RU2824520C1 - Infant formula with special fat structure for improving postnatal growth of infants born by cesarean section - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to infant formula for infants born by caesarean section. Method for non-therapeutic improvement of the dynamics of postnatal growth or development of the body in an infant born by caesarean section, comprises administering a nutritional composition to an infant containing carbohydrates, protein and fat, where: fat contains linoleic acid and alpha-linolenic acid in weight ratio from 2 to 20 and at least 10 wt.% of palmitic acid in terms of total amount of fat. At least 15 wt.% of palmitic acid is esterified in sn-2 position of triglyceride in terms of total amount of palmitic acid. Nutritional composition contains fat globules that 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 fat content. 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.% of phospholipids in terms of total fat content.

EFFECT: invention makes it possible to improve dynamics of postnatal growth or body development in an infant born by caesarean section.

26 cl, 4 tbl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

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

LEVEL OF TECHNOLOGY

Breast milk is the undisputed gold standard for infant nutrition. However, in some cases, breastfeeding is inappropriate or ineffective due to medical reasons or failure to breastfeed. For these situations, infant formulas or second-tier infant formulas have been developed. Infant formulas available on the market today are often used to provide a supplemental or sole source of nutrition during early life. These formulas contain a range of nutrients to meet the nutritional needs of a growing infant and typically include fats, carbohydrates, proteins, vitamins, minerals, and other nutrients beneficial to the optimal growth and development of an infant. Infant formulas available on the market are designed to mimic the composition and function of human milk as closely as possible.

It has long been recognized that breastfed infants have a different pattern or trend of weight gain compared to formula-fed infants. After the first week of life, breastfed infants tend to lose more weight than formula-fed infants. Although breastfed infants take slightly longer to regain their birth weight, the weight gain patterns of breastfed and formula-fed infants are similar during the first 4 months of life. Breastfed infants typically have slightly higher weights 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 significantly between breastfed and formula-fed infants. The difference in mean 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). Li et al., 2010, Pediatrics 125:e1386–e1393 found that infants who were bottle-fed in early infancy were more likely to empty a bottle or cup in late infancy than those who were directly breastfed. Bottle feeding, regardless of milk type, differs from breastfeeding in its effects on infants' self-regulation of milk intake.

Over the past decade, the rate of caesarean section births has increased worldwide, making it the most common surgical procedure performed on women of childbearing age today. While the WHO recommends that caesarean sections be performed only in those who require them, in many countries the rate of caesarean sections far exceeds this recommendation. In recent years, the medical profession has come to recognise the health risks associated with caesarean section births, and the obstetrician is therefore advised to assess these long-term and short-term health consequences for the mother and baby, as well as the risks associated with the procedure itself versus not performing the procedure (Robson et al. MJA 206, 181-185, 2017).

Currently, cesarean section is associated with a delay in the colonization of beneficial bacteria in the gut, impaired immune function, and an increased risk of asthma and obesity in infants. Huh et al., 2012, Arch Dis Child 97(7): 610–616 reported that infants born by cesarean section may be at increased risk of childhood obesity. This was later studied, for example, by Mesquita et al., 2013, PLoS ONE 8(6):e66827, who compared peripheral and central adiposity in young adults born by cesarean section and vaginal delivery. Mesquita et al. found that cesarean section was consistently associated with obesity. Mueller et al., 2015, Int J Obes 39(4):665-670 also noted that cesarean section and antibiotic exposure in the second or third trimester were associated with a higher risk of childhood obesity in the offspring.

As discussed above, caesarean section delivery is a risk factor associated with obesity in later life. Obesity is a major public health problem in the Western world. Breastfed infants are less likely to be obese in later life compared to standard formula-fed infants. Early feeding has a long-term programming effect on the risk of such diseases in adulthood. There is a need to provide improved infant nutrition that positively influences the dynamics of postnatal growth or body development in infants born by caesarean section.

Human milk fats are known to have a well-defined physical structure consisting of large fat globules with a mean modal diameter of about 4 μm, consisting of a triglyceride core covered by a three-layer membrane called the milk fat globule membrane (MFGM). The diameter of the fat globules in standard infant formula is typically about 0.3-0.5 μm due to industrial processing procedures to obtain stable and reproducible end products. The fat globules of standard infant formula are not surrounded by MFGM but are predominantly surrounded by proteins such as casein.

An infant formula with fat globules having a structure more similar to that of human milk fat globules has been described. International application WO 2015/065193 discloses nutritional compositions comprising specially formulated fat globules for preterm infants, small for gestational age infants and infants with growth retardation due to physical or mental stress after birth, in order to stimulate catch-up growth and/or improve 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 the presence in the form of fat globules of a certain size and/or coating is described for the diet in early life in order to improve the development of a 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 prevention of obesity in later life. International application WO 2017/064304 describes a comparison of the growth dynamics of infants receiving infant formulas with large fat globules coated with phospholipids with the growth dynamics of infants from a control group who are breastfed, considering weight and body mass index (BMI) at the age of 12 months.

