The Efficacy of Various Probiotics In Premature Newborns With Necrotizing
Enterocolitis
Cassandra Bloom, Rachael DeVaux, Erin Lee, and MacKenzie Schiltz
I. Introduction
The microbiota of the human body is a dynamic network, new microbial
organisms are constantly leaving and entering the system13. There are innate and
environmental factors that impact the diversity and stability of the microbiota of the
human body, which are affected by things as complex as the human genome, to things as
simple as aging and body growth. This is evidently true in neonates and infants, whose
microsomal community must change rapidly as the body grows, develops, and changes
environments. The uterus of the human female is sterile, meaning that the acquisition of
the human microbiota must begin at birth, when the newborn is colonized by
microorganisms from its immediate environment13. This can either be from the vaginal
canal of the mother or via the first contacts (caregivers such as nurses and doctors) after a
cesarean section13. Stability of the microbiota at this point is low and heavily susceptible
to change and infection13.
Members of the actinobacterial genus Bifidobacteria are representative of more
than 90% of the bacteria present in the intestinal tract of breast-fed infants (bottle-fed
infants have considerably less of this genus) with Enterobacteriaceae and the phyla
Proteobacteria and Firmicutes accounting for smaller amounts13. Data suggests that these
bacteria may be feeding off of a selective medium, breast milk, which inhibits the growth
of pathogenic bacteria13. As the infant grows and switches to cow’s milk or solid food, the
microbiota will change, losing much of their Bifidobacteria and instead having an
intestinal tract dominated by bacteria like lactobacillia, enterococci, and clostridia for
example13. These resident microorganisms, from infancy to childhood to adulthood,
appear to assist in the host defense against other microbial and fungal pathogens by
producing chemicals that ward off infection13.
The Food and Agricultural Organization of the United Nation- World Health
Organization (FAO-WHO) defines a probiotic as a “live microorganisms, which, when
administered in adequate amounts, confer a health benefit to the host.”13 Often organisms
like Bifidobacterium are sold as probiotics, due to proposed health benefits on immune
function. Lactobacilla and bifidobacteria have been shown to stimulate immune
maturation and minimize inflammation, not only in the gastrointestinal tract where their
human gut residing cousins reside13.
The genus Lactobacillus is one of the genera commonly found in probiotic
supplements. This genus depends on sugar fermentation for energy and produce lactic
acid as a byproduct to their fermentation13. Since they lack cytochromes and rely on
substrate-level phosphorylation, they thrive in anaerobic environments, like the human
gastrointestinal tract13. Lactobacilli serve an important set of functions in the everyday
human existence: not only are the basis behind products such as dairy products, they are
also found in meats, water, sewage, beer, and fruits and are a part of the normal flora of
the human body, especially in the normal vaginal flora and gastrointestinal tract13. Often,
the species sold for probiotic use is L. acidophilus.
Bifidobacteriales is the order that contains another common probiotic B. bifidum.
Members of this order are found in the human genital and urinary tract, and
Bifidobacteria are gaining rapid attention as we learn more about the human gut
microflora. These are Gram-positive rods that are anaerobic and actively ferment
carbohydrates to product acetic and lactic acids13. They are the pioneer colonizer and most
common bacteria present in the human intestinal tract in babies that are breastfed13.
Interest in probiotics outside of the recreational use for general health has been
increasing, but especially more so in the area of neonatology. Recently, the use of
probiotic supplements has been suggested and is being tested as a treatment for a
debilitating and potentially fatal disease, necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is characterized by damage to the intestinal tract,
ranging from mucosal epithelial cell injury to necrosis of the full thickness of the tract
and perforation of the bowel12. Signs and symptoms usually include including abdominal
distention, emesis and/or increased gastric residuals, bloody stools, lethargy, apnea and
bradycardia, respiratory distress, metabolic acidosis, thrombocytopenia, neutropenia,
capillary leak, and hypotension3,4. Diagnosis is confirmed via a radiologic evidence of
pneumatosis intestinalis or portal venous air via surgical pathology3. Often surgical
intervention is required, in about 30-50% of cases reported, and approximately one third
of the patients will die from NEC3. Implications from surviving the disease are an
increased risk for recurrent strictures and bowel obstruction that can occur weeks,
months, or years following3. These patients may also have a higher risk two-fold higher
risk of neurodevelopmental disability3. An unacceptably high risk of mortality and
significant morbidity, thus remains in this variable disease.
There are three major risk factors that point down the road to NEC: prematurity,
the infant being on enteral feeding after birth, and abnormal bacterial colonization in the
gastrointestinal tract. NEC most often presents in preterm infants that weigh less than
1500g (~3.3lbs), though it less commonly can present in full term infants. Incidence for
NEC averages between 6 and 14% worldwide for babies weighing less than 1500g, but in
some neonatal units, rates have been recorded as high as 22%3. Enteral feeding is
common in very-low birth weight infants and is the second major risk factor for NEC;
almost 95% of the NEC patients received enteral feedings after birth3.
It is hypothesized that preterm infants and very-low birth weight infants have
multiple components of intestinal physiology that function abnormally; most often this
includes things like intestinal wall perforations, however, the third major risk factor,
abnormal bacterial colonization, is starting to show that it plays a large role in the
propagation of NEC3,4. When these factors are bound to feeding intolerance, this creates a
recipe for infection3,4. Studies have shown that healthy infants develop bacterial diversity
that includes colonization by commensal probiotic organisms such as Bifidobacteria
species and Lactobacillus species, whereas, preterm infants do not develop diversity to
the same extent3. One study found that full-term newborns shed Bifidobacteria by 1 to 2
weeks after birth, but preterm infant colonization of this species low, if it occurred at all.
Similar studies have shown a high prevalence of the phylum proteobacteria, and the DNA
of Trichinella, roundworms, and adenoviruses in preterm infants, while this is not present
in infants that were carried to term3. Citrobacter-like species was also present in preterm
infant GI tracts and while Citrobacter are normally present in the human gut flora, they
are also a cause of infant meningitis and sepsis and the risk for these maladies increases
with the intestinal perforations that coincide with NEC 3.
In the mature intestine, including that of a full term infant, the gut mucosa
provides a barrier that may prevent the translocation of bacteria that could be pathogenic3.
