Hypoallergenic formula with Lactobacillus rhamnosus GG for babies with colic: A pilot study of recruitment, retention, and fecal biomarkers.
ABSTRACT: AIM:To investigate recruitment, retention, and estimates for effects of formula supplementation with Lactobacillus rhamnosus GG (LGG) on inflammatory biomarkers and fecal microbial community in infants with colic. METHODS:A prospective, double-blind, placebo-controlled trial was conducted in otherwise healthy infants with colic. We screened 74 infants and randomized and analyzed results in 20 infants [9 receiving LGG (LGG+) and 11 not receiving LGG (LGG-)]. LGG was incorporated in the formula (Nutramigen(®)) (minimum of 3 × 10(7) CFU/d) in the LGG+ group. Fecal microbiota and inflammatory biomarkers, including fecal calprotectin (FC), plasma cytokines, circulating regulatory T cells (Tregs), and crying + fussing time were analyzed to determine optimal time points and effect sizes for a larger trial. RESULTS:Recruitment in this population was slow, with about 66% of eligible infants willing to enroll; subject retention was better (75%). These rates were influenced by parents' reluctance to volunteer their infant for a clinical trial and by their tendency to change formulas. The maximal difference of crying + fussing time was observed at day 14, comparing the 2 groups, with a mean difference of -91 (95%CI: -76, 259) min (P = NS). FC showed no significant difference, but the optimal time to determine a potential effect was at day 90 [with a mean difference of 121 (95%CI: -48, 291) ?g/g stool], observing a lower level of FC in the LGG+ group. The fecal microbial communities were chaotic, as determined by Shannon's diversity index and not apparently influenced by the probiotic. No significant change was observed in plasma inflammatory cytokines or Tregs, comparing LGG+ to LGG- groups. CONCLUSION:Designing future colic trials involving a probiotic-supplemented formula for infants in the United States will require consideration for difficult enrollment. Infants with colic have major variations in feal microbiota and calprotectin, both of which improve with time, with optimal time points for measurement at days 14 and 90 after treatment.
Project description:<h4>Objective</h4>To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community based sample of breastfed infants and formula fed infants with colic aged less than 3 months.<h4>Design</h4>Double blind, placebo controlled randomised trial.<h4>Setting</h4>Community based sample (primary and secondary level care centres) in Melbourne, Australia.<h4>Participants</h4>167 breastfed infants or formula fed infants aged less than 3 months meeting Wessel's criteria for crying or fussing: 85 were randomised to receive probiotic and 82 to receive placebo.<h4>Interventions</h4>Oral daily L reuteri (1 × 10(8) colony forming units) versus placebo for one month.<h4>Main outcomes measures</h4>The primary outcome was daily duration of cry or fuss at 1 month. Secondary outcomes were duration of cry or fuss; number of cry or fuss episodes; sleep duration of infant at 7, 14, and 21 days, and 1 and 6 months; maternal mental health (Edinburgh postnatal depression subscale); family functioning (paediatric quality of life inventory), parent quality adjusted life years (assessment of quality of life) at 1 and 6 months; infant functioning (paediatric quality of life inventory) at 6 months; infant faecal microbiota (microbial diversity, colonisation with Escherichia coli), and calprotectin levels at 1 month. In intention to treat analyses the two groups were compared using regression models adjusted for potential confounders.<h4>Results</h4>Of 167 infants randomised from August 2011 to August 2012, 127 (76%) were retained to primary outcome; of these, a subset was analysed for faecal microbial diversity, E coli colonisation, and calprotectin levels. Adherence was high. Mean daily cry or fuss time fell steadily in both groups. At 1 month, the probiotic group cried or fussed 49 minutes more than the placebo group (95% confidence interval 8 to 90 minutes, P=0.02); this mainly reflected more fussing, especially for formula fed infants. The groups were similar on all secondary outcomes. No study related adverse events occurred.<h4>Conclusions</h4>L reuteri DSM 17938 did not benefit a community sample of breastfed infants and formula fed infants with colic. These findings differ from previous smaller trials of selected populations and do not support a general recommendation for the use of probiotics to treat colic in infants.<h4>Trial registration</h4>Current Controlled Trials ISRCTN95287767.
