Intervention Review

You have free access to this content

Prebiotics in infants for prevention of allergy

  1. David A Osborn1,*,
  2. John KH Sinn2

Editorial Group: Cochrane Neonatal Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 23 AUG 2012

DOI: 10.1002/14651858.CD006474.pub3


How to Cite

Osborn DA, Sinn JKH. Prebiotics in infants for prevention of allergy. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD006474. DOI: 10.1002/14651858.CD006474.pub3.

Author Information

  1. 1

    University of Sydney, Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, Sydney, NSW, Australia

  2. 2

    Royal North Shore Hospital, The University of Sydney, Department of Neonatology, Sydney, New South Wales, Australia

*David A Osborn, Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, NSW, 2050, Australia. david.osborn@email.cs.nsw.gov.au.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 28 MAR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Gruber 2010

MethodsRandomised double-blind, placebo-controlled trial


ParticipantsInclusion criteria: healthy, term infants (gestation 37 to 42 weeks) with birth weight >10th percentile and <90th percentile for gestational age, age up to eight weeks, without a positive history of allergic disease (hay fever, asthma or AD) of any parent or sibling and without a metabolic disorder requiring a special diet

Exclusion criteria: mothers with hepatitis B, HIV, or group B streptococcal infection during pregnancy; mothers taking antibiotics during breast-feeding; infants with known congenital or postnatal diseases that could interfere with the study; and study pre-feedings of the infants that could interfere with the study


InterventionsPrebiotics group (n=414): received a regular non-hydrolyzed cow’s milk–based formula to which a specific mixture of neutral scGOS and lcFOS ratio 9:1 (85% weight) and specific pAOS (15% weight). The total amount of oligosaccharides was 8 g/L with 6.8 g/L neutral and 1.2 g/L pAOS

Control group (n=416): received a similar regular non-hydrolyzed cow’s milk–based formula without added oligosaccharides

For both groups, starter formula was provided during the first six months of life; thereafter, follow-on formula offered. Infants randomised to the prebiotic group continued to receive the oligosaccharides in the follow-on formula

It was advised to all participating mothers not to start weaning from either exclusive formula feeding before the age of four months


OutcomesPrimary outcome: incidence of fever episodes in healthy term-born infants during the first year of life

Secondary outcomes: Included atopic dermatitis diagnosed according to the criteria recommended by the European Task Force on Atopic Dermatitis

Primary endpoint occurrence of AD up to the first birthday. Eczema free survival was defined as the length of time from randomisation to the first occurrence of eczema. For patients who left the study without AD, eczema free survival was conservatively defined as the time from randomisation to the last date on which the patient was known to be free of eczema (censored observations)


NotesSponsored: C Gruber receives honoraria from Danone. F Mosca receives research support from Danone/Numico. CP Braegger has consultant arrangements and receives research support from Danone. J Riedler is on the advisory board for Numico and receives research support from MIPS. U Wahn receives research support from Danone


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation stratified according to study centre. Time-balanced randomisation performed with the software RANCODE professional 3.6 with a random permuted block size of four

Allocation concealment (selection bias)Low riskRandomisation to one of the two formula groups performed immediately after study entry. The hospital pharmacist only had a copy of the randomisation list with the actual treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe tins and the milk powder looked and smelled identical. The parents and the study physicians were unaware of the group allocation

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe study nurses were unaware of the group allocation

Incomplete outcome data (attrition bias)
All outcomes
High riskIt is unclear whether 300 breast feeding women were part of initial randomisation. 129 patients (11%) dropped out: prebiotic group n=53 (eight change to another formula, 10 intolerance of formula, seven 'occurrence of any disease', 28 withdrawals); control group n=42 (10 change to another formula, seven intolerance of formula, six occurrence of any disease, 19 withdrawal)

Selective reporting (reporting bias)Low riskProtocol reported secondary outcome atopic dermatitis during first 12 months

Other biasUnclear riskGroups well balanced after allocation

Target sample size 1500, only 1130 infants participated. Reason for premature stopping not reported

Moro 2006

MethodsRandomised placebo-controlled trial


ParticipantsInclusion criteria: term infants with a parental history of atopic eczema, allergic rhinitis, or asthma in either mother or father. Gestational age 37 to 42 weeks, birth weight appropriate for gestational age, and start of formula feeding within the first two weeks of life
Exclusion criteria: infant excluded if breast feeding continued beyond six weeks


InterventionsBoth formula based on extensively hydrolysed cow's milk whey protein supplemented with:
Prebiotic group (n=129): 0.8 grams GOS/FOS per 100 mL, or
Control group (n=130): 0.8 grams maltodextrin per 100 mL
Co-interventions: none reported


