RU2822197C1 - Infant formula with special fat structure for improving postnatal growth of infants born to overweight and obese mothers - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to infant formulas for babies born to mothers with overweight or obesity at the moment of conception of an infant. Method for non-therapeutic improvement of dynamics of postnatal growth or body development in an infant born of an overweight mother or obesity at the moment of conception of an infant, provides for the introduction of a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat. Fat contains linoleic acid and alpha-linolenic acid in a weight ratio of 2 to 20, at least, 10 wt. % of palmitic acid in terms of total amount of fat, and at least 15 wt. % of this palmitic acid is esterified in sn-2 position of triglyceride in terms of total amount of palmitic acid. Nutrient composition contains fat globules, which have modal diameter in terms of volume of at least 1.0 mcm and/or diameter from 2 to 12 mcm in amount of at least 45 vol. % in terms of total content fat. Said fat globules are at least partially coated on the surface with phospholipids. Amount of phospholipids present in the nutritional composition ranges from 0.5 to 20 wt. % phospholipids in terms of total fat content.

EFFECT: invention makes it possible to improve dynamics of postnatal growth or development of body of infants.

26 cl, 6 tbl, 1 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The invention relates to the nutrition of infants, in particular to infant formulas intended for use as a source of nutrition.

BACKGROUND OF THE ART

Breast milk is the undisputed gold standard for baby nutrition. However, in some cases, breastfeeding is inappropriate or ineffective due to medical reasons or due to refusal of breastfeeding. For such situations, infant formulas or level 2 infant formulas have been developed. Commercially available infant formulas today are often used to provide an additional or sole source of nutrition during early childhood. These formulas contain a range of nutrients to meet the nutritional needs of the growing infant and typically include fats, carbohydrates, proteins, vitamins, minerals and other nutrients beneficial for the optimal growth and development of the infant. Commercially available infant formulas are designed to closely mimic the composition and function of human milk.

It has long been recognized that breastfed infants have a different pattern or pattern of weight gain compared to formula-fed infants. After the first week of life, when breastfed infants initially tend to lose more weight than formula-fed infants and take slightly longer to regain their birth weight, infant weight gain charts breastfed and bottle-fed are the same during the first 4 months of life. Breastfed infants typically have a slightly higher weight at 3 months of age (Andres et al. 2013, J Pediatrics 163:49–54). After approximately 4 months of age, the rate of weight gain differs markedly between breastfed and formula-fed infants. The difference in average weight at 12 months is approximately 500-650 g (Dewey et al. 1993, Am J Clin Nutr 57:140-145; Dewey et al. 1992 Pediatrics 89:1035). In Li et al. 2010, Pediatrics 125:e1386-e1393 reveals that infants who are bottle-fed in early infancy are more likely to empty the bottle or cup in late infancy than those who are directly breastfed. Bottle feeding, regardless of milk type, differs from breastfeeding in its impact on infants' self-regulation of milk intake. Breastfed infants are less likely to become obese later in life compared to conventional formula-fed infants.

Obesity is a major health problem in the Western world. It is a disease in which excess fat accumulates to such an extent that it can have adverse health effects, leading to a shortened lifespan, and is associated with many diseases, particularly cardiovascular disease and type 2 diabetes. A higher pre-pregnancy body mass index (BMI) is associated with an increased risk of developing gestational diabetes mellitus, which in turn is associated with a higher risk of perinatal morbidity, as well as childhood obesity, psychomotor retardation and early onset of type 2 diabetes mellitus in the offspring (Torloni M et al. 2009, Obesity reviews 10:194-203).

Children born to overweight and obese women are themselves more likely to be overweight and obese and themselves have an increased risk of developing cardiometabolic diseases. Compared with children of normal-weight mothers before pregnancy, children of overweight mothers increase in weight and BMI more rapidly during the first year of life (Oostvogels A et al. 2017, Early human development 113:62-70). This effect also occurs later in life: higher prepregnancy BMI is associated with higher BMI in offspring of such mothers in adolescence and an unfavorable cardiometabolic profile in adolescents (Gaillard R et al. 2016, BJOG 123:207–216). Thus, infants born to overweight or obese mothers are at risk for unbalanced postnatal growth dynamics.

It is known that human milk fats have a distinct physical structure consisting of large fat globules with an average modal diameter of about 4 μm, having a triglyceride core covered by a three-layer membrane called the milk fat globule membrane (MFGM). The diameter of the fat droplets in standard infant formula is typically around 0.3-0.5 µm due to industrial processing procedures to produce stable and reproducible end products, and the fat droplets are not surrounded by MFM but predominantly by proteins such as casein. An infant formula has been described with fat globules whose structure is more similar to that of human milk.

International application WO 2017/064304 describes a comparison of the growth dynamics of infants receiving infant formula containing large fat globules coated with phospholipids with the growth dynamics of breastfed control infants, looking at weight and body mass index ( BMI) at 12 months of age. International application WO 2015/065193 discloses nutritional compositions containing specially formulated fat globules for premature infants, small for gestational age infants and infants with growth retardation due to physical or mental stress after birth, to promote catch-up growth and /or improving body composition. International application WO 2012/173467 discloses the use of a specially formulated fat component with an optimal fatty acid profile, an increased proportion of palmitic acid residues at the sn-2 position and present as fat globules with a defined size and/or coating in early life diets to improve development of healthy body composition, in particular the prevention of obesity in later life. International applications WO 2010/0027258 and WO 2010/0027259 relate to infant formulas with large fat globules coated with phospholipids for the purpose of preventing obesity in later life.

The present invention is aimed at providing infant nutrition with a fat component that has a beneficial effect on the dynamics of postnatal growth or the development of BMI in an infant born to an overweight or obese mother.

SUMMARY OF THE INVENTION

We compared BMI during the first 12 months of life of 3 groups of healthy full-term infants born to mothers classified on the basis of their pre-pregnancy BMI as underweight, normal weight, overweight, or obese. One group was a non-randomized control group of breastfed infants, one group received an experimental infant formula containing a fat component in the form of large fat globules coated with phospholipids, and one group received a control infant formula without a fat component in the form of large fat globules coated with phospholipids, but in the form of standard fat globules with a modal diameter, in terms of volume, of about 0.3-0.5 microns, coated with protein. Both infant formulas were administered before 17 weeks of age. The control and experimental infant formulas were similar in caloric content, as well as in the content of fats, carbohydrates and proteins.

The inventors found that when analyzing BMI for the entire study period up to 12 months of age in both the intent-to-treat (ITT) and per-protocol (PP) populations, the BMI of the group of infants receiving the experimental infant formula was statistically significant. lower than the BMI of the control formula-fed group of infants for both the groups of infants born to mothers who were normal weight before pregnancy and those born to mothers who were overweight or obese before pregnancy. The BMI of infants fed the experimental formula was more comparable to the BMI of breastfed infants, and this effect was particularly strong in infants born to mothers who were overweight or obese before pregnancy. In the last group of infants, the dynamics of BMI became comparable to the dynamics of BMI of breastfed infants born to mothers with normal weight before pregnancy. On the other hand, the control formula group had a higher BMI at 4 and 12 months compared to the breastfed group. Additionally, the control formula group had a higher BMI compared to the experimental formula group at 12 months of age.

We unexpectedly found that from baseline to 4 months of age, infants born to overweight or obese mothers who were fed the experimental formula had a statistically significantly lower increase in BMI than infants born to overweight mothers. or obese who were fed control infant formula. The effect of the experimental diet on increase in BMI was found to be greater and earlier apparent, particularly at 4 months of age, in infants born to overweight and obese mothers than in infants born to mothers of normal pre-pregnancy weight. .