Project description:OBJECTIVE:To assess the safety of probiotic Lactobacillus reuteri strain Deutsche Sammlung von Mikroorganismen (DSM) 17938 with daily administration to healthy infants with colic and to determine the effect of L reuteri strain DSM 17938 on crying, fussing, inflammatory, immune, and microbiome variables. STUDY DESIGN:We performed a controlled, double-blinded, phase 1 safety and tolerability trial in healthy breast-fed infants with colic, aged 3 weeks to 3 months, randomly assigned to L reuteri strain DSM 17938 (5?×?108 colony-forming units daily) or placebo for 42 days and followed for 134 days. RESULTS:Of 117 screened infants, 20 were randomized to L reuteri strain DSM 17938 or placebo (sunflower oil) (in a 2:1 ratio) with 80% retention. Eleven of the 20 (55%) presented with low absolute neutrophil counts (<1500/mm3), which resolved in all subjects by day 176. L reuteri strain DSM 17938 produced no severe adverse events and did not significantly change crying time, plasma bicarbonate, or inflammatory biomarkers. Fecal calprotectin decreased rapidly in both groups. In the infants with dominant fecal gram negatives (Klebsiella, Proteus, and Veillonella), resolution of colic was associated with marked decreases in these organisms. CONCLUSIONS:Daily administration of L reuteri strain DSM 17938 appears to be safe in newborn infants with colic, including those with neutropenia, which frequently coexists. A placebo response of 66% suggests that many infants with colic will have resolution within 3 weeks. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01849991.
Project description:Evidence for treating infantile colic with acupuncture is contradictory.To evaluate and compare the effect of two types of acupuncture versus no acupuncture in infants with colic in public child health centres (CHCs).A multicentre, randomised controlled, single-blind, three-armed trial (ACU-COL) comparing two styles of acupuncture with no acupuncture, as an adjunct to standard care, was conducted. Among 426 infants whose parents sought help for colic and registered their child's fussing/crying in a diary, 157 fulfilled the criteria for colic and 147 started the intervention. All infants received usual care plus four extra visits to CHCs with advice/support (twice a week for 2?weeks), comprising gold standard care. The infants were randomly allocated to three groups: (A) standardised minimal acupuncture at LI4; (B) semi-standardised individual acupuncture inspired by Traditional Chinese Medicine; and (C) no acupuncture. The CHC nurses and parents were blinded. Acupuncture was given by nurses with extensive experience of acupuncture.The effect of the two types of acupuncture was similar and both were superior to gold standard care alone. Relative to baseline, there was a greater relative reduction in time spent crying and colicky crying by the second intervention week (p=0.050) and follow-up period (p=0.031), respectively, in infants receiving either type of acupuncture. More infants receiving acupuncture cried <3?hours/day, and thereby no longer fulfilled criteria for colic, in the first (p=0.040) and second (p=0.006) intervention weeks. No serious adverse events were reported.Acupuncture appears to reduce crying in infants with colic safely.NCT01761331; Results.
Project description:BACKGROUND:The pathogenesis of infant colic is poorly defined. Gut microbiota seems to be involved, supporting the potential therapeutic role of probiotics. AIMS:To assess the rate of infants with a reduction of ?50% of mean daily crying duration after 28 days of intervention with the probiotic Bifidobacterium animalis subsp. lactis BB-12® (BB-12). Secondary outcomes were daily number of crying episodes, sleeping time, number of bowel movements and stool consistency. METHODS:Randomized controlled trial (RCT) on otherwise healthy exclusively breastfed infants with infant colic randomly allocated to receive BB-12 (1 × 109 CFU/day) or placebo for 28 days. Gut microbiota structure and butyrate, beta-defensin-2 (HBD-2), cathelicidin (LL-37), secretory IgA (sIgA) and faecal calprotectin levels were assessed. RESULTS:Eighty infants were randomised, 40/group. The rate of infants with reduction of ?50% of mean daily crying duration was higher in infants treated with BB-12, starting from the end of 2nd week. No infant relapsed when treatment was stopped. The mean number of crying episodes decreased in both groups, but with a higher effect in BB-12 group (-4.7 ± 3.4 vs -2.3 ± 2.2, P < 0.05). Mean daily stool frequency decreased in both groups but the effect was significantly higher in the BB-12 group; stool consistency was similar between the two groups. An increase in Bifidobacterium abundance (with significant correlation with crying time reduction), butyrate and HBD-2, LL-37, sIgA levels associated with a decrease in faecal calprotectin level were observed in the BB-12 group. CONCLUSIONS:Supplementation with BB-12 is effective in managing infant colic. The effect could derive from immune and non-immune mechanisms associated with a modulation of gut microbiota structure and function.