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 body development in an infant born by caesarean section.

ESSENCE OF THE INVENTION

The inventors compared the postnatal body mass index (BMI) of groups of healthy full-term infants delivered either vaginally or by cesarean section during the first 12 months of life. One group received an experimental infant formula containing a fat component in the form of large phospholipid-coated fat globules, and one group received a control infant formula without a fat component in the form of large phospholipid-coated fat globules, but in the form of standard protein-coated fat globules with a modal diameter per volume of about 0.3-0.5 μm. Both infant formulas were administered before 17 weeks of life. The control and experimental infant formulas were similar in caloric content, as well as in fat, carbohydrate, and protein content.

It was found that when BMI was analyzed over the entire study period up to 12 months of age, the BMI gain in the experimental formula-fed infants was statistically significantly lower than the BMI gain in the control formula-fed infants for both cesarean section and vaginal delivery infants. Surprisingly, the difference in BMI gain between the experimental and control formula-fed infants was approximately 3 times greater in cesarean section infants than in infants born vaginally. This measured difference is a statistically significant difference. Thus, overall, the inventors unexpectedly found a stronger effect of the experimental infant formula in infants born by cesarean section compared to infants born vaginally.

Therefore, feeding an infant formula with similar energy and macronutrient content but with a different fat globule structure has a beneficial effect on the growth pattern or early postnatal growth trajectory, making it preferably more similar to the growth pattern or early growth trajectory of breastfed infants. However, it also has a differential effect in that infants delivered by caesarean section benefit more than infants delivered vaginally. Infants delivered by caesarean section benefit more from the experimental infant formula than infants delivered vaginally in developing the desired growth trajectory or body development. Therefore, the improvement in postnatal growth trajectory or body development is achieved in infants delivered by caesarean section. infants. Similarly, infants born by caesarean section benefit from the prevention or reduction of the risk of unbalanced postnatal growth patterns or body development in such infant at risk of unbalanced postnatal growth patterns or body development, compared to the effect it has on infants born by vaginal delivery. Therefore, prevention or reduction of the risk of unbalanced postnatal growth patterns or body development is achieved in infants born by caesarean section.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for improving the dynamics of postnatal growth or body development in an infant born by caesarean section, said method comprising feeding said infant a nutritional composition selected from an infant formula for infants 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is 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-stage 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content,

for the purpose of using it to improve the dynamics of postnatal growth or body development in a breastfed infant born by caesarean section.

The invention may also be formulated as the use of fat globules for the production of a nutritional composition selected from an infant formula for infants or a second-stage infant formula for use in improving the dynamics of postnatal growth or body development in an infant born by caesarean section, wherein the nutritional composition comprises 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 comprises at least 10 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

It can be considered that the improvement of the dynamics of postnatal growth or body development in an infant born by caesarean section includes a non-therapeutic effect. In this regard, the present invention can also be considered as relating to a method for non-therapeutic improvement of the dynamics of postnatal growth or body development in an infant born by caesarean section by administering a nutritional composition selected from an infant formula for infants 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

The present invention relates to a method for preventing or reducing the risk of unbalanced dynamics of postnatal growth or body development in an infant at risk of unbalanced dynamics of postnatal growth or body development, said infant being born by caesarean section, said method comprising feeding said infant with a nutritional composition selected from an infant formula for infants 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is 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-stage 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content,

for use in the prevention or reduction of the risk of unbalanced postnatal growth dynamics or body development in an infant at risk of unbalanced postnatal growth dynamics or body development, said infant being delivered by caesarean section.

The invention may also be formulated as the use of fat globules for obtaining a nutritional composition selected from an infant formula for infants or a second-stage infant formula for preventing or reducing the risk of unbalanced dynamics of postnatal growth or body development in an infant at risk of unbalanced dynamics of postnatal growth or body development, said infant being born by caesarean section, wherein the nutritional composition comprises 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 comprises at least 10 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

