Running head: PROBIOTICS AND NECROTIZING ENTEROCOLITIS

The use of Probiotics in Neonates Less Than 34 Weeks

Gestation to Reduce the Incidence of

Necrotizing Enterocolitis

The use of Probiotics in Neonates less than 34 Weeks Gestation to Reduce the Incidence of

Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal etiologies in

the preterm neonate, “between 0.3 and 2.4 per 1000 live births in the United States”

[CITATION Chr10 \p 185 \l 1033 ]. Although the etiopathogenesis of NEC remains unclear,

feedings with breast milk or formula and bacterial growth play an important role [CITATION

AlF14 \l 1033 ]. Among premature neonates born less than 32 weeks gestational age in the

neonatal intensive care unit, does the use of probiotic supplementation given with the first

feeding and continued until discharge, decrease the incidence of severe necrotizing enterocolitis?

Severe NEC is defined as stage II or greater using Bell’s clinical staging criteria[ CITATION

Bel78 \l 1033 ]. In a review of recent studies, Alfaleh and Anabrees (2014) found that

supplementation with probiotics at any dose and any duration of seven days or longer, prevents

NEC and NEC related mortality in the preterm infant. The use of probiotics has been

demonstrated in a number of research studies to have positive outcomes, including reducing the
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incidence of NEC, in premature infants (AlFaleh & Anabrees, 2014; Dilli, et al., 2015; Janvier,

Malo, & Barrington, 2014; Parker, 2014).

Evidence

Parker (2014) developed an evidence based clinical practice guideline for the use of

probiotics for the prevention of NEC in the very low birth weight (VLBW) infant. The studies

that were appraised in the development of this guideline exhibit positive evidence of a clear

decrease in NEC, which supports the need and benefits of a guideline for VLBW

infants[ CITATION Par14 \l 1033 ]. Weaknesses of this guideline include: narrow weight range

of 1000 grams to 1500 grams for treatment inclusion. Strengths of this guideline are: high level

of research evidence with clearly defined recommendations for clinical practice and published in

a peer reviewed journal. This guideline was developed using the best available research

evidence, clearly demonstrating clinical significance and positive outcomes in reducing NEC in

VLBW infants[ CITATION Par14 \l 1033 ].

AlFaleh and Anabrees (2014) conducted a systematic review of twenty-four randomized

trials, with a total of 5529 infants enrolled, that compared the effects of probiotics versus placebo

or no treatment for the prevention of necrotizing enterocolitis (NEC) in the preterm infant.

These authors concluded that the use of probiotic supplementation in the preterm infant

significantly reduced the incidence of severe NEC stage II or greater (RR 0.43, 95% confidence

interval (CI) 0.33 to 0.56) [ CITATION AlF14 \l 1033 ]. Weaknesses of this systematic review

were: the validity of the review’s results were possibly compromised due to the difference in

intervention preparation and dosing among studies and data on the highest risk population,

infants less than 1000 grams, could not be retrieved[ CITATION AlF14 \l 1033 ]. Strengths of

this systematic review included: large sample size, data collection, extraction and analysis
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independently assessed by two review authors, only randomized and quasi-randomized

controlled trials were included and consistency among results across all studies. The results of

this review are statistically and clinically significant, demonstrating the vital need for a change in

practice in the prevention of NEC in the premature infant.

To determine if any updated studies were conducted from 2014 to present, a evidence

based literature search using the key terms: “preterm infant and probiotics and necrotizing

enterocolitis” and “neonates and probiotics” was performed. The search was limited to

randomized controlled trials and other quantitative studies. Two studies were included that

matched the criteria for preterm infant, NEC and probiotic prophylaxis. These studies were

appraised for evidence establishing that the use of probiotic prophylaxis decreased NEC in the

preterm infant.

Dilli et al. (2015) found that the use of probiotic prophylaxis decreased NEC in a

prospective, randomized controlled trial (RCT) of 400 preterm infants from five neonatal

intensive care units in Turkey. The rate of NEC in the probiotic group was 2% compared to 18%

in the placebo group, demonstrating a clinically significant difference. Weaknesses of this study

were: findings can not be generalized to all probiotics due to different doses and types of

probiotics. Strengths of this study included: prospective RCT design, blinded care givers,

measurement tools were valid and reliable and study was published in a peer reviewed journal.

The findings of this study were statistically and clinically significant demonstrating a significant

reduction in NEC, supporting the use of probiotic prophylaxis in the preterm infant.

Janvier, Malo, and Barrington (2014) conducted a study on the use of probiotic

prophylaxis and the incidence of NEC with 294 preterm infants enrolled in the probiotic group

and 317 infants in the comparison group. The study revealed a decrease in NEC in the probiotic
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group from 9.8% to 5.4% (P < .02)[ CITATION Jan14 \l 1033 ]. Weaknesses of this study

included: prospective cohort study with a historical comparison cohort design, conveinence

sample, and confounding of results from changes in practice from year to year. Strengths of this

study were: measurement tools were valid and reliable, a strict feeding protocol was adhered too

throughout study, and study was published in a peer reviewed journal. The results of the study

were clinically and statistically significant in this patient population and supports the initiation of

a probiotic prophylaxis protocol in this setting.

Hoyos (1999) conducted a study of the use of probiotics in 1237 infants in a 25 bed

neonatal intensive care unit (NICU) in Bogota, Colombia, where the occurrence of NEC is a

frequent cause of morbidity and mortality. The oral administration of prophylactic Lactobacillus

acidophilus and Bifidobacterium infantis decreased the incidence of NEC, with 34 cases in the

group of 1237 infants that received probiotic prophylaxis compared to 85 cases in the historic

control group of 1282 infants[ CITATION Hoy99 \l 1033 ]. Weaknesses of this study included:

use of a historical control group, convenience sampling, and possible confounding results from

changes in practice from year to year. Strengths of the study included: measurement tools were

valid and reliable, the hypothesis was clearly stated, and the study was published in a peer

reviewed journal. The findings of the study were clinically and statistically significant, providing

positive evidence that probiotic prophylaxis decreased NEC in this patient population.

Summary of Evidence

NEC is one of the leading causes of death in the premature infant, creating an urgent need

for an intervention to reduce this risk[ CITATION Chr10 \l 1033 ]. Current evidence has shown

that probiotic prophylaxis significantly reduces severe NEC without significant adverse effects to

the preterm infant population (AlFaleh & Anabrees, 2014; Dilli, et al., 2015; Janvier, Malo, &
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Barrington, 2014; Parker, 2014). Assessment of the most effective strains, dose, duration,

benefits and safety of probiotics has been assertained in multiple studies, concluding that current

evidence justifies routine use in the preterm neonate (AlFaleh & Anabrees, 2014; Dilli, et al.,

2015; Janvier, Malo, & Barrington, 2014; Parker, 2014). Among recent studies the most

commonly used probiotics are lactobacillus and bifidobacterium, indicating that this is an

effective intervention to decrease NEC in the preterm infant [ CITATION AlF14 \l 1033 ].

The safety of probiotics in the extemely low birth weight (ELBW, < 1000 grams)

population remains a debate among researchers and care givers[ CITATION Dil15 \l 1033 ].

The study of the use of probiotics in this population should be considered high priority due to the

increased risk of NEC in this group[ CITATION Dil15 \l 1033 ]. Parental involvment in the

decision to treat the ELBW neonate could be a defining factor in administering this intervention

to this neonatal population[ CITATION AlF14 \l 1033 ]. Decreasing the risk of NEC with

probiotic prophylaxis has been proven a consistent intervention in decreasing NEC, supported by

the magnitude of significant evidence presented here.