Abrahamsson T, 2007 Sweden
Prevention of atopic eczema in infants 0-2 years old.
R, DB, PC 12 months
L. reuteri: 95 (1×108 CFU) Placebo: 93
No clinical tolerance problems during the 12 months supple mentation or at follow-up at 2 years of age
Abrahamsson TR, 2013 (Substudy of Abrahamsson 2007) Sweden
In a study on prevention of al lergy in newborns, L. reuteri ATCC 55730 reduced the incidence of IgE-associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhino con junctivitis in school age, which this follow-up study set out to investigate. It also evaluated whether this supplementation was associated with any long term side effects. The age at follow-up was 7y.
Original study: R, DB, PC
L. reuteri: 94 (1×108 CFU) Placebo: 90 In the 2007 trial 232 in fants were randomised and 188 completed
• Growth indices and gastrointestinal symptoms were similar in the two groups
• No severe adverse events were reported
Connolly E, 2005
Sweden
To investigate if levels of D(-) lactic acid levels in the blood is a safety issue in infants who get L. reuteri ATCC 55730 as a long term daily supplement from birth.
R, DB, PC 12 months
L. reuteri: 14 (1×108 CFU) Placebo: 10
• All infants had very low levels of D(-)-lactic acid (20-130µM) as measured after 6 and 12 months, i.e. far below levels as sociated with D(-)-lactic acidosis
• This D(-)-lactic acid producing probiotic can be safely given to infants
Kosek MN, 2019
Peru
A phase I study to assess the safety and tolerability of L. reu teri DSM 17938 in oil suspension in healthy children, 2-5y old, before doing a phase II/III treatment-of diarrhoea study in children.
R, DB, PC 5 days follow-up until day 28, and at 6 mo post enrollment
L. reuteri: 41 (1×108 CFU) Placebo: 19
Results support no reason for safety concern of use of L. reuteri. No difference in markers for iron status, liver, kidney and immune functions. Same incidence of fever and diarrhoeal episodes, but days with diarrhoea, rash or pruritus were fewer in Lr group, based on parental reporting for 28 days. No difference in rates of adverse events between groups, all evaluated as non-related to study products. No serious adverse events.
Gutiérrez Castrellón P, 2014
Mexico
Evaluate if daily administration of L. reuteri DSM 17938 reduces the frequency and duration of diarr hoea episodes and respiratory tract infections in Mexican day school children aged 6-36 months. A cost-effectiveness analysis was also made.
R, DB, PC 3 months of intervention, follow-up at 6 months
L. reuteri: 168 (1×108 CFU) Placebo: 168
During the study, parents/guardians reported 34 cases of exanthematous disease (18 cases of rubella and 16 cases of exanthema subitum) and 22 cases of minor trauma. None of these adverse events were deemed to be related to the study products, and no related serious adverse events were reported in any group.
Indrio F, 2014 Italy
Investigate if oral supplemen tation with L. reuteri DSM 17938 during the first 3 months of life can reduce the onset of colic, gastroesophageal reflux, and constipation in term newborns, and in addition reduce the socio-economic impact of these conditions
R, DB, PC 90 days
Multicentre study
L. reuteri: 238 (1×108 CFU) Placebo: 230
Adverse events were monitored by weekly telephone calls that also monitored compliance to study products. No adverse events were reported that were related to the trial.
Savino F, 2010
Italy
To study the effect of L. reuteri DSM 17938 on infant colic in infants 2-16 weeks old, and investigate changes in the faecal microbiota.
R, DB, PC 21 days
L. reuteri: 25 (1×108 CFU) Placebo: 21
• Infants in both groups increased their growth parameters significantly during the 3-week study, with no statistical differences between groups.
• The study products were well tolerated. 5 adverse events were reported, whereof one in the probiotic group. All were evaluated as unrelated to the study product.
Fatheree NY, 2017
USA
A phase 1 study that investigated the safety and tolerability of L. reuteri DSM 17938 in healthy breastfed infants with colic, aged 3 weeks to 3 months. Secondary outcomes were ef fect on crying and fussing time, inflammatory biomarkers and microbiota composition.
R, DB, PC 42 days + 134 days follow-up
L. reuteri: 12 (1×108 CFU) Placebo: 7
NOTE: The dose was 5 drops, equivalent to 1×108 CFU, not 5×108 CFU, as stated in the article.
Adverse events were monitored strictly based on the FDA Adverse Events Response System and clinical severity index.
• No severe adverse events were reported
• ÅNo significant differences between L. reuteri and placebo in any of the outcomes
Urbanska M, 2016
Poland
The efficacy of L. reuteri DSM 17938 in prevention of nosoco mial diarrhoea in hospitalized children, 1-48 months old. A repeat of Wanke’s trial but with a 10 times higher dose.
R, DB, PC During hospi tal stay
L. reuteri: 91 (1×109 CFU) Placebo: 93
L. reuteri did not affect the incidence of hospital-acquired diarrhoeal disease.
There was also no difference between the L. reuteri and pla cebo groups for any of the secondary outcomes, including adverse effects. Rotavirus vaccination status had no impact on the results.
Handschur M, 2007
South Africa
To test identification methods for detection and persistence of L. reuteri ATCC 55730 in the feces of 4-12 months old infants hospi talized for diarrhoea.