Overall, this indicates that feeding an infant formula with similar caloric and macronutrient contents, but a different fat globule structure, may have a specific and beneficial effect on the early growth chart or growth pattern, making it preferentially more similar to the early growth pattern or pattern of breastfed infants born to mothers who were of normal weight before pregnancy. Infants receiving the experimental infant formula exhibited BMI patterns and postnatal growth patterns that were more comparable to breastfed infants compared with infants receiving the control infant formula; the effect was unexpectedly greater in infants born from overweight or obese mothers to pregnancy. It is believed that this is due to the difference in the structure of the fat component of the composition, namely that it is more reminiscent of human milk fat globules due to the fact that they are larger in size and covered with phospholipids.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of improving the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of conception (pre-pregnancy) of the infant, said method comprising feeding said infant a nutritional composition selected from an infant formula infants or second level infant formula containing carbohydrates, protein and fat,

i) where the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

In other words, the present invention relates to a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content,

for the purpose of use to improve the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of conception of the infant.

The invention may also be formulated as the use of fat globules to obtain a nutritional composition selected from infant formula or infant formula for the purpose of use for improving the dynamics of postnatal growth or body development in an infant born from the mother overweight or obese at the time of conception of the infant, where the nutritional composition contains carbohydrates, protein and fat, where,

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content; and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

Improving postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of the infant's conception may be considered to include a non-therapeutic effect. In this regard, the present invention can also be considered as relating to a method of non-therapeutically, or in a non-therapeutic manner, improving the dynamics of postnatal growth or body development in an infant born from a mother overweight or obese at the time of conception of the infant, by administering a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

The present invention relates to a method of preventing or reducing the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, said infant is born to a mother who is overweight or obese at the time the infant is conceived, said method includes feeding said infant a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat,

i) where the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

The invention also relates to a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20% by weight of phospholipids, based on the total fat content,

for use in preventing or reducing the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, said infant is born to a mother who is overweight or obese at the time the infant is conceived.

The invention may also be formulated as the use of fat globules to provide a nutritional composition selected from an infant formula or a second-stage infant formula to prevent or reduce the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, said infant is born from a mother who is overweight or obese at the time of conception of the infant, wherein the nutritional composition contains carbohydrates, protein and fat, wherein,

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, and wherein the nutritional composition contains fat globules that have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

In a preferred embodiment of the method, application or composition for use according to the invention, the growth or development of the body is the growth or development of the body in the first 12 months of life of the infant.

In the context of the present invention, the infant formula or second level infant formula is not natural cow's milk or human milk.

In the context of the present invention, the mother is overweight or obese at the time of conception of the infant, based on the mother's pre-pregnancy BMI. In one embodiment, pre-pregnancy BMI is defined as BMI measured at a time period at least six months before conception.

As used herein, the following terms have the meanings defined below (Chiu M et al. Diabetes Care, 2011, 34:1741-1748):

BMI is defined as body weight divided by the square of body height and is expressed in units of kg/ ^m2 . In general, a person's BMI is categorized as underweight, normal weight, overweight, or obese, depending on the calculated BMI value.

Underweight is defined as a BMI˂18.5 kg/ ^m2 for all women.

Normal weight for Asian women is considered to be BMI≥18.5 and ˂23 kg/ ^m2 ; for non-Asian women, normal weight is BMI≥18.5 and <25 kg/ ^m2 .

For Asian women, a BMI of ≥23 and ˂27.5 kg/m ² is considered overweight; for non-Asian women, a BMI of ≥25 and ˂30 kg/m ² is considered overweight.

Obesity for Asian women is considered to be a BMI ≥27.5 kg/m ² , and for non-Asian women, obesity is considered to be a BMI ≥30 kg/m ² .

Fat globules

According to the present invention, the nutritional composition contains fat globules. In liquid form, these fat globules are emulsified in the aqueous phase. Alternatively, the fat globules are present in powder form, and the powder is suitable for reconstitution with water or other food grade aqueous phase, preferably to form a ready-to-feed infant formula. Fat globules consist of a core and a coating. The core preferably contains vegetable fat and preferably contains at least 90 wt.% triglycerides and more preferably consists essentially of triglycerides. Not all vegetable fats present in the composition must necessarily be in the core fat globules, but preferably the main part, preferably more than 50 wt.%, more preferably more than 70 wt.%, even more preferably more than 85 wt.%, even more preferably more than 95 wt.%, most preferably more than 98 wt.%, vegetable fats present in the composition are contained in the core of fat globules. In one embodiment, the fat globule core contains at least 40 wt.% plant triglycerides, more preferably at least 50 wt.%, even more preferably at least 70 wt.% plant triglycerides, more preferably the fat globule core contains at least 85 wt.%, more preferably at least 95 wt.% plant-derived triglycerides. The fat globules in the nutritional composition in the method or use of the present invention have a volume-weighted diameter of greater than 1.0 μm, preferably greater than 3.0 μm, more preferably 4.0 μm or greater, preferably 1.0 to 10 μm, more preferably from 2.0 µm to 8.0 µm, even more preferably from 3.0 to 8.0 µm, most preferably from 4.0 µm to 8.0 µm. Moreover, preferably the size distribution is such that at least 45 volume %, preferably at least 55 volume %, even more preferably at least 65 volume %, even more preferably at least 75% by volume have a diameter between 2 and 12 µm. More preferably at least 45 volume %, preferably at least 55 volume %, even more preferably at least 65 volume %, even more preferably at least 75 volume % have a diameter of from 2 to 10 µm. Even more preferably, at least 45 volume %, preferably at least 55 volume %, even more preferably at least 65 volume %, even more preferably at least 75 volume % have a diameter of 4 to 10 microns. Preferably less than 5 volume % have a diameter greater than 12 µm.

The percentage of fat globules is based on the volume of total fat. Mode diameter refers to the diameter that is most present in terms of volume of total fat, or the peak value in a graphical representation having the X-axis as diameter and the Y-axis as volume (%).

Fat globule volume and its size distribution can be determined using a particle size analyzer such as a Mastersizer (Malvern Instruments, Malvern, UK), for example, by the method described in Michalski et al., 2001, Lait 81:787-796.

Phospholipids

The nutritional composition for administration in the method or use of the present invention contains phospholipids, preferably the nutritional composition contains phospholipids derived from the milk of mammals, preferably from the milk of non-human mammals. Phospholipids derived from the milk of non-human mammals include phospholipids isolated from milk fat, cream fat, whey fat, whey fat, beta whey fat, whey fat, cheese fat, and/or buttermilk fat. Buttermilk fat is usually obtained during the production of buttermilk. Whey fat or beta whey fat is usually obtained by producing anhydrous milk fat from cream or butter. Preferably, the phospholipids are obtained from dairy cream. The phospholipids are preferably obtained from the milk of cows, mares, sheep, goats, buffalos, horses and camels, most preferably from cow's milk. It is most preferable to use a fat extract isolated from cow's milk. A suitable source of phospholipids derived from the milk of non-human mammals is a fraction that can be isolated from milk called milk fat globule membrane (MFGM). Therefore, in one embodiment, the phospholipids used in the nutritional composition in the method or use of the present invention are derived from or form part of the milk fat globule membrane (MFGM), or are provided as MFGM, preferably cow's milk MFGM.

The nutritional composition contains from 0.5 to 20 wt.% phospholipids based on total fat, more preferably from 0.5 to 10 wt.%, more preferably from 1 to 10 wt.%, even more preferably from 2 to 10 wt. .%, even more preferably from 3 to 8 wt.% phospholipids, based on the total amount of fat.

