Background
Outcome | RRa(95% CI) |
Pvalue | NNTb(95% CIc) |
---|---|---|---|
NEC | 0.35 (0.23 to 0.55) | 0.00001 | 25 (17 to 34) |
Mortality | 0.42 (0.29 to 0.62) | 0.00001 | 20 (14 to 34) |
Sepsis | 0.98 (0.81 to 1.18) | 0.80 | N/A
d
|
Methods
Results
Selection of strains
Study | Probiotic agent/s | Dose and duration |
---|---|---|
Kitajima 1997 [52] |
Bifidobacterium breve
| 0.5 × 109 cfua once daily from first feed for 28 days. |
Dani 2002 [53] |
Lactobacillus rhamnosus GG | 6 × 109 cfu once daily from first feed until discharge |
Costalos 2003 [54] |
Saccharomyces boulardii
| 109/kg twice daily from first feed for 30 days |
Bin Nun 2005 [55] |
Bifidobacterium infantis, Streptococcus thermophilus, Bifidobacterium bifidus
| 0.35 × 109 cfu B. infantis, 0.35 × 109 cfu S. thermophilus and 0.35 × 109 cfu B. bifidus once daily from first feed to 36 weeks corrected age |
Lin 2005 [56] |
Lactobacillus acidophilus, B. infantis
| 1004356 L. acidophilus and 1015697 B. infantis organisms twice daily from day 7 until discharge |
Manzoni 2006 [57] |
Lactobacillus casei
| 6 × 109 cfu once daily from 3 days to 6 weeks of age, or discharge from NICUb
|
Mohan 2006 [28] |
Bifidobacterium lactis
| 1.6 × 109 cfu once daily from day 1 to day 3; 4.8 × 109 cfu once daily from day 4 to day 21 |
Stratiki 2007 [59] |
B. lactis
| Preterm formula: 1 × 107 cfu/g started within 48 hours to 30 days |
Lin 2008[60] |
B. bifidus, L. acidophilus
| 2 × 109 cfu daily for 6 weeks |
Samanta 2009[61] |
B. bifidus, B. lactis, B. infantis, L.s acidophilus
| 2.5 × 109 cfu daily until discharge |
Rouge 2009 [62] |
Bifidobacterium longum, Lactobacillus GG | 1 × 108 cfu daily until discharge |
Dose
When to start?
When to stop?
Supplementation in the presence of potentially compromised gut integrity
Clinical monitoring during supplementation
Ongoing laboratory surveillance for safety
Practical issues
Role of prebiotics in probiotic products
Regulatory issues
Other potentially useful strategies
Data monitoring
Information for parents
Role of placebo-controlled trials
Advancing knowledge by further research while not denying probiotics to preterm neonates
Accessing probiotic products for research versus routine use
Conclusion
Specific recommendations | LOEa[reference] | |
---|---|---|
Selection of strains | Combination containing Lactobacillus and at least one Bifidobacterium species is preferable. Lactobacillus GG alone may not be effective | |
Dose | 3 × 109 organisms per day, preferably in a single dose | |
When to start? | When the neonate is ready for enteral feeds, preferably within first 7 days of life | |
How long to continue? | At least until 35 weeks corrected age, or discharge | |
Supplementation during acute illness | Stopping the supplementation during an acute illness such as sepsis, NEC
b
or perinatal asphyxia may be safe |
Guidelines | References |
---|---|
1. Starting dose for ELBW
b
neonates: 1.5 × 109 cfu/day
c
until reaching 50-60 ml/kg/day feeds | [84] and authors' opinion |
2. Osmotic load: solution should be diluted to keep the osmolality below 600 mOsm/L | |
3. Diluent: sterile water or breast milk | Authors' opinion |
4. Volume for administration: 1 to 1.5 ml per dose | [86] and authors' opinion |
5. Clinical monitoring: patients should be monitored for intolerance (abdominal distension, diarrhea, vomiting), probiotic sepsis, and adverse effects (flatulence, loose stools) of additives such as prebiotic oligosaccharides. | |
6. Ongoing laboratory surveillance: Expertise in taxonomy confirmation (16S rRNA sequencing and PFGE
d
), ruling out contaminants, recovering probiotic strains at low inoculums from sterile sites, familiarity with the Gram stain and phenotypic appearance of probiotics, and monitoring for antibiotic susceptibility/resistance and cross-contamination are crucial. | [107] |
7. Cold chain: maintenance of cold chain should be checked. Refrigerate at 4 to 10°C | Manufacturer recommendation |
8. Product stability: stability should be checked by regular microbiological tests | |
9. Leftover solution should be discarded after giving small doses as it may get contaminated | Manufacturer recommendation |
10. Regulatory issues: importing may be easier for research than for clinical use. National regulations on drugs and food supplements and customs quarantine guidelines should be checked | |
11. Data monitoring: high-quality data monitoring and collaboration between regional neonatal networks is crucial for monitoring outcomes at a population level | |
12. Information for parents: parents should be kept well informed about benefits and adverse effects, including the possibility of cross-contamination | |
13. Other potentially useful strategies: early preferential use of breast milk, strategies for prevention of sepsis, standardised feeding protocols, avoidance of undue prolonged exposure to antibiotic |