Prophylactic Use of Lactobacillus acidophilus

Prophylactic Use of Lactobacillus acidophilus/Biﬁdobacterium infantis
Probiotics and Outcome in Very Low Birth Weight Infants
Christoph H€artel, MD1, Julia Pagel, MD1, Jan Rupp, MD2, Meike Bendiks, MD1, Florian Guthmann, MD3,
Esther Rieger-Fackeldey, MD4, Matthias Heckmann, MD5, Axel Franz, MD6, Jan-Holger Schiffmann, MD7,
Beate Zimmermann, MD8, Nico Hepping, MD8, Axel von der Wense, MD9, Christian Wieg, MD10, Egbert Herting, MD, PhD1,
and Wolfgang G€opel, MD1, on behalf of the German Neonatal Network*
Objective To evaluate outcome data in an observational cohort of very low birth weight infants of the German
Neonatal Network stratified to prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics.
Study design Within the observational period (September 1, 2010, until December 31, 2012, n = 5351 infants)
study centers were categorized into 3 groups based on their choice of Lactobacillus acidophilus/Bifidobacterium
infantis use: (1) no prophylactic use (12 centers); (2 a/b) change of strategy nonuser to user during observational
period (13 centers); and (3) use before start of observation (21 centers). Primary outcome data of all eligible infants
were determined according to center-specific strategy.
Results The use of probiotics was associated with a reduced risk for necrotizing enterocolitis surgery (group 1 vs
group 3: 4.2 vs 2.6%, P = .028; change of strategy: 6.2 vs 4.0%, P < .001), any abdominal surgery, and hospital
mortality. Infants treated with probiotics had improved weight gain/day, and probiotics had no effect on the risk
of blood-culture confirmed sepsis. In a multivariable logistic regression analysis, probiotics were protective for
necrotizing enterocolitis surgery (OR 0.58, 95% CI 0.37-0.91; P = .017), any abdominal surgery (OR 0.7, 95% CI
0.51-0.95; P = .02), and the combined outcome abdominal surgery and/or death (OR 0.43; 95% CI 0.33-0.56;
P < .001).
Conclusions Our observational data support the use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics to reduce the risk for gastrointestinal morbidity but not sepsis in very low birth weight infants. (J Pediatr
2014;165:285-9).
N
osocomial infection and necrotizing enterocolitis (NEC) are leading causes of neonatal morbidity and mortality in very
low birth weight (VLBW) infants with an estimated rate of associated death up to 30% and significant impact on longterm neurodevelopment.1-5 For both entities, a multifactorial pathophysiology has been hypothesized, including
endogenous host factors, eg, gestational age and immaturity of the immune response. Moreover, environmental factors
such as enteral feeding and exposure to the endemic hospital milieu are important as these issues influence abnormal gastrointestinal colonization and translocation of enteropathogenic bacteria through vulnerable intestinal mucosa.6 The clinical
courses of sepsis and NEC often are fulminant, and the effectiveness of therapeutic interventions is limited.
Consequently, there is an urgent need to improve prevention strategies of NEC and sepsis. In recent years, several metaanalyses have been published that demonstrated that probiotics are beneficial to preterm infants (ie, by reducing the risk
for NEC and/or death but not nosocomial sepsis).7-10 These reports prompted the majority of neonatal intensive care units
(NICUs) collaborating in the German Neonatal Network (GNN) to implement
probiotic prophylaxis Lactobacillus acidophilus/Bifidobacterium infantis into their
From the Department of Pediatrics and Institute for
clinical care. However, the discussion—whether probiotics are to be recommenMedical Microbiology and Hygiene of the University at
ded for routine use—is still controversial. This controversy is related to concerns
L€
ubeck, L€
ubeck; Children’s Hospitals Hannover Auf der
Bult, Hannover, Germany; Department of Pediatrics at
regarding efficacy and safety in populations of greatest vulnerability; comparaUniversity of M€
unster, M€
unster; Department of
Pediatrics, University of Greifswald, Greifswald,
bility of study designs as the result of differences in patient cohorts, dosage,
Germany; Department of Neonatology, University of
and composition of probiotics; and, last but not least, lack of knowledge on
T€
ubingen, T€
ubingen, Germany; Children’s Hospital
€dtisches Klinikum) N€
11
(Sta
urmberg, N€
urnberg, Germany;
the evolution of the gut microbiota in individual infants.