Fat globules

According to the present invention, the nutritional composition comprises fat globules. In liquid form, these fat globules are emulsified in an aqueous phase. Alternatively, the fat globules are present in powder form, and the powder is suitable for reconstitution with water or another edible aqueous phase, preferably to obtain a ready-to-use infant formula. The fat globules consist of a core and a coating. The core preferably comprises vegetable fat and preferably comprises at least 90% by weight of triglycerides and more preferably consists essentially of triglycerides. Not all of the vegetable fats present in the composition necessarily have to be in the core of the fat globules, but preferably a major portion, preferably more than 50% by weight, more preferably more than 70% by weight, is % by weight, even more preferably more than 85 % by weight, even more preferably more than 95 % by weight, most preferably more than 98 % by weight of the vegetable fats present in the composition are contained in the core of the fat globules. In one embodiment, the core of the fat globules comprises at least 40 % by weight of triglycerides of vegetable origin, more preferably at least 50 % by weight, even more preferably at least 70 % by weight of triglycerides of vegetable origin, more preferably the core of the fat globules comprises at least 85 % by weight, more preferably at least 95 % by weight of triglycerides of vegetable origin. The fat globules in the nutritional composition in the method or use according to the present invention have a volume-weighted diameter of more than 1.0 μm, preferably more than 3.0 μm, more preferably 4.0 μm or more, preferably from 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. Furthermore, the size distribution is preferably such that 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 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 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 μm. 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. The modal diameter refers to the diameter that is most present per volume of total fat, or the peak value in a graphical representation with the diameter on the x-axis and the volume (%) on the y-axis.

The fat globule volume and its size distribution can be determined using a particle size analyzer such as the 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 according to the present invention comprises phospholipids, preferably the nutritional composition comprises phospholipids originating from the milk of mammals, preferably from the milk of mammals other than humans. Phospholipids originating from the milk of mammals other than humans include phospholipids isolated from milk fat, cream fat, whey cream 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 during the production of anhydrous milk fat from cream or butter. Preferably, the phospholipids are obtained from milk cream. Phospholipids are preferably obtained from the milk of cows, mares, sheep, goats, buffaloes, horses and camels, most preferably from cow's milk. Most preferably, a fat extract isolated from cow's milk is used. A suitable source of phospholipids derived from the milk of mammals other than humans 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 MFGM from cow's milk.

The nutritional composition contains from 0.5 to 20 wt.% phospholipids based on the total amount of 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" is meant that the outer surface layer of the fat globule contains phospholipids, while these phospholipids are substantially absent in the core of the fat globule. It has been found that the presence of phospholipids as a coating or outer layer of the fat globule in the administered diet effectively stimulates growth dynamics or body development, which is more similar to the growth dynamics of infants fed with human milk. Not all phospholipids present in the composition necessarily have to be contained in the coating, but preferably constitute a major part. 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 coating of the fat globules. Preferably, the phospholipids comprise at least 15% by weight sphingomyelin based on the total amount of phospholipids.

According to the present invention, the nutritional composition preferably comprises glycerophospholipids. Glycerophospholipids are a class of lipids formed from fatty acids esterified at the hydroxyl groups on carbon 1 and carbon 2 of the glycerol backbone and a negatively charged phosphate group attached to carbon 3 of glycerol via an ester bond and, optionally, a choline group (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 one acyl chain of fatty acid. Preferably, the present composition comprises PC, FS, FI and/or PE, more preferably at least PC.

Preferably, the nutritional composition comprises 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 comprises 0.05 to 10 wt.% sphingomyelin based on the total amount of fat, more preferably 0.1 to 5 wt.%, even more preferably 0.2 to 2 wt.%.

According to the present invention, the nutritional composition preferably comprises cholesterol. The nutritional composition preferably comprises at least 0.005 wt.% cholesterol based on the total amount of 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 wt.% of the total amount of fat, more preferably does not exceed 5 wt.%, even more preferably does not exceed 1 wt.% of the total amount of fat.

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

Infant formula or level 2 infant formula

The nutritional composition for administration in the method or use according to the present invention is selected from an infant formula or a second-stage 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 an artificial second-stage infant formula or a synthetic infant formula and a second-stage synthetic infant formula. In this context, an infant formula refers to artificially prepared nutritional compositions intended for infants aged 0 to about 4-6 months and intended as a substitute for human milk. Typically, infant formulas are suitable for use as a sole source of nutrition. Such infant formulas are also known as first-stage infant formulas. Infant formula for infants from 4-6 months of age up to 12 months of age is intended for supplementary feeding of infants who are beginning to be weaned on other foods. Such infant formula is also known as a second-level infant formula. Infant formula and second-level infant formula are subject to strict regulations, such as EU Commission Directive 2006/141/EC.

