Prebiotics in infants for prevention of allergy

  • Conclusions changed
  • Review
  • Intervention

Authors

  • David A Osborn,

    Corresponding author
    1. University of Sydney, Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, Sydney, NSW, 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.

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  • John KH Sinn

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

Background

Prebiotics (commonly oligosaccharides) added to infant feeds have the potential to prevent sensitisation of infants to dietary allergens.

Objectives

To determine the effect of prebiotic given to infants for the prevention of allergy.

Search methods

We performed an updated search in August 2012 of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8), MEDLINE, EMBASE, conference proceedings, citations, expert informants and clinical trials registries.

Selection criteria

Randomised and quasi-randomised controlled trials that compared the use of a prebiotic to no prebiotic, or a specific prebiotic compared to a different prebiotic in infants for prevention of allergy.

Data collection and analysis

Assessment of trial quality, data extraction and synthesis of data were performed using the standard methods of The Cochrane Collaboration.

Main results

The 2012 update identified 13 studies classified as ongoing or awaiting classification (yet to report allergy outcomes). Forty-three studies were excluded, primarily as no allergy data were reported, although none of these enrolled infants were at high risk of allergy. Four studies enrolling 1428 infants were eligible for inclusion. All studies were at high risk of attrition bias. Allergy outcomes were reported from four months to two years of age.

Meta-analysis of two studies (226 infants) found no significant difference in infant asthma although significant heterogeneity was found between studies. Meta-analysis of four studies found a significant reduction in eczema (1218 infants, typical risk ratio 0.68, 95% CI 0.48 to 0.97; typical risk difference -0.04, 95% CI -0.07 to -0.00; number needed to treat to benefit (NNTB) 25, 95% CI 14 to > 100; P = 0.03). No statistically significant heterogeneity was found between studies. One study reported no significant difference in urticaria.

No statistically significant subgroup differences were found according to infant risk of allergy or type of infant feed. However, individual studies reported a significant reduction in asthma and eczema from supplementation with a mixture of galacto- and fructo-oligosaccharide (GOS/FOS 9:1 ratio) (8 g/L) in infants at high risk of allergy; and in eczema from supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic oligosacccharide (1.2 g/L) in infants not selected for allergy risk.

Authors' conclusions

Further research is needed before routine use of prebiotics can be recommended for prevention of allergy in formula fed infants. There is some evidence that a prebiotic supplement added to infant feeds may prevent eczema. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma.

Résumé scientifique

Prébiotiques chez les nourrissons pour la prévention des allergies

Contexte

Les prébiotiques (généralement des oligosaccharides) ajoutés à l'alimentation des nourrissons ont la capacité de prévenir la sensibilisation des nourrissons aux allergènes alimentaires.

Objectifs

Déterminer l'effet des prébiotiques administrés aux nourrissons pour la prévention des allergies.

Stratégie de recherche documentaire

En août 2012, nous avons effectué une mise à jour des recherches dans le registre Cochrane des essais contrôlés - Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, numéro 8), MEDLINE, EMBASE, des actes de conférence, des références bibliographiques, auprès d'informateurs experts et dans des registres d'essais cliniques.

Critères de sélection

Essais contrôlés randomisés et quasi-randomisés qui comparaient l'utilisation d'un prébiotique à l'absence de prébiotique, ou d'un prébiotique spécifique à un prébiotique différent chez les nourrissons pour la prévention des allergies.

Recueil et analyse des données

L'évaluation de la qualité des essais, l'extraction des données et la synthèse des données ont été réalisées en utilisant les méthodes standard de la Cochrane Collaboration.

Résultats principaux

La mise à jour de 2012 a permis d'identifier 13 études classées comme en cours ou en attente de classification (résultats sur les allergies restant à indiquer). Quarante-trois études ont été exclues, principalement parce qu'elles ne présentaient pas de données sur les allergies, bien qu'aucun des nourrissons recrutés dans ces études n'ait présenté un risque d'allergie élevé. Quatre études portant sur 1 428 nourrissons étaient éligibles à l'inclusion. Toutes les études présentaient un risque élevé de biais d'attrition. Les résultats d'allergie présentés concernaient des nourrissons de quatre mois à deux ans.

La méta-analyse de deux études (226 nourrissons) n'a permis d'identifier aucune différence significative en ce qui concerne l'asthme infantile, bien qu'une hétérogénéité significative ait été observée entre les études. La méta-analyse de quatre études a révélé une réduction significative de l'eczéma (1 218 nourrissons, risque relatif type 0,68, IC à 95 % 0,48 à 0,97 ; différence de risque type -0,04, IC à 95 % -0,07 à -0,00 ; nombre de sujets à traiter pour observer un bénéfice (NSTb) 25, IC à 95 % 14 à > 100 ; P = 0,03). Aucune hétérogénéité statistiquement significative n'a été observée entre les études. Une étude n'a trouvé aucune différence significative pour ce qui est de l'urticaire.

Aucune différence statistiquement significative entre les sous-groupes n'a été observée en fonction du risque d'allergie des nourrissons ou du type d'alimentation des nourrissons. Cependant, des études individuelles indiquaient une réduction significative de l'asthme et de l'eczéma avec une supplémentation composée d'un mélange de galacto- et de fructo-oligosaccharide (GOS/FOS rapport 9/1) (8 g/l) chez des nourrissons à haut risque d'allergie ; et de l'eczéma avec une supplémentation en GOS/FOS (9/1) (6,8 g/l) et en oligosacccharide acide (1,2 g/l) chez des nourrissons non sélectionnés en fonction de leur risque d'allergie.

Conclusions des auteurs

Des recherches supplémentaires seront nécessaires avant que l'utilisation systématique des prébiotiques puisse être recommandée pour la prévention des allergies chez les enfants nourris au lait maternisé. Certaines données indiquent qu'un complément prébiotique ajouté à l'alimentation des nourrissons pourrait prévenir l'eczéma. Il est difficile de savoir si l'utilisation des prébiotiques devrait se restreindre aux nourrissons à haut risque d'allergie ou si elle pourrait avoir un effet chez les populations à faible risque, ou bien si elle pourrait avoir un effet sur les autres maladies allergiques, notamment sur l'asthme.

Plain language summary

Prebiotics in infants for prevention of allergic disease and food allergy

There is some evidence that prebiotic added to infant formula may prevent eczema and asthma in infants. However, there is some concern about the reliability of the evidence due to not all trials reporting allergy outcomes and trials not reporting the outcome for all infants. Reactions to foods and allergies (including asthma, eczema and hay fever) are common and may be increasing. Many infants become sensitised to foods, including infant formula, through their gastrointestinal tract, a process that may be affected by the composition of the intestinal bacteria. Attempts to promote the growth of normal gastrointestinal bacteria and prevent sensitisation to foods have included the addition of prebiotic to infant formula. Prebiotics are nondigestible food components that help by selectively stimulating the growth or activity of 'healthy' bacteria in the colon. This review found some evidence that a prebiotic supplement added to infant feeds may prevent eczema in infants up to two years of age. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma. However, further research is needed to confirm the findings before routine use of prebiotics can be recommended for prevention of allergy.

