One high-quality double-blind RCT of 55 infants and young children aged 5 to 24 months in a chronic medical care hospital in a developed country found that administration of standard infant formula supplemented with Bifidobacterium lactis (formerly called Bifidobacterium bifidum) (1.9 × 108 CFU/g powdered formula) and Streptococcus thermophilus (0.14 × 108 CFU/g) reduced the prevalence of nosocomial diarrhea compared with placebo (7% versus 31%; relative risk [RR]: 0.2; 95% confidence interval [CI]: 0.06–0.8). The risk of rotavirus gastroenteritis was significantly lower in those receiving probiotics supplemented formula (RR: 0.3; 95% CI: 0.09–0.8). Feeding B. bifidum and S. thermophilus led to a significantly lower rate of rotavirus shedding (25).
One low quality RCT (no blinding, allocation concealment unclear, dropout and withdrawal rate not documented) involving 175 children living in an orphanage in a developing country reported no protective effect of infant formula supplemented with Bifidobacterium Bb12 (108 CFU/g) alone on episodes of diarrhea (40/62; 65%) or in combination with S. thermophilus (dose not given) (29/56; 52%) compared with placebo (14/57; 25%). Rotavirus accounted for only 3 of 81 (3.7%) episodes of diarrhea, and bacterial pathogens accounted for 45 of 81 (56%) episodes of diarrhea (26).
Two small RCTs of infants with atopic dermatitis and cow’s milk allergy during formula feeding or breastfeeding were found (29,30). Neither study provided details of randomization and blinding. Allocation concealment was unclear. In the first study (29), infants (n = 27) with atopic eczema and cow’s milk allergy were randomly assigned to receive extensively hydrolyzed whey formula supplemented with Lactobacillus GG (5 × 108 CFU/g formula) or placebo for 1 month. There was a statistically significant reduction in the clinical score of atopic dermatitis (SCORAD) during the 1-month study. However, by 2 months the SCORAD was similar in both groups. In the second study (30), infants (n = 27) with atopic eczema during exclusive breastfeeding were randomly assigned to receive extensively hydrolyzed whey formula supplemented with Lactobacillus GG (3 × 108 CFU/g), or Bifidobacterium lactis Bb-12 (1 × 109 CFU/g), or the same formula without probiotics. No details on the duration of intervention were given. After 2 months, a statistically significant reduction in SCORAD score was observed in the groups consuming probiotics compared to placebo. A significant change in the SCORAD scores at the 2-month evaluation was seen in 9 of 9 patients receiving B. lactis Bb-12, and in 9 of 9 patients in the Lactobacillus GG group, as compared with 4 of 9 patients not receiving probiotics.
In conclusion, there are very limited published data on the clinical effects of probiotic supplementation of infant formulas, follow-up formulas, and special medical foods. Although some short-term benefits are scientifically demonstrable, until more studies are available it is not possible to conclude that the clinical effects of probiotic supplementation are preventive or therapeutic for any childhood disease.
It is recommended that the safety of breast milk substitutes be evaluated carefully before they are introduced to the market (32,33). An important part of this evaluation is assessing the impact on growth. Below we have summarized growth data from studies evaluating the effect of infant formulas and foods for special medical purposes.
Three RCTs evaluating growth of children fed formulas supplemented with probiotic bacteria were found (Table 1) (25,27,28). The first RCT (27) evaluated newborn infants randomized to formula with or without Streptococcus thermophilus and Lactobacillus helveticus for the first 2 months of life. There were 20 infants in each group, and the two groups were compared with a group of 14 fully breast-fed infants. Weight, length, and head circumference were recorded at birth, 1 month, and 2 months. No data on growth were given. It was stated that that the three kinds of feeding assured normal growth during the first 2 months of life without any significant difference, but there was no information on how this conclusion was tested.
Only one study has measured growth in 27 infants randomly assigned into three groups: extensively hydrolyzed whey formula with either Bifidobacterium lactis Bb-12, Lactobacillus GG, or no probiotics added (30). Weight and length were measured at start and after 2 and 6 months of intervention. It was stated that the growth of all children was normal, but the groups were not compared.
In conclusion, only one study has provided growth data adequate to assess the effects of infant formula with added probiotics. This study was performed in malnourished infants living in a residential facility in Thailand. One limitation of that study was its large age range, from 6 to 36 months, because growth velocity and regulation of growth are different in young infants and toddlers. This study found a positive effect of probiotics on linear growth, but because the evidence is of poor quality, the conclusion is of limited value. The other studies were too small with insufficient power to identify relevant effects on growth. Furthermore, most of the studies did not present the growth data. With a lack of robust evidence, no conclusions can be made regarding the impact of probiotic bacteria in dietetic products on infant growth. However, there are no indications from the available data that probiotics have any adverse effects on growth.