In a neonate intestine, permeability is high and there is a reduced production of the
protective mucus of the GI tract. There is also decreased synthesis and secretion of
defensin, a host defense peptide, and diminished production of IgA, an antibody
important in mucosal cell immunity3. If we link these downed defenses to the abnormal
bacterial flora, we can see a pattern of infection. It is hypothesized that derangements in
the bacterial and intestine ecosystem may contribute to a variety of allergic and
inflammatory responses. “Bad” bacteria can instigate atopic dermatitis, inflammatory
bowel disease, asthma, and other inflammatory responses3. These responses lead to an
increased cytokine production and the resulting inflammation causes the tissue to die,
leading to NEC3. The idea behind using probiotics as a preventative treatment is getting
“good” bacteria back to where they need to be; these new residents can fight off the
bacteria that are causing disease, restore the balance of the bacterial colonies, and
increase the production of protective mucus layer of the intestines3,10. These healthful
bacteria may increase mucin synthesis, which may improve the integrity of the cell walls
of the intestine3,10.
The three major risk factors, prematurity, abnormal bacterial colonization, and
enteral feeding, all tie together to explain why probiotics is such a promising treatment10.
But that does not mean that the treatment does not have potential complications. One
foreseeable complication is that exposing neonates to bacteria when they have intestinal
epithelia with poor defenses and a tendency for inflammation may result in more
inflammation, injury, sepsis, or in an effort to prevent NEC, actually increase the
probability10.
II. Assessing the Evidence
Lin H., Hsu, C., Chen, H., et al. Oral Probiotics Prevent Necrotizing Enterocolitis in
Very Low Birth Weight Preterm Infants: A Multicenter, Randomized, Controlled
Trial. American Academy of Pediatrics. 2008; 122:693-700.
This study investigated the efficacy of orally administered probiotics in
preventing Necrotizing Enterocolitis for very low birth weight (VLBW) preterm infants.
It examined the effect of probiotics in the form of B. bifidum and lactobacilli, called
Infloran, in VLBW infants to see if it would reduce the prevalence and harshness of
NEC. This was a six week prospective, masked, randomized, controlled trial that was
conducted in seven different level III NICU’s in Taiwan. To be included in the study,
VLBW preterm infants had to have a gestational age of less than 34 weeks, have a birth
weight off less than 1500 grams and had to have survived to feed enterally. The exclusion
criteria included VLBW preterm infants who had severe asphyxia, fetal chromosomal
anomalies, cyanotic heart disease, congenital heart disease, congenital intestinal atresia,
gastroschisis, or omphalocele, those who were fed exclusively with formula, and those
who were fasted for more than three weeks. The infants were assigned to study or control
groups randomly by the investigator at each NICU after they had received parental
consent. The computer center located at the China Medical Hospital was the location
where the randomization took place, using sequential numbers generated from the
computers.
Infloran is a probiotic that contains Bifidobacterium bifidum and Lactobacillus
acidophilus, which are both bacteria that are commonly found in the stool of breastfed
infants. The 217 preterm infants in the study group were given Infloran and B bifidum at
125 mg/kg per dose twice daily added to breast milk or mixed feedings, for six weeks.
The control group was just given breast milk or mixed feeding, with no Infloran. The
breast milk and/or feedings were made by a group of people who were blinded to the
probiotic colony counts and also did not have anything to do with the responsibility of the
infants. Each infant in the study and control group tolerated one trial of distilled water,
before the breast milk was given. The first day consisted of 1 mL/kg of distilled water
two times, followed by breast milk. The amount of breast milk slowly increased with no
more than 20mL/kg each day per feeding. Feeding would halt if there were any signs of
intolerance.
At each of the seven centers, data was collected and sent to the office of the main
investigator at China Medical University Hospital. The diagnosis of NEC in each of the
groups was determined by two physicians who were blinded to the groups that the infants
were assigned to. If these two physicians were to disagree on the diagnosis, the
neonatologist in each NICU would make the final decision. The primary outcome of this
study was either death or stage 2 NEC or higher. The secondary outcomes were sepsis
without NEC, CLD, IVH, PVL, amount of feeding per week, days to complete enteral
feeding and weight gain each week.
Results showed that the incidence of death or stage 2 NEC or higher was
significantly lower in the study group when compared to the control group (4 of 217 in
study and 20 of 217 in control; P= .002). In the study group, 2 infants developed stage 2
NEC and 2 infants developed stage 3 NEC and in the control group, 9 infants developed
stage 2 NEC and 5 infants developed stage 3 NEC. There was no significant difference
between the two groups in the incidence of death attributable to NEC, but for the
incidence of death not attributable to NEC, the study group had a significantly lower
number (0 of 217 infants vs 6 of 217 infants; P= .04). In order to find out that the
probiotic group has less deaths and NEC, a multivariate logistic regression model was
used. The variables consisted of birth weight, surfactant use, pH, gestational age, and the
NICU. Incidence of death or NEC stage 2 or higher was lower in infants weighing 500750 grams. The incidence of stage 2 NEC of higher was significantly lower in infants
who weighed 1001-1500 grams. There seemed to have been a trend in the incidence
being lower for stage 2 NEC in infants who weighed 500-700 grams and 751-1000
grams.
The researchers concluded that probiotics containing B. bifidum and L.
acidophilis, administered orally for six weeks, reduces the incidence of death or NEC for
VLBW preterm infants. The number needed to treat in order to prevent one case of NEC
was 20 patients and the number needed to treat in order to prevent one death or case of
NEC was 14 patients.
One limitation in the study was that during the randomization process, they
ignored to stratify according to birth weight. The difference was with there being 33
infants weighing less than 750 grams in the study group and only 18 infants weighing this
much in the control group. Although, there were lower incidence rates of death in the
study group of different weight groups. This calls for needed additional studies with an
adequate number of weight stratified infants in order to come to the conclusion that
probiotics are efficient in each weight group. Based on the study’s limitations and
strengths it is given a quality rating (+) and given a class Grade A due to its prospective,
masked, randomized, controlled design.
Hartel C, Pagel J, Rupp J, et al. Prophylactic Use of Lactobacillus
acidophilus/Bifidobacterium infantis Probiotics and Outcome in Very Low Birth
Weight Infants. J Pediatr. 2014; 165 (2):285-9.
This study evaluated data in an observational cohort of very low birth weight
infants cared for in 46 neonatal intensive care units of the German Neonatal Network.