The fat globules present in the nutritional composition for use according to the present invention are at least partially coated on the surface with phospholipids. By "coating" it is meant that the outer surface layer of the fat globule contains phospholipids while these phospholipids are essentially absent in the core of the fat globule. The presence of phospholipids as a coating or outer layer of fat globule in the administered diet has been found to be effective in stimulating growth dynamics or body development that is more similar to the growth dynamics of human milk-fed infants, the effect being particularly evident in infants born to mothers overweight or obese at the time of conception. Not all phospholipids present in the composition need to be contained in the coating, but preferably constitute a major portion. Preferably more than 30 wt%, more preferably more than 50 wt%, more preferably more than 70 wt%, even more preferably more than 85 wt%, most preferably more than 95 wt% of the phospholipids that are present in the composition are contained in the fat coating globule Preferably, the phospholipids include at least 15 wt.% sphingomyelin, based on the total amount of phospholipids.

According to the present invention, the nutritional composition preferably contains glycerophospholipids. Glycerophospholipids are a class of lipids formed from fatty acids esterified at hydroxyl groups on carbon 1 and carbon 2 of the glycerol moiety, and a negatively charged phosphate group attached to carbon 3 of glycerol via an ester bond, and optionally a choline group (in in the case of phosphatidylcholine, PC), a serine group (in the case of phosphatidylserine, PS), an ethanolamine group (in the case of phosphatidylethanolamine, PE), an inositol group (in the case of phosphatidylinositol, PI) or a glycerol group (in the case of phosphatidylglycerol, PG) attached to the phosphate group . Lysophospholipids are a class of phospholipids with a single fatty acid acyl chain. Preferably, the present composition contains PC, PS, PI and/or PE, more preferably at least PC.

Preferably the nutritional composition contains sphingomyelin. Sphingomyelins have a phosphorylcholine or phosphorylethanolamine molecule, an esterified hydroxyl group at C-1 of ceramide. They are classified as phospholipids as well as sphingolipids, but are not classified as glycerophospholipids or glycosphingolipids. Preferably, the nutritional composition contains from 0.05 to 10% by weight of sphingomyelin based on total fat, more preferably from 0.1 to 5% by weight, even more preferably from 0.2 to 2% by weight.

According to the present invention, the nutritional composition preferably contains cholesterol. The nutritional composition preferably contains at least 0.005 wt% cholesterol based on total fat, more preferably at least 0.01 wt%, more preferably at least 0.02 wt%, more preferably at least 0.05 wt.%, even more preferably at least 0.1 wt.%. Preferably, the amount of cholesterol does not exceed 10% by weight of the total fat, more preferably does not exceed 5% by weight, even more preferably does not exceed 1% by weight of the total fat.

Methods for producing fat globules with increased size and coating with phospholipids are disclosed in international applications WO 2010/0027258, WO 2010/0027259 and WO 2013/135738.

Infant formula or second level infant formula

The nutritional composition to be administered in the method or use of the present invention is selected from infant formula or second level infant formula. This means that the present nutritional composition is not human milk. Alternatively, the term "infant formula" means that it refers to a composition that is prepared artificially, or in other words, that is synthetic. Therefore, in one embodiment, the nutritional composition is selected from an artificial infant formula and a second level artificial infant formula or a synthetic infant formula and a second level synthetic infant formula. As used herein, infant formula refers to artificially prepared nutritional compositions intended for infants from 0 to about 4-6 months of age and intended as a substitute for human milk. Generally, infant formula is suitable for use as the sole source of nutrition. These infant formulas are also known as level 1 infant formulas. Infant formula for infants, from 4-6 months of life to 12 months of life, is intended for additional feeding of infants who are beginning to be introduced to other foods. These infant formulas are also known as level 2 infant formulas. Infant formulas and second level infant formulas are subject to strict regulations, such as EU Commission Directive 2006/141/EC.

The nutritional composition preferably contains 3 to 7 g fat/100 kcal, preferably 4 to 6 g fat/100 kcal, more preferably 4.5 to 5.5 g fat/100 kcal, 1.25 to 5 g protein/ 100 kcal, preferably 1.35 to 4 g protein/100 kcal, more preferably 1.5 to 3 g protein/100 kcal, more preferably 1.25 to 2.5 g protein/100 kcal, more preferably 1 .25 to 2.25 g/100 kcal, even more preferably 1.25 to 2.1 g protein/100 kcal and 6 to 18 g digestible carbohydrates/100 kcal, preferably 8 to 16 g digestible carbohydrates/100 kcal , more preferably 10 to 15 g digestible carbohydrates/100 kcal. The nutritional composition for administration in the method or use of the present invention contains carbohydrates, protein and fats, where fats preferably provide from 30% to 60% of total calories, protein provides from 5% to 20% of total calories, and carbohydrates provide from 25% to 75% of total calories. Preferably, the nutritional composition contains from 10 to 50% by weight fat, based on the dry weight of the entire composition.

Fat

Here LA refers to linoleic acid and/or acyl chain (18:2 n6); ALA refers to α-linolenic acid and/or acyl chain (18:3 n3); PUFA refers to polyunsaturated fatty acids and/or acyl chains; MUFA refers to monounsaturated fatty acids and/or acyl chains; LC-PUFA refers to long-chain polyunsaturated fatty acids and/or acyl chains containing at least 20 carbon atoms in the fatty acid acyl chain and with 2 or more unsaturated bonds; DHA refers to docosahexaenoic acid and/or acyl chain (22:6 n3); EPA refers to eicosapentaenoic acid and/or acyl chain (20:5 n3); ARA refers to arachidonic acid and/or acyl chain (20:4 n6); DPA refers to docosapentaenoic acid and/or acyl chain (22:5 n3). PC refers to palmitic acid and/or acyl chains (C16:0). Medium chain fatty acids (MCFAs) refer to fatty acids and/or acyl chains with a chain length of 6, 8 or 10 carbon atoms.

The fat in the nutritional composition for administration in the method or use of the present invention preferably includes vegetable fats. The fat present in the nutritional composition in the method or use of the invention preferably contains PUFAs, more preferably LC-PUFAs, since LC-PUFAs further improve the growth pattern and development of BMI. The nutritional composition preferably contains from 5 to 35 wt.% PUFA, more preferably from 10 to 30 wt.% PUFA, most preferably from 15 to 20 wt.% PUFA, based on total fat. In one embodiment, the fat in the nutritional composition for the method or use of the invention contains at least 10% by weight polyunsaturated fatty acids, based on total fat. Also preferably, the nutritional composition contains MUFA, preferably 10 to 80 wt% MUFA, more preferably 20 to 70 wt% MUFA, most preferably 35 to 55 wt% MUFA, based on total fat.

LA is preferably present in an amount sufficient to promote healthy growth and development, but in as small an amount as possible to prevent the occurrence of imbalances in the growth or development of the body. Thus, the nutritional composition preferably contains less than 20 wt.% LA based on total fat, preferably less than 15 wt.% LA based on total fat. Preferably the nutritional composition contains at least 5 wt.% LA based on total fat, preferably the nutritional composition contains from 5 to 15 wt.% LA based on total fat. Preferably, ALA is present in an amount sufficient to promote healthy growth and development of the infant. Thus, the nutritional composition preferably contains at least 1.0 wt.% ALA based on total fat. Preferably, the nutritional composition contains at least 1.5 wt.% ALA based on total fat, more preferably at least 2.0 wt.%. Preferably, the nutritional composition contains less than 12.5 wt% ALA, more preferably less than 10.0 wt%, most preferably less than 5.0 wt% ALA, based on total fat. Preferably, the nutritional composition contains from 1 to 5% by weight ALA, based on total fat. Preferably, the nutritional composition contains less than 15% by weight linoleic acid and more than 1% by weight alpha-linolenic acid, based on total fat. The nutritional composition contains a LA/ALA weight ratio of 2 to 20, more preferably 3 to 16, more preferably 4 to 14, more preferably 5 to 12.

