Gastrointestinal Tolerance, Growth and Safety of a Partly Fermented Formula with Specific Prebiotics in Healthy Infants: A Double-Blind, Randomized, Controlled Trial

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed infants.

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A Partly Fermented Infant Formula with Postbiotics Including 3′-GL, Specific Oligosaccharides, 2′-FL, and Milk Fat Supports Adequate Growth, Is Safe and Well-Tolerated in Healthy Term Infants: A Double-Blind, Randomised, Controlled, Multi-Country Trial

Nutrients ◽

10.3390/nu12113560 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3560

Author(s):

Yvan Vandenplas ◽

Virginie de Halleux ◽

Małgorzata Arciszewska ◽

Piotr Lach ◽

Valeriy Pokhylko ◽

...

Keyword(s):

Weight Gain ◽

Infant Formula ◽

Milk Fat ◽

Controlled Trial ◽

Gastrointestinal Symptoms ◽

Test Group ◽

Control Group ◽

Anthropometric Measures ◽

Double Blind ◽

Term Infants

This study investigated growth, safety, and tolerance in healthy infants consuming a partly fermented infant formula (IF) with postbiotics, 2′-linked fucosyllactose (2′-FL), a specific prebiotic mixture of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS), and milk fat. This double-blind, controlled trial randomised 215 fully IF-fed infants ≤ 14 days of age to either: Test Group (IF) containing 26% fermented formula with postbiotics derived from Lactofidus fermentation process (including 3′-Galactosyllactose; 3′-GL), 0.8 g/100 mL scGOS/lcFOS (9:1), 0.1 g/100 mL 2′-FL, and milk fat), or Control group (IF with 0.8 g/100 mL scGOS/lcFOS (9:1)) until 17 weeks of age. Fully breastfed infants were included as a reference. Anthropometric measures, gastrointestinal symptoms, and safety were assessed monthly. Equivalence in weight gain (primary outcome) between the Test and Control groups was confirmed (difference in means −0.08 g/day; 90% CI (−1.47;1.31)) with estimated mean weight gain (SE) of 31.00 (0.59) g/day and 31.08 (0.60) g/day, respectively, (PP population, n = 196). Equivalence in length and head circumference gain between the randomised groups was also confirmed. No statistically significant differences were observed in adverse events or gastrointestinal tolerance between randomised IF groups. A partly fermented IF with postbiotics, specific oligosaccharides, 2′-FL, and milk fat supports adequate infant growth and is safe and well-tolerated in healthy term infants.

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An infant formula with large, milk phospholipid–coated lipid droplets containing a mixture of dairy and vegetable lipids supports adequate growth and is well tolerated in healthy, term infants

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy322 ◽

2019 ◽

Vol 109 (3) ◽

pp. 586-596 ◽

Cited By ~ 8

Author(s):

Laura M Breij ◽

Marieke Abrahamse-Berkeveld ◽

Yvan Vandenplas ◽

Sabine N J Jespers ◽

Amerik C de Mol ◽

...

Keyword(s):