The aim was stratified to prophylactic use of Lactobacillus acidophilus/Bifidobacterium
infantis probiotics. This study was categorized into three different groups based on their
strategy for probiotic use; the first having no Lactobacillus acidophilus/Bifidobacterium
infantis probiotics prophylactically, the second group changed strategy during the
observational period, and the third group adopted prophylactic use before the
observational study. Inclusion criteria involved infants having a weight of less than 1500
grams and a gestational age of >22 + 6 and <32 + 0 weeks. Gestational age was
calculated from the best obstetric estimation based on early prenatal ultrasound and
obstetric examination. The data was collected prospectively from infants born between
September 1, 2010 and December 31, 2012, which resulted in 3229 infants. Most of the
neonatal intensive care units administered Lactobacillus acidophilus/Bifidobacterium
infantis to VLBW infants from day two or three of life for fourteen days or until full
enteral feeds were tolerated. Exclusion criteria were lethal malformations.
To compare the statistical findings of the three infant groups, the SPSS 20.0 data
analysis package was used, which performs a multivariate test of differences between
groups. Hypotheses were evaluated with the chi-square test, Fisher exact test, and MannWhitney U test. The Fisher’s exact test is a statistical significance test used in the analysis
of contingency tables and is valid for all sample sizes. The Mann-Whitney U test is used
to compare differences between independent groups when the dependent variable is
either ordinal or continuous, but not normally distributed. A chi-square test was the third
method that was used to determine whether there was significant association between the
three categorical variables from a single population.
Results were measured in multiple categories to assess outcome, both at baseline
and after observational period. The categories included birth weight at baseline, weight
gain per day, weight at discharge, length at discharge, duration of hospital stay, time to
full enteral feeds, time of intravenous line, together with clinical characteristics. During
the study period, it was observed that infants born in centers that used probiotics had a
decreased risk for surgery for Necrotizing Enterocolitis infants compared with infants
being born in centers without probiotic use. The use of probiotics in group three was
associated with a reduced risk for Necrotizing Enterocolitis surgery with 2.6 percent
compared to group one with 4.2 percent (P=0.028). In a multivariable logistic regression
analysis, probiotics were also found to have a protective effect for NEC surgery (CI 0.370.91; P=0.017), any abdominal surgery (CI 0.51-0.95; P=0.02) and the combined
outcome of abdominal surgery and/or death (CI 0.33-0.56; P=0.001). Lactobacillus
acidophilus/Bifidobacterium infantis probiotics was shown statistically significant
(P<0.001) to be associated with increased weight gain per day, given that group three had
an average of 22.2g per day gained, whereas group one had an increase of 20.8g per day
(P=0.01).
These results led researchers to reach the conclusion of probiotics supporting the
use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics to reduce the risk for
gastrointestinal morbidity in very low birth weight infants.
The authors conclude that the data represents current clinical practice and support
results from previous randomized controlled trials that show positive outcomes when
very low birth weight infants are treated with probiotics. These outcomes include shorter
hospital stay, improved weight gain per day, protection against necrotizing Enterocolitis
requiring surgery, any abdominal surgery and the composite outcome any abdominal
surgery and/or death. Further studies may want to take into account the impact of
probiotics on families’ quality of life, risk for nosocomial infections and health care costs
as well as studies that include data on human milk feeding, evaluation of stool cultures,
and culture-dependent methods to determine the gut microbiota in extremely vulnerable
infants.
The strength of this study includes the sample size, 3229 very low birth weight
infants at the study’s conclusion. Having the German Neonatal Network to provide a
platform to study aspects of probiotic prophylaxis that have not been considered is also
an asset. Limitations include the observational study design, though implementing
comparison between centers for those using probiotics, those not using probiotics and
those who changed their practice during the data collection diminished bias. It was
assumed that blinding was not used in the study to prevent introduction of bias.
Braga TD, Silva GAP da, Lira PIC de, Lima M de C. Efficacy of Bifidobacterium
breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in
very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial.
Am J Clin Nutr. 2011;93:81–6.
This study examined the efficacy of orally administered probiotics through breast
milk in preventing Necrotizing Enterocolitis (NEC) for very low birth weight (VLBW)
preterm infants. It assessed the effect of probiotics in the form of Lactobacillus casei (L.
casei) and Bifidobacterium breve (B. breve), on prevalence and severity of NEC in
VLBW infants. This was a two year prospective, randomized, controlled trial conducted
in the Neonatal Intensive Care Unit (NICU) at the Instituto de Medicina Integral
Professor Fernando Figueira in Northeast Brazil. The VLBW preterm infants had to have
a gestational age of less than 34 weeks, have a birth weight off less than 1499 grams to be
included in the study. The exclusion criteria included VLBW preterm infants who had
one or more of the following: major congenital malformations, or previously diagnosed
life-threatening chromosomal alterations, or congenital infections diagnosed at birth.
After parental consent was given, the infants were randomly assigned by two trained
external personnel to the probiotics group or control group. Randomization was generated
by the subprogram Epitable at the Centers for Disease Control and Prevention in Atlanta,
GA.
At 0900 on the second day of life, the 122 infants from the probiotics group
received 3 mL human milk supplemented with L. casei and B. breve. They received this
treatment once a day for 28 days. The control group received the same volume of milk
without the probiotics. All of the milk was prepared by 2 nutrition assistants, supervised
by a nutritionist and had no contact with the team or NICU patients. The amount of breast
milk slowly increased with no more than 20mL/kg each day per feeding and feeding
would discontinue if there were any signs of intolerance.
Four confirmed cases of NEC were observed in the control group, and it was
unclear who made the diagnosis, but the Bell’s stage criteria of greater than or equal to
stage 2 NEC was used. The primary outcome of this study was either death or NEC at
stage 2 or greater. No differences were discerned between the groups in relation to the
start of enteral feeding and advancements in volume, but infants in the probiotics group
achieved full enteral feeding faster than the control group (CI 0.65-0.98; P=0.02). The
transition time of the orogastric feeding tube to breastfeeding was shorter in the
probiotics group (CI 0.63-0.92; P = 0.03). There were no confirmed NEC cases observed
in the probiotics group, suggesting that the use of L. casei and B. breve may prevent the
occurrence of stage 2 NEC or higher.
This study recorded the duration of time to reach full enteral feeding, considered
to be a volume of 150 mL/kg indirectly indicating intestinal motility. A time reduction
was observed in the probiotics group. The researchers concluded that probiotics
containing L. casei and B. breve, administered via supplementation in breast milk,
reduces the incidence of death or NEC for VLBW preterm infants by increasing intestinal
motility in the immature gut.The four confirmed NEC cases were only those classified
according to Bell’s criteria as equal to or above stage 2. In the initial stages, conditions
occur that can lead to a swollen abdomen and may have a distinct pathogenesis from
NEC. This results in a study limitation since cases less than stage 2 could potentially be
identified and prevented.