Department of Pediatrics, GFO Hospitals Bonn, St.
Marien Hospital, Bonn, Germany; Department of
The authors of previous studies were not able to demonstrate a benefit of proNeonatology, Children’s Hospital Hamburg-Altona,
Hamburg-Altona, Germany; and Department of
biotics administration for the prevention of nosocomial sepsis12-14 or found a
1
2
3
4
5
6
7
8
9
10
Neonatology and Pediatric Intensive Care, Klinikum
Aschaffenburg, Aschaffenburg, Germany
*List of members of the GNN is available at www.jpeds.
com (Appendix).
GNN
NEC
NICU
SGA
VLBW
German Neonatal Network
Necrotizing enterocolitis
Neonatal intensive care unit
Small for gestational age
Very low birth weight
GNN is funded by the German Ministry for Education and
Research (01ER0805). The authors declare no conflicts
of interest.
0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc.
All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2014.04.029
285
THE JOURNAL OF PEDIATRICS
www.jpeds.com
trend to greater incidence of sepsis in infants receiving probiotics.15 Our aim was to evaluate outcome data in a large
cohort of VLBW infants born in GNN centers stratified to
prophylactic use of Lactobacillus acidophilus/Bifidobacterium
infantis probiotics, including infants born in 13 participating
NICUs that changed their strategy within the observational
period.
Methods
We performed an observational study on the effects of the
prophylactic use of Lactobacillus acidophilus/Bifidobacterium
infantis (Infloran; Berna, Berne, Switzerland) probiotics in
VLBW infants cared for in 46 NICUs in Germany (GNN).
Within the study period, the data were collected prospectively from infants born between September 1, 2010, and
December 31, 2012. We also evaluated a primary data set
of each group (according to strategy of probiotic use) before
the study period which was defined as “baseline” (n = 2828).
The study parts were approved by the local committee on
research in human subjects of the University of L€
ubeck
(08-022; 03.12.2010) and the local ethical committees at
the other study centers.
The inclusion criteria were as follows: birth weight
<1500 g and gestational age >22 + 6 and <32 + 0 weeks.
Exclusion criteria were lethal malformations (eg, trisomy
13 and trisomy 18). In all infants born in GNN centers during the study period, a primary data set documented the
important outcome measures (n = 5351). After written
informed consent was given by the parents, a predefined
GNN data set with additional variables including antenatal/postnatal treatment (eg individual data on probiotic
use, or weight gain) and outcome data were recorded
(n = 3527). After discharge, data sheets were sent to the
GNN center in L€
ubeck.
We categorized the participating study centers into
3 groups based on their choice for one of the following strategies of probiotic use: group 1, no Lactobacillus acidophilus/
Bifidobacterium infantis probiotics prophylactically (n = 12);
group 2, changed strategy during the observational period
(n = 13; infants were 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 period (n = 21). In group 2b and 3 centers, there
was some variability regarding dosage and time of Lactobacillus acidophilus/Bifidobacterium infantis administration.
Most study centers administered Lactobacillus acidophilus/
Bifidobacterium infantis to VLBW infants (1 1 capsule/
day or 2 1/2 capsule/day) from day 2 or 3 of life for
14 days or until full enteral feeds (150 mL/kg/d) were tolerated. Some centers restricted prophylactic use of probiotics
to infants with birth weight <1000g.