Weight Gain ◽

Adverse Events ◽

Human Milk ◽

Infant Formula ◽

Lipid Droplets ◽

Daily Weight Gain ◽

Milk Lipid ◽

Double Blind ◽

Term Infants ◽

Breastfed Infants

ABSTRACT Background Lipid droplets in human milk have a mode diameter of ∼4 μm and are surrounded by a native phospholipid-rich membrane. Current infant milk formulas (IMFs) contain small lipid droplets (mode diameter ∼0.5 μm) primarily coated by proteins. A concept IMF was developed mimicking more closely the structure and composition of human milk lipid droplets. Objectives This randomized, controlled, double-blind equivalence trial evaluates the safety and tolerance of a concept IMF with large, milk phospholipid–coated lipid droplets (mode diameter 3–5 μm) containing vegetable and dairy lipids in healthy, term infants. Methods Fully formula-fed infants were enrolled up to 35 d of age and randomly assigned to 1 of 2 formulas until 17 wk of age: 1) Control IMF with small lipid droplets containing vegetable oils (n = 108); or 2) Concept IMF with large, milk phospholipid–coated lipid droplets comprised of 48% dairy lipids (n = 115). A group of 88 breastfed infants served as reference. Primary outcome was daily weight gain during intervention. Additionally, number and type of adverse events, growth, and tolerance parameters were monitored. Results Equivalence of daily weight gain was demonstrated (Concept compared with Control IMF: −1.37 g/d; 90% CI: −2.71, −0.02; equivalence margin ± 3 g/d). No relevant group differences were observed in growth, tolerance and number, severity, or relatedness of adverse events. We did observe a higher prevalence of watery stools in the Concept than in the Control IMF group between 5 and 12 wk of age (P < 0.001), closer to the stool characteristics observed in the breastfed group. Conclusions An infant formula with large, milk phospholipid–coated lipid droplets containing dairy lipids is safe, well tolerated, and supports an adequate growth in healthy infants. This trial was registered in the Dutch Trial Register (www.trialregister.nl) as NTR3683.

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Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial

Nutrients ◽

10.3390/nu12051481 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1481 ◽

Cited By ~ 1

Author(s):

Mireille Castanet ◽

Christos Costalos ◽

Nadja Haiden ◽

Jean-Michel Hascoet ◽

Bernard Berger ◽

...

Keyword(s):

Reference Group ◽

Controlled Trial ◽

Bovine Milk ◽

Double Blind ◽

Term Infants ◽

Early Effect ◽

Breastfed Infants ◽

Infant Formulae ◽

Formula Group ◽

Gut Maturation

Background: Post-natal gut maturation in infants interrelates maturation of the morphology, digestive, and immunological functions and gut microbiota development. Here, we explored both microbiota development and markers of gut barrier and maturation in healthy term infants during their early life to assess the interconnection of gut functions during different infant formulae regimes. Methods: A total of 203 infants were enrolled in this randomized double-blind controlled trial including a breastfed reference group. Infants were fed starter formulae for the first four weeks of life, supplemented with different combination of nutrients (lactoferrin, probiotics (Bifidobacterium animal subsp. Lactis) and prebiotics (Bovine Milk-derived Oligosaccharides—BMOS)) and subsequently fed the control formula up to eight weeks of life. Stool microbiota profiles and biomarkers of early gut maturation, calprotectin (primary outcome), elastase, α-1 antitrypsin (AAT) and neopterin were measured in feces at one, two, four, and eight weeks. Results: Infants fed formula containing BMOS had lower mean calprotectin levels over the first two to four weeks compared to the other formula groups. Elastase and AAT levels were closer to levels observed in breastfed infants. No differences were observed for neopterin. Global differences between the bacterial communities of all groups were assessed by constrained multivariate analysis with hypothesis testing. The canonical correspondence analysis (CCA) at genus level showed overlap between microbiota profiles at one and four weeks of age in the BMOS supplemented formula group with the breastfed reference, dominated by bifidobacteria. Microbiota profiles of all groups at four weeks were significantly associated with the calprotectin levels at 4 (CCA, p = 0.018) and eight weeks of age (CCA, p = 0.026). Conclusion: A meaningful correlation was observed between changes in microbiota composition and gut maturation marker calprotectin. The supplementation with BMOS seems to favor gut maturation closer to that of breastfed infants.

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Do prebiotics reduce the number of fever episodes in healthy children in their first year of life: a randomised controlled trial

British Journal Of Nutrition ◽

10.1017/s0007114511004053 ◽

2011 ◽

Vol 106 (11) ◽

pp. 1740-1748 ◽

Cited By ~ 23

Author(s):

Margriet van Stuijvenberg ◽

Annemieke M. Eisses ◽

Christoph Grüber ◽

Fabio Mosca ◽

Sertac Arslanoglu ◽

...