Project description:A limited number of nondigestible oligosaccharides are available for use in infant formula. This study evaluated growth and safety in infants fed formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS). This mixture, which was generated from whey permeate, contains galactooligosaccharides and other oligosaccharides from bovine milk, such as 3'- and 6'-sialyllactose. We hypothesized that growth in infants fed BMOS-supplemented formula would be noninferior to that in infants fed standard formula.Healthy term infants ?14 days old were randomly assigned to standard formula (control; n?=?84); standard formula with BMOS (IF-BMOS; n?=?99); or standard formula with BMOS and probiotics (Bifidobacterium longum, Lactobacillus rhamnosus) (IF-BMOS?+?Pro; n?=?98). A breastfed reference group was also enrolled (n?=?30). The primary outcome was mean weight gain/day from enrollment to age 4 months (noninferiority margin: -3.0 g/day).189 (67.3%) formula-fed infants were included in the primary analysis. Mean differences in weight gain between the control and IF-BMOS and IF-BMOS?+?Pro groups were <1 g/day, with 97.5% confidence intervals above -3.0 g/day, indicating noninferior weight gain in the BMOS formula groups. Compared with control, infants in the BMOS groups had more frequent (p?<?0.0001) and less hard (p?=?0.0003) stools. No significant differences were observed between the control and BMOS groups in caregivers' reports of flatulence, vomiting, spitting up, crying, fussing, and colic. When based on clinical evaluation by the investigator, the incidence of colic was higher (p?=?0.01) in IF-BMOS than in control; the incidence of investigator-diagnosed colic was not significantly different in control and IF-BMOS?+?Pro (p?=?0.15). Stool bifidobacteria and lactobacilli counts were higher with IF-BMOS?+?Pro compared with control (p?<?0.05), whereas Clostridia counts were lower (p?<?0.05) in both BMOS groups compared with control.Infant formula containing BMOS either with or without probiotics provides adequate nutrition for normal growth in healthy term infants. Further studies are needed to fully explore the digestive tolerance of BMOS formula.ClinicalTrials.gov NCT01886898 . Registered 24 June 2013.
Project description:<h4>Background</h4>Few studies have evaluated nutritive effects of prebiotics on infant behavior state, physiology, or metabolic status.<h4>Methods</h4>In this double-blind randomized study, infants (n = 161) received cow's milk-based infant formula (Control) or similar formula with an added prebiotic blend (polydextrose and galactooligosaccharides [PDX/GOS]) from 14-35 to 112 days of age. Infant wake behavior (crying/fussing, awake/content) and 24-h sleep-wake actograms were analyzed (Baseline, Days 70 and 112). Salivary cortisol was immunoassayed (Days 70 and 112). In a subset, exploratory stool 16S ribosomal RNA-sequencing was analyzed (Baseline, Day 112).<h4>Results</h4>One hundred and thirty-one infants completed the study. Average duration of crying/fussing episodes was similar at Baseline, significantly shorter for PDX/GOS vs. Control at Day 70, and the trajectory continued at Day 112. Latency to first and second nap was significantly longer for PDX/GOS vs. Control at Day 112. Cortisol awakening response was demonstrated at Days 70 and 112. Significant stool microbiome beta-diversity and individual taxa abundance differences were observed in the PDX/GOS group.<h4>Conclusions</h4>Results indicate faster consolidation of daytime waking state in infants receiving prebiotics and support home-based actigraphy to assess early sleep-wake patterns. A prebiotic effect on wake organization is consistent with influence on the gut-brain axis and warrants further investigation.<h4>Impact</h4>Few studies have evaluated nutritive effects of prebiotics on infant behavior state, cortisol awakening response, sleep-wake entrainment, and gut microbiome. Faster consolidation of daytime waking state was demonstrated in infants receiving a prebiotic blend in infant formula through ~4 months of age. Shorter episodes of crying were demonstrated at ~2 months of age (time point corresponding to age/developmental range associated with peak crying) in infants receiving formula with added prebiotics. Results support home-based actigraphy as a suitable method to assess early sleep-wake patterns. Prebiotic effect on wake organization is consistent with influence on the gut-brain axis and warrants further investigation.
Project description:OBJECTIVE:To conduct a systematic review of systematic reviews and national guidelines to assess the effectiveness of four treatment approaches (manual therapy, probiotics, proton pump inhibitors and simethicone) on colic symptoms including infant crying time, sleep distress and adverse events. METHODS:We searched PubMed, Embase, Cochrane and Mantis for studies published between 2009 and 2019. Inclusion criteria were systematic reviews and guidelines that used evidence and expert panel opinion. Three reviewers independently selected articles by title, abstract and full paper review. Data were extracted by one reviewer and checked by a second. Selected studies were assessed for quality using modified standardised checklists by two authors. Meta-analysed data for our outcomes of interest were extracted and narrative conclusions were assessed. RESULTS:Thirty-two studies were selected. High-level evidence showed that probiotics were most effective for reducing crying time in breastfed infants (range -25 min to -65 min over 24 hours). Manual therapies had moderate to low-quality evidence showing reduced crying time (range -33 min to -76 min per 24 hours). Simethicone had moderate to low evidence showing no benefit or negative effect. One meta-analysis did not support the use of proton pump inhibitors for reducing crying time and fussing. Three national guidelines unanimously recommended the use of education, parental reassurance, advice and guidance and clinical evaluation of mother and baby. Consensus on other advice and treatments did not exist. CONCLUSIONS:The strongest evidence for the treatment of colic was probiotics for breastfed infants, followed by weaker but favourable evidence for manual therapy indicated by crying time. Both forms of treatment carried a low risk of serious adverse events. The guidance reviewed did not reflect these findings. PROSPERO REGISTRATION NUMBER:CRD42019139074.
