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WO2010070613A2 - Formule pour nourrisson et système - Google Patents

Formule pour nourrisson et système Download PDF

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Publication number
WO2010070613A2
WO2010070613A2 PCT/IB2009/055832 IB2009055832W WO2010070613A2 WO 2010070613 A2 WO2010070613 A2 WO 2010070613A2 IB 2009055832 W IB2009055832 W IB 2009055832W WO 2010070613 A2 WO2010070613 A2 WO 2010070613A2
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Prior art keywords
formula
infants
feeding
nutrient
term
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WO2010070613A3 (fr
WO2010070613A9 (fr
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Atul Singhal
Alan Lucas
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University College London
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University College London
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Priority claimed from US12/318,678 external-priority patent/US8815279B2/en
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Publication of WO2010070613A9 publication Critical patent/WO2010070613A9/fr
Publication of WO2010070613A3 publication Critical patent/WO2010070613A3/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to infant formulas and methods for using the formulas in feeding newborn infants.
  • infant nutritional formulas that are commercially available or otherwise known in the infant formula art. These infant formulas comprise a range of nutrients to meet the nutritional needs of the growing infant, and typically include lipids, carbohydrates, protein, vitamins, minerals, and other nutrients helpful for optimal infant growth and development.
  • human milk changes over the first few weeks following delivery of an infant.
  • Human milk is referred to as colostrum during the first 5 days after birth, transition milk during days 6-14 after birth, and mature milk thereafter, and during each stage of lactation, the corresponding human milk composition differs considerably.
  • Colostrum and transition milk for example, have lower caloric densities than mature milk, as well as higher protein and lower carbohydrate concentrations. Vitamin and mineral concentrations also vary in the three defined human milk groups.
  • Preterm formula compared with standard formula, was enriched in protein and fat (2*0 g protein and 4*9 g fat per 100 mL compared with 1*5 g protein and 3*8 g fat per 100 mL) but not in carbohydrate (7*10 g per 100 mL in both).
  • Diastolic blood pressure was 3*2 mm Hg lower in infants assigned banked breastmilk than in those assigned a preterm formula, a benefit similar to the 2*3 mm Hg difference in diastolic and 3*5 mm Hg difference in systolic blood pressure observed previously in the non-randomised study of children born at term.
  • a decrease of about 3 mm Hg in diastolic blood pressure estimated from the authors' and previous epidemiological studies, could have substantial public-health implications.
  • a mean reduction in blood pressure of 3 mm Hg underestimates the degree of lowering and benefit to children at the extremes of the distribution for blood-pressure change and, because blood pressure tracks from childhood into adult life with amplification of early differences, the blood-pressure difference between breastfed and nonbreastfed populations is likely to be substantially greater in adulthood.
  • donor breastmilk (provided by unrelated donors to a milk bank) was generally the low-fat foremilk that dripped from the contralateral breast during breastfeeding of the donor's own baby.
  • the authors considered the possibility that the lower fat and therefore energy content of such donor breastmilk, rather than any unique property of human milk itself, accounted for their findings but concluded that this possibility was unlikely and that non-nutritive factors in breastmilk or dietary factors in breastmilk rather than the formulas used were responsible for the results observed.
  • the preterm formula was enriched in protein and fat (20 g protein/L and 49 g fat/L) but not carbohydrate (70 g/L in both formulas).
  • protein and energy intakes were estimated from 600 donor milk pools collected from multiple donors (-11 g protein, 20 g fat, and 70 g carbohydrate/L).
  • the composition of the mothers' own expressed milk was measured in 4935 complete 24-h collections (-15 g protein, 30 g fat, and 70 g carbohydrate/L).
  • the leptin concentration relative to fat mass was 30% greater in the children who received a preterm formula at birth than in those who received one of the two standard diets.
  • WO 2008/071667 discloses a formula for infants at risk of developing obesity later in life which comprises a protein source, a lipid source and a carbohydrate source and has a protein content of less than 1.8g/100 kcal and an energy density of less than 650 kcal/litre.
  • the formula comprises 63 kcal/litre and 0.945 g/litre protein.
  • the formula is intended for feeding to infants born to overweight or obese mothers from the age of three months and subsequently as part of a mixed diet during the introduction of solid foods until weaning is complete at the age of 12 months. No mention is made of the benefits of avoiding over-nutrition in the period immediately after birth e.g. in the two weeks after birth when the mother would be providing colostrum and transition milk and of the advantages flowing from avoidance of over-nutrition during that period.
