According to my review of clinical trials in the PubMed database, studies regarding the administration of probiotics to neonates date back to 2001 with two studies before that time, one as far back as 1986. The early studies investigated the occurrence or prevention of atopic disease (allergic inflammation and food allergies) related to the administration of probiotics.1, 2
Several papers were published in 2005 reporting clinical trials of probiotic administration and the prevention of necrotizing enterocolitis.3-6 Probiotics are “live micro-organisms which, when administered in adequate amounts confer a health benefit on the host.” Probiotics have long been used to promote adult health, often as a health food supplement but also in some medical situations. Concerns arise about delivery of live organisms to immune-compromised neonates.
While many of the early studies showed a decrease in the occurrence or severity of NEC, not all studies measured that and most importantly, not the same type, dose, or timing of bacteria was administered. In addition, diet types were not the same and in some cases, were not reported. One recent study had an 89% rate of use of breast milk in the study population, both in the group that received the probiotic and in the control group.7 This study showed a very low rate of NEC in both groups with none in the group given the probiotic and only one case in the control group. In a study performed in Canada, the group that received probiotics had a 50% reduction in NEC (9.8% occurrence reduced to 5.4%).8 This group had a 91% and 93% breastfeeding rate although formula supplementation was provided when breast milk was not available. This did not change between the groups. In a search for additional information on this topic, and without a very sophisticated search, 5 papers were located for results of trials with probiotics so far in 2014.7-11
A Cochrane review updated in 2014 analyzed 24 clinical trials of probiotic use for the prevention of NEC.12 The conclusion was that the enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. However, enrollment criteria in the included studies was highly variable, the baseline risk of NEC was different between groups and the timing, dose and formulation of the probiotics as well as feeding regimen were not standardized. The studies reviewed did not report any systemic infections with the organism used for supplementation nor was there any evidence of reduction of nosocomial sepsis. The largest randomized controlled trial, the ProPrems trial was performed in Australia and New Zealand.13 This trial involved 1099 very preterm infants and results showed a 50% decrease in NEC rates in a population with already low NEC rates (4.4% to 2.2%). Both the Cochrane review and another review paper advocate for a change in practice and widespread use of probiotic supplementation.14 So what are the reasons we are not seeing widespread use of probiotics in clinical practice?
Probably most importantly, probiotics are considered a food additive and as such, are not regulated in the same manner as pharmaceutical products. Therefore, the availability of the product in the hospital setting is challenging. One must investigate what bacteria is in the product being obtained and ensure consistency of what is provided. But beyond the availability, there are some other points to consider. Some believed probiotic use was important to provide biodiversity in the microbiome of the neonatal gut. Cilieborg, Boye and Sangild discuss several studies in animals and humans regarding the microbiome of the gut and effect on health.15 There are several perinatal practices that effect gut colonization. Specifically, in all gestational ages, mode of delivery affects the amount of bacteria in the gut. Infants delivered via cesarean section have fewer bacteria in the gut but in at least one animal study, the gut was rapidly colonized within a few hours after birth and before the first feeding. This is probably more important in the preterm infant as maturity at birth in itself effects bacterial growth in the gut. Couple this with delivery via cesarean section and the altered environmental bacteria in the NICU, presence of an oro- or nasogastric tube, frequent antibiotic use upon admission and being NPO (nothing by mouth) for some period of time and the potential for decreased or abnormal colonization of these infants is high. The studies mentioned above show a decrease in the occurrence of NEC and certainly less severe NEC. This occurred in spite of high rates of breast milk use in at least two studies. However, as far as bacterial colonization related to diet, infants who are breast fed have less diversity of bacteria than infants who are formula fed. Breast fed infants, however, have more growth of Bifidobacteria than do formula fed infants. Other protective effects of breast milk have been found, other than bacterial colonization. In a study of preterm pigs, whose intestinal development and bacterial colonization is similar to preterm humans, feeding of colostrum only (no additional breast milk) as compared to formula only, resulted in a decrease of the incidence of NEC from 60% in formula only pigs to 5% in those fed colostrum.16 This is not thought to be related to a difference in gut colonization, however. Rather, it may be more related to other macronutrients and metabolic activity induced by the colostrum. While there are few studies and relatively few participants in the studies, the specific colonization related to diet i.e. formula vs breast milk is less different than may be expected. Some studies show no difference or minor differences in the presence or amount of Bifidobacteria between breast-fed or formula-fed infants.15 This may make an argument for administration of probiotics to preterm infants regardless of diet.