Gestational age was calculated from the best obstetric estimate based on early prenatal ultrasound and obstetric examination. NEC surgery was defined according to modified Bell
criteria ($stage 2) requiring surgery.16 Any abdominal surgery was defined as required abdominal surgery for NEC,
286
Vol. 165, No. 2
focal intestinal perforation, peritoneal adhesions, volvolus,
and meconium obstruction. We excluded herniotomies, pyloromyotomies, or surgery for other congenital malformations (eg, intestinal atresia, gastroschisis, large omphalocele,
or diaphragmatic hernia) from this definition. Bloodculture confirmed sepsis was defined as clinical sepsis with
at least two signs (temperature >38 C or <36.5 C, tachycardia >200/min, new onset or increased frequency of bradycardias or apneas, hyperglycemia >140 mg/dL, base
excess < 10 mval/L, changed skin color, increased oxygen
requirements) and proof of causative agent in blood culture
and one laboratory sign (C-reactive protein >2 mg/dL,
immature/neutrophil ratio >0.2, white blood cell count
<5/nL, platelet count < 100/nL).17
All-cause mortality was defined as death occurring after
admission to NICU before discharge home.
Statistical Analyses
Data analysis was performed using the SPSS 20.0 data analysis
package (Munich, Germany). Hypotheses were evaluated with
c2 test, Fisher exact test, and Mann-Whitney U test. P < .05 was
considered as statistically significant for single tests.
We used a predefined set of well known confounding risk
factors for any abdominal surgery, NEC surgery, and the
combined outcome of death and/or abdominal surgery ie,
gestational age, small for gestational age (SGA), inborn delivery and included Lactobacillus acidophilus/Bifidobacterium
infantis prophylaxis given to the individual infant (all infants
with full GNN data set, n = 3229).
Results
From September 1, 2010, until December 31, 2012, 5351
VLBW infants were born in 46 tertiary level NICUs. The
Figure (available at www.jpeds.com) demonstrates that
probiotics were given across all gestational age groups and
birth weight classes, and lower-risk preterm infants
>30 weeks were less frequently treated. The primary
baseline data sets before the study period for each group of
study centers are presented (n = 2828 VLBW infants born
in GNN centers, n = 1565 born January 1, 2009 to
December 31, 2009, n = 1263 VLBW infants born January
1, 2010 to August 31, 2010; Table I). Interestingly,
nonusers of Lactobacillus acidophilus/Bifidobacterium
infantis probiotics had a relatively low rate of NEC
requiring surgery compared with those centers who chose
to adopt prophylactic use of probiotics before our
observational study (group 1 vs 3, 3.7% vs 5.0%). The
same trend was observed for the combined outcome “any
abdominal surgery or death” (group 1 vs 3, 12.9% vs 14.7%).
Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics was associated with a reduced risk
for surgery for NEC, any abdominal surgery, and all-cause
mortality (Table II). Notably, group 1 had a greater
percentage of SGA infants than group 3. SGA is associated
with adverse outcome. In those centers with a change of
strategy during the study period, we observed a remarkable
€rtel et al
Ha
ORIGINAL ARTICLES
August 2014
Table I. Clinical characteristics of VLBW cohort before observational period (baseline)
Clinical characteristics
Group 1, no use
Group 2, change
Group 3, use
All
No. infants
Gestational age (wk), mean (SD)*
Birth weight (g), mean (SD)*
SGA <10th percentile, %
Male sex, %
Multiple birth, %
Surgery for NEC, %
Any abdominal surgery, %
Blood culture–confirmed sepsis, %
Death, %
Any abdominal surgery or death, %
Cause of death, %
RDS/early failure
BPD
Lung hemorrhage
NEC/FIP
Sepsis
ICH grade IV
Others
Unknown
518
28.2 (2.6)
1023 (306)
13.5
48.6
31.3
3.7
6.8
12.0
7.7
12.9
964
28.5 (2.4)
1052 (301)
14.0
51.3
30.9
4.3
6.5
11.0
8.6
13.6
1346
28.4 (2.5)
1043 (309)
14.5
53.1
31.2
5.0
6.6.
