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;-:---).
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
1
THE JOURNAL OF PEDIATRICS
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 22 + 6 and 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 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
- 2014
ORIGINAL ARTICLES
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
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
1
THE JOURNAL OF PEDIATRICS
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 22 + 6 and 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 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
- 2014
ORIGINAL ARTICLES
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
