[Summary text]
Multicenter randomized controlled double blinded study
101 infants 501-1000 g, appropriate for gestational age, and ⋜14 days of age at the time of feeding initiation
Exclusion: Major congenital anomalies, and have known PS before study
Demographic data:
Probiotics Group N=50, Gestational age (weeks) 25.7 (1.4), birth weight 778 (138)
Placebo Group N=51, Gestational age (weeks) 25.7 (1.4), birth weight 779 (126)
Probiotic group was given supplement consisting of Lactobacillus rhamnosus GG (LGG) (Culturelle, Amerifit Brand, Cromwell, CT, USA) 500 million colony forming units (CFU) and Bifidobacterium infantis (Align, Procter and Gamble, Cincinnati, OH, USA) 500 million CFU suspended in 0.5 mL of infant’s milk.
Probiotic supplementation was added to the first enteral feeding and continued once daily with feedings thereafter until discharge or until 34 weeks postmenstrual age. The control group received unsupplemented milk added to their daily feeding.
Milk type was not known
Primary outcome: Weight <10th percentile at 34 weeks
Secondary outcomes: Average volume of feeding, Growth velocity, Average daily weight gain, Antimicrobial days, Antibacterial days, Antifungal days, NEC, IVH, ROP, and CLD
Single centre randomized study
Method of generating randomization sequence: not described
Blinding of randomization: not described
Blinding of intervention: yes
Blinding of outcome measurement: yes
Completeness of follow-up: not specified
145 infants less than 1500 g at birth
Demographic data:
Probiotics Group N=72, Gestational age (weeks) 29.2 (2.6), birth weight 1152 (262)
Placebo Group
N=73, Gestational age (weeks) 29.3 (4.3), birth weight 1111 (278)
Probiotics group (N=72) received mixture of (ABCDophilus) Lactobacillus bifidus, streptococcus thermophillus, and bifidobactrium infantis added to 3 ml of expressed breast milk or premature formula enteral feeds
Control group (N=73) received 3 ml of expressed milk or premature formula with no supplements added
Stage 2 or 3 NEC
Mortality
NEC or mortality
Sepsis
Days to full feeds
Days till TPN stopped
Israel
Period of study: Sept 2001-Sept 2004
Published: Journal of Pediatrics 2005
Source of Funding: ABC Dophilus
A prospective, double blind, randomized controlled trial
231 Infants with weight 750-1500 g
Demographic data:
Probiotics Group N=119, Gestational age (weeks) 29.5 (2.5), birth weight 1194.7 (206.3)
Placebo Group N=112, Gestational age (weeks) 29.2 (2.6), birth weight 1151.4 (224.9)
The participants randomised into two groups of 231 infants:
Control group: 3 mL of pasteurized human milk once a day
Intervention group: Lactobacillus casei and Bifidobacterium breve (Yakult - LB) diluted with 3 mL of pasteurized human milk once a day on the second day to the 30th day of life, or at discharge if it happens before the 30th day
All enrolled infants received human (expressed breast milk or donor) milk
Primary: Necrotising enterocolitis classified as higher or equal to 2 according to Bell's criteria
Secondary: The pathogenic bacteria in the faeces, duration of birth weight recovery, Time to full enteral feeds, and hospital stay
Brazil
ISRCTN67165178
Supported by Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (grant number 473704/2006-4) and research grants (to PIC de Lira and M de Carvalho Lima)
External Study Committee observed a major benefit in one of the groups and recommended that the study be interrupted; at this time there were a total of 231 participants
Single center randomized double blind study
Method of generating randomization sequence: Cards in sealed envelopes
Allocation concealment: Possibly adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Not described
Complete follow-up: Yes
87 infants, gestational age 28-32 weeks
Exclusion criteria:
Major anomalies, receiving antibiotics or anti-fungals, receiving breast milk
Demographic data:
Probiotics Group N=51, Gestational age (weeks) 31.1 (2.5), birth weight 1651 (470)
Placebo Group N=36, Gestational age (weeks) 31.8 (2.7), birth weight 1644 (348)
Probiotics group (N=51) received preterm formula containing approximately 15 nmol/dL polyamines with added Saccharomyces boulardii 50mg/kg every 12 hours during the first week of life when enteral feed are tolerated for 30 days
Placebo group (N=36) received same formula with maltodextrins
All enrolled infants received formula milk
NEC
Weight gain
Abdominal distension
Vomiting
Gastric retention
Stool characteristics
Sepsis
Greece
Period of study: not specified
Published: 2003
Source of Funding: Unclear
Multicenter randomized double blind study (12 centers)
Method of generating randomization sequence: not described
Allocation concealment: Clearly adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes
585 infants, < 33 weeks gestation or <1500 g birth weight enrolled
Exclusion criteria:
Congenital malformation and death within two weeks of birth
Demographic data:
Probiotics Group N=295, gestational age (weeks) 30.8 (2.4), birth weight 1325 (361)