Other practices that effect gut colonization and microbiota include method of feeding as suckling is thought to have an effect on important physiologic processes, regardless of diet and skin-to-skin holding as this provides for exposure of the infant to the normal flora of the family. Additionally, genetics and gut epigenetics also have an effect. As far as an interaction between gut microbiome and the occurrence of NEC, no specific bacteria can be linked to the occurrence of NEC but two medium-sized studies did show a decrease in diversity of intestinal bacterial colonization in infants who had NEC, likely related to the use of antibiotics.17, 18 Additionally, in some cases, the presence of the bacteria in the gut is found after the infant is diagnosed with NEC making it difficult to know if the bacterial overgrowth is the result or the cause of the NEC.
Another interesting twist to the whole issue of the microbiome of the intestines is the link with brain development. Specific conditions that have been linked with a change in intestinal colonization are type 1 diabetes, autism, and changes in brain neurotransmitters.19 While this research is not yet conclusive, it offers another consideration, particularly in the preterm infant whose brain is undergoing such rapid development. Is it possible that the abnormal gut colonization that may occur in the NICU environment has an effect on brain development and can/should that be artificially manipulated in some way?
So, while the time for use of probiotics may have come, there are still many important questions to be asked and answered. The risks of probiotic administration seem to be low with no reported cases of sepsis from the specific bacteria administered. However, the specific bacteria that would be most beneficial has not been determined although most studies used Bifidobacteria, Lactobacillus or some combination. The amount to be given, when it should be started and for how long the treatment should continue, as well as the benefits of or differences in use in infants fed their own mother’s milk as compared to donor human milk and bovine-based infant formula all bear further investigation.
1. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomized placebo-controlled trial. Lancet. 2001 Apr 7;357(9262):1076-9.
2. Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol. 2002; 109(1):119-121.
3. Kullen MJ, Bettler J. The delivery of probiotics and prebiotics to infants. Curr Pharm Des. 2005;11(1):55-74.
4. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, Oh W. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2005; 115(1):1-4.
5. Kliegman RM, Willoughby RE. Prevention of necrotizing enterocolitis with probiotics. Pediatrics. 2005; 115:171-172
6. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, Hammerman C. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates.J Pediatr. 2005; 147(2):192-6.
7. Patole, Keil, Chang et al. Effect of bifidobacterium beve M-16V Supplementation on fecal bifidobacteria in Preterm neonates – a randomized double blind placebo controlled trial. PLoS ONE. 2014;9(3):e89511. Doi:10.1371/journal.pone.0089511.
8. Janvier A, Malo J, Barrington KJ. Cohort study of probiotics in a North American neonatal intensive care unit. J Pediatr. 2014;164(5):980-5. doi: 10.1016/j.jpeds.2013.11.025.
9. Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, Bisceglia M, Cinquetti M, Brazzoduro E, Del Vecchio A, Tafuri S, Francavilla R. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial.JAMA Pediatr. 2014;168(3):228-33. doi: 10.1001/jamapediatrics.2013.4367.
10. Oncel MY, Sari FN, Arayici S, Guzoglu N, Erdeve O, Uras N, Oguz SS, Dilmen U. Lactobacillus Reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: a randomised controlled trial.Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F110-5. doi: 0.1136/archdischild-2013-304745.
11. Luoto R, Ruuskanen O, Waris M, Kalliomäki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2014;133(2):405-13. doi: 10.1016/j.jaci.2013.08.020.
12. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews. 2014, Issue 4 Art No: CD005496. DOI: 10.1002/14651858.CD005496.pub4.
13. Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, et al. Probiotic effects on late-onset sepsis in very preterm infants: A randomized controlled trial. Pediatrics. 2013;132:1055-1062.
14. Shlomai NO, Deshpande G, Rao S, Patole S. Probiotics for preterm neonates: What will it take to change clinical practice? Neonatology 2014;105:64-70. DOI:10.1159/000354891.
15. Cilieborg MS, Boye M, Sangild PT. Bacterial colonization and gut development in preterm neonates. Early Human Development. 2012;88:S41-S49. DOI:10.1016/j.earlhumdev.2011.12.027.
16. Bjornvad CR, Thymann T, Deutz NE, Burrin DG, Jensen SK, Jensen BB et al. Enteral feeding induces diet-dependent mucosal dysfunction, bacterial proliferation and necrotizing enterocolitis in preterm pigs on parenteral nutrition. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1092-2103.
17. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, et al. 16S rRNA gene based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 2009;3:944-954.
18. Millar MR, Linton CJ, Cade A, Glancy D, Hall M, Jalal H. Application of 16SrRNA gene PCR to study bowel flora of preterm infants with and without necrotizing enterocolitis. J Clin Microbiol. 1996;34:2506-2510.
19. Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatrics. 2013;167(4):374-379.
Looking for additional reading from Sandy Beauman’s professional perspective?
View her blog entry, Caring for Critical Patients in an Era of Drug Shortages.