  • the invention provides a method for reducing the extent of or occurrence of long-term adverse health effects in human infants, comprising feeding to said infants when newborn a nutrient-containing formula providing not more than 1 gram of protein per 100 ml of formula and/or not more than 50 kcal per 100 ml of formula.
  • the present invention is also directed to a method of providing long- term health benefits in individuals by feeding methods directed to those individuals as newborn infants. These methods include a method of reducing the occurrence or extent of insulin resistance in an individual later in life, said method comprising the administration to an individual as a newborn infant the newborn infant formula of the present invention. These methods also include a method of reducing the occurrence or extent of atherosclerosis in an individual later in life, said method comprising the administration to an individual as a newborn infant the newborn infant formula of the present invention.
  • the invention provides a method for reducing the extent of or occurrence of long-term obesity in humans, comprising feeding to said humans when newborn infants a nutrient-containing-formula providing not more than 1 gram of protein per 100 ml of formula and/or not more than 50 kcal per 100 ml of formula.
  • Embodiments of the invention are also directed to a method of providing nutrition to newborn infants, said method comprising the administration of the newborn infant formulas of the present invention to newborn infants during the first two months of life, preferably during at least about the first or first and second weeks of life.
  • Embodiments of the invention give effect to an observed relationship between feeding and growth rates among newborn infants and certain biochemical markers suggestive of long-term health effects of those infants later in life.
  • rapid growth rates of newborn infants appear to correlate with certain biochemical markers that are suggestive of an increased potential development of long-term adverse health effects in those infants later in life such as atherosclerosis or coronary artery disease and insulin resistance or non-insulin dependent diabetes.
  • a more controlled growth rate of newborn infants may result in long term health benefits.
  • the infant feeding formula of the present invention may include those compositions comprising from 0.5 to 1.00 grams of protein per 100 ml of formula and/or 25 to 50 kilocalories per 100 ml of formula. These compositions include those in which the protein component is selected from bovine caseins, whey proteins and individual proteins thereof, alpha-casein, P-lactoglobulin, serum albumin, lactoferrin, immunoglobulins and combinations of these proteins and also mixtures with other proteins. In these embodiments, the infant feeding formulas may contain energy in the form of carbohydrate and fat.
  • the present invention is also directed to a liquid infant feeding formula which comprises water and the above-described infant feeding formula.
  • the inventors have found that faster growth (upward centile crossing on growth charts) in infancy adversely programmes the metabolic syndrome. Consistent with this, faster neonatal growth (first two weeks of life) programmes insulin 5 resistance and endothelial dysfunction which has a central role in the initiation and progression of atherosclerosis and can be measured non-invasively using vascular ultrasound as the vasodilatator response to increased blood flow - flow- mediated dilation, or FMD. The size of the effect is substantial. Adolescents with the greatest weight gain in the first 2 weeks of life show 4% lower FMD of the brachial artery than those with the lowest weight gain, an effect similar to that of insulin dependent diabetes mellitus (4%) and smoking (6%) in adults.
  • the volume of intake of milk is lower in breast-fed than formula-fed infants in the first week of life, and this is especially marked in the first few days which the inventors believe to be critical for long- term health. Therefore in order to achieve the same or similar nutrient intake for formula fed infants as for breast fed infants, the nutrient composition of the new formula should be lower to compensate for the higher volume of intake and mimic the growth pattern in a breastfed infant.
  • a low-nutrient formula modeled to be closer to early breast-milk, can reduce the rate of weight gain of formula-fed infants in the first week and make weight gain more similar to that of a breast-fed infant.
  • infants fed the new lower-nutrient formula had weight loss in the first week rather than weight gain as seen in infants given conventional formula.
  • Fig. 1 is a graph showing weight against time from birth for female infants given standard formula and lower nutrient starter formula in a study reported in Example 3;
  • Figs. 2a and 2b are graphs of energy and protein intake against time from birth for infants randomized to lower-nutrient (starter formula) or standard formula (Similac), data for breast-fed infants being calculated from published values of breast- milk composition and volume intake in the study of Example 3.
  • the newborn infant formula and methods of the present invention are directed to the formulation and use of defined amounts of macronutrients, i.e., protein, carbohydrate, and fat, and energy in newborn infants.
  • macronutrients i.e., protein, carbohydrate, and fat, and energy in newborn infants.
  • the terms “fat” and “lipid” are used interchangeably herein, and unless otherwise specified, refer generally to fats, oils, and combinations thereof.