The nutritional composition preferably comprises 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 comprises carbohydrates, protein and fats, wherein fats preferably provide from 30% to 60% of the total calories, protein provides from 5% to 20% of the total calories, and carbohydrates provide from 25% to 75% of the total calories. Preferably, the nutritional composition comprises from 10 to 50% by weight of fats, 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 alpha-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 acyl chain of a fatty acid 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 comprises vegetable fats. The fat present in the nutritional composition in the method or use of the invention preferably comprises PUFAs, more preferably LC-PUFAs, since LC-PUFAs further improve the growth schedule and the development of BMI. The nutritional composition preferably comprises 5 to 35 wt.% PUFAs, more preferably 10 to 30 wt.% PUFAs, most preferably 15 to 20 wt.% PUFAs, based on the total amount of fat. In one embodiment, the fat in the nutritional composition for the method or use of the invention comprises at least 10 wt.% polyunsaturated fatty acids, based on the total amount of fat. Also preferably, the nutritional composition comprises MUFA, preferably from 10 to 80 wt.% MUFA, more preferably from 20 to 70 wt.% MUFA, most preferably from 35 to 55 wt.% MUFA based on the total amount of fat.

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

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

According to the present invention, the nutritional composition preferably comprises LC-PUFA, more preferably n-3 LC-PUFA, since n-3 LC-PUFA contribute to the preferential growth dynamics. More preferably, the nutritional composition comprises 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 are important, the content of n-3 LC-PUFA in the nutritional composition, more preferably DHA, preferably does not exceed 15 wt.% of the total fat, preferably does not exceed 10 wt.%, even more preferably does not exceed 5 wt.%. Preferably, the nutritional composition comprises 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, of the total fat. In one embodiment, the present composition comprises 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 n-6 fatty acid group, in particular arachidonic acid (ARA) and LA as its precursor, counteracts the n-3 fatty acid group, in particular DHA, EPA and ALA as their precursor, the nutritional composition contains relatively low amounts of ARA. The content of n-6 LC-PUFA, more preferably ARA, is preferably not more than 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 total fat. Since the presence of ARC is not necessary to promote growth dynamics or the development of BMI similar to that of breastfed infants, ARC may also be absent.

Palmitic acid in the sn-2 position of the triglyceride

Fat in nutritional composition for administration in the method or use according to the present invention comprises triglycerides. Triglycerides comprise a glyceride molecule to which three fatty acid residues are attached via ester bonds, which may be the same or different, and which are typically 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 comprises 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 the total amount of fat. The 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 wt.% or more based on the total amount of fatty acid present in the triglycerides, preferably more than 15 wt.%. The nutritional composition in the method or use according to the invention comprises a fat which comprises at least 10 wt.% palmitic acid based on the total amount of fat, and wherein at least 15% of the palmitic acid is present in 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 wt.%, more preferably in the range from 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, at least 20%, more preferably at least 30%, even more preferably at least 35% and most preferably at least 40% are in the sn-2 or beta position of the triglyceride.

Suitable triglycerides for the nutritional composition in the method or use according to 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 0 698 078 and/or EP 0 758 846. Another suitable source is InFat^TMfrom Enzymotec. In case these fats are obtained by trans- or interesterification of vegetable triglycerides, these sources are considered as vegetable fats in the context of the present invention. Preferably, the amount of triglyceride with an increased amount of palmitic acid residues in the sn-2 position of the triglyceride molecule, which is contained in the fat fraction of the composition to be administered according to the present method or use, 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 in the sn-2 or beta position of the triglyceride is an animal fat other than human, more preferably milk fat of a mammal other than human, even more preferably cow's milk fat. Preferably, the milk fat of a mammal other than human, 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, and not 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 wt.% based on the total amount of fat, preferably from 10 to 80 wt.% based on the total amount of fat, more preferably from 10 to 70 wt.%, 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 for improving the postnatal growth dynamics or body development of an infant born by caesarean section, said method comprising feeding said infant a nutritional composition selected from an infant formula or a second-stage infant formula containing carbohydrates, protein and fat,

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

ii) the fat comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

In other words, in an alternative embodiment, the present invention relates to a nutritional composition selected from an infant formula or a second-stage infant formula comprising 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 comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content,

for the purpose of using it to improve the dynamics of postnatal growth or body development in a breastfed infant born by caesarean section.

The invention in an alternative embodiment may also be formulated as the use of fat globules for the production of a nutritional composition selected from an infant formula for infants or a second-stage infant formula for use in improving the dynamics of postnatal growth or body development in an infant who is born by caesarean section, wherein the nutritional composition comprises 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 comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

The present invention in an alternative embodiment relates to a method for preventing or reducing the risk of unbalanced postnatal growth dynamics or body development in an infant at risk of unbalanced postnatal growth dynamics or body development, said infant being delivered by caesarean section, said method comprising feeding said infant a nutritional composition selected from an infant formula for infants or a second-stage 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 comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is 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-stage 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 comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content,

for use in the prevention or reduction of the risk of unbalanced postnatal growth dynamics or body development in an infant at risk of unbalanced postnatal growth dynamics or body development, said infant being delivered by caesarean section.

