Bifidobacterium longum subsp infantis (EVC001) is Associated with Reduced Incidence of Necrotizing Enterocolitis Stage &gt;2 and Bloody Stools in Premature Babies

doi:10.21203/rs.3.rs-4687889/v1

Objective To utilize an evidence-based probiotic protocol to achieve a 50% reduction in necrotizing enterocolitis (NEC) > stage 2 and bloody stools.

Study design From January 2022 through September 2023, we administered daily enteral EVC001 to babies <33 6/7 weeks gestation until 36 weeks post menstrual age. We compared feeding tolerance and complications to babies admitted during the prior two-year period. Fisher’s Exact test was used to analyze proportional data and student t-test was used for continuous variables.

Results 265 babies received EVC001. 277 babies formed the pre-probiotic cohort. Probiotic use was associated with decreased NEC > stage 2 (p=0.0058), reduced bloody stools (p<0.0001), decreased time to full enteral feeds (p<0.0001), and decreased total parenteral nutrition (TPN) days (p<0.0001).

Conclusion Supplementation with B. infantis was associated with a decrease in NEC, a decrease in bloody stools, and improvement in feeding tolerance in premature babies.

Health sciences/Diseases/Gastrointestinal diseases/Intestinal diseases/Colonic diseases/Colitis

Health sciences/Risk factors

The premature gut microbiome exhibits delayed colonization and decreased biodiversity, and premature babies are at high risk for dysbiosis due to multiple factors, including cesarean section, prolonged hospitalization, nutrition, and perinatal antibiotics. Dysbiosis is associated with chronic, life-long diseases, including diabetes, inflammatory bowel disease, and cancer. More immediately, dysbiosis is known to precede the development of NEC, with a relative increased abundance of Proteobacteria and a decreased abundance of Firmicutes and Bacteroidetes prior to disease onset.

NEC is a devastating gastrointestinal disease with life-long complications. Mortality for NEC ≥ stage 2 is 23.5%, while mortality of surgical NEC is 34.5%. Among survivors, neurodevelopmental disability is between 24.8% and 61.1% and intestinal failure occurs in 15.2–35%.

Probiotics are foods or supplements that contain live microorganisms intended to maintain or improve health. The dysbiosis in premature babies offers a unique time point to affect life-long health with the use of probiotics. In fact, human milk oligosaccharides (HMOs), the third largest component of human milk, are only digestible with the help of glycosidases possessed by specific bacteria, and EVC001, specifically, has the unique ability to consume HMO as its sole carbon source. Probiotics containing B.infantis offer protection, anti-inflammatory properties, and decrease intestinal permeability³. In January 2022, after completing a quality review and careful review of the literature, we implemented an evidence-based probiotic protocol. Our goal was to determine if our change in care would reduce feeding intolerance and achieve a 50% reduction in NEC ≥ stage 2 within two years of protocol implementation.

This was a single-center prospective cohort study of probiotic use in preterm babies at Renown Children’s Hospital NICU, a 49-bed level III unit staffed by 7 neonatologists, 4 neonatal nurse practitioners/physicians assistants, 76 nurses, pediatric pharmacists, dieticians, speech therapists, and lactation specialists. The study was approved by the University of Nevada, Reno Institutional Review Board (IRB), ID 1777112-3, and the Pediatrix Clinical Research Department, ID 770695214. A waiver of informed consent was approved by the IRB, as probiotics were adopted as standard of care in our unit; however, written parental consent for probiotics was obtained to facilitate risk and benefit discussion with families. No parents declined probiotic treatment. The study was performed in accordance with the Declaration of Helsinki.

Intervention

B. infantis was chosen due to its dominance in the microbiome of healthy breastfed babies. EVC001 (Infinant Health, Davis, California, USA) was chosen for both its possession of the complete gene cluster for H5 ABC-type transporter, which binds to core HMO structures and completely metabolizes them, and the company’s high quality manufacturing process, cold chain distribution practices, safety testing, ensured CFUs, and availability of ready-to-use single-dose vials, which decreases risk of contamination.