Keyword(s):

Reference Group ◽

Controlled Trial ◽

Formula Feeding ◽

Control Group ◽

First Year ◽

Healthy Children ◽

Double Blind ◽

Standard Formula ◽

First Year Of Life ◽

To Receive

The objective of the present study was to assess the effect of adding specific prebiotics to standard formula feeding on the number of fever episodes in the first year of life. In the present randomised, double-blind, placebo-controlled trial in seven centres in five West European countries, 830 healthy term infants, without a first-degree family history of allergic disease, of mothers who indicated to give only formula feeding were randomised either to receive a standard non-hydrolysed cows' milk-based formula to which a mixture of specific oligosaccharides was added (prebiotics group (PG)), or to receive a similar formula without oligosaccharides (control group (CG)). A separate reference group consisted of 300 breast-fed infants. The primary outcome was the number of fever episodes prospectively documented by the parents. There was no difference in the number of fever episodes between the PG (median value 1·19; 25th–75th percentile 0·09–2·34) and CG (1·16; 25th–75th percentile 0·06–2·38). The median number of fever episodes in the separate breast-feeding reference group was 1·24 (25th–75th percentile 0·51–3·45). There was no effect of adding specific prebiotics to standard formula feeding in reducing the number of fever episodes in the present study.

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A Partially Hydrolyzed Whey Infant Formula Supports Appropriate Growth: A Randomized Controlled Non-Inferiority Trial

Nutrients ◽

10.3390/nu12103056 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3056

Author(s):

Eva Karaglani ◽

Inge Thijs-Verhoeven ◽

Marjan Gros ◽

Christina Chairistanidou ◽

Giorgos Zervas ◽

...

Keyword(s):

Weight Gain ◽

Infant Formula ◽

Controlled Trial ◽

Daily Weight Gain ◽

Intact Protein ◽

Control Group ◽

Intervention Period ◽

Term Infants ◽

Randomized Controlled ◽

Secondary Outcomes

The aim of the current study was to investigate the effects of a partially hydrolyzed whey infant formula (PHF) on growth in healthy term infants as compared to a standard infant formula with intact protein (IPF). In a double-blind, non-inferiority, randomized controlled trial, a total of 163 healthy formula-fed infants, 55–80 days old, were recruited and randomly allocated to either the PHF (test) or the IPF (control) group. They were followed up for three months during which they were evaluated monthly on growth and development. In total, 21 infants discontinued the study, while 142 infants completed the study (test n = 72, control n = 70). The primary outcome was daily weight gain during the three months. Secondary outcomes included additional anthropometric indices at every timepoint over the intervention period. Daily weight gain during the three-month intervention period was similar in both groups with the lower bound of 95% confidence interval (CI) above the non-inferiority margin of −3 g/day [mean difference (95% CI) test vs. control: −0.474 (−2.460, 1.512) g/day]. Regarding secondary outcomes, i.e., infants’ weight, length, head circumference, body mass index (BMI), and their Z-scores, no differences were observed between the two groups at any time point. The PHF resulted in similar infant growth outcomes as the standard IPF. Based on these results, it can be concluded that the partially hydrolyzed whey infant formula supports adequate growth in healthy term infants.

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Stool Composition and GI Tolerance in Infants Fed a Term Infant Formula with a New Lipid Blend and Lactobacillus reuteri (L.reuteri): A Randomized Controlled Trial

Current Developments in Nutrition ◽

10.1093/cdn/nzaa054_031 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 959-959

Author(s):

Yipu Chen ◽

Rachel Lawenko ◽

Katherine Buluran ◽

Ivana Jankovic ◽

Jowena Lebumfacil ◽

...