OutcomesPrimary outcomes: atopic dermatitis to two years
Other outcomes: infant examined for atopic dermatitis according to diagnostic criteria described by Harrigan and Rabinowitz and Muraro et al
Definition:
Atopic dermatitis: pruritus, involvement of the face, skull facial and/or extensor part of the extremities, and a minimal duration of the symptoms of four weeks. The severity of the skin alterations was scored by the SCORAD index

Asthma: ≥ 3 episodes physician diagnosed wheeze

Urticaria: ≥ 2 episodes urticaria precipitated by same antigen
Anthropometric measurements, recording of crying, regurgitation, vomiting, and stool characteristics


NotesSponsored: grant from Numico Research Friedrichsdorf, Germany and the EARNEST program

Data for allergy outcomes at two years calculated from percentages


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table. Time balanced randomisation was performed with the software RANCODE with a random permuted block size of four

Allocation concealment (selection bias)Low riskRandomisation occurred when formula started

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention "maintained by coding the two trial formulae with the suffix ‘‘N’’ or ‘‘O’’ to the product name."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow up: 53/259 (20%) at six months. Only 134/259 reported at two years (48% losses)

Selective reporting (reporting bias)Low risk

Other biasLow riskGroups well balanced after allocation

Westerbeek 2010

MethodsDouble-blind placebo-controlled randomised trial


ParticipantsInclusion criteria: preterm infants gestational age < 32 weeks and/or birth weight < 1500 grams

Exclusion criteria: gestational age ≥ 33 weeks, major congenital or chromosomal anomalies, death within 48 hours after birth and transfer to another hospital within 48 hours after birth


InterventionsRandomly allocated to receive:

Treatment group (55): enteral acidic and neutral oligosaccharides supplementation (20%/80%) or

Control group (n=58): placebo supplementation (maltodextrin)

Supplementation of prebiotics or placebo was administered in increasing doses between days three and 30 of life to a maximum of 1.5 g ⁄ kg ⁄ day to breast milk or preterm formula

Exclusive breast milk - prebiotic group: 38/55 (69%); control: 33/58 (57%)


OutcomesPrimary outcome: infectious morbidity

Other outcomes:

Atopic dermatitis and bronchial hyperreactivity needed to be physician - diagnosed to one year

To determine the incidence of allergic and infectious disease in the first year of life standardized questionnaires sent to the parents prior to the follow-up visit at the corrected age of one year

The role of acidic and neutral oligosaccharides in modulation of the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora

Incidence of allergic and infectious disease in the first year of life standardized questionnaires sent to the parents prior to the follow-up visit at the corrected age of one year

Faecal samples (FISH, calprotectin and IL-8) and IgE/IgG4 levels in blood measured at the age of five and 12 months
Neurodevelopmental outcome, neurological status, vision, hearing and Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II (BSID-II) at the corrected age of one and two years


NotesAllergy outcomes reported in conference abstract only to date

Sponsor: Danone Research, Friedrichsdorf, Germany


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation table

Allocation concealment (selection bias)Low risk

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInvestigators, parents, medical and nursing staff were blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Incomplete outcome data (attrition bias)
All outcomes
High risk11 infants died, three excluded. Of survivors 10/102 (10%) not reported. Overall, 19% not followed for allergy outcomes

Selective reporting (reporting bias)Low riskDefinition and time point for atopic dermatitis and bronchial hyper-reactivity pre-specified

Other biasUnclear riskGroups well balanced after allocation but, of those followed up, baseline characteristics not reported to date

Ziegler 2007

MethodsDouble-blind, randomised, controlled, parallel-group, prospective trial was conducted at 14 clinical sites


ParticipantsInclusion criteria: healthy term infants, gestational age > 37 weeks, birth weight > 2500 grams, and solely formula fed for at least 24 hours before randomisation
Exclusion criteria: history of disease or congenital malformation, evidence of formula intolerance or poor intake, weight at visit 1 of <98% of birth weight, or born large-for-gestational age from a mother who was diabetic at childbirth


InterventionsFormula feeding began after randomisation on visit one (14 days of age) and was to be continued through 120 days of age
Prebiotic group 1 (n = 74): control formula supplemented with 4 g/L of a prebiotic blend containing polydextrose (PDX) and galacto-oligosaccharides (GOS), 50:50 ratio
Prebiotic group 2 (n = 76): control formula supplemented with 8 g/L of a prebiotic blend containing PDX, GOS, and lactulose (LOS), 50:33:17 ratio
Control group (n = 76): control group (Enfamil LIPIL with iron, Mead Johnson & Co, Evansville, IN)
Co-interventions: none reported


OutcomesPrimary outcomes: overall growth and tolerance in healthy term infants to 120 days
Other outcomes: anthropometric measurements and adverse events
Definition: physician (paediatrician or family doctor) diagnosed eczema entered into participant's diary. No definition given for eczema


NotesSponsored: supported by a grant from Mead Johnson & Co. Co-authors from Mead Johnson Nutritionals, Evansville, IN
Treatment groups one and two are combined in comparisons 01 and 01 in the review. Numbers are calculated from reported percentages