Résumé simplifié

Prébiotiques chez les nourrissons pour la prévention des maladies allergiques et des allergies alimentaires

Certaines données indiquent que les prébiotiques ajoutés au lait maternisé peuvent prévenir l'eczéma et l'asthme chez les nourrissons. Cependant, il existe des doutes quant à la fiabilité des données puisque tous les essais ne présentent pas de résultats sur l'allergie et que certains essais n'indiquent pas les résultats pour tous les nourrissons. Les réactions aux aliments et les allergies (notamment l'asthme, l'eczéma et le rhume des foins) sont fréquentes et il se pourrait qu'elles soient en progression. De nombreux nourrissons deviennent sensibles à certains aliments, notamment au lait maternisé, via leur tractus gastro-intestinal, un processus qui peut être affecté par la composition des bactéries intestinales. Les tentatives pour favoriser la croissance des bactéries gastro-intestinales normales et prévenir la sensibilisation aux aliments ont porté sur l'addition de prébiotiques dans le lait maternisé. Les prébiotiques sont des composants alimentaires non digestibles qui sont utiles en ce qu'ils stimulent sélectivement la croissance ou l'activité des bactéries « saines » du côlon. Cette revue a trouvé certaines données indiquant qu'un complément prébiotique ajouté à l'alimentation des nourrissons pourrait prévenir l'eczéma chez les nourrissons jusqu'à l'âge de deux ans. Il est difficile de savoir si l'utilisation des prébiotiques devrait se restreindre aux nourrissons à haut risque d'allergie ou si elle pourrait avoir un effet chez les populations à faible risque, ou bien si elle pourrait avoir un effet sur les autres maladies allergiques, notamment sur l'asthme. Cependant, des recherches supplémentaires doivent être effectuées pour confirmer les résultats avant que l'utilisation systématique des prébiotiques puisse être recommandée pour la prévention des allergies.

Notes de traduction

Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�

Laički sažetak

Prebiotici kao sredstvo za prevenciju alergijskih bolesti i alergije na hranu u djece

Postoje dokazi da prebiotici dodani u hranu za dojenčad mogu u dojenčadi spriječiti ekcem i astmu. Međutim, postoji sumnja u pouzdanost dokaza jer svi klinički pokusi ne prikazuju rezultate o ishodima alergije i ishodima za svu dojenčad. Reakcije na hranu i alergije (uključujući astmu, ekcem i peludnu groznicu) su česte i sve učestalije. Mnoga djeca postaju osjetljiva na hranu, uključujući i hranu za dojenčad, koja prolazi kroz probavni trakt, gdje sastav probavnih bakterija može utjecati da hrana postane alergogena. Pokušaji da se potakne rast normalnih probavnih bakterija i spriječi osjetljivost na hranu uključivali su dodavanje prebiotika u hranu za dojenčad. Prebiotici su neprobavljive sastavnice hrane koje povoljno djeluju tako što selektivno stimuliraju rast ili aktivnost „zdravih“ bakterija u debelom crijevu. Ovim Cochrane sustavnim pregledom pronađeni su dokazi da korištenje prebiotika kao dodataka dječjoj hrani može spriječiti ekcem u djece u dobi do 2 godine. Nije jasno treba li davanje prebiotika ograničiti na djecu s visokim rizikom za razvoj alergije ili pak oni mogu imati utjecaj i na populaciju nižeg rizika, a isto tako mogu li imati učinak na druge alergijske bolesti uključujući astmu Prije nego se preporuči rutinska upotreba prebiotika u prevenciji alergija, potrebno je provesti daljnja istraživanja za potvrdu tih rezultata.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Karla Mišur-Milinković
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Streszczenie prostym językiem

Stosowanie prebiotyków u niemowląt w celu zapobiegania chorobom alergicznym i alergiom pokarmowym

Istnieją pewne dane naukowe, które wskazują, że prebiotyk dodany do mieszkanki dla niemowląt może zapobiegać wypryskowi (egzemie) oraz astmie u niemowląt. Jednakże, istnieją pewne wątpliwości dotyczące wiarygodności tych danych, gdyż nie we wszystkich badaniach oceniano wystąpienie alergii lub nie opublikowano wyników dla wszystkich niemowląt. Alergie lub nietolerancje pokarmowe oraz inne alergie (w tym astma, egzema oraz katar sienny) występują powszechnie i mogą być coraz częstsze. Wiele niemowląt uczula się na żywność, włączając w to mieszanki dla niemowląt, poprzez swój przewód pokarmowy, co może mieć związek ze składem flory bakteryjnej kolonizującej ich przewód pokarmowy. Podejmowano próby promowania wzrostu prawidłowej flory bakteryjnej przewodu pokarmowego oraz zapobiegania uczuleniom na pokarm, które obejmowały dodawanie prebiotyku do mieszanek dla niemowląt. Prebiotyki to nietrawione składniki pożywienia, które pomagają wybiórczo stymulować wzrost lub aktywność "zdrowych" bakterii w jelicie grubym. W przeglądzie tym odnaleziono dane naukowe wskazujące, że dodanie do mieszanek dla niemowląt suplementu zawierającego prebiotyk może zapobiegać egzemie u niemowląt do drugiego roku życia. Nie jest jasne, czy stosowanie prebiotyku powinno być ograniczone tylko do niemowląt obciążonych dużym ryzykiem alergii, czy ten efekt może także występować w populacji o małym ryzyku, czy też stosowanie prebiotyku może mieć wpływ na występowanie innych chorób alergicznych, w tym astmy. Jednakże, dalsze badania są niezbędne w celu potwierdzenia dotychczasowych doniesień, zanim zacznie się zalecać rutynowe stosowanie prebiotyków w zapobieganiu alergii.

Uwagi do tłumaczenia

Tłumaczenie Magdalena Koperny Redakcja Joanna Zając

Ringkasan bahasa mudah

Prebiotik untuk mencegah penyakit alahan dan alahan terhadap makanan dalam bayi

Terdapat beberapa bukti bahawa prebiotik yang ditambah kepada formula bayi boleh mencegah ekzema dan asma dalam bayi. Walau bagaimanapun, terdapat kebimbangan mengenai kebolehpercayaan bukti kerana tidak semua ujian melaporkan keputusan alahan dan ujian tidak melaporkan keputusan untuk semua bayi. Reaksi kepada makanan dan alahan (termasuk asma, ekzema dan demam yang diakibatkan oleh debuan) adalah biasa dan semakin meningkat. Banyak bayi menjadi sensitif kepada makanan, termasuk formula bayi, melalui saluran gastrousus mereka, satu proses yang mungkin terjejas oleh komposisi bakteria usus. Percubaan untuk menggalakkan pertumbuhan bakteria gastrousus yang normal dan mencegah pemekaan kepada makanan telah melibatkan penambahan prebiotik dalam formula bayi. Prebiotik adalah komponen makanan yang tidak boleh dihadam yang membantu merangsang pertumbuhan atau aktiviti bakteria 'sihat' di dalam kolon secara terpilih. Ulasan ini mendapati terdapat beberapa bukti bahawa penambahan prebiotik kepada suapan bayi boleh mencegah ekzema dalam bayi sehingga dua tahun. Adalah tidak jelas sama ada penggunaan prebiotik harus dihadkan kepada bayi yang berisiko tinggi untuk mempunyai alahan atau mungkin mempunyai kesan dalam populasi berisiko rendah, atau sama ada ia mungkin mempunyai kesan ke atas penyakit alahan lain termasuk asma. Walau bagaimanapun, kajian lanjut diperlukan untuk mengesahkan penemuan sebelum penggunaan prebiotik secara rutin boleh disyorkan untuk pencegahan alahan.