The invention in an alternative embodiment may also be formulated as the use of fat globules for the preparation of a nutritional composition selected from an infant formula or a second-stage infant formula for use in the prevention or reduction of the risk of unbalanced postnatal growth dynamics or body development in an infant at risk of unbalanced postnatal growth dynamics or body development, said infant being born by caesarean section, wherein the nutritional composition comprises 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 comprises from 10 to 70% by weight, based on the total amount of fat, of milk fat of mammals other than humans, derived from the group consisting of butter, butter fat, ghee and anhydrous milk fat, and wherein the nutritional composition comprises fat globules that have

a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume based on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content.

Non-human mammalian milk fat, as used herein, refers to all fat components of milk produced by mammals such as cows and 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% by weight of milk fat.

Butter fat in the present invention refers to all the fat 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, AMF contains more than 99% fat by weight based on total weight. It can be prepared by extracting milk fat from cream or butter. Anhydrous oil is synonymous with AMF in the present invention.

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

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

Preferably, the milk fat of mammals other than humans is anhydrous milk fat or ghee. Such milk fat sources have a high level 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 milk fat of mammals other than humans is from 10 to 70 wt.% based on the total amount of fat, preferably from 20 to 70 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.

Protein

The nutritional composition comprises proteins, preferably in the amounts specified above. Preferably, the protein provides 5% to 9% of the total calories in the nutritional composition. The protein source should be selected to meet the minimum requirements for the content of essential amino acids and to ensure satisfactory growth. Therefore, protein sources based on cow's milk proteins, such as whey, casein and mixtures thereof, and proteins based on soy, potato or pea are preferred. In the case of using whey proteins, 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 comprises at least 3 wt.% casein, based on dry weight. Preferably, the casein is intact and/or non-hydrolyzed. For the present invention, protein includes peptides and free amino acids.

Digestible carbohydrates

The nutritional composition comprises digestible carbohydrates, preferably in the above-mentioned 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 advantageously has a low glycemic index. The nutritional composition preferably comprises lactose. The nutritional composition preferably comprises a digestible carbohydrate, wherein at least 35 wt.%, more preferably at least 50 wt.%, more preferably at least 75 wt.%, even more preferably at least 90 wt.%, most preferably at least 95 % by weight of the digestible carbohydrates is lactose. On a dry weight basis, the present composition preferably comprises at least 25 wt. % lactose, preferably at least 40 wt. %.

Indigestible carbohydrates

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

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

Preferably, the nutritional composition comprises from 80 mg to 2 g of indigestible 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. In terms of dry weight, the nutritional composition preferably comprises from 0.25 to 20 wt.%, more preferably from 0.5 to 10 wt.%, even more preferably from 1.5 to 7.5 wt.%.

Application

In the method or use according to the present invention, the nutritional composition is administered to an infant or used for an infant born by caesarean section. In the context of the present invention, the infant is under 12 months of age. Preferably, the nutritional composition is administered or used for a full-term infant. The term "full-term infant" means an infant born at a gestational age of 37 to 42 weeks. Preferably, the nutritional composition is administered or used for a healthy infant. Preferably, the nutritional composition is used for at least the first 2 months of life, preferably at least the first 3 months of life of the infant, more preferably at least the first 4 months of life of the infant. 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 in an infant born by caesarean section 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 an infant, more preferably the dynamics or development of body mass index (BMI) in the first 12 months of life of an infant. In one embodiment, the improvement of the dynamics of postnatal growth or body development in an infant consists in a decrease in the increase in BMI of an infant. Preferably, the improvement is compared with the dynamics of postnatal growth or body development in an infant born by vaginal delivery, preferably an infant born by vaginal delivery fed with infant formula for infants or a second-level infant formula, as determined in accordance with the present invention. Preferably, for a fair comparison, the age of the infant and the period of time during which the nutritional composition is administered coincide.

According to the present invention, the risk of unbalanced postnatal growth dynamics or body development in an infant exposed to the risk of unbalanced postnatal growth dynamics or body development is prevented or reduced, said infant being born by caesarean section. Preferably, the growth dynamics or body development is the dynamics or development of the body mass index (BMI), preferably the dynamics or development of the body mass index (BMI) in the first 4 months of the infant's life, preferably the dynamics or development of the body mass index (BMI) in the first 12 months of the infant's life. Preferably, the prevention or risk reduction is compared with the dynamics of postnatal growth or body development in an infant born by vaginal delivery, preferably an infant born by vaginal delivery fed with infant formula or second-level infant formula as defined in accordance with the present invention. Preferably, for a fair comparison, the age of the infant and the period of time during which the nutritional composition is administered coincide.