No allergy outcomes reported to date


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not reported

Allocation concealment (selection bias)Low risk

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskReported to be 'double-blind' but details not reported

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskReported to be 'double-blind' but details not reported

Incomplete outcome data (attrition bias)
All outcomes
High risk62/226 (27%) did not complete study

Selective reporting (reporting bias)Unclear riskPhysician (paediatrician or family doctor) diagnosed eczema entered into participant's diary. No definition given for eczema

Other biasLow riskGroups well balanced after allocation

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alliet 2007Enrolled healthy, term infants with a normal birth weight, without double heredity for atopic diseases. Formula fed infants in first six months were randomised to receive a standard infant formula with a specific mixture of GOS/FOS or control formula

Did not report allergy

Ashley 2008Double-blind, randomised trial cow's milk-based infant formula versus formula supplemented with 4 g/L (1:1 ratio) of a prebiotic blend of PDX and GOS or 4 g/L of GOS alone. Reported adverse events and tolerance. Did not report allergy

Bakker-Zierikzee 2005Enrolled infants with normal birth weight and no congenital abnormality, congenital disease or gastrointestinal disease within 3 days after delivery. Randomised to prebiotic (galacto-oligosaccharide and fructo-oligosaccharide) versus probiotic (Bifidobacterium animalis) versus standard formula. Did not report allergy

Ben 2004271 term infants randomly assigned to test formula supplemented with GOS 2.4 g/L or another formula without oligosaccharide

Did not report allergy

Bisceglia 2009Double-blind, clinical trial on 76 consecutive healthy newborns randomly assigned to receive a formula containing 0.8 g/dL mixture of scGOS and lcFOS (ratio 9:1), or maltodextrin placebo for 28 days

Did not report allergy

Boehm 200225 preterm infants gestational age < 32 weeks randomised to formula supplemented with 90% GOS and 10% FOS or control

Did not report allergy

Bongers 200738 constipated infants aged 3 to 20 weeks randomised to new formula (containing high concentration of sn-2 palmitic acid, mixture of prebiotic oligosaccharides and partially hydrolyzed whey protein) or a standard formula

Did not report allergy

Brunser 2006Randomised healthy term infants to prebiotic (FOS) supplemented formula, probiotic (Lactobacillus johnsonii) or control

Did not report allergy

Bruzzese 2009Healthy infants aged between 15 and 120 days randomised to a formula with added mixture of galacto- and fructo-oligosaccharides or a control formula

Did not report allergy

Chouraqui 2008Randomised trial in healthy full-term infants exclusively fed a control formula or study formulas containing various probiotic and prebiotic combinations

Did not report allergy

Costalos 2008Healthy term infants randomised to formula with mixture galacto- and long-chain fructo oligosaccharides or the same formula without added prebiotic

Did not report allergy

Decsi 2005Randomised healthy infants to oligosaccharide supplemented formula or control

Did not report allergy

Euler 2005Randomised, crossover study of fructo-oligosaccharide supplement

Fanaro 2005Vaginally born healthy infants randomly allocated to term infant formula supplementation with 0.2 g/dL of acidic OS, or concentration of acidic OSs in human milk or with maltodextrin

Did not report allergy

Fanaro 2009172 healthy infants four to six months old being weaned from breast feeding randomised to standard follow-on formula with 5 g/L maltodextrins (control) or a standard follow-on formula supplemented with 5 g/L GOS

Did not report allergy

Indrio 2009a32 newborns randomly received prebiotic-added formula (0.8 g/dl of a mixture from scGOS and lcFOS, ratio 9:1) (n=10), a probiotic-added formula (L. reuteri 1x108 CFU per day, delivered in an oil formulation) (10) and 12 newborns were fed with an indistinguishable placebo formulation for 30 days

No allergy outcomes reported to date

Indrio 2009b20 term infants randomly assigned to receive GOS-FOS mixture or placebo (maltodextrin) for one month. Published in abstract form only to date

No allergy outcomes reported to date

Indrio 2009c20 healthy preterm infants randomised to prebiotic supplemented standard preterm formula (0.8 g/dL of a mixture from scGOS and lcFOS, ratio 9:1) or the same formula supplemented with the same quantity of maltodextrin as placebo

Did not report allergy

Kapiki 2007Bottle-fed preterm infants randomised to receive formula with fructo-oligosaccharides or same formula with maltodextrin as a placebo for 14 days

Did not report allergy

Kim 2007Randomised bottle fed infants at 12 weeks to formula with inulin or control formula

Did not report allergy

Knol 2005Randomised healthy formula-fed infants aged 7 to 8 weeks to formula supplemented with GOS and FOS or standard formula

Did not report allergy

Kukkonen 2006Randomised mothers to probiotics or placebo and their infants to probiotics mixed with prebiotic oligosaccharide (i.e. synbiotic) or to placebo (no probiotic or prebiotic)