Study Populations

In January 2022, our NICU implemented a new treatment plan to promote intestinal health. We administered EVC001 enteral supplementation at a dose of 0.5 mL [8 billion Colony Forming Units (CFUs) of Bifidobacterium longum subspecies infantis suspended in 0.47 mL medium chain triglyceride oil] per day with the first or second feed of day shift. EVC001 was ordered to start when enteral feeds were initiated and was continued until babies were 36 weeks post menstrual age (last dose at 35 6/7 weeks). EVC001 was held during any period of NPO (nil per os). The study was originally planned, approved, and funded for two years, ending December 2023; however, due to an abundance of caution, probiotic administration was discontinued on September 29, 2023, after the U.S. Food and Drug Administration (FDA) issued a warning regarding possible risks of probiotic use in premature babies. There were no adverse events related to probiotic use in our unit during the period of probiotic implementation.

All patients admitted to the NICU were screened for the inclusion criteria of gestational age ≤ 33 and 6/7 weeks. Exclusion criteria were the presence of a lethal medical condition or a congenital gastrointestinal anomaly. Data was collected from electronic medical record review and cross-referenced with Pediatrix BabySteps Data Warehouse, retrospectively for the pre-implementation control cohort and in real-time for the probiotic cohort.

The control cohort consisted of 253 babies born from January 2020 through December 2021. Both cohorts received a human milk-based diet, consisting of either maternal breast milk or donor human milk. We use a standardized feeding protocol, which was consistent between the two cohorts. We start trophic human milk feedings at 20 ml/kg/d at the discretion of the attending neonatologist, and advanced by 20 ml/kg each day, except for days on which feeds are fortified, to a goal of 150–160 mL/kg/d. Babies < 1250 grams at birth receive five days of trophic feeds before advancement and receive fortification with Prolacta Human Milk Fortifier. Babies ≥ 1250 grams receive fortification with Enfamil liquid Human Milk Fortifier. Donor Human Milk and Prolacta Human Milk Fortifier are weaned to bovine milk-based fortifier and/or formula over a three-day period, starting at either 34 weeks corrected gestation age or 5 days of life, whichever occurs later.

Covariables

Variables analyzed as potential predictors, confounders, or modifiers included gestational age at birth, birth weight, sex, small for gestational age (SGA) status, mode of delivery, maternal antibiotics (defined as ≥ 1 dose prior to delivery), maternal betamethasone (defined as ≥ 1 dose prior to delivery), and days of antibiotics in the immediate post-natal period.

Outcomes

Primary outcomes were bloody stools at any time during NICU hospitalization and NEC ≥ stage 2. Bloody stools were diagnosed visually with confirmatory hemoccult testing if diagnosis was uncertain. The diagnosis of NEC was determined using the modified Bell staging system. Secondary outcomes included NPO days, TPN days, days to achieve full enteral nutrition, late antibiotic days (after initial infectious screen period), late onset sepsis, urinary tract infections (UTI), tracheitis, meningitis, length of hospital stay, and corrected gestational age (CGA) at discharge.

Statistical Analysis

Data was initially analyzed by descriptive statistics. Subsequent comparison of outcome measures was analyzed with Microsoft Excel (Version 16.82, 2024) using the Fisher’s Exact test for proportional data and student t-test for continuous variables. Two-sided p-values < 0.05 were considered statistically significant.

Figure 1 shows the patient flowchart. Of 937 babies admitted to the NICU and screened for eligibility during the probiotic implementation period, 265 babies met the inclusion criteria of being < 34 weeks gestational age at birth. Data collection and analysis was completed in 250 babies. Of the seven babies transferred out of our facility, all received EVC001, but they were not included in data analysis due to incomplete data availability for primary and secondary outcomes. Reasons for transfer included post-hemorrhagic hydrocephalus (3), PDA coil treatment (3), and insurance coverage (1); none of the babies transferred had documented bloody stools, NEC, or infections prior to transfer. Of the 7 deaths in the probiotic cohort, 3 received at least one dose of EVC001. Deaths were due to neurological or respiratory complications of prematurity (pulmonary hemorrhage, respiratory failure, severe IVH).