  • infant formula and "nutritional formula” are used interchangeably herein and refer to nutritional compositions designed for infants, which preferably contain sufficient protein, carbohydrate, lipid, vitamins, minerals, and electrolytes to potentially serve as the sole source of nutrition when provided in sufficient quantities.
  • synthetic nutritional formulas and therefore specifically exclude human milk, cows milk, or any other natural whole milk product, except when such natural whole milk product is modified by manufacturing processes to form a modified milk product, e.g., milk-based infant formula.
  • Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, 5, 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.
  • compositions and methods of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in nutritional infant formula applications.
  • Embodiments of the newborn infant formulas of the present invention have low energy content relative to conventional term and preterm infant formulas, wherein these newborn infant formulas comprise or otherwise provide a caloric density of from about 25 to about 50 kcal per 100 ml, including from about 35 to about 45 kcal per 100 ml, also including from about 37 to about 42 kcal per 100 ml.
  • the caloric density of the newborn infant formulas of the present invention are easily distinguished from that of conventional term and preterm infant formulas, wherein such conventional formulas typically have a caloric density or energy content of from 66 to 88 kcal per 100 ml (i.e., 19-25 kcal/fl oz).
  • the newborn infant formulas of the present invention are in powder form, then the powder is intended for reconstitution prior to use to obtain the above-noted caloric densities and other nutrient requirements.
  • the infant formulas of the present invention are in a concentrated liquid form, then the concentrate is intended for dilution prior to use to obtain the requisite caloric densities and nutrient requirements.
  • the newborn infant formulas can also be formulated as ready-to-feed liquids already having the requisite caloric densities and nutrient requirements.
  • the newborn infant formulas of the present invention are preferably administered to newborn infants in accordance with the methods described herein. Such methods may include feedings with the newborn infant formulas in accordance with the daily formula intake volumes described hereinafter.
  • Embodiments of the newborn infant formulas of the present invention comprise protein in the requisite amounts as described hereinbefore relative to the total energy content of the formula. Any known or otherwise suitable protein or protein source may be used in the newborn infant formulas of the present invention, provided that such proteins are suitable for feeding infants, especially newborn infants.
  • Proteins or protein sources for use in the infant formulas of the present invention may include intact or non-hydrolyzed protein, hydrolyzed protein, partially hydrolyzed protein, free amino acids, and combinations thereof, which protein or protein source may be derived from any known or otherwise suitable source such as milk (e.g., casein, whey, milk protein isolates), animal (e.g., meat, fish), cereal (e.g., rice, com), vegetable (e.g., soy), or combinations thereof.
  • milk e.g., casein, whey, milk protein isolates
  • animal e.g., meat, fish
  • cereal e.g., rice, com
  • vegetable e.g., soy
  • the protein can include, or be entirely or partially replaced by, free amino acids which are known or otherwise suitable for use in nutritional products, non-limiting examples of which include L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-carnitine, L-cystine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-Ieucine, L-Iysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-taurine, L-threonine, L-tryptophan, L-tyrosine, L-valine, and combinations thereof.
  • free amino acids which are known or otherwise suitable for use in nutritional products, non-limiting examples of which include L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-carnitine, L-cystine, L-glutamic acid
  • the newborn infant formulas of the present invention comprise fat and carbohydrate nutrients in addition to the protein nutrients described hereinbefore, and should further comprise still other nutrients such as vitamins, minerals, and combinations thereof, of sufficient types and amounts to help meet the special nutritional needs of the newborn infant.
  • the newborn infant formulas may be used as the sole source of nutrition during the initial weeks or months of life, and can be used in combination with human milk during that same period.
  • the newborn infant formulas comprise a fat or lipid component.
  • fats suitable for use in the newborn infant formulas include coconut oil, soy oil, com oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, structured triglycerides, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils, and combinations thereof.
  • the newborn infant formulas of the present invention also comprise carbohydrates.
  • suitable carbohydrates or carbohydrate sources include hydrolyzed or intact, naturally and/or chemically modified, starches sourced from com, tapioca, rice or potato, in waxy or non-waxy forms.
  • suitable carbohydrates or carbohydrate sources include hydrolyzed cornstarch, maltodextrin (i.e.
  • the carbohydrates can comprise lactose or can be substantially free of lactose.