Keyword(s):

Infant Formula ◽

Lactobacillus Reuteri ◽

Calcium Absorption ◽

Reference Group ◽

Controlled Trial ◽

Saturated Fatty Acids ◽

Gastrointestinal Symptoms ◽

Stool Consistency ◽

Intact Protein ◽

Gi Symptoms

Abstract Objectives Differences in dietary fat and calcium absorption between breastfed and formula-fed infants may impact gastrointestinal (GI) tolerance and stooling patterns. We hypothesized that infant formula containing L. reuteri and a new lipid blend with low levels of long-chain saturated fatty acids (LCSFAs) (<13% of triacylglycerols [TAG]) in sn-1,3 positions would result in reduced stool calcium-fatty acid (Ca-FA) soaps and improved stool consistency. Methods Healthy term infants 21–28 days (d) of age were randomized in a double-blind manner to receive intact protein cow's milk-based experimental formula (EF, n = 70) with new lipid blend and L. reuteri at 1 × 10,7 CFU/g or control formula (CF, n = 70) without probiotic and containing a lipid blend with high levels of LCSFAs (∼25% of TAG) in sn-1,3 positions until 3 months (m) of age. A breastfed (BF, n = 75) reference group was also included. Co-primary endpoints were stool consistency (via 3-day diary using validated scale from 1 = watery to 5 = hard) and stool total Ca-FA soaps (expressed as mg/g dry stool weight). Overall GI tolerance was assessed using a validated Infant Gastrointestinal Symptoms Questionnaire (IGSQ) (score range: 13 [no GI distress] - 65 [extreme GI distress]). Results Of 215 enrolled infants, 206 completed the study. Infants fed EF had softer stools vs those fed CF by age 1.5 m (stool consistency score: 2.6 ± 0.1 vs 3.0 ± 0.1, P < .0001) and similar to BF (2.7 ± 0.1, P = .089). This positive effect was sustained until age 3 m (EF vs CF, P = .0006; EF vs BF, P = .373; CF vs BF, P = .014), without increased stool frequency in EF vs CF group throughout the study (1.48 vs 1.50 stools/d, P = .884). Infants fed EF (vs CF) had lower stool total Ca-FA soaps at 3 m of age (60.3 ± 10.1 vs 207.9 ± 10.1, P < .0001), largely explained by stool palmitate soaps which was 7 times lower in EF vs CF (20.7 ± 7.0 vs 142.5 ± 6.9 for CF, P < .0001). Mean IGSQ scores remained very low in EF (≤16.2) and CF (≤15.6) groups over the study period. Incidences of parent-reported GI symptoms and physician-confirmed GI adverse events (including diarrhea) were low and similar for EF and CF groups. Conclusions Infant formula containing L. reuteri and enhanced lipid blend with reduced LCSFAs in sn-1,3 positions reduces stool soaps and promotes softer stools closely resembling the stools of breastfed infants. Funding Sources Sponsored by Nestle Nutrition.

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An α-lactalbumin-enriched and symbiotic-supplemented v. a standard infant formula: a multicentre, double-blind, randomised trial

British Journal Of Nutrition ◽

10.1017/s000711451100479x ◽

2011 ◽

Vol 107 (11) ◽

pp. 1616-1622 ◽

Cited By ~ 25

Author(s):

Jean-Christophe Rozé ◽

Sébastien Barbarot ◽

Marie-José Butel ◽

Nathalie Kapel ◽

Anne-Judith Waligora-Dupriet ◽

...

Keyword(s):