Placebo Group N=290, gestational age (weeks) 30.7 (2.3), birth weight 1345 (384)
Milk type was not known
Probiotics group (N=295) received standard milk with Lactobacillus GG (Dicoflor®, Dicofarm, Rome, Italy) with an added dose of 6×109 colony forming units (cfu) once a day until discharge, starting with first feed
Placebo group (N=290) received standard milk with placebo which was an indistinguishable dried powder of maltodextrins
Severe NEC
Incidence of PDA
Duration of parenteral nutrition
Urinary tract infection
Bacterial sepsis (culture proven)
Stage 2 and 3 NEC
Single course of antibiotics treatment
NEC related mortality
Italy
Period of study: not specified in paper
Published: 2002
Source of Funding: not specified in paper
Double blind placebo controlled randomized trial
271 infants
Inclusion criteria: Infants with gestational age 32 weeks and birth weight 1500 g who survived to start enteral feeding were enrolled in the study
Exclusion criteria: major congenital anomalies and lack of parental consent
Demographic data:
Probiotics group N=135, gestational age (weeks) 29.4 (2.3), birth weight 1164 (261)
Placebo group N=136, gestational age (weeks) 29.2 (2.5), birth weight 1131 (284)
All enrolled infants received breast milk or formula
The infants in the study group were given 250 mg (5 billion CFU) S. boulardii added to breast milk or formula once a day, starting with the first feed, until they were discharged. The infants in the control group were fed as usual, without supplementation. The supplementation did not change the physical appearance of the milk or formula
Feeding commenced within 48 h of birth when the infant had stable vital signs, active bowel sounds without abdominal distension, and no bile or blood from the nasogastric tube
Primary Outcome: NEC stage 2 and death
Secondary Outcomes: clinical or culture-proven sepsis, feeding difficulties, and days required to reach full enteral feeding
NCT01315821
A randomized, double blind clinical trial
150 infants <1500 g birth weight enrolled
Demographic data:
Probiotics Group N=75, gestational age (weeks) 31.2 (26–35.4), birth weight 1090 (580–1495)
Placebo Group N=75, gestational age (weeks) 31 (27–36), birth weight 1170 (540–1492)
Exclusion criteria: Preterm newborns with a low Apgar score (<6 at 5 min), gastrointestinal malformations, genetic syndromes, asphyxia and IA–IB NEC stages were excluded
Infants were randomly assigned to:
The study group received their regular feeds and a daily multi species probiotic feeding supplement of 1 g/d diluted in 3 ml of expressed mother’s milk when available or a premature infant formula
The control group received their regular feeds from their mother’s own milk when available with nothing added, or a premature infant formula
Primary outcome: the occurrence of NEC
Secondary outcomes: sepsis, apnea, anaemia, patent ductus arteriosus, and death
Single center randomized study
Method of generating randomization sequence: Not described
Allocation concealment: Not described
Blinding of intervention: Not described
Blinding of outcome measurement: Not described
Complete follow-up: No (6 patients dropped)
91 infants, birth weight <1500 g enrolled
Exclusion criteria:
Major anomalies, severe asphyxia, severe IUGR
Demographic data:
Probiotics Group N=45, gestational age (weeks) 28.3 (2.3), birth weight 1026 (24)
Placebo Group N=46, gestational age (weeks) 28.2 (2.1), birth weight 1026 (205)
Probiotics group (N=45) received 1 ml supplement of Bifidobacterium breve with distilled water 0.5×109 of live B. breve within the 1st 24 hrs of life once per day for 28 days
Control group (N=46) received distilled water
All enrolled infants received expressed breast milk and premature formula
Colonization rate
Mean aspired air volume
Vomiting times/week
Apnoea times/week
Weight gain
Mental retardation and cerebral palsy outcome at 6 years
Japan
Period of study: May 1990-April 1991
Published: 1997
Source of funding: Unclear
Single center randomized study
30 infants, of low birth weight.
Exclusion criteria:
Major anomalies, chromosomal anomalies, intrauterine infection
Demographic data:
Probiotics Group A N=10, gestational age (weeks) 33.8 (2.9), birth weight 1523 (490)
Probiotics Group B N=10, gestational age (weeks) 33.8 (3.2), birth weight 1354 (280)
Control (C) Group N=10, gestational age (weeks) 32.4 (3.1), birth weight 1480 (237)
Probiotics group (N=10) received through gastric tube Bifidobacterium breve twice a day with feeds till discharge. Group A within several hours of birth, while group B after the 1st 24 hrs
Control group (N=10) received no supplement
Breast and artificial milk was utilized for feeding
Colonization rate
Sepsis
Japan
Period of study: Jan 2000- Aug 2002
Published: 2004
Source of funding: Morinaja Milk industry and Meiji Dairies
Single centre randomized study
Method of generating randomization sequence: Random-number table sequence.
Allocation concealment: Clearly adequate
Blinding of intervention: Yes, only investigators and breast milk team were unblinded.