  • the newborn infant formulas may further comprise any of a variety of vitamins, nonlimiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K., thiamine, riboflavin, pyridoxine, vitamin B 12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • vitamins nonlimiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K., thiamine, riboflavin, pyridoxine, vitamin B 12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • the newborn infant formulas of the present invention can be prepared in any of a variety of product forms, but will most typically be in the form of a ready-to- feed liquid, a liquid concentrate for dilution prior to consumption, or a powder that is reconstituted prior to consumption.
  • the present invention is also directed to a method of providing nutrition to a newborn infant, said method comprising the administration or feeding to a newborn infant the newborn infant formula of the present invention.
  • Such methods include the daily administration of the newborn infant formulas, including administration at the daily intake volumes and relative daily macronutrient intakes, as described hereinbefore.
  • Such methods therefore include the daily administration to a newborn infant a formula having a caloric density of from about 25 to 50 kcal per 100 ml. including from about 35 to about 45 kcal per 100 ml, also including from about 37.5 kcal per 100 ml to about 42.5 kcal per 100 ml.
  • the methods of the present invention may further comprise average feeding volumes as described herein, wherein the newborn infants are provided increasing formula volumes during the initial weeks of life.
  • Such volumes most typically range up to about 100 ml/day on average during the first day or so of life; up to about 200 to about 700 ml/day, including from about 200 to about 600 ml/day, and also including from about 250 to 500 ml/day, on average during the first two weeks; and thereafter up to about 1100 ml/day, including from about 600 to about 1100 ml/day, and also including from about 800 to about 1000 ml/day, on average during the remainder of the 3 month newborn feeding period. It is understood., however, that such volumes can vary considerably depending upon the particular newborn infant and their unique nutritional needs during the initial weeks or months of life, as well as the specific nutrients and caloric density of the formulated newborn infant formula.
  • the present invention is also directed to a method of reducing the extent or occurrence of insulin resistance in an individual later in life, said method comprising the administration to an individual as a newborn infant the newborn infant formula described herein, all in accordance with the above-described method.
  • the term "later in life” refers to the phase in an individuals life beyond the newborn infant stage.
  • the present invention is also directed to a method of reducing the extent or occurrence of atherosclerosis or coronary artery disease in an individual later in life, said method comprising the administration to an individual as a newborn infant the newborn infant formula described herein, all in accordance with the above-described methods.
  • the present invention is further directed to a method of reducing the extent or occurrence of obesity in an individual in later life, said method comprising the administration to an individual as a newborn infant the newborn infant formula described herein, all in accordance with the above-described methods.
  • the corresponding method may further comprise reconstituting the powder with an aqueous vehicle, most typically water or human milk, to form the desired caloric density, which is then orally or enterally fed to the newborn infant to provide the desired nutrition.
  • an aqueous vehicle most typically water or human milk
  • each is reconstituted with a sufficient quantity of water or other suitable fluid such as human milk to produce the desired caloric density, as well as the desired feeding volume suitable for one infant feeding.
  • the newborn infant formulas of the present invention may be prepared by any known or otherwise effective technique suitable for making and formulating infant or similar other nutritional formulas. Many such methods are described in the relevant arts or are otherwise well known to those skilled in the nutrition formula art, and are easily reapplied by one of ordinary skill in the formulation arts to the newborn infant formulas of the present invention.
  • the newborn infant formulas of the present invention can be prepared by any of a variety of known or otherwise effective methods. These methods most typically involve the initial formation of an aqueous slurry containing carbohydrates, proteins, lipids, stabilizers or other formulation aids, vitamins, minerals, or combinations thereof.
  • the slurry is emulsified, pasteurized, homogenized, and cooled.
  • Various other solutions, mixtures, or other materials may be added to the resulting emulsion before, during, or after further processing.
  • This emulsion can then be further diluted, heat-treated, and packaged to form a ready-to-feed or concentrated liquid, or it can be heat-treated and subsequently processed and packaged as a reconstitutable powder, e.g., spray dried, dry mixed, agglomerated.
  • a reconstitutable powder e.g., spray dried, dry mixed, agglomerated.
  • the formulas of the present invention which provide not more than 1 gram of protein per 100 ml of formula or not more than 50 kcal per 100 ml of formula or both not more than 1 gram of protein per 100 ml of formula and not more than 50 kcal per 100 ml of formula may be prepared by conventional manufacturing methods, using conventional fat (e.g., blend of high oleic sunflower, coconut and soy oil), carbohydrate (e.g., blend of lactose, maltodextrin, and com syrup), protein (e.g., milk protein isolate or soy protein isolate), minerals, vitamins, and other common ingredients, to achieve the targeted nutrition profile.