Catatan terjemahan

Diterjemahkan oleh Ng Chia Shyn (International Medical University). Disunting oleh Tuan Hairulnizam Tuan Kamauzaman (Universiti Sains Malaysia). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi Ng.ChiaShyn@student.imu.edu.my.

Background

Description of the condition

Food allergy and allergic disease are prevalent and represent a substantial health problem that may be increasing in developed countries (Burr 1989; Schultz Larsen 1996; Halken 2004; Prescott 2005). Genetic susceptibility plays a large role in the development of food allergy. Although less than half of those who develop childhood allergic disease have a first degree relative with a history of allergy, the risk of development of allergy increases substantially with a positive family history of allergic disease. Approximately 10% of children without an allergic first degree relative develop allergic disease compared to 20% to 30% with an allergic first degree relative (parent or sibling) and 40% to 50% with two affected relatives (Kjellman 1977; Hansen 1993; Bergmann 1997; Arshad 2005). The manifestations of allergic disease are age dependent. Infants commonly present with symptoms and signs of atopic eczema, gastrointestinal symptoms and recurrent wheezing. Asthma and rhinoconjunctivitis become prevalent in later childhood. Sensitization to allergens tends to follow a characteristic pattern (Halken 2004), with sensitization to food allergens in the first two to three years of life, followed by indoor allergens (for example, house dust mite and pets) and, subsequently, outdoor allergens (for example, rye and timothy grass). The cumulative prevalence of allergic disease in childhood is high, with up to 7% to 8% developing a food allergy, 15% to 20% atopic eczema, and 31% to 34% developing asthma or recurrent wheezing (Halken 2004). Of these, 7% to 10% will continue to have asthma symptoms beyond five years of age (Halken 2004). Food hypersensitivities affect approximately 6% of infants less than three years of age, with the prevalence decreasing over the first decade (Sampson 2004; Osterballe 2005).

Description of the intervention

A major focus of current research is the mechanisms for the development of immune tolerance and allergen sensitization in the fetus and newborn as well as primary prevention strategies. This review focused on the evidence for use of prebiotic in infants for the prevention of food allergy and allergic disease. A separate review examines the effects of probiotics compared to no probiotics in infants for prevention of allergic disease and food allergy (Osborn 2007a). Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of bacteria in the colon. Prebiotics have frequently been added to infant formula. The most common prebiotic used in infant food is indigestible oligosaccharide, although other nitrogen and lipid containing compounds may also have a prebiotic effect (Agostoni 2004). To be effective, prebiotic should escape digestion and absorption in the upper gastrointestinal tract, reach the large bowel, and be used selectively by microorganisms that have been identified as having health promoting properties. To date, studies in infants have demonstrated significant increases in faecal bifidobacteria in response to formula supplementation with oligosaccharides (Boehm 2002; Moro 2002; Schmelzle 2003; Decsi 2005; Moro 2006). One study also demonstrated an increase in fecal lactobacilli (Moro 2002).

How the intervention might work

An altered microbial exposure in the gastrointestinal tract may be partly responsible for the increase of allergic diseases in populations with a western lifestyle (Holt 1997). Differences in intestinal microflora are found in infants delivered by caesarean section when compared to those delivered vaginally, and in breast fed versus formula fed infants (Agostoni 2004). Breast feeding promotes the colonization of bifidobacteria and lactobacilli that inhibit growth of pathogenic microorganisms and compete with potentially pathogenic bacteria for nutrients and epithelial adhesion sites. The gastrointestinal flora may modulate mucosal physiology, barrier function and systemic immunologic and inflammatory responses (Sudo 1997; Agostoni 2004). Food allergy is a manifestation of an abnormal mucosal immune response to ingested dietary antigens (Sampson 2004). The gastrointestinal barrier is a complex physiochemical barrier and cellular barrier. However, some ingested food antigens are absorbed. The efficiency of this gastrointestinal barrier is reduced in the newborn period (Sampson 2004). Perinatal risk factors reported for asthma or allergy, or both, have included prematurity (Jaakkola 2004; Raby 2004; Bernsen 2005) and fetal growth restriction (Bernsen 2005), both of which are associated with an immature and potentially injured gastrointestinal mucosal barrier. The composition of the intestinal microflora may be different in those with atopic eczema, and such differences may precede the development of eczema. The most consistent finding in such studies is a reduced proportion of bifidobacteria species in the faeces of infants with eczema (Bjorksten 2001; Murray 2005) and atopic sensitization (Kalliomaki 2001), but not in the faeces of children with asthmatic symptoms (Murray 2005). The recognition of the importance of intestinal flora has led to the development of strategies aimed at manipulating bacterial colonization in formula fed infants, including the use of prebiotics and probiotics.

Prevention of allergy is divided into primary prevention, the prevention of immunological sensitization (development of IgE antibodies); and secondary prevention, the prevention of allergic disease following sensitization (Asher 2004). A substantial proportion of infants who develop sensitization will not go on to develop clinical manifestations of allergic disease or food allergy (Halken 2004). This review focused on the prevention of clinical allergic disease (including asthma, eczema and allergic rhinitis) and food allergy. Since the risk of allergy and food allergy is affected by heredity, subgroup analysis examined the effect of prebiotic in populations of infants at high risk of allergy separately from infants at low risk or not selected on the basis of heredity. Since breast feeding promotes the colonization of bifidobacteria and lactobacilli (Agostoni 2004), subgroup analysis examined the effect of prebiotic in human milk fed infants separately from prebiotic in formula fed infants.

Why it is important to do this review

Food allergy and allergic disease are prevalent and represent a substantial health problem. Dietary interventions have the potential for preventing or delaying the onset of these conditions. This review focused on the evidence for use of prebiotic in infants for the prevention of food allergy and allergic disease.

Objectives

Primary objective

To determine the effect of prebiotic given to infants for the prevention of allergy.

Secondary objectives

  • To determine the effect of specific prebiotic.

  • To determine the effect of prebiotic in:

    • breast fed infants;

    • human milk fed infants;

    • formula fed infants.

  • To determine the effect of prebiotic used for:

    • early or short term infant feeding;

    • prolonged infant feeding.

  • To determine the effect of prebiotic in:

    • infants not selected for risk of allergy, or at low risk;

    • in infants at high risk of allergy.

  • To determine the effect of prebiotic given to:

    • low birth weight or preterm infants;

    • appropriate weight for gestational age term infants.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised and quasi-randomised controlled trials that compared the use of a prebiotic to a control (placebo or no treatment); or used a specific prebiotic compared to a different prebiotic.

We excluded studies that included other allergic disease prevention interventions (for example, maternal dietary avoidance measures, environmental allergy reduction measures) in the treatment group and not the control group. We considered as eligible studies that had other allergy prevention interventions in both treatment and control groups.

Types of participants

Infants in the first six months of life without clinical evidence of allergy, both with and without risk factors for allergic disease and food allergy.

Types of interventions

Prebiotics added to human milk or infant formula, whether added in the manufacturing process or given separately, compared to control (placebo or no treatment) or a different prebiotic.

Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of bacteria in the colon that provide a health benefit.

Types of outcome measures

Definitions of allergic disease and food allergy had to be consistent with the 'Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003' (Johansson 2004). Clinical manifestations of allergy, including asthma, eczema, rhinitis and urticaria, are commonly IgE mediated so a clinical diagnosis of disease was accepted. However, as the majority of food reactions are not associated with proven allergic mechanisms, only those food reactions likely to be allergic (for example, causing urticaria and angioedema) and those proven to be caused by allergic mechanisms were accepted.