There were little differences between both groups in the areas of birthweight and
gestational age which is a strength to this study. However, there are few studies published
that have evaluated the role of Lactobacillus and Bifidobacteria in the prevention of
NEC. It has been observed that the effects of probiotics are species specific; therefore it is
important to recognize that more research needs to be done on Lactobacillus and
Bifidobacteria to determine if they are the most suitable probiotic strains to prevent NEC
in VLBW infants. Based on this study’s limitations and strengths it is given a quality
rating (+) and Grade A class because of the prospective, randomized, controlled design.
Demirel, G., Erdeve, O., Celik, I., & Dilmen, U. Saccharomyces bouldardii for
Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized
Controlled Study. Acta Pædiatrica. 201; 102:560-565.
This study assessed the effects of the probiotic Saccharomyces boulardii, a yeastbased probiotic, for the prevention of necrotizing enterocolitis in very low birth weight
infants. The study group aimed to assess if the efficacy of orally administered S.
boulardii reduced the incidence and severity of NEC. Using a randomly controlled trial
design, this study observed 278 infants in the Neonatal Intensive Care Unit at Samsun
Maternity and Child Health Hospital, in Samsun, Turkey.
Inclusion criteria were limited to preterm infants of gestational age of less than or
equal to 32 weeks and a birth weight of under 1500 g who survived to start enteral
feeding. Children were excluded on the presence of major congenital defects or
anomalies and lack of parental consent. The control group and study group were
randomly assigned, resulting in a study group of 138 and a control group of 140. The
breast milk team were the only personnel who were aware of the group assignments, and
they were not directly involved in the care of the infants. The study group had a mean
birth weight of 1164 ± 261 grams and the control group was at 1131 ± 284 grams.
While infants in the control group were fed as normal, 250 mg of S. boulardii was
added to the breast milk of formula once a day until the infants were discharged. The
supplementation did not change the physical appearance of the milk or the formula.
Feeding commenced within 48 hours of the birth when the infants had stabilized and had
active bowel sounds; feedings started between 10 and 20 ml/kg and then slowly was
increased, maxing out at 20 ml/kg per day. If signs of feeding intolerance were observed,
including abdominal distension and gastric residuals of more than half the amount of the
previous feedings, then feeding was halted and withheld until these feeding intolerance
signs were no longer present. For the infants weighing less than or equal to 1000 grams,
total parenteral nutrition was used with the S. boulardii probiotic agents added to the
formula.
Statistics for the results were conducted using SPSS for Windows, version 19.0
and the Mann–Whitney U-test was used to compare continuous variables, and the chisquare test was used to compare categorical variables. Results illustrated that the
incidence of NEC and death did not differ between the probiotic and the control group
[4.4% (95% CI: 0.97–7.91) vs. 5.1% (95% CI: 1.44–8.86) P= 1.000]; there were two
diagnosed cases of NEC during the trial period, one each in both the study group and the
control, but neither child died during the course of the trial period. However, despite this
lack of evidence for preventing NEC, it appears that incidence of feeding intolerance was
greatly reduced in the study group as compared with the control [22.9% (95% CI: 15.21–
29.23) vs. 48.1% (95% CI: 37.22–53.96) P= <0.001]. Data also suggests that a secondary
outcome for the study, rate of clinical sepsis, was also significantly reduced during the
trial period [47% (95% CI: (26.77–42.85) vs. 65% (95% CI: 39.39–56.19) P= 0.030], but
rate of culture proven clinical sepsis did not.
There were several different limitations to this study. Due to the nature of the
disease, that it occurs mostly in pre-term and VLBW infants, the sample size for the
study was small, meaning that some of these numbers may be insignificant in a larger
population size. This study is also one of the first that was conducted using the S.
boulardii probiotic, meaning the researchers had a lack of data to pull from for evidence.
The researchers also noted that while their study showed a significant reduction of
feeding intolerance in these infants, they suggest that this effect may also be attributed to
the regulation of intestinal motility. The lack of evidence to pull from and small sample
size thus limited the conclusions that these researchers were able to make. The strength of
this study, while the data was limited, is that it was well conducted and data was
scrupulously collected and presented in the article. Based on the study’s limitations and
strengths it is given a quality rating (+) and given a class Grade A due to its prospective,
masked, randomized, controlled design.
Sari, F., DIzdar, E., Oguz, S., Uras, N., & Dilmen, U. Oral Probiotics: Lactobacillus
sporogenes for the Prevention of Necrotizing Enterocolitis in Very Low-Birth
Weight Infants: A Randomized Controlled Trial. European Journal of Clinical
Nutrition. 2011. 65: 434-439.
This randomized controlled trial, observed effects of the probiotic Lactobacillus
sporogenes on the prevalence of necrotizing enterocolitis in very low-birth weight infants
in the Neonatal Intensive Care Unit in Zekai Tahir Burak Maternity and Teaching
Hospital, in Altindag-Ankara, Turkey. Observed in this study were 242 preterm infants
with a with a gestational age of less than 33 weeks or birth weight of less than 1500 g.
Inclusion criteria for the study included preterm neonates with a gestational
age of less than 33 weeks or birth weight less than 1500 g, who survived to feed
enterally. Those that were excluded from the study were neonates with major congenital
malformations or a lack of parental consent. The eligible infants were randomly assigned
to the intervention and control groups, resulting in 121 neonates in each category. The
breast milk team, were the only personnel who were aware of the group assignments, and
they were not directly involved in the care of the infants. Demographics for the groups,
including preeclampsia, prenatal steroids, birth weight, gestation week, asphyxia, and
multi-pregnancy were very similar among the two study groups. Birth weight in grams
for the study group and control group were 1231±262 and 1278±282 respectively, and
consisted of roughly half male and half female.
The study group received 350,000,000 c.f.u. of L. sporogenes with their breast
milk or formula once a day. This supplementation did not change the physical appearance
of the milk and the formula. Feeding was started when the infant had stable vital signs,
had active bowel sounds without abdominal distention and had no bile or blood from the
nasogastric tube. Feeding consisted of breastmilk or formula, and amount was determined
by gestational age of the infant varying between 10-20 ml/kg/day. Feeding was advanced,
if tolerated, and maxed at 20 ml/kg. If two or more signs of feeding intolerance were
observed, including gastric residuals in the amount that was more than half of the
previous feeding, abdominal distention or heme-positive stools, feeding was discontinued
and withheld as long as these signs continued. Infants weighing less than 1000 grams
were put onto parenteral nutrition until half of the calories were taken in orally.