  • conventional fat e.g., blend of high oleic sunflower, coconut and soy oil
  • carbohydrate e.g., blend of lactose, maltodextrin, and com syrup
  • protein e.g., milk protein isolate or soy protein isolate
  • minerals e.g., vitamins, and other common ingredients
  • the above described formulas may then fed to newborn infants, or otherwise diluted or reconstituted prior to such feeding, in accordance with the methods of the present invention, wherein such feeding is administered by a conventional infant formula bottle at a daily average volume of from about 150 ml/day to about 900 ml/day on average during the first two weeks of life, and from 300 to about 1200 ml/day on average during the remaining first 3 months of life.
  • Subjects were part of a cohort of 926 who were born preterm and participated in studies that investigated the effects of early diet on later cognitive function and cardiovascular disease. Between 1982 and 1985, babies free from major congenital anomalies and below 185Og in birthweight were recruited in 5 centres (Norwich, Cambridge, Sheffield, Ipswich and King's Lynn). A reference group of subjects of the same age, but born at term and with birthweight above the 10 th centile, was also recruited from schools in the same communities as those born preterm.
  • preterm formula was enriched in protein and fat (2.Og protein and 4.9g fat per 100 ml preterm formula compared to 1.5g protein and 3.8g fat per 100 ml of term formula) but not carbohydrate (7.0g/100ml) in both formulas.
  • Preterm formula was also enriched in vitamins, zinc and copper.
  • protein and energy intakes were estimated from 600 donor milk pools collected from multiple donors (approximately 5g protein, 2g fat and 7g carbohydrate per 100 ml).
  • Mother's own expressed milk composition was measured in 4935 complete 24-hour collections (approximately 5g protein, 3g fat, and 7g carbohydrate).
  • brachial artery Flow-Mediated endothelial dependent Dilation (FMD), an indicator of endothelial dysfunction relevant to the atherosclerotic process in a population subject to avoidance of neonatal over-nutrition and in healthy controls. This was determined by researchers who were unaware of the subject's gestational age. Subjects were rested supine for 10 minutes prior to the ultrasound scan, which was conducted by a single observer in a temperature controlled (22-24°C), darkened room, between 0900-1300. The brachial artery was imaged in longitudinal section, 5-10 cm above the elbow, using a 7 MHz linear array transducer and an Acuson 128XP/10 system.
  • FMD Flow-Mediated endothelial dependent Dilation
  • the transducer was then fixed using a stereotactic clamp and fine position adjustments made when necessary using micrometer screws.
  • a pneumatic cuff was inflated around the forearm to 300 mm Hg for 5 minutes followed by rapid deflation causing a large increase in blood flow (reactive hyperaemia).
  • the resting and posthyperaemic blood flow velocities in the centre of the imaged artery were determined using pulsed Doppler.
  • End diastolic B-mode images were randomized and stored offline sequentially every 3 seconds throughout the scan procedure for arterial diameter measurements immediately after the scan procedure (for 1 minute resting, 5 minutes cuff inflation and 3 minutes post cuff deflation). Blood pressure was monitored using an automated oscillometric device (Accutorr, Datascope Corp.
  • FMD was expressed as the absolute maximal change between pre-and posthyperaemic brachial artery diameter adjusted for prehyperaemic diameter (using regression analysis) and as the absolute change in diameter expressed as a percentage of pre-hyperaemic diameter (FMD%).
  • Plasma concentrations of LDL cholesterol were determined using standard laboratory methods.
  • Neonatal weight gain was expressed as the absolute value and as the standard deviation score from expected weight (z score) using centiles for infants born preterm. Growth beyond the neonatal period was calculated as the change in z score for weight between discharge and age 18 months, 18 months and 9-12 years, and 9-12 and 13-16 years. All regression analyses were adjusted for potential confounding factors (age, sex, neonatal morbidity - number of days in > 30% oxygen and the number of days of ventilation and social class, and for height, weight, serum LDL cholesterol concentration at follow-up, and room temperature).
  • FMD was significantly related to birthweight z score and this association remained significant after adjustment for potential confounding factors (age, sex, height, weight, fasting LDL concentrations, room temperature, social class and neonatal morbidity expressed as the number of days of ventilation or days in > 30% oxygen) (Table 2).
  • Adolescents with the greatest weight gain during this period had 4.0% lower FMD than those with the lowest weight gain; a substantial effect on FMD, similar to that of insulin dependent diabetes (4%) and smoking (6%) in adults.