Preferably, the nutritional composition contains less than 10% by weight of short chain fatty acids based on total fat, preferably less than 8% by weight, preferably less than 6% by weight, preferably less than 5% by weight. Preferably the nutritional composition contains at least 0.5 wt% short chain fatty acids based on total fat, preferably at least 0.6 wt%, less than 8 wt%, preferably at least 0.9% by weight, more preferably at least 1.2% by weight, more preferably at least 2.0% by weight. Short chain fatty acids are fatty acids with an acyl chain of 2 to 6 carbon atoms. Preferably, the nutritional composition contains less than 10% by weight butyric acid (4 carbon acyl chain) of total fat, preferably less than 8% by weight, preferably less than 6% by weight, preferably less than 5% by weight, preferably less than 4% by weight. %. Preferably the nutritional composition contains at least 0.5% by weight butyric acid based on total fat, preferably at least 0.6% by weight, preferably at least 0.9% by weight, more preferably at least 1.2 wt.%. The nutritional composition preferably contains at least 3 wt.% MUFA based on total fat, more preferably at least 10 wt.%, even more preferably 15 wt.%. The present composition preferably contains less than 50 wt.% MUFA based on total fat, more preferably less than 30 wt.%, even more preferably less than 20 wt.%.

According to the present invention, the nutritional composition preferably contains LC-PUFA, more preferably n-3 LC-PUFA, since n-3 LC-PUFA promote preferential growth dynamics. More preferably, the nutritional composition contains EPA, DPA and/or DHA, even more preferably DHA. Since a low concentration of DHA, DPA and/or EPA is already effective and normal growth and development is important, the n-3 LC-PUFA content of the nutritional composition, more preferably DHA, preferably does not exceed 15 wt.% of total fat, preferably does not exceed 10 wt.%, even more preferably does not exceed 5 wt.%. Preferably the nutritional composition contains at least 0.15 wt%, preferably at least 0.35 wt%, more preferably at least 0.75 wt% n-3 LC-PUFA, more preferably DHA, based on total fat. In one embodiment, the present composition contains at least 0.15 wt.% n-3 LC-PUFA, based on total fat, selected from the group consisting of DHA, EPA and DPA, more preferably DHA.

Since the group of n-6 fatty acids, in particular arachidonic acid (ARA) and LA as its precursor, counteracts the group of n-3 fatty acids, in particular DHA, EPA and ALA as its precursor, the nutritional composition contains relatively low amounts of ARA. The content of n-6 LC-PUFA, more preferably ARA, preferably does not exceed 5 wt.%, more preferably does not exceed 2.0 wt.%, more preferably does not exceed 0.75 wt.%, even more preferably does not exceed 0.5 wt.% based on the total amount of fat. Since the presence of ARA is not necessary to promote growth dynamics or BMI development similar to those in breastfed infants, ARA may also be absent.

Palmitic acid at the sn-2 position of the triglyceride

Fat in nutritional composition for administration in the method or use of the present invention contains triglycerides. Triglycerides contain a glyceride molecule to which three fatty acid units, which may be the same or different, are attached via ester bonds and which are usually selected from saturated and unsaturated fatty acids containing from 6 to 26 carbon atoms, including, but not limited to, LA , ALA, oleic acid (C18:1), PC and/or stearic acid (C18:0). Preferably, the nutritional composition contains at least 70 wt.%, more preferably at least 80 wt.%, more preferably at least 85 wt.% triglycerides, even more preferably at least 90 wt. % triglycerides based on total fat. Fatty acid triglycerides may differ in the fatty acid residues present and/or the respective position(s) of the fatty acid residues, for example, in the sn-1, -2 and/or -3 position. The triglycerides used in the nutritional composition are selected such that the amount of PC residues present in the triglycerides is 10% by weight or more based on the total amount of fatty acid present in the triglycerides, preferably more than 15% by weight. The nutritional composition in the method or use of the invention contains a fat that includes at least 10% by weight palmitic acid, based on total fat, and wherein at least 15% of the palmitic acid is present at the sn-2 position of the triglycerides, preferably at least 30% of the palmitic acid is in the sn-2 position of the triglycerides. Preferably, the amount of PC residues present in the triglycerides is less than 30% by weight, more preferably in the range of 16% to 24%. Preferably, the triglycerides used in the nutritional composition are selected such that, of the total amount of PC residues present in the triglyceride, it is at least 20%, more preferably at least 30%, even more preferably at least 35% and most preferably, at least 40% is at the sn-2 or beta position of the triglyceride.

Suitable triglycerides for the nutritional composition in the method or use of the invention are commercially available, for example from Loders Croklaan under the name Betapol^TM, and/or can be obtained in a well known manner, for example as described in European patent EP 0698078 and/or EP 0758846. Another suitable source is InFat^TM from Enzymotec. If these fats are obtained by trans- or trans-esterification of vegetable triglycerides, these sources are considered to be vegetable fats in the context of the present invention. Preferably, the amount of triglyceride with an increased number of palmitic acid residues in the sn-2 position of the triglyceride molecule that is contained in the fat fraction of the composition to be administered according to the present method or application is in the range of from 10 to 100 wt.%, preferably from 20 to 100 wt.%, more preferably from 20 to 80 wt.%, even more preferably from 50 to 80 wt.%.

A preferred source of triglycerides containing palmitic acid at the sn-2 or beta position of the triglyceride is non-human animal fat, more preferably non-human mammal milk fat, even more preferably cow's milk fat. Preferably, the milk fat of a non-human mammal, in particular cow's milk fat, preferably comes from the group consisting of butter, butter fat, ghee and anhydrous milk fat, more preferably anhydrous milk fat and ghee. Preferably, the milk fat source is in a homogeneous fat phase, such as ghee or anhydrous milk fat, rather than in the form of an oil-in-water emulsion, such as cream, since the fat globules of the present nutritional composition can be more easily obtained in a homogeneous fat phase. Preferably, the amount of milk fat is from 10 to 100% by weight based on the total amount of fat, preferably from 10 to 80% by weight based on the total amount of fat, more preferably from 10 to 70% by weight, more preferably from 20 to 80 wt.%, more preferably from 15 to 60 wt.%, more preferably from 20 to 60 wt.%, even more preferably from 25 to 50 wt.% based on the total amount of fat.

In an alternative embodiment, the present invention relates to a method of improving the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of conception (pre-pregnancy) of the infant, said method comprising feeding said infant a nutritional composition selected from infant formula or second level infant formula containing carbohydrates, protein and fat,

i) wherein the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of from 2 to 20, and

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

In other words, in an alternative embodiment, the present invention provides a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20% by weight of phospholipids, based on the total fat content,

for the purpose of use to improve the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of the infant's conception.

The invention, in an alternative embodiment, may also be formulated as the use of fat globules to obtain a nutritional composition selected from an infant formula or a second-stage infant formula for use in improving postnatal growth or body development dynamics in an infant who is born to a mother with overweight or obese at the time of conception of the infant, wherein the nutritional composition contains carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

The present invention, in an alternative embodiment, provides a method for preventing or reducing the risk of unbalanced postnatal growth or body development in an infant at risk for unbalanced postnatal growth or body development, said infant being born to a mother who is overweight or obese at the time the infant is conceived , said method comprises feeding said infant a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat,

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

The invention in an alternative embodiment also relates to a nutritional composition selected from an infant formula or a second level infant formula containing carbohydrates, protein and fat, wherein

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter per volume of at least 1.0 µm and/or a diameter from 2 to 12 µm in an amount of at least 45% by volume based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20% by weight of phospholipids, based on the total fat content,

for use in preventing or reducing the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, said infant is born to a mother who is overweight or obese at the time the infant is conceived.