Blinding of outcome measurement: Yes
Completeness of follow up: Yes
367 infants less than 1500 g at birth, survived beyond 7 days of life, and started on enteral feed were enrolled
Demographic data:
Probiotics Group N=180, gestational age (weeks) 28.5(2.5), birth weight 1104 (242)
Placebo Group N=187, gestational age (weeks) 28.2 (2.5), birth weight 1071 (243)
Probiotics group (N=180) received Infloran® (L. acidophilus and B. infantis) obtained from the American Type Culture Collection in 1973, 125 mg/kg/dose twice daily with breast milk until discharge. All enrolled infants received maternal or banked breast milk
Control group (N=187) received breast milk without any addition (no placebo)
Death
Stage 2 or 3 NEC
Sepsis (culture proven)
Composite outcomes of death + NEC, sepsis + NEC, death + NEC + sepsis
Duration of parenteral nutrition
Hospitalization days
Taiwan
Period of study: July 1999- December 2003
Published: 2005
Source of funding: supported by research department of China medical university hospital
Multicenter trial
Method of generating randomization sequence: Sequential numbers generated at the computer center
Allocation concealment: Adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Completeness of follow up: Yes
Very low birth weight infants (birth weight <1500 g)
Demographic data:
The study group N=217, birth weight 1028.9 (246)
The control Group N=217, birth weight 1077 (214.4)
Infants in the study group were given Bifidobacterium bifidum and Lactobacillus acidophilus, added to breast milk or mixed feeding (breast milk and formula), twice daily for 6 weeks
Infants in the control group were fed with breast milk or mixed feeding
Death or severe NEC
NEC, stage 2
Death not attributable to NEC
Death attributable to NEC
Sepsis
CLD
PVL
IVH, grade 3
7 NICUs in Taiwan
Period of study: January 2005 - May 2007
Published: 2008
Sources of support: National Science Council of Taiwan
Single center randomized study
Method of generating randomization sequence: Computer generated randomization
Allocation concealment: Unclear
Blinding of intervention: Can't tell
Blinding of outcome measurement: Can't tell
Completeness of follow up: Yes
80 infants less than 1500 g at birth, survived beyond 3 days of life, and started on human or donor milk enteral feed were enrolled
Demographic data:
Probiotics Group N=39, gestational age (weeks) 29.6 (5), birth weight 1212 (290)
Placebo Group N=41, gestational age (weeks) 41 (4), birth weight 1174 (340)
Probiotics group (N=39) received LGG (Diclofor 60; Dicofarm spa); single dose (1/2 packet of Diclofor 60) daily mixed with human or donor milk till end of the sixth week or discharge
Control group (N=41) received human or donor milk without any addition (no placebo)
Fungal colonization rates
Stage 2 or 4 NEC
Death
Sepsis (culture proven)
Time to full feeds
Italy
Period of study: 12 months
Published: 2006
Sources of support: non reported
Multicenter trial
Method of generating randomization sequence: using ralloc.ado version 3.2.5 in Stata 9.2 (Stata-Corp, College Station, Texas)
Allocation concealment: Yes
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Completeness of follow up: Yes
VLBW neonates younger than 3 days
Demographic data:
Probiotics Group N=151, gestational age (weeks) 29.8 (23-35), birth weight 1138 (550-1500)
Control Group N=153, gestational age (weeks) 29.5 (23-39), birth weight 1109 (437-1500)
Infants received either BLF (Bovine Lactoferrin) (100mg/d) (LF100; Dicofarm SpA, Rome, Italy) alone or BLF plus LGG (6x109 colony-forming units/d) (Dicoflor60; Dicofarm SpA); the control group received placebo (2 mL of a 5% glucose solution).
Treatment lasted 6 (birth weight 1000 g) or 4 (birth weight 1001-1500 g) weeks, unless neonates were discharged earlier.
Drug administration began on the third day of life with 1 daily dose; all doses including placebo were diluted in prepared milk so as to maintain blinding.
Enrolled infants received any combination of expressed breast milk, donor breast milk, and preterm formula.
First episode of late-onset sepsis
Incidence of gram-positive/gram-negative bacterial and fungal sepsis
Mortality prior to discharge
Incidence of urinary tract infections, fungal colonization, progression from fungal colonization to invasive fungal infection
Severe NEC
Threshold ROP
Severe (grade 3-4) IVH
BPD
Alteration of liver function
Adverse effects or intolerance
11 Italian tertiary NICU
Period of study: October 1, 2007, and July 31, 2008
Published: 2009
Source of Funding: Dicofarm SpA
A randomized controlled trial
183 VLBW infants <30 weeks of gestation and <1500g
Demographic data:
Probiotics Group N=91, gestational age (weeks) 26.6 (1.8), birth weight 856 (251)
Control Group N=89, gestational age (weeks) 26.7 (1.7), birth weight 871 (287)
Exclusion criteria were major congenital malformations and anomalies which might interfere with nourishing
B. lactis BB12 suspension or placebo was given in addition to human milk, fortified human milk or preterm formula. BB12 was provided as lyophilized powder mixed with a standard preterm infant human milk fortifier. Human milk fortifier powder only (FM85; Nestlé) was used as placebo. In infants <1,500 g, 1 g of powder was dissolved once a day in 10 ml of sterile water. In infants 1,500 g, 2 g of powder were dissolved once a day in 20 ml of sterile water.
The control group received the identical volume of placebo suspension
All enrolled infants received maternal breast or formula milk
Primary outcome was the ‘incidence density’ of nosocomial infections from day 7 after initiation of milk feeding until the 42nd day of life
Secondary outcomes was the incidence of necrotizing enterocolitis (NEC; stage 2)
Division of Neonatology (Children’s Hospital, University of Ulm, Germany)
The study was supported by Nestlé AG, Frankfurt, Germany.
Single center randomized blinded study
Method of generating randomization sequence: Not described
Allocation concealment: Not described
Blinding of Intervention: Yes
Blinding of outcome measurement: Unclear
Complete follow-up: Yes
20 infants, < 33 weeks gestation enrolled
Demographic data:
Probiotics Group N=10, gestational age (weeks) 30.5(26-33), birth weight 1445 (800-2560)
Placebo Group N=10, gestational age (weeks) 30.0 (24-33), birth weight 1500 (830-2150)
Probiotics group received milk feeds with Lactobacillus GG 108 (cfu) twice a day for 14 days, starting with first feed
Placebo group received unsupplemented milk. Enrolled infants received any combination of expressed breast milk, formula, and preterm formula
Weight gain
Sepsis clinical or lab proven
Antibiotics treatment
Oxygen and ventilatory requirements
Hospital stay
Perineal candidal infection
Duration of hospital stay
UK
Period of study: Sept 1991-Jan 1992
Published: 1993
Source of Funding: Wessex Medical Trust
A double blind, placebo controlled, randomized trial
Method of generating randomization sequence: Randoma software version 4.3
Allocation concealment: Not described
Blinding of intervention: Yes
Blinding of outcome measurement: Unclear
Complete follow-up: Yes
Gestational age of less than 37 weeks
No demographic data were provided
69 preterm infants
The probiotic and placebo groups contained 37 and 32 preterm infants, respectively
The verum contained 2 x109 cells of Bifidobacterium lactis Bb12 per gram of powder. The concentration of Bb12 in 1 ml solution of verum in water was 4 x108. The verum group received 1.6 x109 cells on day 1 to 3 and 4.8 x109 cells from day 4 onward. Started on the first day after birth and continued for 21 days. The study ended at the 35th day after birth or when the infant was discharged from the hospital, if earlier.