EVC001 was started at a mean day of life 1.9 (range 0–19; delays were due to prolonged NPO status). The mean duration of EVC001 was 30 days (range 3–73), with 7 586 total EVC001 days completed during the study.

There were no significant differences in baseline characteristics between the two cohorts (Table 1). The mean gestational age at birth was 31 weeks in the control cohort and 31.1 weeks in the probiotic cohort. The mean birthweight was 1579 grams in the control cohort and 1568 grams in the probiotic cohort. Most babies in both cohorts were male, born via cesarean section, and received antenatal steroids.

Babies who required G-tubes for discharge due to poor PO feeds were excluded from two outcomes, length of hospital stay and CGA (corrected gestational age) at discharge, but they were included in the analysis of all other outcomes for both cohorts. There were 11/253 (4%) babies in the pre-implementation cohort and 16/250 (6%) babies in the post-implementation cohort who required GTs.

Regarding primary outcomes, there was a significant reduction in incidence of bloody stools in the probiotic group, a decrease from 19–4.8% (p < 0.0001). Incidence of NEC stage ≥ 2 was also significantly decreased in the probiotic cohort, from 4.7–0.4% (p = 0.0058). Of the 12 NEC cases in the control cohort, one resulted in death due to NEC. The singular case of stage 2 NEC in the probiotic cohort was a 657 gram 25-week male who received prolonged antibiotics due to thrombus in the setting of MSSA sepsis and did not receive EVC001 until day of life 19 due to clinical instability, hypotension, and prolonged NPO. He was treated with bowel rest and antibiotics and survived to discharge.

Regarding secondary outcomes, there was a statistically significance decrease in day of life to achieve full enteral feeds, with a mean of 16.2 days in the control cohort and 12.7 days in probiotic cohort (p < 0.0001). In direct correlation, there was also a statistically significant decrease in mean TPN days in the probiotic cohort, from 14.1 days to 12.7 days (p < 0.0001). Unexpectedly, there was a statistical significance in the day of life enteral feeds were started, with a mean of 1.3 days in the control cohort and 0.9 days in the probiotic cohort (p = 0.0008). There was no statistically significant difference in mortality, NPO days, late antibiotic days, late onset sepsis, UTI, tracheitis, or meningitis.

Subgroup analyses showed consistent results. In babies born at 28 weeks completed gestation, there was a statistically significant decrease in mean days of life to full enteral feeds in the probiotic cohort, from 21.8 days to 17.1 days (p = 0.04). In babies born at 29 weeks completed gestation, there was a statistically significant decrease in mean TPN days, from 21.2 to 15.1 (p = 0.0019) and a decrease in mean NPO days from 3 to 0.5 (p = 0.02). In babies born at 30 weeks completed gestation, there was a statistically significant decrease in mean TPN days from 13.8 to 9.1 (p = 0.01). In babies born at 31 weeks completed gestation, there was a decrease in mean days to full enteral feeds from 17.2 to 12.4 (p = 0.002) and mean TPN days from 17.2 to 8.8 (p = 0.0005). In babies born at 33 weeks gestational age, there were statistically significant decreases in mean days of life to full enteral feeds from 11.5 to 8.4 (p = 0.002) and mean TPN days from 9.7 to 5.5 (p = 0.0006).

In addition, babies born at 31 weeks completed gestation, had a statistically significant decrease in mean duration of hospital stay, from 49 days to 41 days (p = 0.03) and CGA at discharge from 38.5 weeks to 37.4 weeks (p = 0.03).

There were no cases of probiotic sepsis; however, one patient had a positive peripheral blood culture for Bifidobacterium longum. The patient was a 28-week baby who had a negative blood culture on admission and underwent an infectious screen on day of life 3 due to decreased perfusion and metabolic acidosis. The baby received 36 hours of empiric broad-spectrum antibiotic coverage, but the cause of the clinical symptoms was ultimately determined to be due to a large PDA, and symptoms resolved with indomethacin. The blood culture grew B.longum on culture day 5 and was determined to be a contaminant. A repeat blood culture remained negative for B. longum.