The invention, in an alternative embodiment, may also be formulated as the use of fat globules to provide a nutritional composition selected from an infant formula or a second-tier infant formula for use in preventing or reducing the risk of unbalanced postnatal growth or body development in an infant at risk unbalanced dynamics of postnatal growth or body development, said infant is born to a mother who is overweight or obese at the time of conception of the infant, wherein the nutritional composition contains carbohydrates, protein and fat, wherein,

i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20,

ii) the fat contains from 10 to 70% by weight, based on the total fat, of non-human mammalian milk fat originating from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition contains fat globules who have

a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and

b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content.

Non-human mammalian milkfat, as used herein, refers to all fatty components of milk produced by mammals, such as cows, and is found in commercially produced milk and milk-derived products.

The butter in the present invention is a water-in-oil emulsion containing more than 80 wt.% milk fat.

Butter fat in the present invention refers to all the fatty components of milk that are separated by churning, in other words, present in the butter.

Anhydrous milk fat (AMF) is a term known in the art and refers to extracted milk fat. Typically, BMJ contains more than 99 wt.% fat in terms of total weight. It can be prepared by extracting milk fat from cream or butter. Anhydrous oil in the present invention is synonymous with BMG.

Oil is also a term known in the art. It generally refers to a milk fat extract with more than 98% fat by weight and is usually a precursor in the process of making anhydrous milk fat or anhydrous ghee.

Preferably, the milk of non-human mammals contains at least 70% by weight triglycerides, more preferably at least 90% by weight, more preferably at least 97% by weight.

Preferably, the non-human mammalian milk fat is anhydrous milk fat or ghee. Such fat sources of milk fat have high levels of triglycerides. In addition, these fat sources are in the form of a continuous fat phase or in the form of a water-in-oil emulsion, rather than in the form of an oil-in-water emulsion such as cream, since the fat globules of the present nutritional composition can be more easily obtained in a homogeneous fat phase.

Preferably, the amount of non-human mammalian milk fat is from 10 to 70% by weight based on the total amount of fat, preferably from 20 to 70% by weight, more preferably from 15 to 60% by weight, more preferably from 20 to 60 wt.%, even more preferably from 25 to 50 wt.% based on the total amount of fat.

Protein

The nutritional composition contains proteins, preferably in the above amounts. Preferably, the protein provides from 5% to 9% of the total calories in the nutritional composition. The protein source should be selected to meet the minimum essential amino acid requirements and ensure satisfactory growth. Therefore, protein sources based on cow's milk proteins such as whey, casein and mixtures thereof, and soy, potato or pea based proteins are preferred. When whey proteins are used, the protein source is preferably based on acid whey or sweet whey, whey protein isolate or a mixture thereof and may include α-lactalbumin and β-lactoglobulin. More preferably, the protein source is based on acid whey or sweet whey from which casein-glyco-macropeptide (CGMP) has been removed. Preferably the composition contains at least 3% by weight casein on a dry weight basis. Preferably the casein is intact and/or non-hydrolyzed. For the purposes of the present invention, the protein includes peptides and free amino acids.

Digestible carbohydrates

The nutritional composition contains digestible carbohydrates, preferably in the above amounts. Preferred sources of digestible carbohydrates are lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin. Lactose is the main digestible carbohydrate present in human milk. Lactose predominantly has a low glycemic index. The nutritional composition preferably contains lactose. The nutritional composition preferably contains a digestible carbohydrate of at least 35 wt%, more preferably at least 50 wt%, more preferably at least 75 wt%, even more preferably at least 90% by weight, most preferably at least 95% by weight of the digestible carbohydrate is lactose. On a dry weight basis, the present composition preferably contains at least 25% by weight lactose, preferably at least 40% by weight lactose.

Indigestible carbohydrates

In one embodiment, the nutritional composition contains non-digestible oligosaccharides. Preferably, the nutritional composition contains non-digestible oligosaccharides with a degree of polymerization (DP) from 2 to 250, more preferably from 3 to 60.

Preferably, the present composition contains fructooligosaccharides, inulin and/or galactooligosaccharides, more preferably galactooligosaccharides, most preferably transgalactooligosaccharides. In a preferred embodiment, the composition contains a mixture of transgalactooligosaccharides and fructooligosaccharides or inulin. Suitable non-digestible oligosaccharides are, for example, ^Vivinal® GOS (FrieslandCampina DOMO), ^RaftilinHP® or ^Raftilose® (Orafti).

Preferably the nutritional composition contains from 80 mg to 2 g of non-digestible oligosaccharides per 100 ml, more preferably from 150 mg to 1.50 g, even more preferably from 300 mg to 1 g per 100 ml. On a dry weight basis, the nutritional composition preferably contains from 0.25 to 20% by weight, more preferably from 0.5 to 10% by weight, even more preferably from 1.5 to 7.5% by weight.

Application

In the method or use of the present invention, the nutritional composition is administered to or used for an infant. In the context of the present invention, the infant is under 12 months of age. Preferably, the nutritional composition is administered to or used for a full-term baby. The term “term baby” means an infant born at a gestational age of 37 to 42 weeks. Preferably, the nutritional composition is administered or used to a healthy infant. Preferably, the nutritional composition is used for at least the first 2 months of life, preferably for at least the first 3 months of the infant's life, more preferably for at least the first 4 months of the infant's life. Preferably, the nutritional composition is administered to an infant under 6 months of age, more preferably under 4 months of age.

According to the present invention, the dynamics of postnatal growth or body development of an infant born to a mother who is overweight or obese at the time of conception of the infant is improved. Preferably, the dynamics of body growth or development is the dynamics or development of body mass index (BMI), preferably the dynamics or development of body mass index (BMI) in the first 4 months of life of the infant, preferably the dynamics or development of body mass index (BMI) in the first 12 months life of an infant. In one embodiment, improving the postnatal growth or body development dynamics of the infant is to reduce the increase in the infant's BMI. Preferably, the improvement is compared with the postnatal growth or body development of an infant born to a mother who is overweight or obese at the time of conception of the infant fed an infant formula or a second level infant formula containing carbohydrates, protein and fat, and containing, at least 10 wt.% palmitic acid, based on total fat, but less than 15% of the palmitic acid residues are in the sn-2 position of triglycerides, and does not contain phospholipids and has fat globules with a modal diameter, based on volume , about 0.5 µm. Thus, in such infant formulas or level 2 infant formulas, the volume % of fat globules ranging in size from 2 to 12 μm is less than 10 volume %. Preferably, for fair comparison, the age of the infant and the period of time during which the nutritional composition is administered are the same.

The present invention prevents or reduces the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, said infant being born to a mother who is overweight or obese at the time the infant is conceived. Preferably, the dynamics of body growth or development is the dynamics or development of body mass index (BMI), preferably the dynamics or development of body mass index (BMI) in the first 4 months of life of the infant, preferably the dynamics or development of body mass index (BMI) in the first 12 months life of an infant. Preferably, the prevention or risk reduction is compared with the postnatal growth or body development of an infant born to a mother who is overweight or obese at the time of conception, fed an infant formula or a second-tier infant formula containing carbohydrates, protein, and fat, and containing at least 10 wt.% palmitic acid in terms of total fat, but less than 15% of the palmitic acid residues are in the sn-2 position of triglycerides and do not contain phospholipids and have fat globules with a modal diameter, by volume, about 0.5 microns. Thus, in these infant formulas or level 2 infant formulas, the volume % of fat globules ranging in size from 2 to 12 μm is less than 10 volume %. Preferably, for fair comparison, the age of the infant and the period of time during which the nutritional composition is administered are the same.

Preferably, the infant formula or level 2 ready-to-feed infant formula has an energy density of 60 to 75 kcal/100 ml, more preferably 60 to 70 kcal/100 ml. This density provides an optimal balance between hydration and calorie intake.