The formula-based placebo (Nestlé FM 2000B) and verum (Nestlé FM 2000A) preparations were supplied by Nestlé, Konolfingen, Switzerland
No clinical outcomes were presented in the published data
NEC and sepsis data were collected by contacting the corresponding author
The Ernst von Bergmann hospital, Potsdam, Germany
Period of study: August 2003 - June 2005
Published: 2006
Source of funding: Not reported
A prospective multicenter, double blinded, placebo controlled, randomized trial
Infants, born <32 completed weeks’ gestation and weighing <1500g, were eligible for enrolment within 72 hours of birth
Infants were excluded if they had major congenital or chromosomal anomalies, if death was considered likely within 72 hours of birth, or if the mother was taking non-dietary probiotic supplements
The intervention was the probiotic combination B. infantis, Streptococcus thermophilus and B. lactis (ABC Dophilus Probiotic Powder for Infants®, Solgar, USA) with 1 x 109 total organisms per 1.5 g, in a maltodextrin base powder.
The placebo was maltodextrin powder. The intervention was only administered when an infant was receiving at least 1mL of milk 4 hourly. The daily dose was two 1mL spoons, equivalent to 1.5g of study powder, reconstituted with 3mL breast milk or formula. When an infant received <3mL milk per feed, one 1mL spoon of powder was mixed with 1·5mL milk and given twice daily. The dose was the same irrespective of the infant’s current weight or postnatal age and was administered daily by gastric tube or mouth, until discharge from hospital or term corrected age.
All enrolled infants received breast or formula milk
The primary outcome was the incidence of at least one episode of definite late-onset sepsis before 40 weeks’ postmenstrual age or discharge home, whichever occurred first
Secondary outcomes were the incidence of definite or clinical sepsis, the composite outcome of definite or clinical late-onset sepsis, the number of courses and duration of antibiotic treatment, the incidence of definite sepsis with a probiotic species, mortality, the incidence of NEC, duration of primary hospitalization and intravenous nutrition, time to enteral feeds of 120 mL/kg/day for 3 days, breast milk feeding rates, days to regain birth weight, weight at 28 days of age and at discharge, PDA treated, IVH grade 3 or 4 or cystic PVL, ROP grade 3, oxygen treatment and/ or respiratory support
ProPrems trial was conducted in Australia (n = 8) and New Zealand (n = 2)
ACTRN12607000144415
Included data in this review are unpublished
Randomized double blind study
Method of generating randomization sequence: random number charts and the last digit of patient's chart number, the next matched infants is assigned to the opposite group
Allocation concealment: clearly inadequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes
45 infants, <2000 gm at birth weight who survived beyond first 24 hrs and are younger than 72 hrs
Demographic data:
Probiotics Group N=15, gestational age (weeks) 30.6 (2.7), birth weight 1366 (302)
Placebo Group N=15, gestational age (weeks) 30.5 (2.8), birth weight 1377 (344)
Untreated group N=15, gestational age(weeks) 30.7 (2.9), birth weight 1329 (337)
Probiotics group received at least 1 mL of formula containing lactobacillus. 5x1010 organisms/mL preparation diluted 100 times in infants formula
Placebo group received 1 mL of formula with no added lactobacillus
Both groups started within 72 hrs of birth
The untreated group received nothing per mouth for 2 weeks
All enrolled infants received formula milk
Death
Colonization rates
Hospitalization duration
Daily weight gain
Hospital acquired infection
US
Period of study: not specified in paper
Published: 1986
Source of Funding: not specified in paper
Multicenter, double blinded, randomized, placebo controlled trial
Inclusion criteria: admission to the NICU, birth weight 2000 g, hemodynamically stable, and 48 hours of age
Infants with evidence or suspicion of congenital intestinal obstruction or perforation, gastroschisis, large omphalocele, congenital diaphragmatic hernia, major congenital heart defects, or anticipated transfer to a NICU not participating in the study were excluded
Infants in the probiotic group received 5 drops of an oil-based suspension containing 108 colony-forming units of L. reuteri DSM 17938 (BioGaia AB, Stockholm, Sweden) once a day
For infants in the placebo group, an equal number of drops from an identical vial containing only the oil base were administered
Enrolled infants received any combination of maternal breast milk and/or preterm formula
The primary outcome was death or NI
Secondary outcomes included nosocomial pneumonia, NEC, feeding intolerance, and duration of hospitalization
Colombia
Prospective randomized trial
249 preterms with a birth weight <2500 g and a gestational age <37 weeks
All the infants were outborn. Inclusion criteria were admission to the NICU, a stable oral feeding within 72 h of birth and an informed parental consent; exclusion criteria were the presence of major congenital malformation or antenatal and perinatal risk factors for sepsis
The newborns were randomized into three groups:
Group I (n=83; 12 with a birth weight <1500 g, 71 1500 g) received supplementation with L. reuteri American Type Culture Collection (ATCC) 55730 5 drops daily
Group II (n=83; 28 <1500 g, 55 1500 g) received supplementation with L. rhamnosus ATCC 53103 1 capsule daily
Group III included newborns with no probiotics (control; n=83; 16 <1500 g, 67 1500 g). Patients received supplementation from the first 72 h after hospitalization for 6 weeks or until they were discharged from the NICU
All enrolled infants received breast or formula milk
The primary outcome was to evaluate the incidence of enteric fungal colonization
The secondary outcomes were days of parenteral nutrition, days of antibiotic treatment, days of hospitalization, etc