Open, PC 3 days
L. reuteri: 4, whereof 2 HIV-pos. (1×1010 CFU) Placebo: 3, whereof 1 HIV-pos.
L. reuteri was detected in feces after 3 days of supplemen tation to infants with diarrhoea and treated with antibiotics. There was no report of any adverse events.
Hoy-Schulz YE, 2016
Bangladesh
A phase I study that investigated the safety and acceptability of two probiotics: drops with L. reu teri DSM 17938 (Lr) and powder with B. longum ssp infantis 35624 (Bi), in healthy infants aged 4 to 12 weeks, from urban slums in Bangladesh. Gastrointestinal and respiratory symptoms as well as breastfeeding rates, hospitalizations, differential withdrawals, and caretakers’ perception of probiotic use were compared among arms. Primary outcome was proportion of days with symptoms.
R, DB, control led 1 month’s invention + follow-up after 2 additional months. Randomized to 1 of 3 different dosing arms (daily, weekly, biweekly – once every two weeks) over one month, or to a 4th arm that received no probiotics.
Lr+Bi daily: 35 (29 doses) Lr+Bi weekly: 35 (5 doses) Lr+Bi biweekly: 35 (3 doses) Control: 32 (Lr: 1×108 CFU + Bi: 1×109 CFU)
The ingestion of the combination of these two probiotics was found safe, also if given daily: they did not cause sudden reactions, increase symptom rates, or diminish breastfeeding rates. They were acceptable to the infants and no problems administering the probiotics were identified. No differences in rates of any reported symptoms were observed among arms; additionally, no sudden adverse or allergic reactions were found after probiotic administration, and no hospitali zations were deemed related to the study products.
Karvonen A, 2001 (abstract) Finland
Safety and colonisation in newborn term infants of L. reuteri ATCC 55730
R, DB, PC 30 days
L. reuteri 12 (1×105 CFU) L. reuteri: 25 (1×107 CFU) L. reuteri: 25 (1×109 CFU) Placebo: 28
• No clinical tolerance problems
• Reduction in frequency of watery stools compared to placebo
Weizman Z, 2006
Israel
Safety of L. reuteri ATCC 55730 in healthy infants 3-65 days old.
R, DB, PC 4 weeks
L. reuteri: 20 (1.2×109 CFU) Bb-12: 20 (1.2×109 CFU) Control: 19
Infant formulas with added probiotics were safe, well tolerated and did not negatively affect growth, defecation habits or infant behaviour.
Papagaroufalis K, 2014
Greece
To assess the safety of starter infant formula containing L. reuteri DSM 17938 during the first month of life, with special reference to D-lactic acid, in comparison to infants fed a control starter formula. Other out comes were GI tolerance, sleeping and crying behaviour, growth and occurrence of adverse events.
R, DB, controlled 28 days
Follow-up on days 112 and 168
L. reuteri: 36 (6.6 x 108 CFU) Control: 35
31 infants in each group took part in the follow-up on days 112 and 168
• Median urinary D-lactate levels were higher in the L. reuteri group than in the control group at 7 and 14 days, but lower at 28 days. Results were consistent with normal ranges of D lactate previously reported for healthy infants, and far below pathological ranges described in adults.
• The occurrence of serious and non-serious AEs was com parable between the two groups. Non-serious AEs were reported in 20% of infants in the probiotics group and 23% of infants in the control group. In both groups, most of these (5 in the probiotics group and 6 in the control group) were respiratory system disorders. None was related to the study products.
• In all, 5% of infants in each group had a serious AE during the study
• Growth was normal, without differences between groups
• There were no differences in the duration of crying or night time sleep
Cekola PL, 2015
USA
To assess the safety of a partially hydrolysed infant formula with added L. reuteri DSM 17938 (Lr) in comparison to a similar product without any probiotic (Con), in healthy full-term neonates, with growth as primary outcome. The formulas differed only with regard to the proportion of carbohydrate sources: lactose:maltodextrin ratio was 70:30 in Con + added prebiotic (GOS), while the ratio was 30:70 and no GOS in the Lr formula.
R, DB, controlled
Infants ingested the formula from day 14 after birth to day 112=14 weeks
L. reuteri 60 (1×108 CFU) Placebo: 62
Infants assigned to either formula had normal and similar rates and patterns of growth. Overall, between groups, there were no significant differences in formula intake, stool fre quency, colour, consistency, flatulence, frequency of spit-up/ vomiting, mood, sleep, or incidence of adverse events (AEs). In both groups a few of the AEs were evaluated as having ‘probable’ relationship to study product.
Lee LY, 2015
Singapore
To establish safety in healthy, full term infants of starter infant formula containing L. reuteri DSM 17938, and L. reuteri same strain) plus prebiotics FOS/GOS, respectively, assessed against WHO Growth Standards (CGS). GI tolerance and urinary L- and D-lactate were also investigated.
R, DB, controlled 6 months
Follow-up at 2 and 4 mo
L. reuteri : 68 L. reuteri + FOS/ GOS: 72 (1×108 CFU)
• Both groups gained weight in accordance with WHO CGS. Other growth parameters were similar between the two groups.
• Excretion of urinary L- and D-lactate were similar in the groups
• GI tolerance and morbidity were similar in the two groups