  • Example 2 The effect of avoidance of over-nutrition on Insulin Resistance.
  • Example 1 The subjects were the same as in Example 1 and subjected to the same regime and trials and 32-33 split insulin concentrations (as a measure of insulin resistance was measured).
  • Sample size was estimated to exclude half a standard deviation in outcomes between randomized dietary groups in each of the trials and we required a maximum subsample of around 250 subjects from our original cohort to detect this difference (with two parallel trials) at 80% power and 5% significance; and a minimum sample of around 200 subjects for 70% power and 5% significance.
  • this sample was sufficient to detect a 0.4 SD difference in fasting 32-33 split proinsulin concentration between randomized groups with 80% power and at 5% significance.
  • Ethical approval for the follow-up study was obtained from national and local research ethics committees and written consent was obtained from all children, parents and their guardians.
  • Intact proinsulin and 32-33 split proinsulin concentrations were assayed using a time resolved fluorometric assay (Delfia).
  • the labeled antibody used in the 32-33 split proinsulin assay was donated by Dako Diagnostics Ltd.
  • Intact proinsulin was supplied by the National Institute for Biological Standards and Controls (1st International Reagent 84/611), and purified 32-33 split proinsulin donated by Lilly Research Labs.
  • the antibodies were labeled with Europium using the Delf ⁇ a Europium labeling kit 1244-302 (Wallac, UK Ltd).
  • the intact proinsulin assay typically shows less than 1% cross-reactivity with insulin and 32-33 split proinsulin at 2500 pmol/L and 400 pmol/L respectively.
  • the 3233 split proinsulin assay shows less than 1% cross-reactivity with insulin at 2500 pmol/L.
  • Neonatal weight gain was expressed as the absolute value and as the standard deviation score from expected weight (z score) using centiles for infants born preterm. Growth beyond the neonatal period was calculated as the change in z score for weight between discharge and age 18 months, 18 months and 9-12 years, and 9-12 and 13- 16 years.
  • Current body mass index (BMI) was expressed as the standard deviation score from expected BMI (z score) using national reference centiles. The distributions of 32-33 split proinsulin, proinsulin, and insulin concentrations were log transformed and then multiplied by 100.
  • log standard deviation multiplied by 100 represented the coefficient of variation and the coefficient in regression analyses represented the mean percentage change in insulin concentration per unit change in independent variable.
  • regression analyses were adjusted for potential confounding factors (sex, age, and BMI z score at current follow-up and neonatal morbidity-number of days in > 30% oxygen and the number of days of ventilation-and social class at birth). Statistical significance was taken asp ⁇ 0.05 for all significance tests, which were two tailed. Results
  • the present study used a formula modified to more closely resemble the energy density of breast-milk in the first postnatal week.
  • the modified formula There were two versions of the modified formula - one for postnatal days 1 and 2 (with 22 kcal/100 ml of energy and 0.7g/100 ml protein) and the other for postnatal days 3-7 (44 kcal/100 ml of energy with 1.4 g/100 ml of protein).
  • the nutritional composition of the study formula in comparison to early breast-milk and standard term formula is given in Table 6 along with the European Union guidelines for composition of infant formula (for both the upper and lower limits according to energy density). After 7 days all formula-fed infants were given a standard formula (i.e. Similac Advance).
  • Inclusion criteria were birth weight greater than the 10 th centile for weight for gestational age and sex; gestation > 37 weeks and living within a defined geographical boundary (to enhance efficiency of follow-up). Exclusion criteria included multiple births, major congenital disease, illness or social problems in mother or baby, temporary residents or those likely to leave the area. The study was approved by National and Local Research Ethical Committees.
  • Table 6b has the composition of the study formula in comparison with the European Union guidelines for composition of infant formula (for both the upper and lower limits according to energy density).
  • Formula was delivered in ready to feed bottles and mothers were advised to feed the infants ad libitum. After 7 days all formula-fed infants were given a standard formula (Similac Advance) until 28 days of age. Infants of mothers who decided to breast-feed and met the inclusion criteria were recruited into the breast-feeding arm of the study. Once randomized, all infants were followed to the study endpoint of 28 days irrespective of whether they continued with or changed their original feeding choice (thereby allowing an intention to treat analysis). Sample size for this pilot study was 25 infants in each of three dietary groups (25 breastfed, 25 fed low nutrient formula, 25 given standard formula). Measurements
  • a random urine sample for ketone analysis was collected daily for the first 3 days. Blood was also obtained by a heel prick to measure pre-feed blood glucose concentration on two occasions during the first three days.