Statistics for the results were conducted using SPSS for Windows, version 15.0
and the Student’s t-test was used to compare continuous variables, and the chi-square test
was used to compare categorical variables. Results for the study were analyzed using 110
of the infants in the study group and 111 infants from the control group, due to infant
death and withdrawal of parental consent. Confidence intervals were not provided for a
majority of the results in this study. The primary outcome of the study, incidence of NEC
was not significantly lower in the probiotic groups than in the control group (5.8 vs 9%,
respectively; P=0.447) nor was the incidence of death significantly lower in the study
group (8.2 vs 11.7%, respectively; P=0.515). Relative risk and risk difference for death
and stage ≥2 NEC were 0.70 (95% CI: 0.32 to 1.53) and 0.04 (95% CI:0.12 to 0.05)
respectively. There were two cases of NEC in the study group and three in the control
group; only one incidence of death was attributable to NEC. The incidence of cultureproven sepsis was not significantly lower in the study group than the control (26.4 vs
23.4%, respectively; P=0.613). Feeding intolerance rates for infants with at least one
episode were significantly lower in the probiotic group when compared with the control
group (44.5 vs 63.1%, respectively; P=0.006). So, in total, this study showed that
supplementation of 350,000,000 c.f.u. of L. sporogenes significantly reduced feeding
intolerance in very-low birth weight infants, however, this supplementation is not
effective in reducing the incidence and severity of NEC.
There were several different limitations to this study. Due to the nature of the
disease, that it occurs mostly in preterm and VLBW infants, the sample size for the study
was small, meaning that some of these numbers may be insignificant in a larger
population size. The researchers also noted that while their study showed a significant
reduction of feeding intolerance in these infants, they suggest that this effect may also be
attributed to the regulation of intestinal motility. As with many other studies that include
probiotics, there is also the consideration that dosage forms may be inadequate to lower
incidence of NEC, thus more studies at different dosages may need to be performed to
determine if these results are truly negative. Confidence intervals were insubstantial in
the study, which limits some of the information that we are able to gain from this study.
The strength of this study, while the data was limited, is that it was well conducted and
most of the data was scrupulously collected and presented in the article. Based on the
study’s limitations and strengths it is given a quality rating (+) and given a class Grade A
due to its prospective, masked, randomized, controlled design.
III. Conclusion
The purpose of the presented studies was to determine the effects of probiotic
supplementation in the treatment and prevention of necrotizing enterocolitis. Three of the
presented studies have evidenced that probiotics, including the species B. bifidum, L.
acidophilus, B. infantis, L.casei, and B. breve, use in very-low birth weight neonates is
protective and reduces the incidence of necrotizing enterocolitis. However, two studies
found insufficient data to suggest any benefit from the probiotics L. sporogenes and S.
boulardii. Data suggests that there is not strong or consistent evidence to conclude that
probiotic supplementation reduces the incidence of NEC. It has been observed that the
effects of probiotics are species specific; therefore it is important to recognize that more
research needs to be done on each probiotic species to determine which strain is the most
suitable for the prevention NEC in VLBW infants.
Overall Level of Evidence
The lack of conclusive data on any one specific strain of microbial flora, resulted
in an inconsistent pattern of conclusions by the research provided. Some of the studies
found positive significant effects after intervention with probiotic supplements in verylow birth weight neonates. Additionally, some of the studies found no significant effects
after interventions with different species of probiotic supplements. Grades for the studies
were based off the Academy of Nutrition and Dietetics Evidence Analysis Library quality
criteria checklist and ranged from C to A. Four of our studies were classified with strong
quality ratings but all resulted in different effects. For these reasons, we assign the overall
level of evidence as Grade III: Limited. More studies with larger sample sizes and an
emphasis of a particular strain of bacteria need to be conducted.
IV. Public Health Recommendation
The published trials to date have used different formulations of probiotics, with
varying protocols for starting and completing therapy, and differing doses of probiotics,
which leads us to judge the data as inconclusive and limited for using all species of
probiotics at this time for treatment for necrotizing enterocolitis in preterm and very low
birth weight infants. At this time, information on the side effects, dosage, and
effectiveness of probiotic bacteria is uncertain, as conducted studies have been limited in
sample size and evidence for one particular strain of probiotics is limited. More research
is needed in this area before a clear recommendation can be made.
References
1. Arciero C. J. Using a Mathematical Model to Analyze the Role of Probiotics and
Inflammation in Necrotizing Enterocolitis. Plos one. 2010; 5: 10.1371.
2. Braga, T., Pontes da Silva, G., Cabral de Lira, P., & Carvalho Lima, M. Efficacy of
Bifidobacterium breve and Lactobacillus casei Oral Supplementation on Necrotizing
Enterocolitis in Very-Low-Birth-Weight Preterm Infants: A Double-Blind, Randomized,
Controlled Trial. American Journal of Clinical Nutrition. 2011. 93:81-86.
3. Caplan, M. (2014). Necrotizing enterocolitis: Insights into the Pathogenesis of this
Challenging Disease. Morgan and Claypool Life Sciences. eBook.
4. Chen, A., Chung, M., Chang, J., & Lin, H. Pathogenesis Implication for Necrotizing
Enterocolitis Prevention in Preterm Very-Low-Birth-Weight Infants. Journal of Pediatric
Gastroenterology. 2014. 58:7-11. [Review].
5. Demirel, G., Erdeve, O., Celik, I., & Dilmen, U. Saccharomyces bouldardii for
Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Controlled
Study. Acta Pædiatrica. 201; 102:560-565.
6. Enterocolitis in Preterm Infants: Epidemiology and Antibiotic Consumption in the
Polish Neonatology Network Neonatal Intensive Care Units in 2009. Plos One. 2014;
9:1-8.
7. Lin H., Hsu, C., Chen, H., et al. Oral Probiotics Prevent Necrotizing Enterocolitis in
Very Low Birth Weight Preterm Infants: A Multicenter, Randomized, Controlled Trial.
American Academy of Pediatrics. 2008; 122:693-700.
8. Hartel C. Prophylactic Use of Lactobacillus acidophilus/Bifidobacterium infantis
Probiotics and Outcome in Very Low Birth Weight Infants. The Journal of Pediatrics.
2014; 165:285-289.
9. Neu J. Necrotizing Enterocolitis. The New England Journal of Medicine.
2011;364:255-64. [Review].
