Recent data from the Cochrane group have supported routine use of probiotics for prevention of severe NEC and all cause mortality in premature neonates born
1,500 grams [6
]. While this population does not exclude infants born
1,000 grams, those authors caution against routine use of prophylactic probiotics in this high risk group until more data is published on their benefits and potential adverse effects [6
]. In our NICU, the team elected to implement probiotics as a NEC prevention strategy. As part of our quality improvement initiative we elected to measure the impact of this strategy in the subpopulation of neonates born
1,000 grams who are at highest risk for developing NEC.10
We found this to be an effective strategy in contributing to reduced NEC rates in our ELBW population (15.1% to 2.5%). This effect is larger than seen in the studies for neonates with birth weight below 1500 grams, reported in the meta-analysis by Deshpande et al. [7
] as decreasing from 6.56% in controls to 2.37% in probiotic-treated patients.
More experience with probiotic use in neonates born
1,000 grams is starting to be published. The first study exclusively evaluating probiotics in ELBW infants [13
] did not find a difference in NEC rates, 4/51 (7.8%) in controls versus 3/50 (6%) in those receiving probiotics. This is likely in part due to inadequate power; however, their results do support safety of administering 500 million colony forming units (CFU) of Lactobacillus GG
and 500 million CFU Bifidobacterium infantis
once daily to their ELBW neonates. One caveat is that our experience with a lactobacillus GG product during our in vitro experiments was that it frequently clogged the nasogastric tube and would thus likely fail to be administered in a reliable manner. This could positively affect safety and negatively affect benefit results in a study. As previously stated, the larger published probiotic trials in neonates born
1,500 grams did not exclude neonates born
1,000 grams. In Lin and colleagues 2008 multicenter study evaluating Lactobacillus acidophilus
and Bifidobactrium bifidum
, presentation of their results by birth weight allows the reader to evaluate NEC rates in neonates born
1,000 grams, even though the study is not exclusive to this population. Their NEC rates in neonates born
1,000 grams were reduced from 7/79 (8.9%) in the control group to 4/102 (3.9%) in the group that received L. acidophilus
and B. bifidum
The rate of NEC in our pre- L. reuteri
control group was highly variable, ranging from 6.1% to 20.5%, and mostly ranging from 16% to 20%, with the average for the total population being 15.1%. This is higher than rates seen in other studies reporting neonates below 1000 gram birth weight, which are typically around 10% [14
] and was a motivation to seek interventions that could improve the results. The dramatic improvement following introduction of L. reuteri
lowered NEC rates below those seen in any NICU reports. In this particularly high-risk population, our progress is not likely to be a coincidence since the cycle of change has now affected 3 different epochs in our longitudinal study (Table ).
Another related question is whether practice changes might account for the improved NEC rates. Against this is that rates of NEC were similar until L. reuteri was introduced and then remained similarly reduced after L. reuteri was made standard practice. Since our group tends to have similar practices and strives for continuity between attending physicians, and the same physician group have all been together throughout this study we cannot identify other practice variables that caused the changed NEC rates. We also did not make any other practice changes starting in 2009, such as increased breast milk usage or a different feeding strategy that we could identify to account for this improved NEC rate.
Neurodevelopmental consequences (cerebral palsy, cognitive impairment, visual impairment, hearing impairment) are of major concern for infants who survive NEC [16
]. Infants born
1000 grams that develop NEC requiring surgical intervention have much poorer neurodevelopmental outcomes than those with medical NEC or no NEC [17
]. In our analysis from July 2009 through April 2011, elimination of medical NEC and NEC-related death in ELBW neonates receiving L. reuteri
prophylaxis is remarkable.
Probiotics have been shown to be a barrier to bacterial translocation and competitively exclude potential pathogens. Given these properties, one would conclude that probiotics should also play a role in reducing rates of infection. However, this has not been demonstrated in a controlled setting. Consistent with published literature [3
] we did not find a significant reduction in incidence of culture-positive late-onset bacterial or fungal infection (31 versus 22.8%). Perhaps, as other authors have suggested, we have yet to understand the optimal probiotic product, dose and duration to reach this infection prevention threshold.
We chose to dose our preterm neonates daily with 0.1
mL of L. reuteri
. This dose was a conservative reduction of what the manufacturer recommends for term infants. After two years of using this product, we wanted to confirm that the product was colonizing the infant gut in effective amounts. In 2011, we collected stool samples at random from 7 infants who had been receiving L. reuteri
for varying lengths of time (12 – 101
days) and found that, while all 7 had some level of fecal colonization, 3 of the 7 infants did not have optimum fecal colonization (106
to 107 L. reuteri
CFU/g stool). As a result, our NICU decided to increase our standard prophylaxis dose from 0.1
mL to 0.2
mL daily in order to more accurately administer the recommended 100 million live, active L. reuteri
cells. Outcomes from this adjusted dose are currently being collected and are not reported in the present study.
One of the major criticisms surrounding probiotic use focuses on generalization of results to all probiotics strains. Therefore, it cannot be assumed that our results obtained with L. reuteri DSM 17938 can be extrapolated to other probiotic products. Each individual preparation must be analyzed separately in the context of other successful NEC prevention strategies.
Although we do not completely understand the pathogenesis of NEC, it is recognized that NEC involves multiple contributing factors unique to preterm infants. Probiotics have been shown to assist in decreasing NEC rates, but given the multi-factorial nature of the disease, we would expect prevention to ultimately require a multi-modal strategy as well.