  • a stool sample was also collected at 1, 3 and 7 days of age, and kept for biochemical analysis (e.g., of fat content) and microbiological analysis (e.g., of stool flora). Some infants also had a blood sample at 1 week of age. Two questionnaires (at age 2 and 5 days) were used to assess the tolerance and feeding behaviors in formula fed infants.
  • Anthropometric variables at birth were compared to the general population by calculating z scores based on UK reference data.
  • the distributions of skinfolds were not normal and so were loge transformed and then multiplied by 100 prior to statistical analyses. Therefore standard deviation for 100 loge transformed data represents the coefficient of variation, while regression coefficients represent the percentage difference in fat mass indices per unit change in independent variable (42).
  • Comparisons between (randomized) groups were made with Student's t-test for continuous variables and Chi-squared for categorical variables. Initial analyses were on an intention to treat basis. Multiple regression analysis was then used to assess differences between randomized groups after adjustment for birth weight z score and sex (factors known to affect post-natal weight gain).
  • breast-fed infants were compared with the two formula-fed groups using one-way analysis of variance and Bonferroni corrections.
  • Statistical analyses were conducted using SPSS for windows (version 15.0; SPSS Inc, Chicago).
  • Randomized formula fed groups did not differ in the main safety outcome (risk of hypoglycemia) as assessed by the presence of ketones in the urine or the blood glucose concentration. In fact the minimum value for blood glucose recorded in formula- fed infants was 2.1 mmol/L.

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  • Pediatric Medicine (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé pour réduire le degré ou l'occurrence d'effets médicaux indésirables à long terme chez des nourrissons humains, comprenant l'alimentation desdits nourrissons nouveaux-nés avec une formule contenant des nutriments n'apportant pas plus de 1 gramme de protéine pour 100 ml de formule et/ou pas plus de 50 kcal pour 100 ml de formule. La présente invention concerne en outre des procédés d'administration des formules pour nourrisson pour réduire l'occurrence ou le degré d'insulinorésistance chez un individu plus tard dans la vie, afin de réduire l'occurrence ou le degré d'obésité ou d'athérosclérose chez un individu plus tard dans la vie, ou des combinaisons de ceux-ci, en alimentant des nourrissons nouveaux-nés avec la formule pour nourrisson nouveau-né présentement décrite.
PCT/IB2009/055832 2008-12-18 2009-12-17 Formule pour nourrisson et système Ceased WO2010070613A2 (fr)

Applications Claiming Priority (4)

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US31486908A 2008-12-18 2008-12-18
US12/314,869 2008-12-18
US12/318,678 US8815279B2 (en) 2003-02-10 2009-01-06 Baby feeding formula and system
US12/318,678 2009-01-06

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WO2010070613A2 true WO2010070613A2 (fr) 2010-06-24
WO2010070613A9 WO2010070613A9 (fr) 2010-09-30
WO2010070613A3 WO2010070613A3 (fr) 2010-12-23

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WO2012078039A1 (fr) * 2010-12-06 2012-06-14 N.V. Nutricia Préparation fermentée pour nourrisson
EP2514435A1 (fr) * 2011-04-19 2012-10-24 Nestec S.A. Formule infantile à utiliser pour la prévention des maladies cardiovasculaires
EP2520181A1 (fr) * 2011-05-02 2012-11-07 N.V. Nutricia Formulation fermentée pour nourrissons
US9617327B2 (en) 2012-06-14 2017-04-11 N.V. Nutricia Fermented infant formula with non digestible oligosaccharides
WO2017064309A1 (fr) 2015-10-15 2017-04-20 N.V. Nutricia Préparation pour nourrissons avec de la matière grasse du lait pour favoriser une croissance saine
WO2017064304A1 (fr) 2015-10-15 2017-04-20 N.V. Nutricia Préparation pour nourrissons à architecture lipidique spéciale permettant de favoriser une croissance saine