Primary outcomes
  • All allergic disease including asthma, eczema, rhinitis or food allergy (analysis restricted to studies reporting composite manifestations of all allergic disease)

  • Food allergy

Secondary outcomes
  • Asthma

  • Dermatitis or eczema

  • Allergic rhinitis

  • Cow's milk or soy protein allergy

  • Cow's milk or soy protein allergy

  • Urticaria

  • Anaphylaxis

A specific allergic disease or food allergy may be diagnosed on the basis of:

  • history of recurrent and persistent symptoms typical of the allergic disease or food allergy;

  • a clinician diagnosis allergy based on clinical findings supported by the above history;

  • clinical allergic disease and food allergy confirmed by testing including detection of allergen sensitisation by either skin testing or serological testing for specific IgE (e.g., radioallergosorbent test (RAST) or enzyme allergosorbent test (EAST) or coated allergen particle (CAP) system), asthma confirmed by respiratory function testing for presence of bronchial hyper-responsiveness, and food allergy confirmed by elimination and challenge.

The following definitions of age of allergic disease were used:

  • infant allergic disease incidence, allergic disease occurring up to two years of age;

  • childhood allergic disease incidence, allergic disease occurring up to 10 years of age (or up to age of latest report, between two and 10 years);

  • childhood allergic disease prevalence, allergic disease reported that was present between two and 10 years of age;

  • adolescent allergic disease, allergic disease present from 10 to 18 years of age;

  • adult allergic disease, allergic disease present after 18 years of age.

Search methods for identification of studies

See: Cochrane Neonatal Review Group search strategy (http://neonatal.cochrane.org/).

Electronic searches

2012 update: an updated search was performed of CENTRAL (The Cochrane Library 2012, Issue 8), MEDLINE (1948 to August 2012), and EMBASE (1974 to August 2012). Principle authors from conference presentations and published articles were searched in MEDLINE via PubMed (1966 to August 2012).

Searching other resources

A search of previous reviews including cross references (all articles referenced), abstracts, conferences (Pediatric Academic Societies (PAS) 1998 to 2007; Perinatal Society of Australia and New Zealand (PSANZ) 1998 to 2007).

An updated search was performed of abstracts of conferences (PAS 2000 to 2012 and PSANZ 2008 to 2012), recent review citations and expert informants.

We also searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp), updated August 2012.

Data collection and analysis

The author of one trial (Ziegler 2007) provided their methods for diagnosis of eczema by direct communication. For this study, data for the two prebiotic groups were combined and compared to the placebo group in Comparisons 1 and 3 (see Effects of interventions).

The author of one trial (Gruber 2010) provided the original study protocol and survival analysis data for first development of eczema (atopic dermatitis) up to 12 months of age.

Data for infant asthma and eczema from one included study (Westerbeek 2010) were obtained from the abstract of conference proceedings and have not been published at the time of this analysis.

Selection of studies

Eligibility of studies for inclusion was assessed independently by each review author.

Data extraction and management

Each review author extracted the data separately. Data were compared and differences resolved by consensus. In the 2012 update, all analyses were performed using the Review Manager software (RevMan 2011).

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of the included trials. The quality of included trials was evaluated in terms of adequacy of randomisation and allocation concealment, blinding of parents or caregivers and assessors to the intervention, and completeness of assessment in all randomised individuals.

For the 2010 update, the previous assessments were incorporated into RevMan 5 'Risk of bias' tables. Risk of bias for each study was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

(1) Sequence generation (checking for possible selection bias):
  • adequate (any truly random process, e.g., random number table; computer random number generator);

  • inadequate (any non-random process, e.g., odd or even date of birth; hospital or clinic record number); or

  • unclear.   

(2) Allocation concealment (checking for possible selection bias):
  • adequate (e.g., telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or

  • unclear.   

(3) Blinding (checking for possible performance bias):
  • adequate, inadequate or unclear for participants;

  • adequate, inadequate or unclear for personnel;

  • adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations):
  • adequate (less than 20% missing data);

  • inadequate;

  • unclear.

(5) Selective reporting bias:
  • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear.

(6) Other sources of bias:

The possibility of other possible sources of bias (for example, early termination of trial due to data-dependant process, extreme baseline imbalance, etc.) was assessed as:

  • yes;

  • no;

  • unclear.

(7) Overall risk of bias:

Explicit judgements were made about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, the likely magnitude and direction of the bias and whether it was likely to impact on the findings were assessed. We explored the impact of the level of bias by undertaking sensitivity analyses (see: Sensitivity analysis). 

Measures of treatment effect

We used the standard methods of the Cochrane Neonatal Review Group to synthesise the data. Effects were expressed as risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for categorical data, and weighted mean difference (WMD) and 95% CI for continuous data.

Unit of analysis issues

The unit of analysis was the infant.

Dealing with missing data

We recorded missing data in the 'Risk of bias' tables. We assessed the effect of missing data in the sensitivity analysis.

Assessment of heterogeneity

We used the two formal statistics described below.

1) The Chi2 test, to assess whether observed variability in effect sizes between studies is greater than would be expected by chance. Since this test has low power when the number of studies included in the meta-analysis is small, we planned to set the probability at the 10% level of significance.

2) The I2 statistic to ensure that pooling of data is valid. We planned to grade the degree of heterogeneity as 0% to 30%: might not be important; 31% to 50%: moderate heterogeneity; 51% to 75%: substantial heterogeneity; 76% to 100%: considerable heterogeneity.

Where there was evidence of apparent or statistical heterogeneity, we planned to assess the source of the heterogeneity using sensitivity and subgroup analysis looking for evidence of bias or methodological differences between trials.

Assessment of reporting biases

Studies that reported using a prebiotic in a potentially eligible infant population but which did not report allergy related outcomes have been documented in the table 'Characteristics of excluded studies'. We assessed reporting and publication bias by examining the degree of asymmetry of a funnel plot.

Data synthesis

We used the fixed-effect model using Mantel-Haenszel methods for meta-analysis.

Subgroup analysis and investigation of heterogeneity

The following comparisons were pre-specified:

  1. prebiotic versus no prebiotic (all studies);

  2. specific prebiotic versus no prebiotic (e.g., fructo-oligosaccharide (FOS), galacto-oligosaccharide (GOS), acidic oligosaccharide (acidic OS) etc.);

  3. specific prebiotic versus other prebiotic.

The following subgroup analyses were pre-specified.

  1. According to infant heredity for allergy:

    1. infants at high risk of allergy (at least one first degree relative with allergic disease or food allergy);

    2. infants at low risk of allergy, or not selected on basis of heredity.

  2. According to method of infant feeding:

    1. infants fed human milk;

    2. infants fed formula.

  3. According to duration of supplementation:

    1. infants given early (in first few days), short term (days) supplementation;

    2. infants given prolonged supplementation (weeks or months).

  4. According to infant maturity or birth weight:

    1. infants born at or near term;

    2. infants born preterm (< 37 weeks gestation) or low birth weight (< 2500 grams).

Sensitivity analysis

A sensitivity analysis was pre-specified to determine if the findings were affected by including only studies at low risk of bias, defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and < 10% losses to follow up.

Results

Description of studies

Results of the search

The 2012 search identified two additional eligible studies (Gruber 2010; Westerbeek 2010), although one of these reported allergy related outcomes in the abstract of conference proceedings only (Westerbeek 2010). Additional reports were found for two previously included studies (Moro 2006; Ziegler 2007).