The implementation of a probiotic protocol in our NICU was associated with a 90% reduction in rates of NEC > Stage 2 in babies born < 33 6/7 weeks. These results support the findings of many randomized control trials and metanalysis that have shown probiotics are associated with reduced NEC^7,8,9,10. Although some studies suggest the superiority of multi-strain probiotics, others have suggested that Bifidobacterium alone offers a unique benefit to the premature gut¹¹ and probiotic supplements containing B. infantis are more beneficial than supplements without B. infantis to premature babies¹².

Our probiotic protocol was also associated with improved feeding tolerance, as a cohort and across all gestational ages, evidenced by decreased bloody stools, fewer mean TPN days and fewer mean days to full enteral feeds. Some studies have found that probiotics are associated with decreased time to reach full enteral feeds¹³, while others have found no effect on TPN days¹⁴.

Published data is limited regarding the association between probiotics and bloody stools in preterm babies. Although one study showed a decrease in isolated rectal bleeding in premature babies after initiating treatment with Lactobacillus rhamnosus, it was not of statistically significance¹⁵. To the best of our knowledge, this was the first study to evaluate bloody stools as a primary outcome after introduction of B. infantis. Prior to probiotic implementation, our NICU had a high baseline rate of bloody stools in babies < 34 weeks, which often prompted NEC evaluations, including bowel rest and broad-spectrum antibiotics. As dysbiosis is a likely risk factor for bloody stools¹⁶, we chose to broaden our protocol inclusion criteria to include babies born at 32 and 33 weeks completed gestation. The decrease we observed in bloody stools is consistent with research that has shown the B. infantis colonization decreases enteric inflammation^17,18, reduces colonic mucin degradation¹⁹, and accelerates microbiome maturation leading to improved metabolic and immune function²⁰. Overall, Bifidobacterium has been shown to assist in accelerating and maintaining the protective barrier function of the gastrointestinal tract.

Although metanalyses have shown that decrease late onset sepsis^9,21, we did not find a decrease in late onset sepsis. We did have a reduction in both meningitis (from 3 cases to 0) and tracheitis (from 11 cases to 5), but neither were of statistical significance.

Metanalyses have also shown that probiotic use leads to a decreased duration of hospital stay for premature babies¹⁰. We did find a significant decrease in hospital stay for babies born at 31 weeks completed gestation but did find a significant decrease in duration of hospital stay for other gestational ages or in the probiotic cohort as a whole.

Important to the success of our study was support from attending neonatologists, nursing staff, dieticians, and pharmacists. Before implementation, we achieved consensus from all attending neonatologists, performed in-service training to nursing staff, and attained approval from our hospital’s antimicrobial stewardship.

As a single-center prospective cohort study, there are inherent limitations to this study. Rates of NEC vary year to year; our rate has been consistently 4-6% over the last decade. Another potential confounding variable is changes in clinical practice over time. Our feeding protocol and use of human milk remained consistent over both cohort periods. The decision to initiate enteral feeds is up to the discretion of the neonatologist on service, and we did see a reduction in the mean day of life that feedings were initiated from the control cohort to the probiotic cohort (from 1.3 to 0.9 days, p = 0.0009). Although delayed enteral feeds have been shown to be protective against NEC in formula-fed babies²², early human milk enteral feedings may be protective against NEC by stimulating hormone secretion, mucosal cell signaling, and peristalsis²³, so this is potentially an important confounding variable in this study.

We were fortunate to have strong nursing support for probiotic use in our NICU, and many bedside nurses reported that babies were less fussy and had improved stooling patterns and consistency during the probiotic implementation period. This also represents a potential source of information bias, as bedside nurses may have been less likely to categorize stools as bloody.