NICU of the Policlinico University of Catania, Italy
Prospective randomized trial
249 preterms with a birth weight <2500 g and a gestational age <37 weeks
All the infants were outborn. Inclusion criteria were admission to the NICU, a stable oral feeding within 72 h of birth and an informed parental consent; exclusion criteria were the presence of major congenital malformation or antenatal and perinatal risk factors for sepsis
The newborns were randomized into three groups:
Group I (n=83; 12 with a birth weight <1500 g, 71 1500 g) received supplementation with L. reuteri American Type Culture Collection (ATCC) 55730 5 drops daily
Group II (n=83; 28 <1500 g, 55 1500 g) received supplementation with L. rhamnosus ATCC 53103 1 capsule daily
Group III included newborns with no probiotics (control; n=83; 16 <1500 g, 67 1500 g). Patients received supplementation from the first 72 h after hospitalization for 6 weeks or until they were discharged from the NICU
All enrolled infants received breast or formula milk
The primary outcome was to evaluate the incidence of enteric fungal colonization
The secondary outcomes were days of parenteral nutrition, days of antibiotic treatment, days of hospitalization, etc
NICU of the Policlinico University of Catania, Italy
Two centers
Gestational age, <32 wk, a birth weight, <1500 g
Demographic data:
Probiotics Group N=45, gestational age (weeks) 28.1 (1.9), birth weight 1115 (251)
Placebo Group N=49, gestational age (weeks) 28.1 (1.8), birth weight 1057 (260)
Placebo group (N 49) receive 4 daily capsules of a supplement containing maltodextrin alone
Probiotic group (N 45) 108 lyophilized cells per unit of the probiotics L. rhamnosus GG (Valio, Ltd) and B. longum BB536 (Morinaga Milk Industry Co, Ltd, Tokyo, Japan) and maltodextrin beginning on the day when enteral feeding started until discharge
Infants were fed human (own mother’s expressed milk or bank milk) and/or preterm formula
The percentage of infants receiving more than 50% of their nutritional needs via enteral feeding on the 14th day of life
Nutrition on day 14 (more than 50% of calories received enterally and total calories delivered enterally)
Nosocomial infections
Sepsis with positive blood culture
Duration of antibiotic use
Necrotizing enterocolitis
Duration of ventilatory support
Duration of CPAP
Duration of oxygen therapy
Systemic postnatal corticoid treatment
Duration of hospital stay
Death
France
Period of study: Aprill 2005 - January 2007
Published: 2009
Source of Funding:from the Programme Hospitalier de Recherche Clinique of the French Ministry of Health and the Délégation ŕ la Recherche Clinique, CHU de Nantes
Prospective randomized double blind controlled trial
Gestational age <32 weeks and VLBW infants (<1500 g) started feed enterally and survived beyond 48 h of life
Demographic data:
Probiotics Group N=91, gestational age 30.12 (weeks) (1.63), birth weight 1172 (143)
Control Group N=95, gestational age 30.14 (weeks) (1.59), birth weight 1210 (143)
The probiotic group received a probiotic mixture (Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 billion CFU) with expressed breast milk twice daily, the dosage being 125 g kg -1 till discharge. The control group was fed with breast milk only.
Infants were fed breast milk only
Feed tolerance in terms of days required to reach full enteral feeding
Length of hospital stay
NEC
Sepsis
Death due to NEC or sepsis
Neonatal Care Unit of Medical College and Hospital, Kolkata, India
Period of study: October 2007 - March 2008
Published: 2009
Source of Funding: not specified in paper
Single center
Gestational age <33 weeks or birth weight <1500 g
Demographic data:
Probiotics Group N=110, gestational age 29.5 (weeks) (2.4), birth weight 1231 (262)
Control Group N=111, gestational age 29.7 (weeks) (2.4), birth weight 1278 (282)
VLBW infants who survived to start enteral feeding were randomized
The study group were given L. sporogenes with a dose of 350.000.000 colony forming units added to breast milk or formula once a day starting with first feed until discharge.
The control group were fed without L. sporogenes supplementation.
All enrolled infants received breast milk or mix feeding (breast milk and formula)
Death or severe NEC
NEC (stage 2, 3, 2)
Death (attributable to NEC, not attributable to NEC)
Total parental nutrition
Intraventricular hemorrhage, grade 3-4,
Sepsis (culture proven, gram negative, gram positive, fungus)
NICU stay
Feeding (amount, full feeding, intolerance)
Weight gain
Turkey
Period of study: October 2008 and June 2009
Published: Unpublished
Source of Funding: not specified in paper
Single center
Gestational age between 27 and 37 weeks, stable state, formula fed
Demographic data:
Probiotics Group N=41, gestational age 31 weeks (27–37), birth weight 1500 (900–1780)
Control Group N=34, gestational age 30.5 weeks (26–37), birth weight 1500 (700–1900)
81 infants
Group A (study group) was given a BL supplemented preterm formula – Prenan Nestlé – (BLSPF) at a concentration of 2×107 CFU/g of milk powder
Group B (control) received exactly the same formula but without the addition of BL
All enrolled infants received only formula milk
Intestinal permeability
Somatic growth
Tolerance
Sepsis
Necrotizing enterocolitis
Greece
Period of study: January 2004 - December 2005
Published: 2007
Source of Funding: not specified in paper (Nestlé Company, Vevey provide the B. lactis supplemented milk formula)
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Not mentioned
Method of generating randomization sequence: not described
Method of generating randomization sequence: Cards in sealed envelopes
Computer randomized number generator
Not described
Randomisation was simple and unadjusted and was performed using sequential numbers generated at the computer centre of the NICU
Methods not specified but stated "balanced blocks"
Methods not specified but stated "balanced blocks"
Block randomized sequence generated online.