Study included in review on probiotics

Magne 2008Randomised healthy, full-term, partially breast-fed children, from 1 week to 3 months old, to whey-based formula (control group), whey-based formula with galacto- and long-chain fructo-oligosaccharides, or whey-based formula with galacto and long-chain fructo-oligosaccharides added with pectin derived acidic OSs

Did not report allergy

Manzoni 2009Patients were 472 VLBW infants randomly assigned to orally administered BLF (100mg/d) alone (n=153), BLF plus LGG (6x109 cfu/d) (n=151) or placebo (n=168) from birth until day 30 of life

Did not report allergy

Mihatsch 2006Randomised preterm infants to B. lactis or placebo

Did not report allergy to date

Modi 2010Multicentre randomised controlled trial in infants born gestational age ≤ 32 + 6 weeks and appropriately grown for gestational age. Infants were randomised within 24 h of birth to preterm formula containing 0.8 g/100 mL short chain galacto-oligosaccharides/long chain fructo-oligosaccharides in a 9:1 ratio and an otherwise identical formula, using formula only to augment insufficient maternal milk volume

Did not report allergy

Moro 200290 term infants randomly assigned to one of three formulas, oligosaccharide mixture at concentrations: 0.8 g/dL and 0.4 g/dL or control formula

Did not report allergy

Nakamura 2009Randomised healthy term infants to control or control formula supplemented with polydextrose (PDX) and GOS, or with PDX, GOS, and lactulose

Did not report allergy

Panigrahi 2008Randomised healthy newborns > 35 weeks gestational age and >1800 g birth weight to Lactobacillus plantarum and fructo-oligosaccharides or placebo

Did not report allergy

Puccio 2007Randomised healthy term infants to formula containing Bifidobacterium longum BL999 and prebiotic mixture. Did not report allergy

Rinne 2005Study of breast fed, formula fed with a formula supplemented with prebiotic or breast fed by mothers who had been given probiotics

Non-random allocation

Riskin 2010Randomised controlled trial in 23 to 34 week premature infants of 1% lactulose versus 1% dextrose in feeds. Did not report allergy

Salvini 2011Randomised, placebo-controlled study enrolling 20 newborns of hepatitis C virus-infected mothers who decided not to breast feed assigned to either a formula with 8 g/L of a specific prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides, ratio 9:1) or a formula containing the same amount of maltodextrin (placebo)

Did not report allergy. Infants who developed metabolic, endocrinologic, and immunologic disorders, lactose intolerance and/or allergy to cow’s milk as well as assumption of other pre- or probiotics were planned to be excluded from the study

Savino 2003Observational study of formula containing fructo- and galacto-oligosaccharides, partially hydrolysed proteins, low levels of lactose and palmitic acid in the beta position and higher density in term infants with gastrointestinal symptoms

Did not report allergy

Savino 2005Randomised trial of formula containing fructo- and galacto-oligosaccharides, partially hydrolysed proteins, low levels of lactose and palmitic acid in the beta position and higher density in term infants with gastrointestinal symptoms

Did not report allergy

Scholtens 2006Infants aged 4 to 6 months who were about to start consuming solid foods were randomised to weaning products with a mixture of GOS/FOS or control for six weeks

Did not report allergy

Shadid 2007Randomised pregnant women to prebiotic supplementation during pregnancy ceasing at delivery. Infants not treated

Reported infant eczema

Singhal 2008Infants randomly assigned to nucleotide-supplemented (31 mg/L; n=100) or control formula without nucleotide supplementation (n=100) from birth to the age 20 weeks

Did not report allergy

Underwood 2009Randomised 90 premature infants treated to dietary supplement of 2 lactobacillus species plus fructo-oligosaccharides, a supplement containing lactobacilli and bifidobacteria plus fructo-oligosaccharides or placebo

Did not report allergy

van den Berg 2004Randomised controlled trial enteral glutamine supplementation (L-glutamine 0.3 g/kg/day) from day 3 to 30 for prevention of allergic and infectious diseases during the first year of life

Glutamine not demonstrated to have a prebiotic effect

Vivatvakin 2010Randomised infants to a whey-predominant formula containing long-chain polyunsaturated fatty acids, galacto-oligosaccharides and fructo-oligosaccharides, and infants fed a control casein-predominant formula without additional ingredients. Differences between formulas more than just prebiotic

No allergy outcomes reported to date

Vlieger 2009126 newborns were randomised to receive a prebiotic-containing starter formula supplemented with Lactobacillus paracasei ssp. paracasei and Bifidobacterium animalis ssp. lactis or the same formula without probiotics for the first three months of life. Both groups received prebiotic

Reported rash at three months but not eczema

Ziegler 2007aRandomised non-breast fed infants to partially hydrolyzed whey formula with DHA and ARA or the same formula with a prebiotic and probiotics. No prebiotic only group. Published in abstract form only to date