There are 43 reports of excluded studies. See table 'Characteristics of excluded studies'.

Eight studies are awaiting classification (see 'Studies awaiting classification') as they have completed enrolment but are yet to publish allergy related outcomes (Nyankovskyy 2008; Veereman-Wauters 2008; Zoeren-Grobben 2009; Hicks 2010; Vanderhoff 2010; Campeotto 2011; Holscher 2012; Scalabrin 2012). Of these:

Five studies were assessed as ongoing (Agostoni 2006; Hammerman 2007; Underwood 2009a; Materna Laboratories 2010; Stronati 2010). Of these:

Included studies

Four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) enrolling 1428 infants were assessed as eligible for inclusion. See table 'Characteristics of included studies'.

Participants
  • Risk of allergy:

    • infants at high risk of allergy, one study (Moro 2006) enrolled infants at high risk of allergy (first degree affected relatives);

    • infants not selected for allergy risk, two studies (Ziegler 2007; Gruber 2010) enrolled healthy term infants not selected on basis of risk of allergy;

    • sick or preterm or low birth weight infants, Westerbeek 2010 enrolled preterm infants < 32 weeks or birth weight < 1500 grams, or both, not selected on basis of risk of allergy.

  • Infant feeding:

    • predominantly human milk fed, Westerbeek 2010 enrolled preterm or low birth weight infants predominately human milk fed and supplemented with prebiotics from day three to day 30;

    • predominantly cow's milk formula fed, two studies (Ziegler 2007; Gruber 2010) fed infants a cow's milk formula supplemented with prebiotic or control. Gruber 2010 provided supplements from weaning of breast feeding and continued them in follow on formula for infants up to 12 months age. Ziegler 2007 provided supplements in formula from 14 days and continued to 120 days of age;

    • predominantly hydrolysed formula fed, Moro 2006 provided supplements in an extensively hydrolysed whey protein formula for six months.

Interventions
  • Prebiotic mixtures: Gruber 2010 allocated infants to receive a regular cow’s milk formula with added neutral GOS and FOS (ratio 9:1) and acidic oligosaccharides (OS) (total 8 g/L) versus a control group who received cow’s milk based formula without added oligosaccharides. Moro 2006 allocated infants to an extensively hydrolysed whey protein formula intended for term infants with an added mixture of FOS and GOS (0.8 g/dL) versus the same formula with added maltodextrin (0.8 g/dL). Westerbeek 2010 allocated infants to receive acidic and neutral oligosaccharides supplementation (20%:80%) in increasing doses to a maximum of 1.5 g/kg/day or placebo supplementation (maltodextrin) between days three and 30 of life added to breast milk or preterm formula. Ziegler 2007 allocated infants to formula supplemented with polydextrose and GOS (50:50 ratio) (4 g/L); formula supplemented with polydextrose, GOS and lactulose (LOS) (50:33:17 ratio) (8 g/L); or to control formula (cow's milk formula).

Outcomes
  • Allergic disease or food allergy, or both: Gruber 2010 reported atopic dermatitis diagnosed according to the criteria recommended by the European Task Force on Atopic Dermatitis to one year. Moro 2006 reported eczema up to two years of age based on blinded physician examination and standardised criteria. Westerbeek 2010 reported physician-diagnosed atopic dermatitis and bronchial hyper-reactivity to one year. Ziegler 2007 reported eczema to four months of age, but did not pre-specify this outcome in the methods. Eczema was recorded in the participant's diary and by the physician who diagnosed it (personal communication).

Excluded studies

Excluded studies (n = 43) and reasons for exclusion from the review are found in the table 'Characteristics of excluded studies'. The majority of these were excluded as they did not report allergy outcomes. Assessment of the excluded studies found:

Risk of bias in included studies

All studies had methodological concerns (see: table 'Characteristics of included studies', Figure 1). The studies were evaluated as being at high risk of bias, particularly due to attrition bias (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010).

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation was evaluated as low risk for three studies (Moro 2006; Gruber 2010; Westerbeek 2010). Ziegler 2007 did not report the method of sequence generation.

Allocation concealment was evaluated as low risk for four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010).

Blinding

All four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) reported measures to blind treatment.

Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) reported blinding of measurement. Ziegler 2007 did not report blinding of measurement, although treatment was blinded.

Incomplete outcome data

Gruber 2010 reported 11% of randomised infants lost at 12 months. It was also unclear if 300 breast fed women that were not included in the analysis were part of the initial randomisation.

Moro 2006 reported 20% of randomised infants lost at six months and 48% at two years; Westerbeek 2010 reported 10/102 (10%) of survivors not followed for allergy related outcomes; and Ziegler 2007 reported 27% of randomised infants lost at four months. All studies reported study losses that were related to the intervention.

Selective reporting

Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) were considered as at low risk of reporting bias with pre-specified definitions and time points for reporting allergy outcomes.

Ziegler 2007 used diary entries and physician-diagnosed eczema, no definition was reported.

Other potential sources of bias

All studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) reported analyses according to the group of assignment and groups appeared well balanced after randomisation. Gruber 2010 reported the target sample size of 1500 infants but only 1130 were enrolled. The reason for premature stopping was not reported in the publication. No other potential biases were identified.

Effects of interventions

All analyses related to infant incidence of allergy.

Prebiotic versus no prebiotic (Comparison 1)

Asthma (Outcome 1.1)

Meta-analysis of two studies (Moro 2006; Westerbeek 2010) found no significant difference in asthma (226 infants, RR 0.70, 95% CI 0.41 to 1.19, fixed-effect model). Statistically significant (P = 0.07) and substantial heterogeneity (I² = 70%) was found between studies. Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96) whereas Westerbeek 2010 reported no significant difference (92 infants, RR 1.07, 95% CI 0.56 to 2.06).

Eczema (Outcome 1.2)

Meta-analysis of four studies (Moro 2006; Ziegler 2007; Gruber 2010; Westerbeek 2010) found a significant reduction in eczema (1218 infants, typical RR 0.68, 95% CI 0.48 to 0.97; typical RD -0.04, 95% CI -0.07 to -0.00; number needed to benefit (NNTB) 25, 95% CI 14 to > 100). No statistically significant (P = 0.21) although potentially important (I² = 34%) heterogeneity was found between studies.

Urticaria (Outcome 1.3)

Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) up to two years.

Subgroup analyses

Prebiotic versus no prebiotic - according to infant risk of allergy (Comparison 2)
Asthma (Outcome 2.1)

Infants at high risk of allergy: Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96) to two years.

Infants not selected for risk of allergy: Westerbeek 2010 reported no significant difference in asthma to one year (92 infants, RR 1.07, 95% CI 0.56 to 2.06).

The test for subgroup differences according to risk of allergy found a borderline statistically significant (P = 0.07) and substantial (I² = 69.0%) difference.

Eczema (Outcome 2.2)

Infants at high risk of allergy: Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD -0.14, 95% CI -0.28 to -0.01; NNTB 7, 95% CI 4 to 100) to two years.

Infants not selected for risk of allergy: meta-analysis of three studies (Ziegler 2007; Gruber 2010; Westerbeek 2010) found no significant difference in eczema (1084 infants, RR 0.76, 95% CI 0.51 to 1.14). There was no statistically significant (P = 0.18) but a potentially important (I² = 42%) heterogeneity between studies (Figure 2).

Figure 2.

