (geometric mean of 1.77 vs 1.38 U/mL). The significantly higher Hib antibody response in the Nucleotide group persisted at 12 months. The antibody responses to tetanus and OPV were not enhanced by nucleotide fortification. There also was an effect of breastfeeding on immune response. Infants who breastfed had significantly higher neutralizing antibody titers to polio virus than either formula-fed group (1:346 vs 1:169 and 1:192 in the Control and Nucleotide groups, respectively) at 6 months of age., Conclusion: Infant formula fortified with nucleotides enhanced H influenzae type b and diphtheria humoral antibody responses. Feeding human milk enhanced antibody responses to OPV. Dietary factors play a role in the antibody response of infants to immunization.

Currently available infant formulas can be separated into those intended for normal term infants and those designed for infants with special needs, i.e. infants with low-birth-weight, with allergies to milk proteins, or with metabolic disorders. New formulas are developed when groups of infants with special nutritional needs are identified. A recent example is the introduction of a soy fiber-containing formula for refeeding infants after diarrhea. Existing formulas continually change with new nutritional knowledge; an example is the addition of taurine when its role is visual function became known. The composition of human milk serves as a valuable reference for improving infant formula. However, human milk contains living cells, hormones, active enzymes, immunoglobulins and components with unique molecular structures that can not be replicated in infant formula. Additionally, unlike human milk, infant formula must remain stable on the shelf for up to 36 months. These fundamental differences between human milk and infant formula often mandate differences in composition to achieve similar clinical outcomes. New formulas or changes in formulas should confer a demonstrable advantage to the infant and not be based on compositional changes alone. Before changes are made in formulations or new formulas developed, a thorough assessment of available research needs to be made and any gaps of knowledge identified. Then a research program specific for the question at hand is developed.(ABSTRACT TRUNCATED AT 250 WORDS)