In one embodiment, the infant formula or second level infant formula is a powder. Accordingly, infant formula or level 2 infant formula is in powder form, which can be reconstituted with water or other edible aqueous liquid to form a ready-to-drink liquid, or is in the form of a liquid concentrate, which must be diluted with water to form a ready-to-drink liquid. Fat globules were found to maintain their size and coating when repaired.

In this document and in the claims, the verb “comprise” and its conjugations are used in a non-limiting sense to mean that elements following the word are included, but elements not specifically mentioned are not excluded. In addition, referring to an element by the indefinite article "a" or "an" does not exclude the possibility of the presence of more than one element, unless the context clearly requires the presence of one and only one of the elements. Thus, the indefinite article "a" or "an" usually means "at least one."

EXAMPLES

EXAMPLE 1. TEST AND CONTROL INFANT FORMULA

Diet 1: Control infant formula (control infant formula)

The control infant formula contained 66 kcal per 100 ml of ready-to-use infant formula, 1.3 g of protein (whey protein and casein in a mass ratio of 6/4), 7.3 g of digestible carbohydrates (mainly lactose), 3.4 g of fat and 0.8 g short-chain galacto-oligosaccharides (source Vivinal ^® GOS) and long-chain fructo-oligosaccharides (source RaftilinHP ^® ) in a ratio of 9/1 w/w, plus minerals, vitamins, trace elements and other micronutrients in accordance with the children's directives formulas for infants. Infant formula is provided in powder form with instructions for reconstitution with water, approximately 13.6 g of powder must be dissolved to obtain 100 ml of ready-to-use infant formula.

The fat component consisted predominantly of vegetable fat (a mixture of palm oil, low erucic acid rapeseed oil, coconut oil, high oleic acid sunflower oil, sunflower oil, a small amount of soy lecithin (0.13 wt.%) and about 1. 5 wt.% LC-PUFA premix (fish oil and microbial oil).

The fat component was present in the form of fat globules, and the fat globules had a modal diameter, in terms of volume, of about 0.5 μm, and the volume % of fat globules with a mode of 2 to 12 μm was below 10 vol%.

Diet 2: Test infant formula (test formula)

The infant formula tested was an infant formula similar to diet 1, except for the following differences:

The fat globules in the tested infant formula had a modal diameter, in terms of volume, of about 5.6 μm, and the volume % of fat globules with a mode from 2 to 12 μm was above 45 vol.%.

The fat component consisted of about 51 wt.% vegetable fat (a mixture of low erucic acid rapeseed oil, coconut oil, high oleic sunflower oil, sunflower oil), about 44 wt.% cow's anhydrous milk fat, 1.5 wt. .% LC-PUFA-containing oil (fish oil and microbial oil), 0.13 wt.% soy lecithin, about 3.6 wt.% milk fat derived from buttermilk enriched with milk phospholipids or milk fat globule membranes (milk phospholipids constituted about 1.5 wt.% based on the total amount of fat).

Fatty acid composition was very similar between diets 1 and 2 in terms of saturated, monounsaturated and polyunsaturated acids and n3 and n6 PUFA content. The amount of palmitic acid was 18.4 wt.% and 17.7 wt.% (based on total fat) for diets 1 and 2, respectively. For diet 2, about 36 wt.% of the palmitic acid residues were in the sn-2 position, while for diet 1 it was about 13 wt.%. The amount of C4:0 (butyric acid) was 0.10 wt.% in diet 1 and 1.39 wt.% in diet 2, C6:0 (caproic acid) was 0.24 wt.% in diet 1 and 0.98 % wt in Diet 2. % wt are based on total fat in infant formula unless otherwise noted.

EXAMPLE 2. STUDY PROTOCOL AND STUDY POPULATION

After parent(s)/legal guardian(s) signed informed consent, exclusively formula-fed infants eligible for participation were randomized to receive either the test formula (diet 2) or the control infant formula. formula (diet 1) for a double-blind period of no more than 17 weeks (depending on their age at the start of the study). Exclusively breastfed infants participated in the control group and had the same visit schedule and study assessments as the randomized infants.

At the first visit, baseline and birth data were collected, as well as maternal prepregnancy weight, race, and height to determine BMI (kg/ ^m2 ), and the test product and diaries were provided to the parent(s). Further study visits were carried out at 5, 8, 13, 17 and 52 weeks of age. During the visits, information and anthropometric measurements were collected. At the 52-week visit, anthropometric measurements were taken.

A total of 4 countries with 17 study sites participated, and a total of 313 participants were enrolled; 6 research centers in the Netherlands (121 participants), 3 research centers in France (13 participants), 7 research centers in Belgium (158 participants) and 1 research center in Singapore (21 participants). Of the total 313 participants included in the study, 223 were randomized and 88 were included in the breastfeeding control group; 2 participants were not screened and therefore were not randomized.

The all intent-to-treat (AST) data set consisted of all randomized participants (ASR, n=223) who received at least any study product. Participants (n=8) with sufficient evidence that the test product was not consumed were considered untreated and were not included in the AST group (n=215).

The ITT data set consisted of all participants from the ASR group (ITT=ASR). The results of the ITT analysis reflect the impact on the target population in a real clinical situation/determine the effect (effectiveness) of treatment tactics. Participants' data were analyzed "as randomized" (n=223).

A per-protocol (PP) analysis limits the analysis to participants who met the protocol in terms of eligibility, interventions, instructions/limitations, and outcome measures. The PP dataset consisted of all participants and/or participant visits from the ITT dataset without any major protocol deviations. Thus, the PP data set was not limited to participants who completed the study, and the number of participants per visit varies. The results of the PP analysis determine the effect (efficacy) of the treatment. Participants' data were analyzed “as treated.”

The following rules were used to exclude participants from the PP dataset: age at baseline (=Visit 1) ˃35 days, birth weight missing or ˂9.96th or ˃90.04th percentile (based on standard guidelines WHO Child Growth), head circumference at inclusion is outside the ±2.04 standard deviation (SD) percentile (based on WHO standard child growth guidelines) without at least one valid post-baseline visit. Consumption of the test product began ≥6 days after baseline, receiving another test product as his/her sibling, and not consuming a test product consistent with a medical history, i.e., disease/condition identified by the medical monitor. The following rules were applied to exclude individual visits from the PP data set: any visit ˃3 days after discontinuation of the test product, except for the 52-week visit, regardless of whether the cessation was temporary or not, any visit ˃3 days after the start of feeding others infant formula, any visit ˃3 days after starting solid food feeding. Forty-nine randomized participants plus individual visits were excluded.

For the nonrandomized breastfed control group, data sets corresponding to the ITT and PP populations of randomized infants were also identified. A fully breastfed (FBF) group was defined according to the ITT dataset, and no breastfed participants were excluded. The Protocol Breastfeeding Control (PCBF) data set was defined according to the PP dataset, applying the appropriate rules as defined for the PP dataset. The following rules were used to exclude participants from the PCBF dataset: age at baseline ˃35 days, birth weight missing or ˂9.96th or ˃90.04th percentile (based on WHO standard child growth guidelines) , head circumference at inclusion is outside the ±2.04 standard deviation (SD) percentile (based on WHO standard child growth guidelines), without at least one valid post-baseline visit or relevant medical history, i.e. disease /conditions identified by the medical monitor (observer). The following rules were used to exclude individual visits from the PCBF dataset: any visit ˃3 days after cessation of breastfeeding if cessation of breastfeeding occurred before 13 weeks of age, any visit ˃3 days after initiation of other infant formula feeding if initiation of another formula before 13 weeks of age, any visit ˃3 days after initiation of solids if initiation of other solids occurred before visit 4. 11 breastfed participants plus separate visits were excluded.