There is extensive literature on the effects of probiotics supplied in other forms (e.g., pills, powdered supplements, fermented dairy foods) but relatively few RCTs. Best documented are the therapeutic effects of certain probiotic strains in acute infectious gastroenteritis, as recently summarized in two systematic reviews (34,35). A moderate beneficial effect was found in the treatment of watery diarrhea caused by rotavirus, which was strain and dose dependent. Some benefit also appears to be achieved in diarrhea caused by other viruses, but no efficacy was found in invasive bacterial diarrhea. Beneficial effects were more pronounced when treatment with probiotics was initiated early in the course of disease (36,37).
Two recent systematic reviews show that probiotics given in combination with antibiotics reduce the risk of antibiotic-associated diarrhea (38,39). In particular, the yeast Saccharomyces boulardii and several strains of lactobacilli have been used in this situation. However, with few exceptions, the trials were performed in adults, and thus the authors’ conclusion may not be applicable to children. Thus, the Committee looked specifically at the studies in children. Four trials were identified. One small RCT (38 children treated with L. acidophilus and L. bulgaricus) found no significant prevention of antibiotic-associated diarrhea (odds ratio [OR]: 0.88; 95% CI: 0.22–3.52) (40). A further double-blind RCT looked at L. acidophilus and Bifidobacterium infantis, but methodological limitations (i.e., small sample size, lack of definition of diarrhea as an end point) preclude drawing reliable conclusions (41). Two RCTs showed a moderate preventive effect of L. rhamnosus GG for mild antibiotic-associated diarrhea in children (42,43), but results in adults are conflicting (44). Lower dosage of Lactobacillus GG used in adults, differences in administered antibiotics, and age-related differences in the pathologic mechanism of antibiotic-associated diarrhea may be responsible for conflicting results. There are no randomized studies in children on the incidence of antibiotic-associated diarrhea caused by Clostridium difficile.
Three studies of the efficacy of probiotics for preventing nosocomial diarrhea were identified. One small trial (discussed earlier) suggested beneficial effects of Bifidobacterium bifidum and Streptococcus thermophilus (25). Evidence for the effectiveness of Lactobacillus GG is conflicting, with one RCT claiming substantial benefit (45) and another (using different dosing) showing none (46).
In the same study, significant reduction in the risk of dental caries was seen (OR 0.56; P = 0.01; controlled for age and gender, OR 0.51; P = 0.004) (49). Whether the use of Lactobacillus GG is more cost-effective than fluoride has not been established.
Data from animal models and patients with inflammatory bowel disease have highlighted the importance of the enteric microflora in the pathogenesis of the disease, yet in clinical trials, probiotics have had only limited efficacy against active disease. In children with Crohn disease, a preliminary open-labeled trial of Lactobacillus GG suggested that Lactobacillus GG reduced intestinal permeability and disease activity (53). However, a recent placebo-controlled randomized study (65 children with small and large bowel Crohn disease in remission) showed that Lactobacillus GG in a dose of 109 CFU twice daily was not helpful in maintaining remission when added to standard maintenance therapy for Crohn disease (54).
In children, we conclude that the best proven health effect of probiotics is the reduction of the duration of acute infectious gastroenteritis. The true benefit of probiotics in other conditions is yet to be defined. However, there is a body of promising evidence to suggest that they may be effective in the prevention of nosocomial and antibiotic-associated diarrhea, respiratory diseases, and allergic diseases. Effects appear to be strain specific and cannot be extrapolated from strain to strain.
Prematurity and low birth weight are risk factors for morbidity and mortality from sepsis and neonatal necrotizing enterocolitis (NEC) (55). It has been suggested that enteral administration of probiotics to premature newborns with patterns of intestinal colonization different from those of healthy, full-term newborns could prevent infection and NEC and thus the use of antibiotics (56).
Several studies have examined the ability of probiotics to colonize the gut of preterm and low–birth-weight infants. Reports on the colonizing capability of Lactobacillus GG have varied (57–59). An 86% colonization rate was reported in a randomized controlled trial of L. acidophilus (60). One RCT in 91 very low–birth-weight infants found that infants whose feedings were supplemented with Bifidobacterium breve (109 CFU/day) had higher rates of fecal bifidobacterial colonization at 2 weeks of age (73%v 12%), decreased gastric aspirates, improved weight gain, and improved feeding tolerance. Clinical outcomes were not reported (61). In Columbia, the prophylactic administration of L. acidophilus and Bifidobacterium infantis to all neonates in an intensive care nursery with a high incidence of NEC reduced the incidence of disease compared with historical controls (62). The study is limited by not being appropriately controlled. A recent multicenter randomized controlled trial in 585 preterm infants found that Lactobacillus GG supplementation (6 × 109 CFU once daily) starting with the first feeding did not reduce urinary tract infections, NEC, or sepsis (63).