Atopic Dermatitis ◽

Infant Formula ◽

Controlled Trial ◽

Randomised Trial ◽

Secretory Iga ◽

Control Group ◽

Double Blind ◽

Randomised Controlled ◽

Similar Growth ◽

Experimental Group

The aim of the present study was to evaluate the safety, tolerance and preventive effect on atopic dermatitis of an experimental α-lactalbumin-enriched and symbiotic-supplemented infant formula. A total of ninety-seven non-breastfed term neonates were enrolled into a double-blind, multicentre, randomised controlled trial in which they received experimental (n 48) or standard formula (n 49) for 6 months. The primary outcome was weight at 6 months of age. Secondary outcomes were gastrointestinal tolerance and manifestation of atopic dermatitis. Faecal secretory IgA (SIgA) concentration and microbiota composition of forty-three infants were analysed at 1 and 6 months. Growth was similar in both groups. At 1 month, compared to those in the control group, infants in the experimental group exhibited less crying or agitation, and more quiet behaviour (P = 0·03). At 6 months, atopic dermatitis was less frequently observed in the experimental group (P < 0·05). Decrease of faecal SIgA concentration between 1 and 6 months was mainly observed in the control group. This decrease was significantly associated with atopic dermatitis (P < 0·014) and negatively correlated to the level of colonisation by bifidobacteria (P < 0·005). In conclusion, compared to the control formula, the experimental formula guaranteed a similar growth, was better tolerated at 1 month and had a protective effect against the development of atopic dermatitis.

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Evaluation of the safety, tolerance and efficacy of 1-year consumption of infant formula supplemented with Lactobacillus fermentum CECT5716 Lc40 or Bifidobacterium breve CECT7263: a randomized controlled trial

BMC Pediatrics ◽

10.1186/s12887-019-1753-7 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

J. Maldonado ◽

M. Gil-Campos ◽

J. A. Maldonado-Lobón ◽

M. R. Benavides ◽

K. Flores-Rojas ◽

...

Keyword(s):

Breast Milk ◽

Infant Formula ◽

Controlled Trial ◽

Study Groups ◽

Control Group ◽

Milk Formula ◽

Powdered Infant Formula ◽

Double Blind ◽

Bifidobacterium Breve ◽

Link Type

Abstract Background The microorganism present in breast milk, added to other factors, determine the colonization of infants. The objective of the present study is to evaluate the safety, tolerance and effects of the consumption of a milk formula during the first year of life that is supplemented with L. fermentum CECT5716 or Bifidobacterium breve CECT7263, two strains originally isolated from breast milk. Methods A randomized, double blind, controlled, parallel group study including healthy, formula-fed infants was conducted. Two hundred and thirty-six 1-month-old infants were selected and randomly divided into three study groups according to a randomization list. Infants in the control group received a standard powdered infant formula until 12 months of age. Infants in the probiotic groups received the same infant formula but supplemented with L. fermentum CECT5716 Lc40 or B. breve CECT7263. Main outcome was weigh-gain of infants as safety marker. Results One hundred and eighty-nine infants completed the eleven months of intervention (61 in control group, 65 in Lf group and 63 in Bb group). The growth of infants in the three groups was consistent with standards. No significant differences were observed in the main outcome, weight-gain (Control group: 5.77 Kg ± 0.95, Lf group: 5.77 Kg ± 1.31, Bb group: 5.58 Kg ± 1.10; p = 0.527). The three milk formulae were well tolerated, and no adverse effects were related to the consumption of any of the formula. Infants receiving B. breve CECT7263 had a 1.7 times lower risk of crying than the control group (OR = 0.569, CI 95% 0.568–0.571; p = 0.001). On the other hand, the incidence of diarrhoea in infants receiving the formula supplemented with L. fermentum CECT5716 was a 44% lower than in infants receiving the control formula (p = 0.014). The consumption of this Lactobacillus strain also reduced the duration of diarrhoea by 2.5 days versus control group (p = 0.044). Conclusions The addition of L. fermentum CECT5716 Lc40 or B. breve CECT7263, two probiotic strains naturally found in breast milk, to infant formulae is safe and induces beneficial effects on the health of infants. Trial registration The trial was retrospectively registered in the US Library of Medicine (www.clinicaltrial.gov) with the number NCT03204630. Registered 11 August 2016.

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Infant formula with galacto-oligosaccharides (OM55N) stimulates the growth of indigenous bifidobacteria in healthy term infants

Beneficial Microbes ◽

10.3920/bm2015.0168 ◽

2016 ◽

Vol 7 (4) ◽

pp. 453-461 ◽

Cited By ~ 19

Author(s):

T. Matsuki ◽

S. Tajima ◽

T. Hara ◽

K. Yahagi ◽

E. Ogawa ◽

...