Funnel plot of comparison: 2 Prebiotic versus no prebiotic - according to infant risk of allergy, outcome: 2.2 Eczema.

The funnel plot of the comparison according to infant risk of allergy is displayed in Figure 2. The test for subgroup differences according to risk of allergy found no statistically significant (P = 0.29) or important (I² = 9.0%) difference.

Urticaria (Outcome 2.3)

Infants at high risk of allergy: Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) up to two years.

Infants not selected for risk of allergy: no study reported urticaria.

Prebiotic versus no prebiotic - according to type of infant feed (Comparison 3)
Asthma (Outcome 3.1)

Fed predominately human milk: Westerbeek 2010 reported no significant difference in asthma (92 infants, RR 1.07, 95% CI 0.56 to 2.06).

Fed predominately hydrolysed infant formula: Moro 2006 reported a significant decrease in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96; RD -0.13, 95% CI -0.25 to -0.01; NNT 8, 95% CI 4 to 100).

The test for subgroup differences according to risk of allergy found a borderline statistically significant (P = 0.07) and substantial (I² = 69.0%) difference.

Eczema (Outcome 3.2)

Fed predominately human milk: Westerbeek 2010 reported no significant difference in eczema (92 infants, RR 1.05, 95% CI 0.41 to 2.65).

Fed predominately cow's milk formula: meta-analysis of two studies (Ziegler 2007; Gruber 2010) found no statistically significant difference in eczema (992 infants, typical RR 0.71, 95% CI 0.45 to 1.11). There was statistically significant (P = 0.09) and substantial (I² = 65%) heterogeneity between studies.

Fed predominately hydrolysed infant formula: Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD -0.14, 95% CI -0.28 to -0.01; NNTB 7, 95% CI 4 to 100).

Fed predominately human milk versus cow's milk formula: the test for subgroup differences found no statistically significant (P = 0.46) or important (I² = 0%) difference.

Fed predominately human milk versus hydrolysed infant formula: the test for subgroup differences found no statistically significant (P = 0.20) but a potentially important (I² = 38.6%) difference. The funnel plot of the comparison according to type of infant feed is displayed in Figure 3.

Figure 3.

Funnel plot of comparison: 3 Prebiotic versus no prebiotic - according to type of infant feed, outcome: 3.2 Eczema.

Urticaria (Outcome 3.3)

Fed predominately human milk: no study reported urticaria.

Fed predominately hydrolysed infant formula: no study reported urticaria.

Fed predominately hydrolysed infant formula: Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) to two years.

Prebiotic versus no prebiotic - according to type of prebiotic (Comparison 4)
Asthma (Outcome 4.1)

GOS/FOS (9:1) (8 g/L): Moro 2006 reported a significant reduction in asthma (134 infants, RR 0.37, 95% CI 0.14 to 0.96; RD -0.13, 95% CI -0.25 to -0.01; NNT 8, 95% CI 4 to 100).

GOS/FOS and acidic oligo saccharide (OS) (4:1) (1.5 g/kg/day): Westerbeek 2010 reported no significant difference in asthma (92 infants, RR 1.07, 95% CI 0.56 to 2.06).

The test for subgroup differences found a borderline significant (P = 0.07) and substantial (I² = 69.0%) subgroup difference.

Eczema (Outcome 4.2)

Polydextrose and GOS (4 g/L): Ziegler 2007 reported no significant difference in eczema (116 infants, RR 2.50, 95% CI 0.83 to 7.52) to four months.

Polydextrose, GOS and lactulose (8 g/L): Ziegler 2007 reported no significant difference in eczema (106 infants, RR 0.60, 95% CI 0.12 to 3.16) to four months.

GOS/FOS (9:1) (8 g/L): Moro 2006 reported a decrease in eczema of borderline statistical significance (134 infants, RR 0.49, 95% CI 0.24 to 1.00; RD -0.14, 95% CI -0.28 to -0.01; NNTB 7, 95% CI 4 to 100).

GOS/FOS (9:1) (6.8 g/L) and acidic OS (1.2 g/L): Gruber 2010 reported a significant reduction in eczema (828 infants, RR 0.58, 95% CI 0.35 to 0.97; RD -0.04, 95% CI -0.07 to -0.00; NNTB 25, 95% CI 14 to > 100).

GOS/FOS and acidic OS (4:1) (1.5 g/kg/day): Westerbeek 2010 reported no significant difference in eczema (92 infants, RR 1.05, 95% CI 0.41 to 2.65) to one year.

The funnel plot of the comparison according to type of prebiotic is displayed in Figure 4.

Figure 4.

Funnel plot of comparison: 4 Prebiotic versus no prebiotic - according to type of prebiotic, outcome: 4.2 Eczema.

Urticaria (Outcome 4.3)

GOS/FOS (9:1) (8 g/L): Moro 2006 reported no significant difference in urticaria (134 infants, RR 0.15, 95% CI 0.02 to 1.16) to two years.

Specific prebiotic versus other prebiotic (Comparison 5)
Eczema (Outcome 5.1)

Polydextrose and GOS (4 g/L) versus polydextrose, GOS and lactulose (8 g/L): Ziegler 2007 reported no significant difference in eczema (116 infants, RR 2.50, 95% CI 0.83 to 7.52) to four months.

Sensitivity analysis

Prebiotic versus no prebiotic - studies at low risk of bias (Comparison 6)

Three studies (Moro 2006; Gruber 2010; Westerbeek 2010) reported methods of treatment allocation and blinding that were at low risk of bias. However, no study met the criteria for low risk of bias due primarily to the risk of attrition bias: Gruber 2010 11%, Moro 2006 20% to 48%, Westerbeek 2010 10%, and Ziegler 2007 27%.

All studies reported commercial sponsorship.

Discussion

Summary of main results

The 2012 update identified 13 studies classified as ongoing or awaiting classification (yet to report allergy outcomes). Forty-three studies were excluded primarily as no allergy data were reported, although none of these enrolled infants at high risk of allergy. Four studies enrolling 1428 infants were eligible for inclusion. All studies were at high risk of attrition bias. Allergy outcomes were reported from four months to two years of age.

Meta-analysis of two studies (226 infants) found no significant difference in infant asthma although significant heterogeneity was found between the studies. Meta-analysis of four studies found a significant reduction in eczema (1218 infants, typical RR 0.68, 95% CI 0.48 to 0.97; typical RD -0.04, 95% CI -0.07 to -0.00; NNTB 25, 95% CI 14 to > 100; P =0.03). No statistically significant heterogeneity was found between studies. One study reported no significant difference in urticaria.

No statistically significant subgroup differences were found according to infant risk of allergy or type of infant feed. However, individual studies reported a significant reduction in asthma and eczema from supplementation with galacto-oligosaccharide and fructo-oligosaccharide (GOS/FOS) (9:1) (8 g/L) in infants at high risk of allergy; and in eczema from supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic OS (1.2 g/L) in infants not selected for allergy risk.

The GRADE profile (Figure 5) found the quality of the evidence for use of prebiotics for prevention of asthma was very low, the quality was low for prevention of eczema, and the quality very low for prevention of urticaria. We recommend further research is needed before routine use of prebiotics can be recommended for prevention of allergy. No studies reported food allergy.

Figure 5.