Random number table was used
Random number table was used.
Stated randomized.
Stated randomized. No other details provided.
Not described
Stated randomized, no other information provided.
Method of generating randomization sequence: Random number table sequence
Method of generating randomization sequence: Sequential numbers generated at the computer center
Method of generating randomization sequence: computer generated randomization
Method of generating randomization sequence:using ralloc.ado version 3.2.5 in Stata 9.2 (Stata-Corp, College Station, Texas)
Computer randomization
Computer-generated, blocked randomization lists, block size of four
Stated randomized, no other information provided.
Method of generating randomization sequence: Randoma software version 4.3
Sequential numbers generated at the computer centre of the NICU by 1:1 allocation ratio
Computer generated randomization
Computer-generated randomization constructed independantly of study investigators.
(unspecified method)
Method of generating randomization sequence: random number charts and the last digit of patient's chart number, the next matched infants is assigned to the opposite group
Computer generated balanced block randomization scheme
Random number table
Random number table
Method of generating randomization sequence: In-house software (Nantes University Hospital, Nantes, France)
Random-generated (computer-generated), predetermined number table
Stated used random number table.
Method of generating randomization sequence: Sequential numbers generated at the computer center of the NICU
Computer randomized number generator
Computer generated stratified block randomisation with a permuted block size of four
Random number table
Randomization was done using an online service (www.randomization.com)
Computer-generated list by Investigational Pharmacy
Computer-generated list by Investigational Pharmacy
Randomisation was done by the assigned statistician. Random-number table.
Randomisation was done by the assigned statistician. Random-number table.
randomized no method
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Not mentioned
Blinding of randomization: not described
Allocation concealment: Possibly adequate
Multicenter trial with central randomization
Clearly adequate
The allocations were sealed in opaque, sequentially numbered envelopes
Sealed envelopes
Sealed envelopes
Containers containing full course of treatment were serially numbered. Enrolled patients received sachets from the next serially numbered container.
Not discussed
Not discussed
Not described.
Not discussed.
Not described
Not described
Allocation concealment: Clearly adequate
Allocation concealment: Adequate, envelopes (protocol)
Allocation concealment: Unclear
Allocation concealment: Yes
Pharmacy at each center used computer-generated randomization lists to form the 3 groups and prepared the drug doses.
Sealed envelopes
Not described
Allocation concealment: Not described
The allocations were contained in opaque, sequentially numbered sealed envelopes.
Opaque sealed coated envelopes.
The schedule was provided to the pharmacist at RWH who made up individual bottles for each randomized infant, coded by sequential study number
not reported
Not discussed.
Sealed, sequentially numbered, opaque envelopes, color-coded for strata, available in each NICU pharmacy
Not mentioned
Not mentioned
centralizzed randomization
Not discussed
Not discussed
Allocation concealment:sealed envelopes
Opaque sequentially numbered sealed envelopes
Allocation concealment was ensured by sequentially numbering the sachet packets containing VSL#3 or placebo after block randomisation.
Allocation concealment: Can't tell
Serially numbered opaque sealed envelopes with the allocation were available with the in-charge nurse of the NICU, who dispensed the intervention in a syringe for oral administration.
Not discussed
Not discussed
All randomization procedures were done before the study commencement by the study statistician and an independent entity for both the probiotic and placebo.
All randomization procedures were done before the study commencement by the study statistician and an independent entity for both the probiotic and placebo.
not described
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Fresh suspensions of supplements were individually prepared by study staff who were not directly involved in routine patient care
Blinding of intervention: Yes
To ensure blinding, the interventions were prepared in amber bijou bottles, replacing water with 3 mL 1/8 strength elemental infant formula
Blinding of Intervention: Yes
Supplementation did not change the physical appearance of the milk or formula
Sachets containing the probiotic, prebiotic, and synbiotic powders were similar in color, odor, and texture to the placebo. The nurses who fed the infants were blinded to the group assignments.
Sachets containing the probiotic, prebiotic, and synbiotic powders were similar in color, odor, and texture to the placebo. The nurses who fed the infants were blinded to the group assignments.
External appearance and contents of the sachets were identical looking. Provided by manufacturer.
Both intervention and control arms matched the physical appearance of milk and the bottles were labelled only with the patient’s name and identification
Stated "double-blind". Probiotic mixed with milk or formula.
Not described.
Stated double-blind. No other details provided.
Blinding of Intervention: Not described
Open-label. Blinding status unlikely to have an impact on study outcomes (stool culture).
Blinding of intervention: Yes, only investigators and breast milk team were unblinded
Blinding of intervention: Yes, breastmilk team
Blinding of intervention: probiotic added at milk bank
Blinding of intervention: Yes
All doses including placebo were diluted in prepared milk so as to maintain blinding.
The two indistinguishable powders were provided as blinded coded 10 gram sachets
Stated double-blind. Probiotic was provided in milk.
Blinding of intervention: Yes
Both probiotic and placebo doses were prepared in the pharmacy in sterile conditions, packaged in identical vials of an oil-based suspension labelled with an individual number indicating the randomisation
Identical probiotic/placebo supplied by pharmacist.
Stated in protocol used sealed opaque envelopes.
not reported
Contents of test vials were not distinguishable by colour, odour, or consistency.
Both probiotic and placebo were packaged in identical vials of an oil-based suspension
Unblinded
Unblinded - some outcomes unlikely to be affected by blinding status.
Blinding of intervention: Yes placebo prepared centrally
All doctors, nurses, and parents are blind to the randomized allocation.