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

In one embodiment, the infant formula or the second-stage infant formula is a powder. Accordingly, the infant formula or the second-stage infant formula is in powder form that can be reconstituted with water or another edible aqueous liquid to form a ready-to-drink liquid, or is in the form of a liquid concentrate that must be diluted with water to form a ready-to-drink liquid. It has been found that the fat globules retain their size and coating upon reconstitution.

In this document and in the claims, the verb "to comprise" and its conjugations are used in a non-limiting sense to indicate that elements following the word are included, but elements not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility of more than one element being present, unless the context clearly requires the presence of one and only one of the elements. Thus, the indefinite article "a" or "an" generally 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, 1.3 g protein (whey protein and casein in a 6/4 w/w ratio), 7.3 g digestible carbohydrates (mainly lactose), 3.4 g fat and 0.8 g short-chain galactooligosaccharides (source Vivinal ^® GOS) and long-chain fructooligosaccharides (source RaftilinHP ^® ) in a 9/1 w/w ratio per 100 ml of ready-to-use infant formula, as well as minerals, vitamins, trace elements and other micronutrients in accordance with the guidelines for infant formula. The infant formula is provided as a powder with instructions for dilution 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% of a 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 mode diameter, based on 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 infant formula)

The infant formula tested was the same as Diet 1 except for the following differences:

The fat globules in the tested infant formula had a modal diameter, calculated per volume, of approximately 5.6 µm, and the volume % of fat globules with a mode of 2 to 12 µm was greater than 45 vol.%.

The fat component consisted of about 51 wt.% vegetable fat (a mixture of low-erucic acid rapeseed oil, coconut oil, high-oleic acid sunflower oil, sunflower oil), about 44 wt.% anhydrous cow's 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 originating from buttermilk enriched with milk phospholipids or milk fat globule membranes (milk phospholipids accounted for about 1.5 wt.% based on the total fat).

The fatty acid composition was very similar between diets 1 and 2 for saturated, monounsaturated and polyunsaturated acids and for the content of n3 and n6 PUFA. 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 this 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 expressed as total fat in the infant formula unless otherwise stated.

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 infant formula (diet 2) or the control infant formula (diet 1) for a double-blind period of up to 4 months (depending on their age at study entry). 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 background information, and the parent(s) were provided with the study product and diaries. Study visits were conducted at 4 and 12 months. Information and anthropometric measurements were collected during the visits. Anthropometric measurements were taken at the 12-month visit.

A total of 4 countries with 17 study centres participated in the study and a total of 313 participants were enrolled; 6 study centres in the Netherlands (121 participants), 3 study centres in France (13 participants), 7 study centres in Belgium (158 participants) and 1 study centre in Singapore (21 participants). Of the total 313 participants enrolled in the study, 223 were randomised and 88 were assigned to the breastfeeding control group, 2 participants did not pass the screening and therefore were not randomised.

The all-to-treat (AST) data set consisted of all randomized participants (ASR, n=223) who received at least one study product. Participants (n=8) with sufficient evidence that the study 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 in 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 (efficacy) of the treatment strategy. Participant data were analyzed “as randomized” (n=223).

Per-protocol (PP) analysis limits the analysis to participants who meet the protocol in terms of eligibility, interventions, instructions/restrictions, and outcome measures. The PP data set consisted of all participants and/or participant visits from the ITT data set without any major protocol deviations (n=174). 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 (effectiveness) of the treatment. Participant data were analyzed as-received.

The following rules were applied to exclude participants from the PP dataset: age at baseline (=visit 1) ≥35 days, birth weight missed or ≥9.96th or ≥90.04th percentile (based on standard WHO child growth recommendations), head circumference at inclusion outside ±2.04 standard deviation (SD) of percentile (based on standard WHO child growth recommendations), not having at least one valid visit after baseline, starting test product consumption ≥6 days after baseline, receiving another test product as his/her twin sibling, not consuming a test product consistent with the medical history, i.e. disease/condition detected by the medical monitor. The following rules were applied to exclude individual visits from the PP dataset: any visit ˃3 days after discontinuation of the study product, except for the 12-month visit, regardless of whether the discontinuation was temporary or not, any visit ˃3 days after initiation of other infant formulas, any visit ˃3 days after initiation of solids. Forty-nine randomized participants plus individual visits were excluded.