Overall completeness and applicability of evidence

Only one study (Moro 2006) reported the effect of prebiotic in infants at high risk of allergy. The other included studies enrolled healthy term infants (Ziegler 2007; Gruber 2010) or preterm, low birth weight infants (Westerbeek 2010). There is concern regarding the potential for publication bias for studies not enrolling high risk infants. The 2012 search identified seven studies awaiting classification as they have completed enrolment but are yet to publish allergy related outcomes, although none of these has enrolled infants at high risk of allergy. Six studies were assessed as ongoing, although again none of these enrolled infants at high risk of allergy. Forty-three studies that compared a prebiotic versus no prebiotic were excluded, with 19 of these enrolling healthy term infants but not reporting allergy. Five studies enrolled preterm or low birth weight infants but did not report allergy. None of the other studies enrolled infants at high risk of allergy with the goal of preventing allergy.

Potential benefits for prebiotics are restricted to studies providing supplements for the duration of formula feeding using combinations of prebiotic similar to that found in human milk. Studies reporting a significant reduction in eczema used a GOS/FOS (9:1) combination with or without acidic oligosaccharides at a concentration of 8 g/L. The duration of prebiotic supplementation was prolonged, for the duration of formula feeding (six to 12 months), in two studies with both studies reporting a significant reduction in infant eczema. The duration of prebiotic supplementation was more limited in the other two studies (30 to 120 days). These reported no significant difference in infant eczema. In addition, the studies used differing prebiotic preparations at differing concentrations.

It is unclear if the potential benefit of prebiotic persists beyond infancy. Of the included studies, Ziegler 2007 reported eczema to only four months; Gruber 2010 reported eczema to 12 months; Westerbeek 2010 reported bronchial hyper-reactivity and eczema to 12 months; and Moro 2006 reported asthma, eczema and urticaria to two years.

Quality of the evidence

There is potential for publication bias, particularly regarding studies that do not enrol infants at high risk of allergy. There are a substantial number of studies of prebiotic enrolling healthy, sick, preterm or low birth weight infants that have not reported allergy outcomes. All included studies were assessed as being at high risk of attrition bias. It was also unclear as to whether 300 breast fed infants were part of the initial randomisation and the reason for premature stopping of one trial (Gruber 2010). Only two studies provided prolonged supplementation of prebiotic for the duration of the formula feed and only one study reported the allergy outcome to two years, and none beyond. Only Moro 2006 enrolled infants at high risk of allergy with the primary goal of preventing allergy.

It is unclear if the effect of prebiotic in preventing eczema is clinically important. Meta-analysis found a significant reduction in infant eczema (NNTB 25, 95% CI 14 to > 100; P = 0.03) with the upper confidence limit including a benefit of unclear clinical importance. The single study that enrolled infants at high risk of allergy was also insufficiently powered to determine if the effect on infant eczema was clinically important (NNTB 7, 95% CI 4 to 100; P = 0.05). However, there is some evidence for a possible dose effect with a larger risk decrease in high risk infants compared to low risk infants, although the difference is not statistically significant (high risk infants RD -0.14, 95% CI -0.28 to -0.01; low risk infants RD -0.02, 95% CI -0.06 to 0.01).

Only a single study pre-specified a primary allergy related outcome. All studies appear to have been commercially sponsored.

Potential biases in the review process

The review conducted extensive searches of the published and unpublished literature for trials of prebiotics. However, there is substantial potential for publication bias from under reporting of negative trials in infants not selected for allergy risk. Many of the trials that did not report allergy assessed infants for adverse events and tolerance. The reported trials to date and with positive results have a common commercial sponsor.

In an attempt to avoid publication bias, the review included data from one study reported in an abstract of conference proceedings (Westerbeek 2010), and from another study which had unclear definitions of allergy related outcomes (Ziegler 2007). The review combines studies reporting outcomes at multiple times and differing time periods. The risk of selective reporting bias was minimised in the review by pre-specifying the data from the latest time point reported by each study (infant up to two years).

Two review authors have independently assessed the trials and extracted data. Outcomes included in this review were compatible with standardised definitions of clinical allergy. Surrogate outcomes (sensitisation) including results of skin tests and serological evidence of atopy without clinical allergy were not included as pre-specified outcomes in this review. However, where infants with clinical allergy were confirmed as atopic by skin tests or serological markers, this was pre-specified for inclusion. The authors of this review have no financial or material conflicts of interest.

Agreements and disagreements with other studies or reviews

There are no other systematic reviews of the use of prebiotics in infants for prevention or treatment of allergy found in our search of The Cochrane Library and MEDLINE to August 2012. No systematic reviews were found of the use of prebiotics for treatment of infants with allergy. A 2009 systematic review of trials of prebiotic supplemented formula in full-term infants reported the formula to be well tolerated and to increase stool colony counts of bifidobacteria and lactobacilli and result in stools similar to those of breast fed neonates without affecting weight gain (Rao 2009). A 2009 systematic review of the efficacy and safety of prebiotic oligosaccharide supplementation of formula in preterm neonates born at ≤ 37 weeks gestation reported in one trial that necrotising enterocolitis (NEC) did not occur in any of the enrolled neonates, and meta-analysis found that the prebiotic supplemented formula increased stool colony counts of bifidobacteria and lactobacilli without adversely affecting weight gain (Srinivasjois 2009).

In a related Cochrane systematic review 'Probiotics in infants for prevention of allergy' (Osborn 2007a), one study (Kukkonen 2006) reported a significant reduction in eczema in infants receiving a synbiotic versus no synbiotic (925 infants, RR 0.81, 95% CI 0.66 to 0.99; RD -0.06, 95% CI -0.12 to -0.00; NNTB 17, 95% CI 12 to > 100). The study used a synbiotic preparation containing Lactobacillus rhamnosus GG, Lactobacillus rhamnosus LC705, Bifidobacterium breve, Propionibacterium freudenreichii and GOS 8 g/L and reported a reduction in infant eczema but not all allergic disease. The study was rated as at high risk of attrition bias and had unclear allocation concealment.

Authors' conclusions

Implications for practice

Further research is needed before routine use of prebiotics can be recommended for prevention of allergy. There is some evidence that a prebiotic supplement added to infant feeds may prevent eczema. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma.

Implications for research

Futher large independent trials of prebiotic are needed before prebiotics can be recommended for prevention of allergy in formula fed infants. Current data indicate trials should use preparations of prebiotic that approximate the composition of human milk. Trials are needed both in infants at high risk of allergy and of the routine use of prebiotic in infants not selected by allergy risk. The intervention and measurement of outcomes should be blinded and allergy outcomes measured preferably to two years and beyond using standardised definitions.

Acknowledgements

None made

Data and analyses

Download statistical data

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 incidence2226Risk 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 incidence41220Risk 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 incidence1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]
Analysis 1.1.

Comparison 1 Prebiotic versus no prebiotic, Outcome 1 Asthma.

Analysis 1.2.

Comparison 1 Prebiotic versus no prebiotic, Outcome 2 Eczema.

Analysis 1.3.

Comparison 1 Prebiotic versus no prebiotic, Outcome 3 Urticaria.

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 allergy1134Risk Ratio (M-H, Random, 95% CI)0.37 [0.14, 0.96]
1.2 Infants not selected for risk of allergy192Risk 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 allergy1134Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.24, 1.00]
2.2 Infants not selected for risk of allergy31086Risk 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 allergy1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]
3.2 Infants not selected for risk of allergy00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Prebiotic versus no prebiotic - according to infant risk of allergy, Outcome 1 Asthma.

Analysis 2.2.

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

Analysis 2.3.

Comparison 2 Prebiotic versus no prebiotic - according to infant risk of allergy, Outcome 3 Urticaria.