12.4
10.0
14.7
2828
28.4 (2.5)
1042 (306)
14.2
51.7
31.1
4.5
6.6
11.9
9.1
14.0
0.2
0.4
0.2
0.6
0.4
1.0
0.2
4.9
0.5
0.1
0.5
0.5
1.2
0.1
0.9
4.7
0.3
0.1
0.1
0.5
1.2
0.5
1.2
6.1
P value
.5
.6
.81
.22
.99
.44
.98
.71
.24
.55
.05
0.4
0.1
0.3
0.5
1.1
0.5
0.9
5.3
BPD, bronchopulmonary dysplasia; FIP, focal intestinal perforation; ICH, intracerebral hemorrhage; RDS, respiratory distress syndrome.
*P values are derived from the Fisher exact test or Mann-Whitney U-test if indicated.
decrease in NEC surgery (6.2 vs 4.0%, P < .001), any
abdominal surgery (8.2 vs 6.3%, P = .03), and death (10.0
vs 8.3%, P = .017). There was only a trend towards less
blood-culture confirmed sepsis (15.4 vs 10.6%, P = .05)
after the introduction of probiotics (group 2a vs group 2b,
respectively).
In a multivariable logistic regression analysis, probiotics
were protective for NEC surgery (OR 0.58, 95% CI 0.370.91; P = .017), any abdominal surgery (OR 0.7, 95% CI
0.51-0.95; P = .02), and the combined outcome abdominal
surgery and/or death (OR 0.43; 95% CI 0.33-0.56; P < .001;
Table III).
Clinical Characteristics of GNN Enrolled Infants
Stratified to Center-specific Strategy
GNN enrolled infants prophylactically treated with Lactobacillus acidophilus/Bifidobacterium infantis probiotics had a
shorter stay in hospital and less exposure to glycopeptide antibiotics (Table IV). The use of Lactobacillus acidophilus/
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 < .001; group 2 before change, 21.5 g/d vs
after change, 22.7 g/d; P = .01). This was not related to
improved feeding tolerance, as infants born in group 1
centers needed less time to establish full enteral feeds
Table II. Clinical characteristics of VLBW cohort categorized according to the centers’ choice for prophylactic use of
Lactobacillus acidophilus/Bifidobacterium infantis probiotics
Clinical characteristics
No. infants
Gestational age (wk), mean (SD)*
Birth weight (g), mean (SD)*
SGA <10th percentile, %
Male sex, %
Multiple birth, %
Surgery for NEC, %
Surgery FIP but no NEC, %
Any abdominal surgery, %
Blood culture–confirmed sepsis, %
Death, %
Any abdominal surgery or death, %
Cause of death, %
RDS/early failure
BPD
Lung hemorrhage
NEC/FIP
Sepsis
ICH grade IV
Congenital anomalies
Others
Group 1,
no use
Group 2a,
before change
Group 2b,
after change
Group 3, use
All
1043
28.2 (2.6)
1012 (318)
16.8
54.6
28.5
4.2
2.5
7.0
11.0
10.4
16.0
519
28.5 (2.5)
1043 (307)
16.4
52.0
38.0
6.2
0.3
8.2
15.4
10.0
16.2
1223
28.4 (2.5)
1041 (304)
14.0
50.9
36.2
4.0
1.7
6.3
10.6
8.3
12.3
2566
28.4 (2.4)
1035 (303)
13.9
50.9
31.1
2.6
1.6
5.2
11.6
7.4
11.6
5351
28.4 (2.5)
1033 (307)
14.7
51.7
32.4
3.6
1.7
6.0
11.5
8.4
13.0
2.2
0.7
0.8
1.2
1.7
1.1
0.9
1.9
1.9
1.0
0.2
1.0
1.7
0.2
0.8
3.7
1.1
0.3
0.3
1.6
1.9
0.7
0.5
1.9
2.1
0.3
0.5
0.7
0.9
1.0
0.4
1.9
P
value (all)
P value
(groups 1 vs 3)
.3
.3
.08
.21
<.001
<.001
.2
.03
.05
.017
<.001
<.001
.3
.2
.02
.05
.1
.028
.14
.04
.9
.001
<.001
1.9
0.4
0.5
1.0
1.4
0.9
0.6
0.55
*P values are derived from the Fisher exact test or Mann-Whitney U test if indicated.
