The images below show how much more prevalent problems with regurgitation, colic, functional diarrhea, dyschezia, and functional constipation in the first 3 months of life compared to later in the first year of life.
A recent study (S Salvatore et al. J Pediatr 2019; 212: 44-51) examines the role of neonatal antibiotics and prematurity on the development of functional gastrointestinal disorders in the first year of life.
What is most striking, though, in this study is how many of these infants have a GI disorder.
Background: Prospective cohort multicenter study with 934 infants who completed study; n=302 premature, n=320 antibiotic recipients
- 718 (77%) had at least one functional GI disorder (FGID) based on Rome III criteria, including 47% with colic, 40% with regurgitation, 32% with dyschezia, 27% with constipation, and 4% with functional diarrhea
- Preterm infants had FGID rate of 86% compared with 73% of full term infants (P=.0001)
- Use of antibiotics was associated with FGIDs as well, with aRR of 1.16 (P=.001)
- The prevalence of FGIDs was highest in the first three months of life and then improved markedly by 6 months of age; by 12 months of age, each of the FGIDs was well below 10%.
Limitation: This study relied on parental reports which could overestimate infant’s symptoms.
My take: More than 75% of infants had at least one FGID.
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There is some debate about whether colic is truly a GI disorder. A recent commentary (V Sung, MD Cabana. J Pediatr 2017; 191: 6-8) provides some insight.
- “‘Colic’ is a term coined by the ancient Greeks…derived from ‘kolikos,’ meaning crampy pain, sharing its root with the the word colon.”
- “Since 1994, there have been at least a dozen case-control studies that have indicated differences in the gut microbiota between infants with and without colic.”
- Studies have had conflicting results with whether calprotectin levels are increased in infants with colic compared with controls.
- Among probiotics, L reuteri DSM17938 “is the best studied strain.” Despite several studies suggesting efficacy, “the largest and only double-blind randomized trial that included both breastfed and formula-fed infants with colic (n=167) in Australia was ineffective.
- The commentary reviews a recent study (Fatheree NY et al. J Pediatr 2017; 191: 170-8) “although very small in comparison, adds to this literature, being the second double-blind randomized, placebo-controlled trial of L reuteri DSM17938 shown to be ineffective in breastfed infants with colic.” Sample size =20. “It is the first to document increased fecal calprotectin levels that decrease with reduced crying” …though this “may be reflections of normal levels in healthy young infants, which change over time.” In addition, this study did not find evidence of systemic inflammation. The authors speculate that the frequent use of antireflux medications could dampen the effects of probiotics.
My take: We still do not know whether efforts at changing an infant’s microbiome improve clinical outcomes in colic.
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According to a very small study, maternal ingestion of a low FODMAP diet reduced crying in colicy babies who were breastfed. This report was presented at the recent United European Gastroenterology meeting (P0609). The study consisted of a single-blind, open-label study of 18 infants. The key finding was reduced crying from 142 minutes to 90 minutes over the 2 week study period.
A summary of this report is available at gastroendonews.com (May 2016, pg 8).
My take: A bigger study is needed to ascertain whether this intervention is worthwhile. Many kids get better during a 2 week period without treatment.
While not all studies have demonstrated benefit of probiotics for infant colic, many have, particularly in breastfed infants. The latest study (J Pediatr 2015; 166: 74-78) shows that “administration of L reuteri DSM 17938 significantly improved colic symptoms by reducing crying and fussing times in breastfed Canadian infants.”
This study was conducted between 2012-2014 and enrolled 52 infants. These infants were randomized to either probiotics or placebo; the study was double-blind as well.
- For the 21 day study: Total average crying and fussing times for probiotic group was 1719 ± 750 minutes compared with 2195 ± 764 minutes in the placebo group. (P=0.028)
- At the end of the study, the probiotic group crying/fussing for 60 minutes per day compared with 102 minutes/day in the placebo group. (P=0.045)
Take-home message: In breastfed infants, the probiotic L reuteri DSM 17938 reduced crying.
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I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”
A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics. The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'” They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”
The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old). The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis. Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).” The rate of C difficile infection was ~1% and lower than expected.
While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.
Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial. Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”
Another probiotic reference:
JAMA Pediatr 2014; 168: 228-33. This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic. Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary. Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”
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This is the question from a recent meta-analysis (JAMA Pediatr 2013; 167: 1150-57 -thanks to Ben Gold for this reference).
Table 1 details the study designs, probiotic intervention, and outcomes.
Results: “Of the 12 eligible studies (1825 infants), 6 suggested that probiotics reduced crying and 6 did not…Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days…However, all trials had potential biases.”
In the three breastfed trials alluded to above, there were concerns regarding inadequate blinding of the intervention, unequal baseline characteristics, and use of non validated crying “diaries” which could be prone to recall bias.
More data are needed; fortunately there are several ongoing trials.
Bottomline (from the authors’ conclusion): “Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants.”
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