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 milk192Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.56, 2.06]
1.2 Fed predominately cow's milk formula00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Fed predominately hydrolysed infant formula1134Risk 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 milk192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]
2.2 Fed predominately cow's milk formula2994Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.11]
2.3 Fed predominately hydrolysed infant formula1134Risk 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 milk00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Fed predominately cow's milk formula00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Fed predominately hydrolysed infant formula1134Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.16]
Analysis 3.1.

Comparison 3 Prebiotic versus no prebiotic - according to type of infant feed, Outcome 1 Asthma.

Analysis 3.2.

Comparison 3 Prebiotic versus no prebiotic - according to type of infant feed, Outcome 2 Eczema.

Analysis 3.3.

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

Comparison 4. Prebiotic versus no prebiotic - according to type of prebiotic
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Asthma2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 GOS / FOS (9:1) 8 grams/L versus1134Risk 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/day192Risk 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/L1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]
2.2 Polydextrose, GOS and lactulose 8 grams/L1106Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.12, 3.16]
2.3 GOS / FOS (9:1) 8 grams/L1134Risk 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/L1830Risk 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/day192Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.41, 2.65]
3 Urticaria1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 4.1.

Comparison 4 Prebiotic versus no prebiotic - according to type of prebiotic, Outcome 1 Asthma.

Analysis 4.2.

Comparison 4 Prebiotic versus no prebiotic - according to type of prebiotic, Outcome 2 Eczema.

Analysis 4.3.

Comparison 4 Prebiotic versus no prebiotic - according to type of prebiotic, Outcome 3 Urticaria.

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/L1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Ezcema1116Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.83, 7.52]
Analysis 5.1.

Comparison 5 Specific prebiotic versus other prebiotic, Outcome 1 Polydextrose and GOS 4g/L versus polydextrose, GOS and lactulose 8g/L.

Appendices

Appendix 1. MEDLINE search strategy

Searched using OVID 23rd August 2012 (retrieved = 250):

1 infant*

2 exp Infant/

3 newborn*

4 neonat*

4 pediatric*

5 paediatric*

6 1 OR 2 OR 3 OR 4 OR 5

7 prebiotic*

8 exp Prebiotics/

9 oligosaccharide

10 fructo-oligosaccharides

11 galacto-oligosaccharide

12 7 OR 8 OR 9 OR 10 OR 11

13 6 AND 12

14 limit 14 to clinical trial, all

Appendix 2. CENTRAL search strategy

Searched 23rd August 2012 (retrieved = 206):

1 prebiotic*

2 oligo*

3 infant

4 #1 OR #2

5 #4 AND #3

Appendix 3. EMBASE search strategy

Searched 23rd August 2012 (retrieved = 1126):

1. 'prebiotic'/exp OR prebiotic AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim)

2. 'oligosaccharide'/exp OR oligosaccharide AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim) AND ([newborn]/lim OR [infant]/lim OR [preschool]/lim OR [school]/lim OR [child]/lim) AND [humans]/lim)

3. 1 OR 2

What's new

DateEventDescription
23 August 2012New citation required and conclusions have changed

This is a substantive update with two new included trials and conclusions changed.

Food hypersensitivity no longer reported.

23 August 2012New search has been performedThis updates the review 'Prebiotics in infants for prevention of allergy' (Osborn 2007b).

History

Protocol first published: Issue 2, 2007
Review first published: Issue 4, 2007

DateEventDescription
14 September 2009New search has been performedUpdate includes new study and updated conclusion.
14 September 2009New citation required and conclusions have changedAddition citations found for previously included studies reporting 2 year outcomes.
25 August 2008AmendedConverted to new review format.
31 May 2007New citation required and conclusions have changedSubstantive amendment

Contributions of authors

DAO and JKS wrote the protocol.
DAO wrote the review.
Both review authors performed the literature search, independently assessed studies for eligibility, performed critical appraisal of eligible studies and data extraction, and formed a consensus on the conclusions.
For the August 2012 update, DAO and JSK independently assessed studies for eligibility, performed critical appraisal of eligible studies and data extraction, and formed a consensus on the conclusions.

Declarations of interest

KS has been an invited speaker to industry funded meetings.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Australian Satellite of the Cochrane Neonatal Review Group, Australia.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Gruber 2010

MethodsRandomised double-blind, placebo-controlled trial
Participants

Inclusion 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

Interventions

Prebiotics 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

Outcomes

Primary 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 risk

Groups 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
Outcomes

Primary 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

Notes

Sponsored: 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
Participants

Inclusion 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

Interventions

Randomly 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%)

Outcomes

Primary 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

Notes

Allergy 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
Notes

Sponsored: 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 2007

Enrolled 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 2004

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

Did not report allergy

Bisceglia 2009

Double-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 2002

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

Did not report allergy

Bongers 2007

38 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 2006

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

Did not report allergy

Bruzzese 2009

Healthy 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 2008

Randomised 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 2008

Healthy 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 2005

Randomised healthy infants to oligosaccharide supplemented formula or control

Did not report allergy

Euler 2005Randomised, crossover study of fructo-oligosaccharide supplement
Fanaro 2005

Vaginally 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 2009

172 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 2009a

32 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 2009b

20 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 2009c

20 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 2007

Bottle-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 2007

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

Did not report allergy

Knol 2005

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

Did not report allergy

Kukkonen 2006

Randomised 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 2008

Randomised 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 2009

Patients 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 2006

Randomised preterm infants to B. lactis or placebo

Did not report allergy to date

Modi 2010

Multicentre 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 2002

90 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 2009

Randomised 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 2008

Randomised 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 2005

Study 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 2011

Randomised, 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 2003

Observational 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 2005

Randomised 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 2006

Infants 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 2007

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

Reported infant eczema

Singhal 2008

Infants 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 2009

Randomised 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 2004

Randomised 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 2010

Randomised 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 2009

126 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 2007a

Randomised 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
Participants

Inclusion 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

Interventions

Intervention: 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
Notes

Inactivated organisms potentially prebiotic

No allergy outcomes reported to date

Hicks 2010

MethodsRandomised, parallel, double-blind
Participants

Inclusion criteria:

  • healthy, term infants

Exclusion criteria:

  • breast fed infants

  • use of vitamin/mineral supplements

  • currently on medication

Interventions

Cow'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
Notes

Published in abstract form only to date

No allergy outcomes reported to date

Holscher 2012

MethodsRandomised controlled trial
Participants

Inclusion 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

Interventions

Randomised 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
Notes

No 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
Notes

Published in abstract form only to date

No allergy outcomes reported to date

Vanderhoff 2010

MethodsDouble-blind, parallel design randomised controlled trial
Participants419 healthy infants
Interventions

Randomised 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)

Outcomes

Anthropometric 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
Participants

Inclusion 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

Interventions

Infants 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

Outcomes

Tolerance and bifidogenic effect

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

Notes

No allergy outcomes reported to date. Adverse events monitored

Sponsor: supported by Beneo-Orafti

Zoeren-Grobben 2009

MethodsDouble blind placebo-controlled randomised prospective cohort study
Participants

Heathy 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
Outcomes

Primary 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
Participants

Inclusion 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

Interventions

Control 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
Participants

Inclusion 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
Participants

Inclusion 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)
Outcomes

Primary 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
Participants

Inclusion 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

Interventions

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

Standard infant formula without functional ingredients

Outcomes

Primary 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
Participants

Inclusion 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

Interventions

Group 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 

Ancillary