THE ROLE OF PROBIOTICS IN PRETERM NEONATES
Girish C Deshpande Department of Neonatal Paediatrics, KEM Hospital for Women, Perth, Western Australia Address for Correspondence: Girish C. Deshpande, Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Perth, Western Australia 6008. E-mail: firstname.lastname@example.org
Probiotics are defined as live non-pathogenic microbial supplements that colonise the gut while providing benefits to the host.(1) Almost a century ago (1908) Russian scientist and Nobel prize Laureate Elie Metchinkoff proposed the idea of non-pathogenic bacteria for healthy lifestyle on observing the association between prolong lifespan (Average 87 years) and dairy products in the diet of Bulgarian people. What he thought was contained in the diet is what we now know as probiotics. Moro formally discovered lactobacillus in 1990 and gene was mapped in 1999. Probiotics organisms usually consist of Lactobacillus, bifidobacteria and streptococcus species.
Probiotics for neonates
Hoyas et al (1999) were the first to report significant reduction in the incidence of necrotising enterocolitis (NEC) following probiotic supplementation in a cohort of preterm neonates. (2) Lactobacillus acidophilus and Bifidobacterium infantis were given to 1237 preterm neonates and the results were compared with 1282 historical controls from the previous year. Significant reduction in NEC (85 vs. 34) was noted in probiotics group. Since then many trials have assessed the benefits of probiotics in reducing NEC, sepsis, and allergy in neonates and infants. Prevention of NEC and sepsis in preterm neonates however has been the main focus of probiotics in neonatology (Table1).
Table 1: Probiotics RCTs in neonates
Reuman (3) 1986
Stansbridge (4) 1993* and Millar (5) 1993*
Kitajima (6) 1997
Gut colonisation by BB
Uhlemann (7) 1999
Dani (8) 2002
UTI, Sepsis, NEC
Costalos (9) 2003
Gut function and stool colonisation
Agarwal (10) 2003
Bin Nun (11) 2005
Lin (12) 2005
Manzoni (13) 2006
Gut colonisation by Candia species
Mohan (14) 2006
Gut colonisation by BB-L and enteric pathogens BB: Bifidobacterium breve, LB GG : Lactobacillus GG , SB: Saccharomyces boulardii BI: Bifidobacteria infantis, ST: Streptococcus thermophilus , , BBB: Bifidobacterium bifidus, LB - A: Lactobacillus acidophillus , LB-C: Lactobacillus Casei; BB-L: Bifidobacterium lactis *Two publications from the same cohort of study population. Development of intestinal microfloraIt is important to understand the development of intestinal microflora in preterm and term neonates to appreciate the role of probiotics. Human gastrointestinal tract harbours a complex eco-system of microbes. Approximately 1014 microbes exist in the colon and intestines and consist of more than 500 species. (15) Microbial flora exists in symbiotic relationship with the host. A neonate is born with a sterile gut that is usually colonised within 12 to 24 hrs. Intestinal microbes from the mother are usually the first source of bacteria. Colonisation by anaerobes usually commences in next 2 or 3 days. Lactobacilli and bifidobacteria from breast milk colonise the gut subsequently. It is important to note that many other factors including mode of birth, surrounding environment and dietary factors also influence initial colonisation in a neonate.(16) There are at least four different strains of lactobacilli and bifidobacteria isolated form human breast milk (17,18), which help to colonise newborn gut.The microbial flora of the intestines of preterm neonates in neonatal intensive care units differs from that of normal term neonates. Very low birth weight (VLBW) preterm neonates usually acquire microbial flora mainly from intensive care environment rather than from their own mother. Few studies have demonstrated that there is delay in appearance of Bifidobacteria species in VLBW neonates until third week of life, even in those receiving only breast milk. (19,20) Stools of breastfed neonates have predominance of Bifidobacterium and Lactobacillus species, which compete with pathogens such as Bacteroides, Clostridia and Enterobacteriaceae species. (20)Unfortunately VLBW preterm neonates are at risk of gut colonisation with pathogens which can alter the permeability of intestines and promotes inflammatory cascade which facilitates NEC.(21,22) Probiotics for prevention of sepsis and NECNEC is the commonest neonatal gastrointestinal emergency. It is mainly associated with prematurity with full term neonates accounting for only 5-25% of all cases (23). The incidence of this potentially fatal illness is reported to be 5-10% in VLBW neonates (24). Extremely low birth weight (ELBW) neonates (birth weight < 1000 grams) with gestation under 28 weeks are most susceptible. (25) The mortality (20-40%) and morbidity including poor long term neurodevelopmental outcome after a diagnosis of definite NEC continue to be high, especially in ELBW neonates. (26) Despite decades of research the pathogenesis of NEC continues to be poorly understood. Prematurity however continues to be accepted as the single most important risk factor for the illness. Interplay of various risk factors including hypoxia, immaturity of intestinal tract, microbial colonisation with pathogenic organisms, formula feeding, sepsis and intestinal ischemia-reperfusion (I-R) injury against the background of a vulnerable gut is proposed to contribute to the inflammatory cascade that in some situations precipitates NEC. (27) Probiotics may prevent NEC and sepsis by promoting colonisation with beneficial organisms (e.g. bifidobacteria species), preventing colonisation by pathogens (e.g. enterobacteria, clostridia, and staphylococcal species), improving the maturity and function of gut mucosal barrier in dealing with the flow of food and microbial antigens across it, and by modulating the immune system to the advantage of the host (1,28). Systematic review of Randomised controlled trials of probiotics in preterm neonatesDani et al have evaluated the effectiveness of probiotics supplementation in reducing the incidence of urinary tract infections (UTI), sepsis and NEC in preterm neonates.