Intervention and control products were identical in appearance. Probiotic mixed with expressed breast milk.
Blinding of intervention:
No change in appearance
A similar-looking maltodextrin preparation in the same outer packing was administered to the control group.
Blinding of intervention: Yes - mixed in formula
Both the probiotic and the placebo were dispensed in 2ml syringes and were identical in appearance.
The 3 products were similar in appearance and had no discernible scent.
The 3 products were similar in appearance and had no discernible scent.
No differences in the colour and appearance of the probiotic and placebo were noted.
No differences in the colour and appearance of the probiotic and placebo were noted.
not reported
Detection bias due to knowledge of the allocated interventions by outcome assessors
Attending physicians and nurses caring for the infants were blinded to the group assignments.
Blinding of outcome measurement: Not described
Parents, clinicians, and outcomes assessors were masked to the treatment allocation
Blinding of outcome measurement: Yes
The supplements were prepared by personnel on the breast milk team following the instructions in the sealed envelope. These individuals were the only personnel who were aware of the group assignments, and they were not involved in the care of the infants
Investigators had knowledge of treatment assignment. Unclear if blinded outcome assessors were used.
Investigators had knowledge of treatment assignment. Unclear if blinded outcome assessors were used.
Parents, nursing, medical, research, and laboratory personnel were masked.
Attending physicians and nurses caring for the infants were blinded to the group assignments.
Stated "double-blind". Probiotic mixed with milk or formula.
Not described.
Stated double-blind. No other details provided.
Blinding of outcome measurement: Not described
Open-label. Blinding status unlikely to have an impact on study outcomes (stool culture).
Blinding of outcome measurement: Yes
Blinding of outcome measurement: Yes, indenpendent physicians
Blinding of outcome measurement: independent assessors
Blinding of outcome measurement: Yes
Clinical and research staff remained unaware of study group assignments during the study.
Blinding status unlikely to have an impact on study outcomes (sepsis rate).
Every infant was examined daily by a physician who was actively involved in the care of the infants on the neonatal unit but who was not aware of the study randomisation schedule.
Blinding of outcome measurement: not described
Whenever an infant was suspected to have NEC, the infant was evaluated by two senior-attending neonatologists who did not know the group assignment of the infant.
Masking of investigators and outcome assessors.
States in protocol "All doctors (who assess the outcomes) will be masked to the randomisation allocation.
not reported
All neonatal intensive care unit staff caring for infants and microbiology staff assaying stool samples were blinded to the patients’ treatment throughout the study.
Stated double-blind (Subject, Caregiver, Investigator).
Unblinded - some outcomes unlikely to be affected by blinding status.
Unblinded - some outcomes unlikely to be affected by blinding status.
Not discussed
All laboratory staff are blind to the randomized allocation.
Intervention and control products were identical in appearance. No other details provided. Some outcomes could be influenced by blinding status.
Blinding of outcome measurement: Yes
Investigator and breast milk teams were not involved in care of the infant.
Parents of enrolled infants, investigators and fieldworkers were masked to treatment allocation. Data analysis was performed in a blinded manner.
Blinding of outcome measurement: Yes
All the investigators were blinded to the intervention.
Product was prepared in Pharmacy. The parents, nurses, dietitians, and physicians were not informed of group assignment.
Product was prepared in Pharmacy. The parents, nurses, dietitians, and physicians were not informed of group assignment.
The attending physician and nurses caring for the infants were blinded to the group assignment. The investigator, research assistants and study participants were also blinded to the group assignment.
The attending physician and nurses caring for the infants were blinded to the group assignment. The investigator, research assistants and study participants were also blinded to the group assignment.
not reported
Attrition bias due to amount, nature or handling of incomplete outcome data
Three infants who never began the protocol were excluded from the final analysis. Unclear if these infants were randomized. Otherwise, an ITT method was employed.
Complete follow-up: Yes
Figure 1 was included. No patients lost to follow-up. Small number of patients not analyzed due to withdrawal of parental consent.
Complete Follow-up: Yes
Figure 1 was included. No patients were lost to follow-up.
All analyses used an intention-to-treat approach. No infants were lost to follow-up.
All analyses used an intention-to-treat approach. No infants were lost to follow-up.
No prespecified protocol was found. There was significant loss to follow-up but ITT was used.
Figure 1 was included. No patients were excluded after randomization.
No patients lost to follow-up.
All patients described were reported.
Figure 1 was included. No patients appear to have been lost to follow-up.
Complete Follow-up: No (6 patients dropped)
Complete follow-up: Unclear, did not report total patients, but no evidence of loss of patients
Completeness of follow up: Yes
Completeness of follow-up: Yes
Completeness of follow up: all patients accounted
Completeness of follow-up: Yes
ITT patient population was used. No patients lost to follow-up.
Figure 1 was included. Only nosocomial infections at least 7 days after initiation of B. lactis therapy were analyzed for study purposes
No figure 1 provided. Data was presented for all infants who were randomized.
Complete follow-up: Yes
Only the cases of NEC or deaths occurring after 7 days were analyzed.
Flow diagram provided. Missing patinets were accounted for.
No patients lost to follow-up. All patients evaluated in the groups to which they were randomized.
No Figure 1 provided. All infants stated to be randomized were analyzed.
No Figure 1 was provided. One eligible infant was randomly assigned before parental consent and was removed from the study after the parents refused consent. No indication of whether this infant was included in the analysis. No patients appear to have been lost to follow-up.
No flow diagram but no patients lost to follow-up.
No flow diagram but no patients lost to follow-up.
Complete follow-up: Yes al patietns reported
No patients lost to follow-up. Only the cases of NEC or deaths occurring after 7 days were analyzed.