Prophylactic Use of Lactobacillus acidophilus/Bifidobacterium infantis Probiotics and Outcome in
Very Low Birth Weight Infants
287
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Vol. 165, No. 2
Table III. Risk factors for NEC surgery, abdominal surgery, and/or death from multiple logistic regression analysis
Risk factor
Surgery for NEC* (n = 82)
Any abdominal surgery* (n = 193)
Abdominal surgery or death* (n = 259)
Gestational age
SGA
Inborn
Probiotics
OR 0.71 (0.65-0.78; P < .001)
OR 1.6 (0.92-2.76; P = .09)
OR 0.24 (0.1-0.55; P = .001)
OR 0.58 (0.37-0.91; P = .017)
OR 0.65 (0.6-0.7; P < .001)
OR 1.7 (1.2-1.5; P = .004)
OR 0.46 (0.22-0.97; P = .04)
OR 0.7 (0.51-0.95; P = .02)
OR 0.63 (0.59-0.67; P < .001)
OR 2.45 (1.78-3.36; P < .001)
OR 0.53 (0.26-1.07; P = .08)
OR 0.43 (0.33-0.56; P < .001)
*aORs, 95% CI, P-value; the database consists of 3229 VLBW infants with full GNN dataset.
(150 mL/kg/d) compared with group 3 infants. In a subgroup
of infants that excluded those who had any abdominal
surgery and/or died (n = 302), we confirmed the
association of probiotics intake and improved weight gain
(group 1, 21.3 [6.1] g/d vs group 3, 22.5 [4.8] g/d;
P < .001; group 2a before change, 21.8 [5.1] g/d vs group
2b after change, 23.3 [4.3] g/d; P < .001).
Discussion
Probiotics have entered routine clinical use in the majority
of NICUs in the GNN (34/46 centers), with 62% of VLBW
infants 23 + 0 < 32 + 0 weeks of gestation prophylactically
treated with Lactobacillus acidophilus/Bifidobacterium infantum probiotics. This development is in association with the
publication of 2 meta-analyses on the beneficial effects of
probiotics to reduce the risk of NEC and/or death.8,9 However, the use of probiotics is still controversial.3
We evaluated the outcome of infants born in participating
study centers that were categorized according to their choice
for probiotic use over time. Our baseline data before the study
period suggested that probiotic use was related to greater
baseline rate of NEC requiring surgery in group 3 (5.0%)
compared with group 1 (3.7%). Within the study period,
we observed that infants born in centers that used probiotics
had a decreased risk for surgery for NEC compared with infants born in centers without probiotic use. The risk for sepsis
was not influenced by center-specific strategy.
Because there were greater proportions of SGA infants in
group 1 centers, we performed a multiple logistic regression
analysis that included known risk factors of greater-stage
NEC (gestational age, SGA, outborn delivery), as recently
published by investigators of the Canadian Neonatal
Network.18 In this multivariate analysis, administration of
Lactobacillus acidophilus/Bifidusbacterium infantum was protective against NEC requiring surgery, any abdominal surgery, and the composite outcome any abdominal surgery
and/or death.
What is the consequence of our observational data? We
focused on surgical NEC, because the diagnostic variability
of medical NEC is well known but the decision for surgery
eliminates many of the milder, questionable cases of NEC.
In general, our data reflect the wide variation among centers,
as seen in other networks (Eunice Kennedy Shriver National
Institute of Child Health and Human Development, Canadian Neonatal Network).18-20 Within a multicenter collaboration, centers with greater incidence of adverse
outcomes—as seen for sepsis and NEC in group 2 centers
before change to probiotic prophylaxis—are more likely to
benefit from implementation of new strategies than those
centers with low incidences. On the other hand, group 2 centers may also have improved by the feedback given through
annual reports and by benchmarking approaches including
optimized infection control protocols.