Keyword(s):

Infant Formula ◽

Controlled Trial ◽

Shannon Index ◽

Present Species ◽

Double Blind ◽

Term Infants ◽

Breastfed Infants ◽

Trial Onset ◽

Α Diversity ◽

Faecal Samples

The objective of the study was to investigate whether an infant formula supplemented with galacto-oligosaccharides (GOS; OM55N) was able to stimulate the growth of indigenous bifidobacteria and to establish microbiota similar to that of breastfed infants. A randomised, double-blind, placebo-controlled trial was performed using 35 healthy term infants (31-54 days of age; 42±6 days) to determine whether infant formula with 0.3 g/dl GOS (OM55N) stimulated the growth of bifidobacteria in the infants’ guts. At the trial onset and 2 weeks after, the infants’ faecal samples were examined for microbiota composition (bacterial abundance and α-diversity) and faecal characteristics. Among the 35 infants, 5 were withdrawn and 8 were excluded from the final evaluation before breaking the blinding since the indigenous bifidobacteria were not detected at the trial onset. After 2 weeks, the abundance of Bifidobacteriaceae was significantly increased in the GOS feeding group compared to the control (+11.6±24.1% vs -3.9±13.0%; P=0.043). The Shannon index, which accounts for both abundance and evenness of the present species, was significantly decreased with GOS supplementation (-0.1±0.4 vs +0.4±0.4; P=0.014). Faecal characteristics such as pH and organic acids were similar in both groups, with no statistical differences. No adverse side effects related to the formula consumption were reported. Although the concentration of GOS was relatively low, the infant formula with GOS increased the abundance of bifidobacteria and resulted in a reduced α-diversity of the microbiota.

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Long-Term Safety and Efficacy of Prebiotic Enriched Infant Formula—A Randomized Controlled Trial

Nutrients ◽

10.3390/nu13041276 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1276

Author(s):

Franka Neumer ◽

Orenci Urraca ◽

Joaquin Alonso ◽

Jesús Palencia ◽

Vicente Varea ◽

...

Keyword(s):

Infant Formula ◽

Controlled Trial ◽

Fecal Microbiota ◽

First Year ◽

Double Blind Study ◽

Double Blind ◽

Term Infants ◽

Intention To Treat ◽

Prebiotic Oligosaccharides ◽

First Year Of Life

The present study aims to evaluate the effects of an infant formula supplemented with a mixture of prebiotic short and long chain inulin-type oligosaccharides on health outcomes, safety and tolerance, as well as on fecal microbiota composition during the first year of life. In a prospective, multicenter, randomized, double-blind study, n = 160 healthy term infants under 4 months of age were randomized to receive either an infant formula enriched with 0.8 g/dL of Orafti®Synergy1 or an unsupplemented control formula until the age of 12 months. Growth, fever (>38 °C) and infections were regularly followed up by a pediatrician. Digestive symptoms, stool consistency as well as crying and sleeping patterns were recorded during one week each study month. Fecal microbiota and immunological biomarkers were determined from a subgroup of infants after 2, 6 and 12 months of life. The intention to treat (ITT) population consisted of n = 149 infants. Both formulae were well tolerated. Mean duration of infections was significantly lower in the prebiotic fed infants (p < 0.05). The prebiotic group showed higher Bifidobacterium counts at month 6 (p = 0.006), and higher proportions of Bifidobacterium in relation to total bacteria at month 2 and 6 (p = 0.042 and p = 0.013, respectively). Stools of infants receiving the prebiotic formula were softer (p < 0.05). Orafti®Synergy1 tended to beneficially impact total daily amount of crying (p = 0.0594). Supplementation with inulin-type prebiotic oligosaccharides during the first year of life beneficially modulates the infant gut microbiota towards higher Bifidobacterium levels at the first 6 months of life, and is associated with reduced duration of infections.

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