For the non-randomized breastfed control group, data sets corresponding to the ITT and PP populations of randomized infants were also defined. The ITT data set was defined as the fully breastfed (FBF) group, with no breastfed participants excluded (n=88). The PP data set was defined as the per-protocol control breastfed (PCBF) data set, applying the appropriate rules as defined for the PP data set (n=77). The following rules were applied to exclude participants from the PCBF dataset: age at baseline ˃35 days, birth weight missing or ˂9.96th or ˃90.04th percentile (based on standard WHO child growth recommendations), head circumference at inclusion outside ±2.04 standard deviation (SD) of percentile (based on standard WHO child growth recommendations), no at least one valid visit after baseline or relevant medical history, i.e. disease/condition detected by medical monitor. The following rules were applied 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 if initiation of other infant formula occurred before 13 weeks of age, any visit ˃3 days after initiation of solids if initiation of other solids occurred before visit 4. Eleven breastfed participants plus individual visits were excluded.

Participants (randomized or breastfed) who were included in the PP/PCBF dataset, including the 4-month visits and who participated in the extension, were included in the PP dataset at the 12-month visit.

There were no statistically significant differences between the experimental groups across data sets (PP, ITT) in terms of stratification factors: gender, age at baseline (≤14 days/˃14 days), region (Europe vs. Asia). There was no difference in study duration between the experimental groups.

Table 1 provides a tabular overview of the ITT population, showing the number and percentage of participants by type of delivery, vaginal or cesarean, for the test formula, control formula, and breastfed group. Table 2 provides a similar overview for the PP population.

Table 1.

Study population statistics for delivery type in ITT population

Test (n=115) Control (n=108) Type of delivery(n(%)): Vaginal 76 (66.09%) 85 (78.70%) C-section 39 (33.91%) 23 (21.30%)

Table 2.

Statistical data of the study population for the type of delivery in the PP population

Test (n=91) Control (n=83) Type of delivery(n(%)): Vaginal 57 (62.64%) 63 (75.90%) C-section 34 (37.36%) 20 (24.10%)

At baseline, the BMI (kg/ ^m2 ) of infants delivered vaginally or by caesarean section were comparable. The BMI of these randomized infants was also comparable to that of the breastfed control group in the PP and ITT populations. At 12 months, the BMI of infants receiving the test formula was closer to that of the breastfed control group than that of infants receiving the control formula in both the PP and ITT populations.

BMI gain, calculated as change from baseline to 4 months and as change from baseline to 12 months, was compared between randomized groups (trial minus control), separately for the group of infants born by cesarean section and the group of infants born vaginally. A parametric growth curve (PGC) model was fitted taking into account the entire study period (baseline to 12 months) and adjusting for stratification factors as described herein previously. All statistical analyses 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 age) and thus describes the development of growth parameters (i.e., BMI) over time with a second-order polynomial function. It does not require that study participants be measured at the same time points. The obtained parameters are compared to assess the differences between the curves.

Tables 3 and 4 (ITT and PP populations, respectively) present the LS mean estimates for the between-group (trial minus control) difference in BMI gain by age interval and delivery type. Infants fed the control formula had a higher BMI gain than infants fed the test formula. Surprisingly, in infants delivered by cesarean section, this difference was approximately 3 times greater than in infants delivered vaginally, reaching statistical significance as early as 4 months for PP and 12 months for PP and ITT.

Table 3.

Differences in BMI gain (kg/ ^m2 ) between treatment and control groups for different types of delivery in the ITT study population

Age range Type of delivery LS mean value (SE P-value Test minus control Baseline up to 4 months Vaginal -0.218 (0.237) 0.359 C-section -0.667 (0.372) 0.074 Test minus control Baseline up to 12 months Vaginal -0.632 (0.278) 0.024 C-section -1.481 (0.409) ˂0.001

Table 4.

Differences in BMI gain (kg/ ^m2 ) between treatment and control groups for delivery types in the study population PP

Age range Type of delivery LS mean value (SE P-value Test minus control Baseline up to 4 months Vaginal -0.320 (0.269) 0.236 C-section -1.045 (0.420) 0,014 Test minus control Baseline up to 12 months Vaginal -0.617 (0.326) 0,060 C-section -1.859 (0.475) ˂0.001

Overall, the results indicate a stronger effect of the tested infant formula in infants born by caesarean section in promoting the postnatal growth or body development of infants towards a more favourable growth or body development (more similar to the growth or body development observed in breastfed infants) compared to the effect it has on infants born vaginally. Infants born by caesarean section benefit more from the supplementation than infants born vaginally in developing the desired growth or body development. Therefore, improved postnatal growth or body development is achieved in infants born by caesarean section. These results also indicate that the tested infant formula has a stronger effect in the feeding of infants born by caesarean section in preventing or reducing the risk of unbalanced postnatal growth or body development in such an infant at risk of unbalanced postnatal growth or body development than in infants born by vaginal delivery. Therefore, prevention or reduction of the risk of unbalanced postnatal growth or body development is achieved in infants born by caesarean section.