The major limitation of our study is its observational
design. To diminish the risk of bias, we implemented the
Table IV. Clinical characteristics of GNN enrolled VLBW infants categorized according to the centers’ choice for
prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics
Clinical characteristics
Group 1,
no use
No. infants
637
Gestational age (wk), mean (SD)*
28.2 (2.5)
Birth weight (g), mean (SD)*
1011 (307)
Probiotic prophylaxis, %
2.5
Antibiotic treatment, %
89.6
Use of carbapeneme, %
21.4
Use of vancomycin/teicoplanin, %
40.7
Weight gain/day (g), mean (SD)*
20.8 (6.6)
Weight at discharge (g), mean (SD)*
2561 (769)
Length at discharge (cm), mean (SD)*
45.7 (4.4)
Head circumference at discharge (cm),
32.6 (2.7)
mean (SD)*
Duration of hospital stay (d), mean (SD)*
75.7 (41.5)
Time to full enteral feeds (d), median (IQR)*
11 (8-17)
Time of intravenous line (d), median (IQR)*
14 (9-23)
Group 2a,
Group 2b,
before change after change
Group 3,
use
All
P value (all) P value (groups 1 vs 3)
213
28.3 (2.5)
1020 (301)
0.5
90.0
26.8
45.5
21.5 (5.3)
2656 (738)
46.2 (4.6)
33.0 (2.6)
745
28.3 (2.5)
1020 (297)
79.2
88.0
23.4
38.9
22.7 (5.2)
2640 (719)
45.8 (4.1)
32.7 (2.6)
1932
28.3 (2.3)
1034 (298)
81.8
90.1
20.0
26.1
22.2 (5.2)
2577 (652)
45.8 (3.9)
32.6 (2.6)
3527
28.3 (2.4)
1026 (300)
62.0
89.6
21.4
32.6
22.0 (5.5)
2592 (694)
45.8 (4.1)
32.7 (2.6)
.13
<.001
.5
.06
<.001
.01
n.s.
n.s.
n.s.
.3
.12
<.001
.8
.4
<.001
<.001
.14
.34
.97
77.9 (36.5)
14 (11-23)
17 (12-25)
71.8 (36.9)
12 (8-18)
13 (9-23)
70.5 (34.7)
14 (10-18)
15 (10-22)
72.1 (36.6)
13 (9-18)
14 (10-23)
<.001
n.a.
n.a.
.038
<.001
.04
n.a., not available; n.s., not significant.
*P values are derived from the Fisher exact test or Mann-Whitney U test if indicated.
288
€rtel et al
Ha
ORIGINAL ARTICLES
August 2014
comparison between centers using probiotics, those not using probiotics, and those who changed their practice during
the data collection period. Thus, our data represent current
clinical practice and support results from previous randomized controlled trials. We also noted improved weight gain/
day in infants treated with probiotics, which may affect secondary outcomes, eg, bronchopulmonary dysplasia, which
are partially explained by impaired growth/deficient utilization of nutrients as well as inflammation (“new bronchopulmonary dysplasia”).21
Probiotics may be the influence of the cross-talk between
the developing immune system and the microbiota that interferes with growth and susceptibility to long-term
morbidity. Animal models have demonstrated a direct link
between body composition and gut microbiota.22,23 Microbial patterns of initial colonization of the intestine are known
to affect host metabolic and endocrine functions (fat deposition, leptin, and insulin levels), although the variables have
not been studied in preterm infants. The finding of shorter
stay of probiotics-treated VLBWs in hospital requires further
investigation. Based on the hypothesis that “protective microbiota” result in an improved weight gain and shorter
stay in hospital, the impact of probiotics on families’ quality
of life, risk for nosocomial infections, and health care costs
should be investigated as important study end points.
Neonatal networks such as GNN provide a platform to
study aspects of probiotic prophylaxis that have not yet been
considered, eg, probiotic administration to the subgroup of
patients with stoma who have different colonization patterns
and a significant exposure to long-term antibiotics.24 Future
studies are needed that include data on human milk feeding,
evaluation of stool cultures, and culture-independent
methods to determine the gut microbiota in extremely vulnerable infants. It would be an important objective to include this
additional information into future guidelines on feeding and
probiotic administration in the individual VLBW infant. n
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
We are grateful to the infants, parents, and health care providers who
supported our study.