No allergy outcomes reported to date

 
Characteristics of studies awaiting assessment [ordered by study ID]
Campeotto 2011

MethodsRandomised, double-blind

ParticipantsInclusion criteria:

  • preterms with gestational age ranging from 30 to 35 weeks
  • eutrophic
  • formula feeding


Exclusion criteria:

  • malformation or metabolic disease
  • newborns whose parents did not provide informed consent
  • contraindication to enteral feeding

InterventionsIntervention: infant formula adapted for pre-term infants that included in its manufacturing process a fermentation step with two probiotic strains, Bifidobacterium breve C50 and Streptococcus thermophilus 065, inactivated by heat at the end of the process

Control: same formula without fermented heat inactivated probiotic

OutcomesPrimary outcome measures: follow-up of the number of colonized infants and the bacterial colonization levels
Secondary outcome measures: clinical tolerance, Levels of intestinal immune and inflammatory markers

NotesInactivated organisms potentially prebiotic

No allergy outcomes reported to date

Hicks 2010

MethodsRandomised, parallel, double-blind

ParticipantsInclusion criteria:

  • healthy, term infants


Exclusion criteria:

  • breast fed infants
  • use of vitamin/mineral supplements
  • currently on medication

InterventionsCow's milk based infant formula with prebiotic

Cow's milk based infant formula without prebiotic

OutcomesPrimary outcome measures: calcium absorption at 14 days
Secondary outcome measures: vitamin D levels at 14 days

NotesPublished in abstract form only to date

No allergy outcomes reported to date

Holscher 2012

MethodsRandomised controlled trial

ParticipantsInclusion criteria: healthy, full-term (37–42 weeks gestation) infants 2–8 weeks old and whose mothers had elected not to continue breastfeeding and who had not received solid foods

Exclusion criteria: known or suspected cow milk allergy; major deformities and/or illness, including cardiovascular, GI, renal, neurological, and/or metabolic; admission to intensive care or required readmission to hospital in the first 14–28 days of life; diarrhoea requiring treatment in the 7 days prior to enrolment; or receiving therapeutic iron supplementation or medication other than multivitamin supplement. In addition, infants receiving antibiotic therapy, or breast fed infants whose mothers had received antibiotic therapy, within 30 days prior to enrolment

InterventionsRandomised to receive:

Teatment (n=43): partially hydrolyzed whey infant formula (Nestlé Good Start Supreme DHA/ARA, Florham Park, NJ) with or without 4g/L galacto-oligosaccharides and short chain fructo-oligosaccharides (9:1), or

Control (n=46): partially hydrolyzed whey infant formula (Nestlé Good Start Supreme DHA/ARA, Florham Park, NJ)

OutcomesFaecal bifidobacteria proportion in infants fed formula with or without prebiotic for 6 weeks

NotesNo allergy outcomes reported to date

Sponsor: financial support was provided by Nestlé Nutrition, Florham Park, NJ. The publication of the supplement in which this article appears is sponsored by Nestlé Nutrition Institute

Nyankovskyy 2008

MethodsRandomised controlled trial

ParticipantsInfants of whom the mothers had decided not to breast feed in first 2 weeks of life

Interventions80 infants in the intervention group received prebiotic formula containing a specific mixture of 0.8g/100ml galacto-oligosaccharides /fructo-oligosaccharides. 80 infants in the control group were fed with the same formula without GOS/FOS

OutcomesSaliva SIgA, alpha-defensins HNP1-3 and faecal lysozyme determined by an ELISA method. Gut microbiota composition assessed in 2 months after onset of the study. Growth parameters (weight, length, head circumference and BMI) determined at enrolment and in 1 and 2 months

NotesPublished in abstract form only to date. No allergy outcomes reported to date

Scalabrin 2012

MethodsMulticentre, randomised, double-blind, parallel-designed study

Participants19 to 35-day old healthy term, vaginally delivered infants

InterventionsRandomised to receive Enfamil Lipil® (Control, Mead Johnson) or control and galacto-oligosaccharide and polydextrose (4 g/L, 1:1 ratio) for 60 days

OutcomesSafety, acceptance, and tolerance of an infant formula supplemented with GOS and PDX and its impact on growth, stool characteristics, faecal microbiota and sIgA

NotesPublished in abstract form only to date

No allergy outcomes reported to date

Vanderhoff 2010

MethodsDouble-blind, parallel design randomised controlled trial

Participants419 healthy infants

InterventionsRandomised to receive from 14 to 120 days of age:

1. cow's milk based infant formula (Enfamil LIPIL, Mead Johnson Nutrition, Evansville, IN; Control) (n = 142) or 2. investigational formulas were supplemented with PDX:GOS 50:50 blend, 4 g/L (n = 139) or

3. investigational formulas were supplemented with GOS, 4 g/L (n = 138)

OutcomesAnthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age

Daily recall of formula intake, tolerance, and stool characteristics was collected from study days 1 to 14 and 24-h recall was collected at 60, 90, and 120 days of age

Medically-confirmed adverse events were recorded throughout

NotesMead Johnson Nutrition, Evansville, IN

Veereman-Wauters 2008

MethodsRandomised, double-blind, placebo-controlled trial

ParticipantsInclusion criteria: term, healthy babies with exclusive formula feeding and normal feeding behavior enrolled before day 5 (n=110)

Exclusion criteria: born by cesarean section, and/or had respiratory, neurological, or GI problems, infections, use of antibiotics by the baby (including eye or nose drops) or by mother in the breast-fed group, fever, feeding problems, the need for therapeutic formulae (semi-elemental, hydrolyzed) or formula thickeners or cereals

InterventionsInfants were randomly assigned to 1 of 4 formula-fed groups for 28 days:
1. standard formula without enrichment (control; n=21)

2. standard formula enriched with SYN1 4 grams/L (n=21)

3. standard formula enriched with SYN1 8 grams/L (n=20) or

4. standard formula enriched with GOS:FOS (90:10) 8 g/L (n=19)

SYN1 = Orafti Synergy1 - a 50:50 combination of oligofructose and long-chain inulin

OutcomesTolerance and bifidogenic effect

Outcomes: weight, length, intake, stool characteristics, crying, regurgitation, vomiting, adverse events, and faecal bacterial population counts

NotesNo allergy outcomes reported to date. Adverse events monitored

Sponsor: supported by Beneo-Orafti

Zoeren-Grobben 2009

MethodsDouble blind placebo-controlled randomised prospective cohort study

ParticipantsHeathy term infants with intercurrent diseases: diarrhoea and respiratory infections

1. healthy term infants with a post-menstrual age of 37 - 42 weeks, either sex
2. birth weight between P10 and P90
3. informed consent of both parents

Exclusion criteria:

1. neonatal sepsis
2. severe congenital malformations
3. birth asphyxia (Apgar less than six at 5 minutes, and/or umbilical cord pH less than 7.00 and/or necessity of reanimation)
4. admission to a paediatric ward
5. no Dutch or English speaking parents
6. antibiotics to the mother during labour
7. antibiotics to the infant in the first week of life
8. history of allergy with parents or siblings

InterventionsTreatment consists of three types of infant formula:
1. standard infant formula (frisolac 1) without addition of prebiotic or probiotics
2. standard infant formula with addition of galacto-oligosaccharides (GOS); 0.8 g/100 ml (Vivinal Domo, The Netherlands. GOS 10 contains: galacto-oligosaccharide 28.5%, lactose 36%, glucose 9.5%, galactose 0.5%, proteins 17.5%, minerals 3.5%, fat 1.5%, moisture 3.0%)
3. standard infant formula with addition of a mixture of prebiotic (GOS [the same as B]) and a probiotic mixture consisting of lactobacillus casei CRL 431 2 x 100,000/ml and Bifidobacterium lactis BB 2 x 100,000/ml
The total duration of treatment 6 months

OutcomesPrimary outcomes:

1. frequency, incidence and duration of diarrhoea and respiratory infections, measured during the first 6 months of life and evaluated by the questionnaires
2. composition of gut flora, evaluated at week 6, 3 months and 6 months of life

Secondary outcomes:

1. growth (head circumference, length and weight), measured in the out-patient clinic at 3 and 6 months
2. feeding tolerance (pattern of defecation, consistence of faeces, crying, vomiting, stomach ache), assessed with standardised questions

NotesCompleted, publication pending

 
Characteristics of ongoing studies [ordered by study ID]
Agostoni 2006

Trial name or titleRandomized, Double Blind Study to Evaluate the Safety and Efficacy of an Infant Formula Supplemented With Galacto-oligosaccharides (GOS) in Healthy, Full Term Infants

MethodsRandomised, parallel assignment, double blind

ParticipantsInclusion criteria:

  1. healthy infants of both sexes, born at term with natural labor or caesarean birth
  2. single birth
  3. infant born between 37th - 42th gestation week (included)
  4. infant with birth weight ≥ 2500 grams
  5. Apgar score after 5 minutes of life > 7
  6. infant born from parents of Caucasian race
  7. exclusive breast feeding or formula feeding within 15 days from birth
  8. consensus form signed by both parents or by the legal tutor properly informed of the study
  9. parents able to understand the protocol requirements and to fill out the infant's diary


Exclusion criteria:

  1. infant with inborn malformation and with hereditary and/or chronic and/or inborn diseases requiring hospital care superior to 7 days
  2. diseases jeopardizing intrauterine growth
  3. infant born from mother suffering from dismetabolic and/or chronic diseases
  4. unknown father
  5. infant with parents who might not report at hospital controls or not follow the protocol
  6. infant already enrolled or selected for another clinical trial