Our probiotic protocol was initially planned and funded for 24 months, but we ceased probiotic use on September 29, 2023, when the FDA issued a warning regarding the risk of invasive, potentially fatal disease caused by use of probiotics in preterm infants. The majority of B. infantis sepsis or bacteremia case reports have occurred in babies with NEC or spontaneous intestinal perforation (SIP)²⁴, and it is well known that when intestinal mucosal barrier is compromised, bacteria can translocate, leading to invasive infection. Bifidobacterium species are traditionally considered ubiquitous nonpathogenic commensal organisms and have low MICs (<0.5 mg/L) to beta-lactam antibiotics²⁵, which makes them less pathogenic than the bloom of Proteobacteria that are known to proceed the development of NEC. Probiotic sepsis is a rare occurrence, and most cases result in recovery.²⁶ On the other hand, NEC is a leading cause of death in premature babies and is a devastating disease with high mortality, morbidity, and neurodevelopmental disability²⁷. Additionally, surgical NEC has been shown to have the highest total cost of all complications of prematurity²⁸

Two proven and widely accepted interventions to decrease the risk of NEC are utilizing human milk²² and a standardized feeding protocol²⁹. Data from meta-analyses support probiotic utilization as an intervention to decrease the risk of NEC. In 2023, just prior to the FDA warning, approximately 39% of NICUs in the U.S were using probiotics³⁰. At that time, the percentage was steadily increasing; however, since the FDA warning, many NICUs have reported cessation of probiotic use.

This study demonstrates the benefits that probiotics can confer to premature babies. We saw a statistically significant decrease in NEC > stage 2, bloody stools, days to full enteral feeds, and TPN days. Our data supports continued research to determine optimal formulations and dosing of probiotics. Current evidence and our data support finding a path to gain FDA approval for probiotics to be used to prevent intestinal dysbiosis.

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Table 1: Characteristics of babies in both cohorts

Characteristics	Control cohort (n=253)	Probiotic cohort (n=250)	p-value
Gestational age at birth, weeks, mean (IQR*)	30.95 (29.0-33.0)	31.14 (29.6-33.1)	0.39
Birth weight, grams, mean (IQR*)	1,579 (1,199-2,002)	1,568 (1,233-1,862)	0.80
Male sex, %	58.5	58.0	0.91
SGA, %	7.5	9.6	0.26
<1250g BW, %	26.5	27.2	0.86
Antenatal steroids, %	87.4	82.4	0.12
Antenatal antibiotics, %	45.8	40.0	0.19
Cesarean delivery, %	66.8	68.0	0.77
Admission antibiotic days**, mean	1.53	1.32	0.08

*IQR = interquartile range, Q1-Q3

**days of antibiotics in immediate post-natal period

Table 2: Clinical outcomes of babies in the two cohorts

Outcome	Control cohort (n=253)	Probiotic cohort (n=250)	p-value
Bloody stools	45 (17.8%)	12 (4.8%)	<0.0001
NEC > stage 2	12 (4.7%)	1 (0.4%)	0.003
DOL to full enteral feeds	16.2	12.7	<0.0001
Customized TPN days	14.1	9.8	<0.0001
NPO days*	1.2	0.8	0.27
Late antibiotic days	2.2	1.3	0.09
Late onset sepsis	8 (3.2%)	9 (3.6%)	0.37
UTIs	7 (2.8)	7 (2.8)	0.42
Tracheitis	11 (4.3%)	5 (2%)	0.14
Meningitis	3 (1.2%)	0	0.25
Duration of hospital stay, mean days	48.3	47.1	0.59
CGA at discharge, mean weeks	38.13	38.16	0.9

*NPO days after initiation of enteral feeds

There is NO conflict of interest to disclose.

Bifidobacterium longum subsp infantis (EVC001) is Associated with Reduced Incidence of Necrotizing Enterocolitis Stage >2 and Bloody Stools in Premature Babies

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Abstract

Figures

Introduction

Methods

Statistical Analysis

Results

Discussion

References

Tables

Additional Declarations

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