In summary, only a limited number of controlled trials have studied health outcomes following enteral administration of probiotic organisms in preterm infants. Additional studies are needed.
Almost all patients with infections in these studies have had underlying conditions predisposing them to infection, e.g. structural heart defects in the case of endocarditis, or indwelling catheters in the case of sepsis. In most cases of infection, the organism appears to have come from the patient’s own microflora. Only a limited number of cases have been reported in which the organism was thought (although not necessarily proven) to be related to the use or consumption of a commercial probiotic product (L. rhamnosus (69,77), Saccharomyces (78), Bacillus (79–81)). In these patients too, serious underlying conditions were common. Cases of infection with Bifidobacterium during supplementation with this organism have not been reported. A recent report from Finland indicated that the increased use of Lactobacillus GG in food has not resulted in an increased incidence of Lactobacillus bacteriemia or in the proportion of Lactobacillus bacteremia among all cases of bacteremia (82). Bacteremia associated with enterally administered probiotics has not been reported in infants or children but is a theoretical risk.
Several evaluations of the published literature have concluded that the risk of infection with probiotic lactobacilli or bifidobacteria is similar to that of infection with commensal strains, and that consumption of such products is a negligible risk to consumers, including immunocompromised hosts (65). Other side effects in which probiotics could theoretically play a role include deleterious metabolic activities, excessive immune stimulation, and gene transfer (83). However, the available data from preclinical and clinical evaluations do not provide any indication that such adverse effects would occur with the probiotic stains currently in use.
In summary, probiotics so far used in clinical trials can be generally considered as safe. However, surveillance for possible side effects, such as infection in high-risk groups, is lacking and is needed.
Our review of available clinical trials found only limited data on the safety and clinical effects probiotic preparations added to infant formulas, follow-up formulas, and special medical foods. There is no published evidence for any long-term clinical benefit of infant formulas supplemented with probiotic bacteria. No data are available on possible long-term effects on intestinal colonization and its effects on long-term gastrointestinal and immune functions. Acquisition of such data would be highly desirable given the suggestion that bacteria ingested during early infancy are more likely to permanently colonize the intestine than those ingested during later life (84). There are some data supporting a short-term benefit of some probiotic strains in infants and young children with infectious diarrhea.
The Committee recommends that when adding probiotics to dietetic products for infants, only bacterial strains for which identity and genetic stability have been demonstrated by cultural and molecular methods and strains considered as generally safe when added to the food in question should be used. The content of viable bacteria in dietetic products must provide a dose shown to be safe and effective with regard to defined outcomes in clinical trials throughout the shelf-life of the product.
The Committee concludes that further evaluation of the safety and efficacy of supplemental probiotic bacteria in dietetic products for infants is necessary. Each strain to be used must be evaluated at the range of doses intended for use, and minimal and optimal effective doses must be defined. Specific safety questions that should be addressed are the effects on nutrient use, the possible transfer of antibiotic resistance, the short- and long-term effects on the immune response, and the risk of infection.
The Committee is concerned that the available data are not sufficient to support the safety of probiotics in healthy newborn and very young infants with immature defense systems, infants with immunocompromised systems, premature infants, and infants with congenital heart disease.
The Committee recommends that infant formulas with added bacteria regarded as probiotics should be marketed only if a full evaluation of benefits and safety following the general principles of current standards (32,33) has been performed. Although the available data on the use of supplemented follow-on formulas is limited, the Committee has fewer concerns about potential adverse effects of these products because they are designed for use in infants older than 5 months, when there is a more mature immune response, an established intestinal colonization, and a history of exposure to a variety of organisms from the environment. The addition of probiotic bacterial strains to infant foods prescribed for special medical purposes and used under strict medical supervision may be justified if a clinical benefit has been established in adequate clinical trials, even if a full evaluation of all safety aspects has not been performed, for example because of the limited number of patients to be treated with a the specific dietetic product.
The Committee recognizes that there is evidence that some probiotic preparations have benefits on health and well-being. Reported benefits include a reduced severity of diarrhea, potential preventive effects on diarrhea, promising results of in vitro and animal studies on digestive and immune functions, and indications from human studies on possible short-term preventative and therapeutic effects on atopic eczema. In view of the potential for benefits on child health that might be achieved by the use of some probiotic bacteria, major efforts on their thorough evaluation are justified.
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