No Figure 1 provided. All infants stated to be randomized were analyzed.
Complete follow-up: flow diagram
Flow diagram provided by author.
A protocol was found in the Indian clinical trials registry: http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=90&EncHid=&userName=probiotics. There was some loss to follow-up but an ITT analysis was employed,
5 patients were excluded after randomization due to relevant outcome events (NEC, infection
No prespecified protocol was found.
Figure 1 was included. No patients excluded after randomization. ITT method was employed.
Figure 1 was included. No patients excluded after randomization. ITT method was employed.
Figure 1 provided by author. No patients lost to follow-up.
Figure 1 provided by author. No patients lost to follow-up.
all patients accounted
Reporting bias due to selective outcome reporting
No prespecified protocol was found. All clinically important outcomes are described
Not all prespecified secondary outcomes were reported as stated based on protocol.
No prespecified protocol was identified.
Protocol was registered on EudraCT and ISRCTN. Prespecified protocol was found
Registered at clinicaltrials.gov (Identifier: NCT01315821). Deaths occurring within 7 days of S. boulardii supplementation were excluded after randomisation
Protocol was registered with clinicaltrials.gov
Protocol was registered with clinicaltrials.gov
All stated and expected outcomes were reported.
No prespecified protocol was found.
No prespecified protocol was found.
No prespecified protocol was found.
No prespecified protocol was found.
Important patient oriented outcomes are not included
No prespecified protocol was found. Incidence of NEC was measured but not published.
no protocol, but all outcomes considered
Non-NEC mortality was defined but not reported.
No prespecified protocol was found.
No prespecified protocol was found.
no protocol, unpublished data used in review
Protocol (clinicaltrials.gov) lists weight gain as a secondary outcome but was not reported in the publication
Registered protocol was identified.
Registered protocol was found. All a priori defined outcomes were reported.
no protocol found
No prespecified protocol was found. Since no significant differences were found on analysis of the data for the first 10 patients, it was decided to collect data on 5 more patients per group before renalyzing the data.
Registered at clinicaltrials.gov (Identifier: NCT00727363). All a priori defined outcomes were reported.
No registered protocol was found.
No registered protocol was found.
registered protocol
No protocol found. Listed trial registry number does not match this trial.
No prespecified protocol was found.
did not include patients after randomization
A registered protocol was identified.
All prespecified outcomes were reported.
No prespecified protocol was found.
All stated and expected outcomes were reported.
Protocol was registered on Clinicaltrials.gov (NCT00282113). All a priori defined outcomes were reported.
Protocol was registered on Clinicaltrials.gov (NCT00282113). All a priori defined outcomes were reported.
Protocol provided by author. All a priori defined outcomes were reported.
Protocol provided by author. All a priori defined outcomes were reported.
no protocol
Bias due to problems not covered elsewhere in the table
Supported by Mr. and Mrs. Stephen Hammerman and the Mirsky Research Fund #18003697. Investigational product supplied by manufacturer.
The interventions for this trial were provided without charge by Yakult Honsha Co Ltd (Tokyo, Japan), until the point of entry to the UK. The manufacturer had no role in the design of the trial, the analysis and interpretation of the results, or preparation of this report.
No funding source was stated. Authors declared no conflict of interest.
Authors declared there were no conflicts of interest. No authors from the company.
Authors declared there were no conflicts of interest. No authors from the company.
Investigational product was provided free of charge by Aristo Pharmaceuticals. Authors made no declaration.
No funding source was stated. Authors declared no conflict of interest.
No COI statement made. Author affiliation was listed as West China Second University Hospital.
Funding source was not specified. No declaration of COI was made.
conflicts not declared, funding not described, no company authors
Morinaga Milk Industry and Meiji Dairies Corporation provided financial support. COI was not declared.
not stated funding, no empoyess, no comnflicts
Drug supplied by manufacturer. COI statement was made. Study continued (from Manzoni 2009) without sufficient justification for the terms of continuation.
The study was supported by Nestlé AG, manufacturer of milk fortifier used for blinding. No COI was declared.
Not funded by manufacturer. Source of probiotic is unclear. No COI was declared.
no conflicts declared, provided by Nestle, some authors
Funding source not stated. No authors from the company. Declared no competing interests. Study was not commissioned.
COI statement included. Funding source was declared. Probiotic product specified in protocol was not used in the final publication.
The authors have indicated they have no potential conflicts of interest to disclose
No funding source was specified. No declaration of COI was made.
Funding source was not provided. COI was not declared.
No funding from manufacturer. Dr Rojas has acted as a consultant for BioGaia without honorarium. The other authors have indicated they have no financial relationships relevant to this article to disclose.
No funding source stated. No company authors. COI statement was included.
No funding source stated. No company authors. COI statement was included.
funding from ministries, authors employed ?,
Funding source was not stated. Declared no competing interests.
Funding source not atated. No author affiliation to manufacturer. COI was not declared.
no protocol, no funding source reported
No authors from the company. Drug supplied by monufacturer.
Funding source played no role in the study design, data collection, analysis and interpretation, writing of the report or decision to submit it for publication.
Unknown funding source. No authors from company.
No COI statement was made. No mention of funding source.
Trial was supported by grants. The authors report no conflicts of interest.
Trial was supported by grants. The authors report no conflicts of interest.
Funding for this study was received from various sources, the main sources being the National Research Foundation, Nestlé Nutrition Institute Africa, the Medical Research Council and the Faculty of Medicine and Health Sciences, Stellenbosch University.
Funding for this study was received from various sources, the main sources being the National Research Foundation, Nestlé Nutrition Institute Africa, the Medical Research Council and the Faculty of Medicine and Health Sciences, Stellenbosch University.
not discussed funding, not conflicts discussed,