Participants (randomized or breastfed) who were included in the PP/PCBF data set including the 17-week visit and who participated in the extension extension were included in the PP data set at the 52-week visit.

There were no statistically significant differences between treatment groups in different data sets (PP, ITT) by stratification factors: sex, age at baseline (≤14 days/˃14 days), regions (Europe versus Asia). There was no difference in study duration between experimental groups.

The weight categories of mothers before pregnancy are determined in accordance with WHO criteria (Obesity: Preventing and managing the global epidemic. Report of a WHO Consultation on Obesity. Geneva: World Health Organization) as follows: underweight with a BMI below 18.5 kg/m ² , normal with a BMI from 18.5 kg/ ^m2 to 25 kg/ ^m2 , overweight or obese with a BMI equal to or greater than 25 kg/ ^m2 . WHO has adapted the recommendations on maternal weight categories for mothers of Asian origin (WHO/IOTF/IASO 2000, WHO Expert consultation 2004, Lancet 363: 157-163) as follows: underweight with a BMI below 18.5, normal weight with a BMI of 18, 5 to 23, overweight or obese with a BMI equal to or greater than 23.

Table 1 provides a tabular overview of the PP population showing numbers and by weight categories by maternal prepregnancy weight category for the test infant formula, control infant formula, and breastfed group.

Table 1.

Study population statistics (n(%)) for different pre-pregnancy maternal weight categories in the PP population

Mothers' BMI before pregnancy Control
(n=83) Trial
(n=91) Breastfeeding (n=77) Underweight 2 (2.44%) 7 (7.69%) 2 (2.6%) Normal 58 (70.73%) 45 (49.45%) 42 (54.55%) Overweight/obesity 22 (26.83%) 39 (42.86%) 33 (42.86%)

Table 2 provides a tabular overview of the ITT population showing the number and percentage of participants by maternal prepregnancy weight category for the test formula, control formula, and breastfeeding groups.

Table 2.

Study population statistics (n(%)) for different maternal pre-pregnancy weight categories in the ITT population

Mothers' BMI before pregnancy Control
(n=108) Trial
(n=115) Breastfeeding (n=88) Underweight 3 (2.80%) 10 (8.77%) 3 (3.41%) Normal 74 (69.16%) 60 (52.63%) 44 (50.00%) Overweight/obesity 30 (28.04%) 44 (38.60%) 41 (46.69%)

Table 3 provides a tabular overview of the PP population showing at baseline, 4 months and 1 year the number of participants and their mean (SD) BMI by maternal pre-pregnancy weight category, for test formula, control formula and group who is breastfed. Table 4 provides the same information for the ITT population.

Table 3.

Statistics of the study population by number of participants (n) and mean (SD) BMI at different time points by weight categories of mothers before pregnancy in the PP population

Baseline Mother's weight category Control
(n=91) Trial
(n=83) Breastfeeding (n=77) Underweight n 7 2 2 mean (SD) 12.7 (1.28) 12.9 (0.23) 12.5 (1.82) Normal n 45 58 42 mean (SD) 13.2 (0.96) 13.1 (1.06) 14.0 (1.49) Overweight/obesity n 39 22 33 mean (SD) 13.1 (1.25) 13.1 (1.24) 14.0 (1.31) 4 months Underweight n 4 1 2 mean (SD) 17.0 (0.59) 16.8 16.3 (0.17) Normal n 35 42 39 mean (SD) 16.6 (1.12) 16.7 (1.26) 16.6 (1.63) Overweight/obesity n 31 15 24 mean (SD) 16.3 (1.32) 17.2 (0.78) 16.8 (1.64) 1 year Underweight n 3 - 2 mean (SD) 16.9 (1.16) 16.5 (0.96) Normal n 25 26 31 mean (SD) 16.4 (1.33) 17.4 (1.37) 16.7 (0.92) Overweight/obesity n 25 13 19 mean (SD) 16.7 (1.09) 17.6 (1.25) 16.6 (1.37)

Table 4.

Study population statistics by number of participants (n) and mean (SD) BMI at different time points by maternal prepregnancy weight category in the ITT population

Baseline Mother's weight category Control
(n=115) Trial
(n=108) Breastfeeding (n=88) Underweight n 10 3 3 mean (SD) 12.7 (1.14) 12.8 (0.26) 13.4 (1.99) Normal n 60 74 44 mean (SD) 13.2 (1.10) 13.0 (1.04) 14.0 (1.50) Overweight/obesity n 44 29 41 mean (SD) 13.2 (1.20) 13.1 (1.28) 13.8 (1.39) 4 months Underweight n 5 2 2 mean (SD) 16.7 (0.78) 16.7 (0.10) 16.3 (0.17) Normal n 45 57 40 mean (SD) 16.8 (1.26) 16.6 (1.17) 16.6 (1.61) Overweight/obesity n 36 22 27 mean (SD) 16.3 (1.35) 17.0 (1.00) 16.7 (1.56) 1 year Underweight n 4 1 2 mean (SD) 16.5 (1.33) 16.7 16.5 (0.96) Normal n thirty 38 32 mean (SD) 16.7 (1.50) 17.4 (1.32) 16.7 (0.90) Overweight/obesity n 29 19 21 mean (SD) 16.7 (1.13) 17.5 (1.13) 16.7 (1.37)

At baseline, the BMI (kg/ ^m2 ) of infants born to normal-weight mothers and those born to mothers who were overweight/obese before pregnancy were comparable. The BMIs of randomized infants were also comparable to breastfed controls in the PP and ITT populations. At 1 year of age, the BMI of infants born to mothers of normal weight or pre-pregnancy overweight/obese who received the test infant formula is similar to the BMI of breastfed controls compared with infants who received the control infant formula. in both the PP and ITT populations. Overall, it is clear that the development of BMI in infants receiving the test infant formula is more comparable to the development of BMI in breastfed infants.

From baseline to 4 months to 1 year, the difference in increase in BMI (test minus control) for the group of infants born to normal-weight mothers and the group of infants born to overweight/obese mothers was calculated using analysis parametric growth curve (PGC) taking into account the entire study period (baseline to 1 year) and adjusting for stratification factors as previously described here. All statistical analyzes were performed by Nutricia Research Utrecht using SAS ^® (SAS Enterprise Guide 4.3 or later) for Windows, SAS Institute Inc., Cary, NC. This approach assumes a parametric function of time (i.e., participant's age) and thus describes the development of growth parameters (i.e., BMI) over time by a second-order polynomial function. It does not require that study participants be measured at the same set of time points. The resulting parameters are compared to evaluate the differences between the curves.

Table 5.

Differences in the increase in BMI (kg/ ^m2 ) between the test and control groups by category of mothers before pregnancy in the study population PP

Age range Maternal weight before pregnancy LS mean (SE) P-value Test minus control Baseline up to 4 months Normal -0.272 (0.294) 0.356 Overweight/obesity -0.980 (0.394) 0.014 Baseline up to 1 year Normal -0.935 (0.358) 0.010 Overweight/obesity -1.200 (0.455) 0.009

Table 6.

Differences in the increase in BMI (kg/ ^m2 ) between the test and control groups by category of mothers before pregnancy in the ITT study population.

Age range Maternal weight before pregnancy LS mean (SE) P-value Test minus control Baseline up to 4 months Normal -0.088 (0.257) 0.733 Overweight/obesity -0.717 (0.346) 0.040 Baseline up to 1 year Normal -0.909 (0.304) 0.003 Overweight/obesity -0.842 (0.386) 0.031

Tables 5 and 6 (ITT and PP populations) provide estimates of mean LS values for the between-group difference (trial minus control) in BMI gain by age interval and maternal prepregnancy category. Infants receiving the control infant formula had a higher increase in BMI compared to infants receiving the test infant formula, which was also statistically significantly higher in all age intervals and weight categories, with the exception of the interval from baseline to 4 months in infants born to mothers of normal weight. Infants of overweight/obese mothers who received the control infant formula had a statistically significantly higher increase in BMI than infants who received the test infant formula; unexpectedly, this difference in increase in BMI was 3 times higher from baseline up to 4 months in PP and even almost 8 times higher in the ITT population.

