Probiotics QI Project

Background
Probiotic use in the NICU is common in many countries and appears to be increasing in the U.S.  Details from recent meta-analyses of probiotic use in premature infants are summarized in the table.(1-4)

Outcome Number of trials Number of infants RR (95% CI) P value
NEC 25 8492 0.55 (0.43-0.70) <0.001
Death 21 7332 0.78 (0.66-0.93) 0.01
Sepsis 24 7894 0.81 (0.69-0.94) 0.02
Hospital stay 19 5443 -3.8d (-5.8 to -1.9) <0.001
Weight gain 15 3751 -0.29 (-1.16-0.58) 0.51
IVH 10 3431 0.91 (0.73-1.14) 0.42
Time to full feeds 19 4527 -1.5d (-2.8 to -0.32) <0.001
BPD at 28 days 6 2009 1.01 (0.91-1.11) 0.90
BPD at 36 weeks 12 4384 1.07 (0.96-1.2) 0.20
ROP 11 4250 1.05 (0.90-1.23) 0.51

Mechanisms of protection and a meta-analysis of 21 studies of probiotics in animal NEC models have recently been summarized.(5)  The Food and Drug Administration (FDA) views probiotics administered to prevent, treat or mitigate any disease or condition as live biotherapeutic products and requires that any research on probiotics for this purpose be conducted under the supervision of the Investigational New Drug process.  They define a food as a substance ingested for its taste, aroma or nutritional value.  Based on these criteria administration of probiotics to prevent NEC or death is viewed by the FDA as off label use. In the words of an FDA official: “The Agency is not involved in regulating the practice of medicine.”  If a physician after review of the literature and discussion with the parents decides to provide a probiotic product to a premature infant, the FDA has no intention of stopping this practice.” However, research on the use of probiotics for the prevention of disease without IND oversight is not allowed under current FDA guidelines.

Primary Outcomes

The goal of this initiative is to monitor differences in key outcomes after adoption of routine use of probiotic products.  The primary outcome is weight gain (i.e. we are viewing the probiotic as a food with potential nutritional value).  Studies to date have been mixed with some showing increased weight gain in infants receiving probiotics while others have shown no difference.

With participation of many NICUs we hope to address the question of whether there are differences between strains in impact on weight gain in premature infants.  The preferred weight measurement is the change in z score from either birth weight or admission weight to the z score for the weight at discharge, death or transfer to another NICU (with the z scores taken from the Fenton growth curve data).

Secondary Outcomes

Secondary outcomes will be of great interest in looking at the safety of probiotics as a food, but are not the main purpose for the research and will include NEC, death, sepsis (including sepsis related to the probiotic product), days to full enteral nutrition, TPN days, and length of hospital stay.  Note that the NEC definition includes only episodes of NEC that occur after day of life 10 and before 36 weeks corrected gestational age.

How to Participate 

Participating NICUs in which the neonatology group has chosen to provide probiotics to premature infants are invited to submit de-identified data for the 18 months before they began probiotic administration and the first 18 months following initiation of probiotic administration.  Retrospective collection of these data will typically require approval by the local IRB and often will qualify as minimal risk and eligible for expedited review.  The probiotics listed here have some degree of evidence for efficacy, safety and purity of the products and would allow key comparisons (e.g. single organisms vs combination products, Lactobacillus vs Bifidobacterium), but data from NICUs using other probiotic products are encouraged and welcome.  The goal is participation by a large number of NICUs (60-100). 

Steps to participate:

1.  Register your NICU in the multi-center QI project by clicking here. Please complete the entire enrollment form.

2.  Signed consent from the parents is not necessary for retrospective collection of de-identified data unless required by your IRB, but parents should have been provided with an explanation for probiotic administration. An example of a written summary explaining the rationale behind provision of mother’s own milk, pasteurized donor human milk, and probiotics is here.