InterventionsControl Infant formula

Infant formula supplemented with 0.4 g/100 mL of oligosaccharides

OutcomesPrimary outcome measures: the nutritional safety through anthropometric controls.
Adverse events: diarrhoea, crying, gaseous colic, regurgitation, vomit, skin rashes, fever
Secondary outcome measures: the prebiotic effect through the control of the faeces consistency and frequency, the incidence of gaseous colic and microbiological analyses of the faecal samples

Starting dateFebruary 2006

Contact informationElisabetta Vacca, Dr 0039-02-52563235 elisabetta.vacca@it.hjheinz.com

Notes

Hammerman 2007

Trial name or titlePrebiotics versus Placebo in the Prevention of Necrotizing Enterocolitis in Premature Neonates

MethodsRandomised, double blind

ParticipantsInclusion criteria:

  • preterm neonates
  • < 1750 grams birth weight


Exclusion criteria:

  • infants who are deemed unlikely to survive
  • infants with significant congenital malformations
  • infants with other gastrointestinal problems

InterventionsThey will be randomly assigned to receive one of two milk additives from the time enteral feeds are begun until 35 weeks post-conceptual age: prebiotic (GOS) or placebo (water)

OutcomesPrimary outcome measures: necrotizing enterocolitis
Secondary outcome measures: fecal calprotectin, urine IFABP NEC related morbidity, ie. perforation, surgery [including peritoneal drain placement], stool bifidobacteria

Starting dateFebruary 8, 2007

Contact informationCathy Hammerman, MD 9722 666-6238 cathy@cc.huji.ac.il ; Alona Bin-nun, MD 97250 868-5757 alona.binnun@gmail.com

Notes

Materna Laboratories 2010

Trial name or titleEvaluation of the Effect of Milk Based Infant Formula Supplemented Either With Probiotic Microorganisms and/or With Prebiotic on the Intestinal Microflora During the First 4 Months of Life of Healthy, Full Term Infants and it's Long Term Effect on Morbidity up to the Age of 9 Months

MethodsRandomised, parallel, double blind

ParticipantsInclusion criteria:

  • healthy term infants of both sexes, born in natural labor
  • single birth
  • full term infants (born between the 37th and 42nd week of gestation)
  • infants with birth weight > 2500 grams
  • recruitment age will be 0-28 days
  • infants whose mothers are unable to breast feed or have chosen not to breast feed prior to the study enrolment
  • infants whose parents have agreed to participate in the study up to the age of 9 months
  • infants whose parents have agreed to remain exclusively on the same product for 16 weeks of age
  • infants whose parents have signed the informed consent form
  • infants whose parents are able to understand the protocol requirements and to fill out the infant's diary and agree to completely fill out the parents' questionnaires during the period of 9 months


Exclusion criteria:

  • twins
  • premature or low birth weight (< 2500 grams)
  • chromosomal abnormalities or congenital malformation
  • suffering jaundice which require phototherapy
  • proven or suspected family history of allergy to cow's milk
  • having been treated with antibiotics or other drugs during the last three days or more prior to the commencement of the study

InterventionsMilk based infant formula supplemented with either probiotic microorganisms and/or prebiotic (3 arms)

OutcomesPrimary outcome measures: anthropometric (weight, length and head circumferences)

Secondary outcome measures: microbiology

Starting dateAugust 2009

Contact informationMaterna Laboratories (Mgr. Chaim Zegerman)

Notes

Stronati 2010

Trial name or titleDouble-blind Randomised Controlled Study for the Evaluation of Nutritional Outcomes of a Cow's Milk Based Infant Formula Containing Galacto-oligosaccharides, Beta-palmitate and Acidified Milk

MethodsRandomised, parallel assignment, double blind

ParticipantsInclusion criteria:

  • infants of both sexes born to natural or cesarean delivery
  • gestational age between 37 and 42 completed weeks
  • birth weight between 10th and 90th percentile of birth weight for gestational age, according to the North-Italian growth charts
  • single birth
  • Caucasian parents
  • infants being exclusively formula-fed by the 14th day of life


Exclusion criteria:

  • infants with genetic and/or congenital diseases
  • infants receiving antibiotic therapy
  • infants with neonatal diseases requiring hospitalisation for longer than 7 days
  • infants at risk for atopy and/or having familial history for atopy
  • mothers with metabolic or chronic diseases
  • infant selected for another clinical study
  • parents refusing to sign a written informed consent

InterventionsInfant formula supplemented with functional ingredients (galacto-oligosaccharides, beta-palmitate, acidified milk)

Standard infant formula without functional ingredients

OutcomesPrimary outcome measures: the nutritional safety of the study formula is evaluated through measure of anthropometric parameters and record of gastrointestinal symptoms

Anthropometric parameters: body weight, recumbent length and head circumference change