10. Patel, R. & Denning, P. Therapeutic Use of Prebiotics, Probiotics, and Postbiotics to
Prevent Necrotizing Enterocolitis: What is the Current Evidence?. Clinics in
Perinatology. 2013; 40(1): 11–25. [Review].
11. Sari, F., DIzdar, E., Oguz, S., Uras, N., & Dilmen, U. Oral Probiotics: Lactobacillus
sporogenes for the Prevention of Necrotizing Enterocolitis in Very Low-Birth Weight
Infants: A Randomized Controlled Trial. European Journal of Clinical Nutrition. 2011.
65: 434-439.
12. Springer, S. (2014, November). Necrotizing Enterocolitis. Retrieved February 2, 2015
from Medscape: http://emedicine.medscape.com/article/977956-overview#a0101
13. Wiley, J., Sherwood, L., & Woolverton, C. (2014) Prescott’s Microbiology, Ninth Ed.
McGraw-Hill, New York, NY.
14. Wojkowska-Mach, J. Rozanska, A., Borszewska-Kornacka, M., Domanska, J.,
Gadzinowski, J., Gulczynska, E., Helwich, E., Kordek, A., Pawlik, D., Szczapa, J., &
Heczko, P. Necrotising enterocolitis in preterm infants: epidemiology and antibiotic
consumption in the polish neonatology network neonatal intensive care units in 2009.
PLOS One
Appendix:
Primary Research Evidence Worksheets
Citation
Lin H. Oral Probiotics Prevent Necrotizing Enterocolitis in Very Low Birth
Weight Preterm Infants: A Multicenter, Randomized, Controlled Trial.
American Academy of Pediatrics. 2008; 122:693-700.
Study Design
Prospective, masked, randomized, controlled trial
Class
A
Quality Rating
(+)
Research
Purpose
To investigate the efficacy of orally administered probiotics in preventing
necrotizing enterocolitis for very low birth weight preterm infants.
Inclusion
Criteria
Very Low Birth Weight (VLBW) preterm infants who survived to feed
enterally were eligible for this trial.
Exclusion
Criteria
-
Description of
Study Protocol
Recruitment: LBW preterm infants who survived to feed enterally were
eligible for the trial. They were assigned randomly to study or control
groups by the principle investigator at each center after informed parental
consent was obtained.
Design: Prospective, masked, randomized, controlled trial conducted in
seven level III NICU's in Taiwan. The study protocol was approved by the
institutional review board of each hospital.
Blinding: Determination of the diagnosis of NEC of stage 2 or greater was
made by 2 independent attending physicians who did not know the group
assignment of the infant.THe breast milk team did not know the colony
counts of probiotics and were not involved in the care of the infants.
Intervention: Study group was given Infloran and B bifidum at 125 mg/kg
per dose twice daily, through addition of breast milk or mixed feeding.
Certain amount of breast milk was initiated after the infant tolerated 1 trial
of distilled water. On the first day, 1 m:/kg distilled water was given twice,
followed by breast milk. Increments of no more than 20 mL/kg per day per
feeding. 100mL/kg per day was defined as complete enteral feeding.
Statistical Analysis:
VLBW preterm infants who had severe asphyxia
Fetal chromosomal anomalies
Cyanotic congenital heart disease
Congenital intestinal atresia
Gastroschisis or omphalocele
Those who were fed exclusively through formula
Those who were fasted for more than 3 weeks
Data Collection Dependent Variables:
Summary
-Incidence of death
- Stage 2 or higher of NEC
-Body weight
Independent Variables:
Infloran and B bifidum were given twice daily at 125 mg/kg in addition to
breast milk or mixed feedings for 6 weeks. On the first day, 1 mL/kg of
distilled water was given twice followed by breast milk. The amount of
feeding increased slowly by no more than 20 mL/kg per day per feeding.
Description of
Actual Data
Sample
Initial: 443 VLBW preterm infants
Final N: 434 VLBW preterm infants
Anthropometrics: birth weight <1500 grams
Location: Taiwan
NICU setting
Summary of
Results
-The incidence of death or stage 2 NEC (4 of 217 infants vs 20 of 217
infants; P .002) was significantly lower in the study group, compared with
the control group.
-Two infants in the study group and 9 infants in the control group
developed stage 2 NEC; 2 infants in the study group and 5 infants in the
control group developed stage 3 NEC. Four and 14 infants developed stage
2 NEC in the study and control groups, respectively (P .02).
- The incidence of death not attributable to NEC (0 of 217 infants vs 6 of
217 infants; P .04) was significantly lower in the study group, compared
with the control group.
-For the secondary outcomes, there were no differences between the 2
groups with respect to PVL and severe IVH; although sepsis was more frequent among infants in the study group, there was no difference in the
univariate analysis or with adjustment for various confounding variables,
such as birth weight, umbilical venous catheter use, intermittent mandatory
ventilation, NICU stay, and center.
Author
Conclusion
The authors concluded that probiotics containing B bifidum and L
acidophilus, administered orally for 6 weeks, reduce the incidence of death
or NEC for VLBW preterm infants.
Reviewer
Comments
Limitations: during the randomization process, they ignored to stratify
according to birth weight. The difference was with there being 33 infants
weighing less than 750 grams in the study group and only 18 infants
weighing this much in the control group. Although, there were lower
incidence rates of death in the study group of different weight groups. This
calls for needed additional studies with an adequate number of weight
stratified infants in order to come to the conclusion that probiotics are
efficient in each weight group.
Funding
Source
This study was funded by the National Science Council of Taiwan
Citation
Hartel C, Pagel J, Rupp J, et al. Prophylactic Use of Lactobacillus
acidophilus/Bifidobacterium infantis Probiotics and Outcome in Very Low
Birth Weight Infants. J Pediatr. 2014; 165 (2):285-9.
Study Design
Observational Study, Prospective
Class
C
Quality Rating
(--)
Research
Purpose
Aim was to evaluate outcome data in a large cohort of VLBW infants born
in German Neonatal Network (GNN) centers stratified to prophylactic use
of Lactobacillus acidophilus/Bifidobacterium infantis probiotics. Risk for
surgery, any abdominal surgery and all-cause mortality were taken into
account.