In particular, improvement in the dynamics of postnatal growth or body development or prevention in infants born by caesarean section is found in comparison with the dynamics of growth or body development in infants born by vaginal delivery and who were fed the same nutritional composition.

In particular, prevention or reduction of the risk of unbalanced dynamics of postnatal growth or body development in infants born by caesarean section is detected in comparison with the dynamics of growth or body development in infants born by vaginal delivery and fed the same nutritional composition.

Claims (36)

1. A method for non-therapeutically improving the dynamics of postnatal growth or body development in an infant born by caesarean section by administering a nutritional composition selected from an infant formula or a second-tier 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have: a) a modal diameter, calculated on a volume basis, of at least 1.0 µm and/or a diameter of 2 to 12 µm in an amount of at least 45% by volume, calculated on the 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content. 2. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to claim 1, wherein the improvement in the dynamics of postnatal growth or body development in infants born by caesarean section is detected when compared to the dynamics of growth or body development in infants born by vaginal delivery and who were fed the same nutritional composition. 3. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the composition contains less than 15% by weight of linoleic acid and more than 1% by weight of alpha-linolenic acid, calculated on the total amount of fatty acids. 4. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the dynamics of growth or body development is the dynamics or development of the body mass index (BMI). 5. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the use is intended to reduce the increase in BMI of an infant. 6. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the dynamics of growth or body development is the dynamics or development of body mass index (BMI) in the first 12 months of life of an infant. 7. A method for non-therapeutically improving the dynamics of postnatal growth or body development according to any of the preceding claims, wherein the infant is a full-term infant. 8. A method for non-therapeutically improving the dynamics of postnatal growth or development of the body according to any of the preceding claims, wherein the phospholipids comprise at least 15% by weight of sphingomyelin, based on the total amount of phospholipids. 9. A method for non-therapeutically improving postnatal growth or body development according to any of the preceding claims, wherein the nutritional composition comprises phospholipids that are derived from or form part of a milk fat globule membrane (MFGM), or are provided as 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 of the preceding claims, wherein the nutritional composition comprises from 0.5 to 20% by weight of phospholipids derived from mammalian milk, calculated 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% by weight 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 have a core containing at least 40% by weight of triglycerides of plant origin. 13. 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 is a powder suitable for reconstitution with water to form a ready-to-use infant formula. 14. Use of a nutritional composition selected from infant formula or second-stage infant formula for the prevention or reduction of the risk of unbalanced postnatal growth dynamics or body development in an infant at risk of unbalanced postnatal growth dynamics or body development, said infant being born by caesarean section, which 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 wt.% palmitic acid based on the total amount of fat, and at least 15 wt.% 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 comprises fat globules that have: a) a modal diameter based on volume of at least 1.0 µm and/or a diameter of 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 is from 0.5 to 20 wt.% phospholipids based on the total fat content. 15. The use according to claim 14, wherein the prevention or reduction in the risk of unbalanced dynamics of postnatal growth or body development in infants born by caesarean section is detected when compared with the dynamics of growth or body development in infants born by vaginal delivery and who were fed the same nutritional composition. 16. Use according to claim 14 or 15, wherein the composition contains less than 15 wt.% linoleic acid and more than 1 wt.% alpha-linolenic acid, based on the total amount of fatty acids. 17. Use according to any one of claims 14-16, wherein the dynamics of body growth or development is the dynamics or development of the body mass index (BMI). 18. Use according to any one of claims 14-17, wherein the use is intended to reduce the increase in BMI of an infant. 19. Use according to any one of claims 14-18, wherein the dynamics of body growth or development is the dynamics or development of the body mass index (BMI) in the first 12 months of life of an infant. 20. Use according to any of paragraphs 14-19, wherein the infant is a full-term infant. 21. The use according to any one of claims 14 to 20, wherein the phospholipids contain at least 15% by weight of sphingomyelin, based on the total amount of phospholipids. 22. The use according to any one of claims 14 to 21, wherein the nutritional composition comprises phospholipids which originate from or form part of the milk fat globule membrane (MFGM), or are provided as MFGM, preferably MFGM from cow's milk. 23. The use according to any one of claims 14 to 22, wherein the nutritional composition contains from 0.5 to 20% by weight of phospholipids derived from mammalian milk, based on the total amount of fat. 24. The use according to any one of claims 14 to 23, wherein at least 30% by weight of palmitic acid is esterified at the sn-2 position of the triglyceride, based on the total amount of palmitic acid. 25. The use according to any one of claims 14 to 24, wherein the fat globules have a core containing at least 40% by weight of triglycerides of plant origin. 26. The use according to any one of claims 14 to 25, wherein the nutritional composition is a powder suitable for reconstitution with water to form a ready-to-use infant formula.