In the group of infants born to overweight or obese mothers, a statistically significant difference in the increase in BMI was evident between infants fed the test infant formula and the control infant formula from baseline to 4 months and from baseline to 1 year. From baseline to 4 months of age, infants born to overweight or obese mothers who were fed the test infant formula had a statistically significant lower increase in BMI than infants born to overweight or obese mothers who were fed the control formula. infant formula (p=0.014 in the PP population, p=0.040 in the ITT study). In infants born to normal weight mothers, the difference in BMI gain between test infant formula and control infant formula was not evident from baseline to 4 months of age, but from baseline to 1 year of age the group of infants born to mothers normal weight infants fed the test formula had a statistically significantly lower BMI than infants fed the control diet (p=0.010 in the PP population, p=0.003 in the ITT population). Thus, the effect of the studied diet on the increase in BMI is stronger and earlier (at 4 months) manifested in infants born to overweight and obese mothers.

These results indicate a stronger effect of the tested infant formula when feeding infants born to overweight or obese mothers in stimulating postnatal growth or body development dynamics in infants towards more favorable growth or body development dynamics that are more similar to the dynamics of growth or body development observed in breastfed infants compared with the effect it has on infants born to normal weight mothers. Infants born to overweight or obese mothers benefit more from dietary supplementation than infants born to mothers of normal weight to achieve adequate growth or body development. Consequently, improvements in postnatal growth or body development are achieved in infants born to overweight or obese mothers. These results also provide evidence of the effect of the test infant formula when feeding infants born to overweight or obese mothers in preventing or reducing the risk of unbalanced postnatal growth or body development in such infants at risk of unbalanced postnatal growth. or body development. In particular, improvement in postnatal growth or body development dynamics, or prevention or reduction of unbalanced postnatal growth or body development dynamics is found when compared with growth or body development dynamics in infants fed infant formula or second-level infant formula containing fat globules about 0.5 microns in size, and which are not coated with phospholipids, and containing at least 10 wt.% palmitic acid, based on total fat, and less than 15 wt.% palmitic acid esterified in sn- 2 position of the triglyceride, based on the total amount of palmitic acid.

Claims (36)

1. A method of non-therapeutically improving the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of the infant's conception, by administering a nutritional composition selected from an infant formula or a second-stage infant formula containing carbohydrates, protein and fat where i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20, ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, And wherein the nutritional composition contains fat globules that have: a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and b) said fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content. 2. The method of non-therapeutically improving the dynamics of postnatal growth or body development according to claim 1, where the improvement is compared with the dynamics of postnatal growth or body development in an infant born to a mother who was overweight or obese at the time of conception of the infant who was fed infant formula children or a second level infant formula containing carbohydrates, protein and fat, and containing at least 10% by weight palmitic acid, based on total fat, with less than 15% of the palmitic acid residues being in the sn-2 position of triglycerides, and does not contain phospholipids, but has fat globules with a modal diameter, in terms of volume, of about 0.5 microns. 3. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to claim 1 or 2, where the nutritional composition contains less than 15 wt.% linoleic acid and more than 1 wt.% alpha-linolenic acid, based on the total amount of fat. 4. A method for non-therapeutically improving the dynamics of postnatal growth or development of the body according to any of the preceding claims, where the dynamics of growth or development of the body represents the dynamics or development of the body mass index (BMI). 5. A method of non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, where the use is intended to reduce the increase in the BMI of an infant. 6. A method for non-therapeutically improving the dynamics of postnatal growth or development of the body according to any of the preceding claims, where the dynamics of growth or development of the body represents the dynamics or development of the body mass index (BMI) in the first 12 months of life of the infant. 7. A method of non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, where the infant is a full-term child. 8. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the phospholipids include at least 15 wt.% sphingomyelin, based on the total amount of phospholipids. 9. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the nutritional composition contains phospholipids that are derived from or form part of the membrane of milk fat globules (MFGM), or are provided in the form of MFGM, preferably MFGM from cow's milk. 10. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any one of the preceding claims, wherein the nutritional composition contains from 0.5 to 20 wt.% phospholipids derived from mammalian milk, based on the total amount of fat. 11. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein at least 30 wt.% of palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid. 12. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the fat globules contain at least 40 wt.% triglycerides of plant origin. 13. A method of non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the nutritional composition is a powder suitable for reconstitution with water into a ready-to-feed infant formula. 14. The use of a nutritional composition selected from an infant formula or a second-stage infant formula to prevent or reduce the risk of unbalanced postnatal growth or body development in an infant at risk of unbalanced postnatal growth or body development, wherein said infant is born from a mother who is overweight or obese at the time of conception of the infant, wherein the composition contains carbohydrates, protein and fat, wherein i) the fat contains linoleic acid and alpha-linolenic acid in a mass ratio of 2 to 20, ii) the fat contains at least 10% by weight palmitic acid, based on the total amount of fat, and at least 15% by weight of this palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid, And wherein the nutritional composition contains fat globules that have: a) a modal diameter, based on volume, of at least 1.0 µm and/or a diameter of from 2 to 12 µm in an amount of at least 45% by volume, based on total fat content, and b) the fat globules are at least partially coated on the surface with phospholipids, the amount of phospholipids present in the nutritional composition being from 0.5 to 20 wt.% phospholipids, based on the total fat content. 15. The use of claim 14, wherein the prevention or risk reduction is compared with the dynamics of postnatal growth or body development in an infant born to a mother who is overweight or obese at the time of conception of the infant who is fed infant formula or infant formula. level, containing carbohydrates, protein and fat, and containing at least 10 wt.% palmitic acid based on total fat, with less than 15% of the palmitic acid residues being in the sn-2 position of triglycerides, and not containing phospholipids, and having fat globules with a modal diameter, in terms of volume, of about 0.5 microns. 16. Use according to claim 14 or 15, wherein the nutritional composition contains less than 15 wt.% linoleic acid and more than 1 wt.% alpha-linolenic acid, based on the total amount of fat. 17. Application according to any one of paragraphs. 14-16, where the dynamics of body growth or development represents the dynamics or development of body mass index (BMI). 18. Application according to any one of paragraphs. 14-17, where the use is intended to reduce the increase in BMI of the infant. 19. Application according to any one of paragraphs. 14-18, where the dynamics of body growth or development represents the dynamics or development of body mass index (BMI) in the first 12 months of life of an infant. 20. Application according to any one of paragraphs. 14-19, where the infant is a full-term baby. 21. Application according to any one of paragraphs. 14-20, where the phospholipids include at least 15 wt.% sphingomyelin based on the total amount of phospholipids. 22. Application according to any one of paragraphs. 14-21, wherein the nutritional composition contains phospholipids that are derived from or form part of the milk fat globule membrane (MFGM), or are provided as MFGM, preferably MFGM from cow's milk. 23. Application according to any one of paragraphs. 14-22, wherein the nutritional composition contains from 0.5 to 20 wt.% phospholipids derived from mammalian milk, based on the total amount of fat. 24. Application according to any one of paragraphs. 14-23, wherein at least 30 wt.% palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid. 25. Application according to any one of paragraphs. 14-24, where the fat globules contain at least 40 wt.% triglycerides of plant origin. 26. Application according to any one of paragraphs. 14-25, wherein the nutritional composition is a powder suitable for reconstitution with water into a ready-to-feed infant formula.