Project description:Background:Infantile colic is a common condition during early childhood affecting around one of six newborns. The condition is characterized by inconsolable crying and fussing in otherwise healthy and thriving infants. The most used definition is excessive crying for at least three hours a day for at least three days for at least three weeks. The cause of colic is still unknown although many hypotheses and thereby many different treatment modalities have been investigated. Chiropractic care is used increasingly in treatment of infants, including for infantile colic, although the evidence worldwide is sparse. A randomized, controlled trial was designed to evaluate the effect of chiropractic treatment on infantile colic. This paper describes the protocol as well as results from a pilot study examining the acceptability and feasibility of the intervention. Method:The study is designed as a single-blind randomized, controlled trial. The invited families are residents on the Island of Funen and information about the project is distributed from the maternity wards and health visitors. Children at the age of 2-14 weeks with unexplained excessive crying are screened for eligibility and recruited by the primary investigator through home visits. Eligible children are then randomized to chiropractic treatment or control. All children attend in the chiropractor clinic two times a week for two weeks. The parents are unaware of their child's allocation during the project period. The primary outcome measure is change in daily hours of crying based on the parental diaries.The study intends to include 200 children, and the intervention has, during a pilot study, been found acceptable and feasible among families with newborns. Discussion:In a single-blind randomized controlled design we will evaluate the effectiveness of chiropractic treatment on infantile colic. The study will contribute to determine the effect of chiropractic treatment on infantile colic in an area where limited evidence exists. Furthermore, the study aims to explore if subgroups of children with suspected musculoskeletal problems will benefit more from the intervention than others. If they obtain better results, this could imply the need for stratified care. Trial registration:Clinicaltrials.gov and Identifier: NCT02595515 (registered 2 November 2015).
Project description:OBJECTIVES: Our aim was to establish whether there is an interconnection between the compositional development of the gut microbiota and the amount of fussing and crying in early infancy. METHODS: Behavioral patterns of 89 infants during the 7(th) and 12(th) week of life were recorded in parental diaries. Total distress was defined as the sum of daily amounts of crying and fussing. Infants' gut microbiota profiles were investigated by several molecular assays during the first six months of life. RESULTS: The median (range) duration of total distress among the infants was 106 (0-478) minutes a day during the 7(th) and 58 (0-448) minutes a day during the 12(th) week. The proportion of Bifidobacterium counts to total bacterial counts was inversely associated with the amount of crying and fussing during the first 3 months of life (p = 0.03), although the number of Bifidobacterium breve was positively associated with total distress (p = 0.02). The frequency of Lactobacillus spp. at the age of 3 weeks was inversely associated with total infant distress during the 7(th) week of life (p = 0.02). CONCLUSIONS: Bifidobacterium and Lactobacillus appear to protect against crying and fussing. Identification of specific strains with optimal protective properties would benefit at-risk infants.
Project description:<h4>Introduction</h4>Infant colic, or excessive crying of unknown cause in infants less than 3 months old, is common and burdensome. Its aetiology is undetermined, and consensus on its management is still lacking. Recent studies suggest a possible link between infant colic and gut microbiota, indicating probiotics to be a promising treatment. However, only a few strains have been tested, and results from randomised controlled trials are conflicting. It is important to clarify whether probiotics are effective for treating infant colic in general, and to identify whether certain subgroups of infants with colic would benefit from particular strains of probiotics.<h4>Methods and analysis</h4>Through an individual participant data meta-analysis (IPDMA), we aim to identify whether the probiotic Lactobacillus reuteri DSM 17938 is effective in the management of infant colic, and to clarify whether its effects differ according to feeding method (breast vs formula vs combined), proton pump inhibitor exposure, and antibiotic exposure. The primary outcomes are infant crying duration and treatment success (at least 50% reduction in crying time from baseline) at 21 days postintervention. Individual participant data from all studies will be modelled simultaneously in multilevel generalised linear mixed-effects regression models to account for the nesting of participants within studies. Subgroup analyses of participant-level and intervention-level characteristics will be undertaken on the primary outcomes to assess if the intervention effect differs between certain groups of infants.<h4>Ethics and dissemination</h4>Approved by the Royal Children's Hospital Human Research Ethics Committee (HREC 34081). Results will be reported in a peer-reviewed journal in 2015.<h4>Trial registration number</h4>PROSPERO CRD42014013210.