Inclusion
Criteria
-Birth weight <1500 g
-Gestational age >22 + 6 and <32 + 0 weeks
-Born between September 1, 2010 and December 31, 2012
Exclusion
Criteria
-Lethal malformations (eg, trisomy 13 and trisomy 18)
Description of
Study Protocol
Recruitment: Categorized the participating study centers into 3 groups
based on choice of following strategies:
-Group 1: no Lactobacillus acidophilus/Bifidobacterium infantis probiotics
prophylactically (n=12)
-Group 2: changed strategy during the observational period (n=13; infants
divided based on date of birth. 2A, before prophylactic use based on date of
birth; 2B, after prophylactic use)
-Group 3: adopted prophylactic use before the observational study (n=21)
Observational Design that measured Necrotizing Enterocolitis surgery, any
abdominal surgery and death in VLBW infants
Statistical Analysis:
-Evaluated using chi-square test, Fisher exact test and Mann-Whitney U
test.
-Multivariable logistic regression analysis was completed to measure the
protectiveness of probiotics related to NEC surgery, any abdominal surgery
and the combined outcome abdominal surgery and/or death
Data
Collection
Summary
September 1, 2010-December 31,2012
Data collected prospectively
Dependent Variables:
- Increased weight gain/day
- Risk of surgery for NEC, any abdominal surgery and all cause-mortality
- Length of hospital stay
Independent Variables:
-Method of probiotic use, or lack thereof. Group 1, group 2, group 3
Description of
Actual Data
Sample
All infants born in GNN centers during study period: N=5351
After written consent given by parents: N=3529 VLBW infants
All infants with full GNN data set: N=3229
Final N = 3229
Anthropometrics: Gestational Age > 22 + 6 and <32 + 0 weeks
Location: Germany
Groups were similar in having a birth weight of < 1500 g
Summary of
Results
Results were measured in multiple categories to assess outcome, both at
baseline and after observational period. The categories included birth
weight at baseline, weight gain per day, weight at discharge, length at
discharge, duration of hospital stay, time to full enteral feeds, time of
intravenous line, together with clinical characteristics.
The baseline data suggested that probiotic use was related to greater
baseline rate of NEC requiring surgery in group 3 (5.0 percentile) compared
with group 1 (3.7 percentile).
The use of probiotics was associated with a reduced risk for necrotizing
enterocolitis surgery (group 1 vs. group 3: 4.2 vs. 2.6 percent, P = 0.028).
Infants born in centers that used probiotics had a decreased risk for surgery
for NEC compared with infants born in centers without probiotic use.
In a multivariable logistic regression analysis, probiotics were protective for
NEC surgery (P = 0.017), any abdominal surgery (P = 0.02) and the
combined outcome abdominal surgery and/or death (P = 0.001).
The use of Lactobacillus acidolphilus/Bifidobacterium infantis probiotics
was associated with increased weight gain per day (group 1, 20.8 g/d vs.
group 3, 22.2 g/d; P < 0.001; group 2 before change, 21.5 g/d vs. after
change, 22.7 g/d; P=0.01).
Duration of hospital stay was also lower in group 3 (70.5) compared to
group 1 (75.5) (P <0.001) and had less exposure to glycopeptide antibiotics.
Successful response to Lactobacilus acidophilus/Bifidobacterium infantis
was associated with positive weight gain in group 3, as well as showing a
protective characteristic against necrotizing enterocolitis (NEC) requiring
surgery, any abdominal surgery and the composite outcome any abdominal
surgery and/or death.
Author
Conclusion
The authors concluded that the data represents current clinical practice and
support results from previous randomized controlled trials. Noted were
improved weight gain per day in VLBW infants treated with probiotics, as
well as shorter stay in hospital. The impact of probiotics on families' quality
of life, risk for nosocomial infections, and health care costs should be
investigated more after receiving the results in this study. Administration of
Lactobacillus acidophilus/Bifidobacterium infantis was found to be
protective against NEC requiring surgery, any abdominal surgery and the
composite outcome any abdominal surgery and/or death.
Reviewer
Comments
Strengths: having a neonatal network such as GNN, which provide a
platform to study aspects of probiotic prophylaxis that have not yet been
considered. Another strength includes the large population size, N=3229.
To diminish the risk of bias implementation of comparison between centers
using probiotics, those not using probiotics and those who changed their
practice during the data collection period were incorporated.
Limitations: observational design. Lack of long-term follow up with the
VLBW patients. Further studies are still needed to include data on human
milk feeding, evaluation of stool cultures, and culture-dependent methods to
determine the gut microbiota in extremely vulnerable infants
Funding
Source
This study was funded by the German Ministry for Education and Research
Citation
Braga TD, Silva GAP da, Lira PIC de, Lima M de C. Efficacy of
Bifidobacterium breve and Lactobacillus casei oral supplementation on
necrotizing enterocolitis in very- low-birth-weight preterm infants: a
double-blind, randomized, controlled trial. Am J Clin Nutr. 2011;93:81–6.
Study Design
Randomized Controlled Trial
Class
A
Quality Rating
(+)
Research
Purpose
To evaluate the efficacy of the combined use of Lactobacillus casei and
Bifidobacterium breve prevent the occurrence of NEC stage >/=2 by the
criteria of Bell in very-low- birth-weight preterm infants
Inclusion
Criteria
Preterm infants of gestational age of less than or equal to 34 weeks and
with a birth weight of under 1499 g who survived to start enteral
feeding
Exclusion
Criteria
Major congenital malformations, lack of parental consent, previously
diagnosed life-threatening chromosomal alterations, or congenital
infections diagnosed at birth
Description of
Study Protocol
Recruitment: Instituto de Medicina Integral Professor Fernando
Figueira maternity unit; a reference center for high-risk pregnancies, all
preterm infants born locally and admitted to the NICU
Design: Randomized Controlled Trial
Blinding: Only the 2 nutrition assistants administering breast milk team
aware of allocations
Intervention: Treatment administered on second day of life and
maintained until thirty days of life, NEC diagnosis, death, or discharge.
L. casei and B. breve were added to the breast milk on the second day
of life for twenty-eight days thereafter as tolerated.
Statistical Analysis: Epi-Info version 6.04, Statistical Package for the
Social Sciences (version 12.0; SPSS Inc, Chi- cago, IL). Student’s t test
or the Mann- Whitney U test, the chi-square test, Fisher’s exact test,
The Kaplan-Meier survival probability method, and the log- rank
test
Statistical significance was set at P 0.05.
Data Collection Timing of Measurements: 0900 on 2nd day of life until 30days of life
Summary
Dependent Variables: Incidence of NEC
Independent Variables: L. casei and B. breve added to diet in 3mL
human milk
Control Variables: Duration and supplementation of probiotics
Description of
Actual Data
Sample
Initial: 258 (113 Males 118 Females)
Attrition: 231
Age: (Gestational) 29weeks +/- 3weeks
Ethnicity: Not mentioned, country of origin: Brazil
Other relevant demographics: Not mentioned.