18.
Submitted for publication Nov 18, 2013; last revision received Jan 28, 2014;
accepted Apr 15, 2014.
19.
€rtel, MD, Department of Paediatrics, University
Reprint requests: Christoph Ha
€beck, Ratzeburger Allee 160, 23538 Lu
€beck, Germany. E-mail: christoph.
of Lu
[email protected]
20.
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THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. 165, No. 2
Appendix
Additional investigators of GNN include: Stefan Avenarius,
MD, Department of Pediatrics, University of Magdeburg;
Kai Bockenholt, MD, Children’s Hospital CologneAmsterdamer Strasse; Bettina Bohnhorst, MD, Department
of Neonatology, Hanover Medical School; Michael
D€
ordelmann, MD, Diakonissenhospital Flensburg; Silke Ehlers, MD, B€
urgerhospital Frankfurt; Ursula FelderhoffM€
user, MD, PhD, Department of Pediatrics, University of
Essen; Corinna Gebauer, MD, Department of Pediatrics,
University of Leipzig; Hubert Gerleve, MD, Children’s Hospital Coesfeld; Ludwig Gortner, MD, Department of Pediatrics, University of Homburg; Peter Groneck, MD, Children’s
Hospital Leverkusen; Friedhelm Heitmann, MD, Children’s
Hospital Dortmund; Georg Hillebrand, MD, Children’s Hospital Itzehoe; Thomas H€
ohn, MD, PhD, Department of Pediatrics, University of D€
usseldorf; Mechthild Hubert, MD,
Children’s Hospital Siegen; Helmut Hummler, MD, PhD,
Department of Neonatology, University of Ulm; Andreas
Jenke, MD, Children’s Hospital Wuppertal; Reinhard Jensen,
MD, Children’s Hospital Heide; Olaf Kannt, MD, Children’s
Hospital Schwerin; Angela Kribs, MD, Department of Pediatrics, University of Cologne; Helmut K€
uster, MD, Department of Pediatrics, University of G€
ottingen; Reinhard
Laux, MD, Children’s Hospital Hamburg-Barmbek; Ursula
Lieser, MD, Department of Pediatrics, University of Halle;
Michael M€
ogel, MD, Department of Pediatrics, University
of Dresden; Jens M€
oller, MD, Children’s Hospital
Saarbr€
ucken; Dirk M€
uller, MD, Children’s Hospital Kassel;
Werner Nikischin, MD, Department of Pediatrics, University
of Kiel; Dirk Olbertz, MD, Children’s Hospital RostockS€
udstadt; Thorsten Orlikowsky, MD, Department of Pediatrics, University of Aachen; Jochen Reese, MD, Children’s
Hospital Eutin; Claudia Roll, MD, PhD, Department of Pediatrics, University Witten-Herdecke, Children’s Hospital Datteln; Thomas Schaible, MD, Department of Pediatrics,
University of Mannheim; Stefan Seeliger, MD, Children’s
Hospital Neuburg/Ingolstadt; Hugo Segerer, MD, Children’s
Hospital St. Hedwig, Regensburg; Norbert Teig, MD,
Department of Pediatrics, University of Bochum; Ursula
Weller, MD, Children’s Hospital Bielefeld; Matthias Vochem, MD, Olgahospital Stuttgart; and J€
urgen Wintgens,
MD, Children’s Hospital M€
onchengladbach.
289.e1
Figure. Percentage of infants treated with prophylactic probiotics in each A, gestational week group or B, birth weight
classes for all centers and for those centers only who had implemented probiotics before start of observation. The
numbers below the gestational week or birth weight class
reflect the total number of GNN enrolled infants vs the number
of GNN enrolled infants in centers with general use of probiotics. Group 1 centers used probiotics in <2% of infants.
€rtel et al
Ha

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