Gastrointestinal symptoms: diarrhoea, constipation, stool frequency and consistency, bowel cramps, abdominal distension, intestinal gas
Secondary outcome measures: immune-modulatory activity, Quantification of salivary IgA, Prebiotic effect - Microbiological analysis of faeces

Starting dateAugust 2010

Contact informationElisabetta Vacca 0039 02 52563235 elisabetta.vacca@it.hjheinz.com

Notes

Underwood 2009a

Trial name or titlePhase 1A Study of Impact of Oligosaccharides and Bifidobacteria on the Intestinal Microflora of Premature Infants

MethodsRandomised, parallel assignment, double blind

ParticipantsInclusion criteria:

  • born in or transferred to UCDMC within the first two weeks of life. Birth weight less < 1500 grams. Gestational age less than 33 completed weeks. Exclusively formula fed


Exclusion criteria:

  • gastrointestinal or cardiac anomalies

InterventionsGroup 1: infants will be fed a concentration of Permeate mixed with formula. The ProlactPlus will be increased each week as follows: week 1 95:5 (formula:ProlactPlus), week 2 90:10, week 3 85:15, week 4 80:20, and week 5 75:25. Caloric content is roughly as follows: week 1 21 kcal/oz, week 2 22 kcal/oz, week 3 23 kcal/oz, week 4 24 kcal/oz, and week 5 25 kcal/oz

Group 2: infants will have their form

ula supplemented with galacto-oligosaccharides (GOS) for each feeding as follows: week 1 0.25 grams/dL, week 2 0.5 grams/dL, week 3 1.0 grams/dL, week 4 1.5 grams/dL, and week 5 2.0 grams/dL

Group 3: infants will have their formula supplemented with B. infantis twice daily increasing the dose each week as follows: week 1 5x107, week 2 1.5x108, week 3 4.5x108, week 4 1.4x109, and week 5 4.2x109

Group 4: infants will have their formula supplemented with B. animalis twice daily increasing the dose each week as follows: week 1 5x107, week 2 1.5x108, week 3 4.5x108, week 4 1.4x109, and week 5 4.2x109

OutcomesPrimary outcome measures: to determine the optimum dose and optimum dietary supplement to promote a fecal microflora in the formula fed premature infant that is similar to that of the term breast fed infant (a predominance of bifidobacteria)

Starting dateJune 2009

Contact informationMajid Mirmiran, MD, PhD 916-734-4790 majid.mirmiran@ucdmc.ucdavis.edu ; Mark A Underwood, MD 916-762-7892 mark.underwood@ucdmc.ucdavis.edu

Notes

 
Comparison 1. Prebiotic versus no prebiotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Asthma2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

    1.1 Infant incidence
2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Infant incidence
41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

    3.1 Infant incidence
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

 
Comparison 2. Prebiotic versus no prebiotic - according to infant risk of allergy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Asthma2226Risk Ratio (M-H, Random, 95% CI)0.67 [0.23, 1.91]

    1.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Random, 95% CI)0.37 [0.14, 0.96]

    1.2 Infants not selected for risk of allergy
192Risk Ratio (M-H, Random, 95% CI)1.07 [0.56, 2.06]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]

    2.2 Infants not selected for risk of allergy
31086Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.51, 1.14]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

    3.1 Infants at high risk of allergy
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

   3.2 Infants not selected for risk of allergy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Prebiotic versus no prebiotic - according to type of infant feed

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Asthma2226Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

    1.1 Fed predominately human milk
192Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.56, 2.06]

   1.2 Fed predominately cow's milk formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.14, 0.96]

 2 Eczema41220Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.97]

    2.1 Fed predominately human milk
192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]

    2.2 Fed predominately cow's milk formula
2994Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.11]

    2.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]

 3 Urticaria1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

   3.1 Fed predominately human milk
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   3.2 Fed predominately cow's milk formula
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Fed predominately hydrolysed infant formula
1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]

 
Comparison 4. Prebiotic versus no prebiotic - according to type of prebiotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Asthma2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 GOS / FOS (9:1) 8 grams/L versus
1134Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.14, 0.96]

    1.2 GOS / FOS and acidic OS (4:1) 1.5 grams/kg/day
192Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.56, 2.06]

 2 Eczema41278Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.51, 1.00]

    2.1 Polydextrose and GOS 4 grams/L
1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]

    2.2 Polydextrose, GOS and lactulose 8 grams/L
1106Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.12, 3.16]

    2.3 GOS / FOS (9:1) 8 grams/L
1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]

    2.4 GOS / FOS (9:1) 6.8 grams/ and acidic OS 1.2 grams/L
1830Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.35, 0.97]

    2.5 GOS / FOS and acidic OS (4:1) 1.5 grams/kg/day
192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]

 3 Urticaria1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 
Comparison 5. Specific prebiotic versus other prebiotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Polydextrose and GOS 4g/L versus polydextrose, GOS and lactulose 8g/L1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ezcema
1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]