RU2627183C2 (ru) * 2011-11-11 2017-08-03 Валио Лтд Способ получения молочного продукта
WO2017194615A1 (fr) 2016-05-10 2017-11-16 N.V. Nutricia Préparation fermentée pour nourrissons
WO2017194607A1 (fr) 2016-05-10 2017-11-16 N.V. Nutricia Préparation fermentée pour nourrissons
WO2018178302A1 (fr) 2017-03-29 2018-10-04 N.V. Nutricia Formule pour nourrisson pour comportement alimentaire amélioré
WO2018178310A1 (fr) 2017-03-29 2018-10-04 N.V. Nutricia Préparation destinée aux nourrissons pour un comportement alimentaire amélioré
US10124016B2 (en) 2008-06-13 2018-11-13 N.V. Nutricia Immune system stimulating nutrition
US10548869B2 (en) 2010-03-17 2020-02-04 N.V. Nutricia Infant nutrition for improving fatty acid composition of brain membranes
US11376222B2 (en) 2013-11-01 2022-07-05 N.V. Nutricia Lipid composition for improving body composition during catch-up growth
US11632974B2 (en) 2016-12-09 2023-04-25 N.V. Nutricia Nutritional composition for improving cell membranes
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US10548869B2 (en) 2010-03-17 2020-02-04 N.V. Nutricia Infant nutrition for improving fatty acid composition of brain membranes
EP2910132A1 (fr) * 2010-12-06 2015-08-26 N.V. Nutricia Formulation fermentée pour nourrissons
WO2012078039A1 (fr) * 2010-12-06 2012-06-14 N.V. Nutricia Préparation fermentée pour nourrisson
CN103327835A (zh) * 2010-12-06 2013-09-25 N·V·努特里奇亚 发酵的婴儿配方物
RU2598707C2 (ru) * 2011-04-19 2016-09-27 Нестек С.А. Детская смесь для применения в профилактике сердечно-сосудистых заболеваний
EP2514435A1 (fr) * 2011-04-19 2012-10-24 Nestec S.A. Formule infantile à utiliser pour la prévention des maladies cardiovasculaires
WO2012143362A1 (fr) 2011-04-19 2012-10-26 Nestec S.A. Préparation pour nourrissons destinée à être utilisée dans la prévention de maladies cardio-vasculaires
EP2520181A1 (fr) * 2011-05-02 2012-11-07 N.V. Nutricia Formulation fermentée pour nourrissons
RU2627183C2 (ru) * 2011-11-11 2017-08-03 Валио Лтд Способ получения молочного продукта
US9717270B2 (en) 2012-06-14 2017-08-01 N.V. Nutricia Fermented infant formula with non digestible oligosaccharides
US9617327B2 (en) 2012-06-14 2017-04-11 N.V. Nutricia Fermented infant formula with non digestible oligosaccharides
US11376222B2 (en) 2013-11-01 2022-07-05 N.V. Nutricia Lipid composition for improving body composition during catch-up growth
US12150466B2 (en) 2013-11-04 2024-11-26 Nutricia N.V. Fermented formula with non digestible oligosaccharides
EP3574771A1 (fr) 2015-10-15 2019-12-04 N.V. Nutricia Préparation pour nourrissons avec architecture de lipides spéciale pour favoriser une croissance saine
WO2017064309A1 (fr) 2015-10-15 2017-04-20 N.V. Nutricia Préparation pour nourrissons avec de la matière grasse du lait pour favoriser une croissance saine
WO2017064304A1 (fr) 2015-10-15 2017-04-20 N.V. Nutricia Préparation pour nourrissons à architecture lipidique spéciale permettant de favoriser une croissance saine
US11389403B2 (en) 2015-10-15 2022-07-19 N.V. Nutricia Infant formula with special lipid architecture for promoting healthy growth
EP4190174A1 (fr) 2015-10-15 2023-06-07 N.V. Nutricia Préparation pour nourrissons dotée d'une architecture lipidique spéciale pour favoriser une croissance saine
EP3841892A1 (fr) 2016-05-10 2021-06-30 N.V. Nutricia Formulation fermentée pour nourrissons
WO2017194607A1 (fr) 2016-05-10 2017-11-16 N.V. Nutricia Préparation fermentée pour nourrissons
WO2017194615A1 (fr) 2016-05-10 2017-11-16 N.V. Nutricia Préparation fermentée pour nourrissons
US11632974B2 (en) 2016-12-09 2023-04-25 N.V. Nutricia Nutritional composition for improving cell membranes
WO2018178310A1 (fr) 2017-03-29 2018-10-04 N.V. Nutricia Préparation destinée aux nourrissons pour un comportement alimentaire amélioré
WO2018178302A1 (fr) 2017-03-29 2018-10-04 N.V. Nutricia Formule pour nourrisson pour comportement alimentaire amélioré

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