Anthropometrics: Body Weight (grams): Study Group: 1194.7 +/206.3
Control Group:1151.4 +/- 224.9
Location: The Neonatal Intensive Care Unit (NICU) of The Instituto de
Medicina Integral Professor Fernando Figueira in the city of Recife,
capital of Pernambuco State, Northeast Brazil
Summary of
Results
The probiotic used in this trial was made of L. casei and B. breve, and
the confirmed cases of NEC occurred only in the control group, which
suggests that the use of probiotics may prevent the occurrence of this
outcome.
Other Findings: The time taken to reach full enteral feeding (or a volume
of 150 mL/kg) is indirect indicator of intestinal motility. A time reduction
was observed in the probiotics group.
Author
Conclusion
The use of probiotics seems to have had a beneficial effect on the
occurrence of NEC at stage !2 according to Bell’s criteria and was
associated with an improvement in intestinal motility, evaluated on the
basis of the time taken to reach full enteral feeding.
Reviewer
Comments
Limitations: small sample size
Funding
Source
Partial donation of probiotics from Yakult and funding from The
Instituto de Medicina Integral Professor Fernando Figueira
Citation
Demirel, G., Erdeve, O., Celik, I., & Dilmen, U. (2013). Saccharomyces
boulardii for prevention of necrotizing enterocolitis in preterm infants: a
randomized, controlled study. Acta Pædiatrica, 102, 560-565. dio:
10.1111/apa.12416.
Study Design
Randomized Controlled Trial
Class
A
Quality Rating
(+)
Research
Purpose
To evaluate the efficacy of orally administered S. boulardii for reducing
the incidence and severity of NEC in very low birth weight infants.
Inclusion
Criteria
Preterm infants of gestational age of less than or equal to 32 weeks and a
birth weight of under 1500 g who survived to start enteral feeding
Exclusion
Criteria
Major congenital defects or anomalies and lack of parental consent
Description of
Study Protocol
Recruitment: Neonatal Intensive Care Unit (NICU) at Samsun Maternity
and Child Health Hospital
Design: Prospective, masked, randomized, controlled trial
Blinding: Determination of the diagnosis of NEC of stage 2 or greater was
made by 2 independent attending physicians who did not know the group
assignment of the infant.Only breast milk team (feeding team) aware of
allocations, but were not involved in the direct care of the infants.
Intervention: 250 mg of S. boulardii added to feeding regime until
discharge.
Statistical Analysis: SPSS, Mann–Whitney U-test (continous), and chisquare test (categorical).
Data Collection
Summary
Dependent Variables: Incidence of NEC or death in infants.
Independent Variables: 250 mg of S. boulardii added to feeding regime.
Control Variables: Duration and supplementation of probiotic use.
Description of
Actual Data
Sample
Initial: 278 (142 Males 136 Females)
Attrition: 271
Age: gestation age of around 29 weeks for both groups.
Ethnicity: Not mentioned, country of origin: Turkey.
Other relevant demographics: Median Mother Age:
Study Group = 28 yr and Control Group = 27yr
Anthropometrics: Body Weight (grams): Study Group: 1164 +- 261
Control Group: 1131 +- 284
Location: Neonatal Intensive Care Unit (NICU) at Samsun Maternity and
Child Health Hospital, Samsun, Turkey
Summary of
Results
The use of 250 mg of S. boulardii did not lower the incidence of NEC.
Supplementation did appear to reduce feeding intolerance in study group
as well as the rate of clinical sepsis.
Author
Conclusion
No detected significant differences in the incidence of NEC between the
probiotic and control groups.
Reviewer
Comments
Limitations: the sample size was very small for this study.
Funding Source
Neonatal Intensive Care Unit, Samsun Maternity and Child Health
Hospital
Citation
Sari, F., Dizdar, E., Oguz, S., Uras, N., & Dilmen, U. Oral Probiotics:
Lactobacillus sporogenes for the Prevention of Necrotizing Enterocolitis in
Very Low-Birth Weight Infants: A Randomized Controlled Trial.
European Journal of Clinical Nutrition. 2011. 65: 434-439.
Study Design
Randomized Controlled Trial
Class
A
Quality Rating
(+)
Research
Purpose
To evaluate the efficacy of orally administered L. sporogenes for reducing
the incidence and severity of NEC in very low birth weight infants.
Inclusion
Criteria
Preterm infants of gestational age of less than or equal to 33 weeks and a
birth weight of under 1500 g who survived to start enteral feeding.
Exclusion
Criteria
Major congenital defects or anomalies and lack of parental consent
Description of
Study Protocol
Recruitment: Neonatal Intensive Care Unit (NICU) at Zekai Tahir Burak
Maternity Training Hospital
Design: Prospective, masked, randomized, controlled trial
Blinding: Determination of the diagnosis of NEC of stage 2 or greater was
made by 2 independent attending physicians who did not know the group
assignment of the infant.Only breast milk team (feeding team) aware of
allocations, but were not involved in the direct care of the infants.
Intervention: 350 000 000 c.f.u. of L. sporogenes once a day
Statistical Analysis: SPSS, chi-square test (categorical), and Student's ttest (continuous)
Data Collection
Summary
Dependent Variables: Incidence of NEC or death in infants.
Independent Variables: L. sporogenes probiotics in diet
Control Variables: Duration and supplementation of probiotic use.
Description of
Actual Data
Sample
Initial: 242 (124 Males 118 Females)
Attrition: 221
Age: 2 days of age of enrollment.
Ethnicity: Not mentioned, country of origin: Turkey.
Anthropometrics: Body Weight (grams):
Study group: 1231±262 Control Group: 1278±282
Location: Neonatal Intensive Care Unit in Zekai Tahir Burak Maternity
and Teaching Hospital, Altindag-Ankara, Turkey
Summary of
Results
L. sporogenes supplementation was not effective in reducing the incidence
of death or NEC in VLBW infants.
Supplementation did appear to reduce feeding intolerance in study group.
Author
Conclusion
L. sporogenes supplementation at the dose of 350 000 000 c.f.u/day is not
effective in reducing the incidence of death or NEC in VLBW infants.
Reviewer
Comments
Limitations: the sample size was very small for this study.
Funding
Source
Neonatal Intensive Care Unit in Zekai Tahir Burak Maternity and Teaching
Hospital