3.  Collect data for an 18 month period (during which probiotic administration was not routine) on all babies born at < 1500 g and gestational age < 33 weeks. You have two options for data collection.  Option one is to report just the primary outcome (change in weight z score) and key secondary outcomes (number of infants with NEC, death and sepsis plus the total number of eligible infants).  Option two is to report the primary outcome (delta weight z score) and all of the secondary outcomes.  For either option one or option two, please use this Excel spreadsheet (tab 1, baseline) to ensure ease of data cleaning and analysis.  Your unique NICU study number should replace X in column A

4.  Collect data for a second 18 month period (during which probiotic administration was routine) on all babies with birth weight < 1500 g OR gestational age at birth < 33 completed weeks. Please report the same data as reported for the baseline period using the same Excel spreadsheet, tab 2, probiotic, ie either option one (just the primary outcomes) or option two (primary and secondary outcomes).  Your unique NICU study number should replace X in column A

5.  Submit your completed Excel spreadsheet by clicking here. The data will be kept in the cloud with access limited to NEC Society personnel.  The submitted version must have column B (patient identifier) deleted in each of the three data sheets prior to submission to ensure protection of privacy.  The purpose for including the identifier initially is only to avoid missing or duplicating patients.  Keep a copy of the spreadsheet in a secure location at your facility.

6.  Note that this is not a clinical trial. There is no placebo arm, no randomization and no blinding.  While this is not research, we believe the results of a multi-center QI project will be of interest to clinicians and researchers and the intention of the NEC Society is to support publication of the de-identified results in the medical literature.  While there is no funding to support data collection, the more NICUs that provide the secondary outcomes data, the more helpful the final published data will be to the field.

7.  Note that routine probiotic administration to premature infants is not recommended by either the American Academy of Pediatrics or the US Food and Drug Administration. The NEC Society and its scientific advisory committee do not endorse any particular probiotic product, do not imply that administration of probiotics is without risk, do not in any way guarantee results and have no financial conflicts of interest to declare. This QI project is not medical advice. All medical decisions are the responsibility of the physician and patient’s guardians.

8.  For any questions, suggestions or concerns please contact Mark Underwood at munderwood@ucdavis.edu

 

References

  1. Sun J, Marwah G, Westgarth M, Buys N, Ellwood D, Gray PH. Effects of Probiotics on Necrotizing Enterocolitis, Sepsis, Intraventricular Hemorrhage, Mortality, Length of Hospital Stay, and Weight Gain in Very Preterm Infants: A Meta-Analysis. Advances in nutrition. 2017 Sep;8(5):749-63. PubMed PMID: 28916575. Pubmed Central PMCID: 5593111.
  2. Athalye-Jape G, Deshpande G, Rao S, Patole S. Benefits of probiotics on enteral nutrition in preterm neonates: a systematic review. The American journal of clinical nutrition. 2014 Dec;100(6):1508-19. PubMed PMID: 25411286.
  3. Villamor-Martinez E, Pierro M, Cavallaro G, Mosca F, Kramer B, Villamor E. Probiotic Supplementation in Preterm Infants Does Not Affect the Risk of Bronchopulmonary Dysplasia: A Meta-Analysis of Randomized Controlled Trials. Nutrients. 2017 Oct 31;9(11). PubMed PMID: 29088103. Pubmed Central PMCID: 5707669.
  4. Cavallaro G, Villamor-Martinez E, Filippi L, Mosca F, Villamor E. Probiotic supplementation in preterm infants does not affect the risk of retinopathy of prematurity: a meta-analysis of randomized controlled trials. Scientific reports. 2017 Oct 12;7(1):13014. PubMed PMID: 29026199. Pubmed Central PMCID: 5638943.
  5. Athalye-Jape G, Rao S, Patole S. Effects of probiotics on experimental necrotizing enterocolitis: a systematic review and meta-analysis. Pediatric research. 2017 Oct 25. PubMed PMID: 28949953.

 

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