(8) Total 585 preterm VLBW neonates were randomized to receive standard milk feed supplemented with Lactobacillus GG or placebo. Although UTI and NEC were less frequent in the probiotics vs. control group, the differences were not statistically significant. Lin HC et al evaluated the efficacy of probiotics in reducing death or stage II NEC (primary outcome) in a masked trial in VLBW neonates who were commenced enteral feeds and survived beyond the 7th day after birth. (12) Total 367 preterm VLBW neonates were randomised to either probiotics (Infloran: Lactobacillus acidophilus and Bifidobacterium infantis) with breast milk twice daily until discharge or breast milk alone. The incidence of death or stage II NEC was significantly lower (60%) in the probiotics group. Bin-Nun et al looked at efficacy of prophylactic probiotics in reducing the incidence and severity of NEC in preterm neonates (11). Total of 145 preterm VLBW neonates were randomised either to receive probiotics (Bifidobacteria infantis, Streptococcus thermophilus, and Bifidobacteria bifidus) of 109 colony forming units per day or placebo. The gestation, birth weight and time to reach full feeds were comparable. The incidence of NEC was reduced significantly in the probiotics group (4% vs. 16.4% in control group, p=0.03). NEC was less severe in the probiotics group and all NEC-related deaths (3/15) occurred in the control group (11). The results of a systematic review indicate that probiotic supplementation has a significant role in prevention/minimisation of all cause mortality and morbidity (specifically NEC, late onset sepsis, and feed intolerance of prematurity) in preterm VLBW neonates.(29) Deshpande et al systematically reviewed the RCTs evaluating efficacy and safety of any probiotic supplementation (Started within first 10 days, duration: 7 days) in preventing stage II NEC in preterm VLBW (gestation < 33 weeks, birth weight < 1500 grams) neonates (29). A total of 7 out of 12 retrieved RCTs (N=1393) were eligible for inclusion in the analysis. Meta-analysis using a fixed effects model (7 trials, N=1393) estimated a lower risk of Stage II NEC [RR: 0.36(95% CI: 0.20, 0.65)] in the probiotic group. The numbers needed to treat (NNT) with probiotics to prevent one case of NEC was 25 [95% CI: 17, 50]. The risk of blood culture positive sepsis (6 trials, N=1355) did not differ significantly between groups [RR: 0.94 (95% CI: 0.74, 1.20)]. The risk of death (5 trials, N=1268) was reduced significantly in the probiotic vs. control group [RR: 0.47(95% CI: 0.30, 0.73)] NNT to prevent one death by treatment with probiotics was 20 [95% CI: 12, 50]. However there was no significant difference in mortality due to NEC or sepsis. Additionally the time to full enteral feeds (3 trials, N= 316) was significantly shorter in the probiotic group [WMD=-2.74 days (95% CI: -4.98, -0.51]. Overall the results indicated that probiotics may significantly reduce the risk of all cause mortality and Stage II NEC in preterm neonates <33 week's gestation while significantly shortening the time to full enteral feeds. SafetySafety of probiotic supplements is an important issue in preterm neonates. Sepsis by the specific organism/s in the probiotic supplement was not reported in any of the trials included in the systematic review.(29) However caution is necessary before adopting probiotics for prophylaxis in immunocompromised hosts such as preterm neonates given that neonatal lactobacillus sepsis has already been reported.(30,31) Unanswered issuesThe unanswered issues include the dose, duration, and type of probiotic agent/s (species, strain, single versus combined, live versus killed) used for supplementation. The remarkably consistent results (29), despite the distinct differences in dose, timing, and type of organisms used, suggest that substantial latitude might be available in the choice of an effective probiotic regimen in the design of further trials. If further large well-designed trial confirms the results of the systematic review by Deshpande et al (29) it is possible that probiotics could be used as a routine in preterm neonates. Given that prematurity is the single most important and unpreventable risk factor, probiotic supplementation alone might not turn out to be the single magic bullet for death and diseases like sepsis, and NEC in preterm neonates.
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Last updated: 1 December 2007 Volume 4 Issue 12 Art # 49
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Deshpande GC.The Role of Probiotics in Preterm Neonates . Pediatric Oncall [serial online] 2007 [cited 2007 December 1];4. Art # 49. Available from: