Do Probiotics Really Help Crying Infants?

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.”

Previous  related posts:

Colic Microbiome

A new study identifies a potential microbiome signature that is associated with colic (Pediatrics 2013; 131: e550-58). Thanks to Mike Hart for this reference.

With new technology, the microbiome’s role in many gastrointestinal conditions is being unraveled.  For colic, there has been concern about that an abnormal microbiome has been contributing to the pathophysiology.  On a personal level, I have had an interest in this subject for quite a while:

In this current study, the authors serially followed the microbiome infants in a prospective longitudinal project.  Nine stool specimens were obtained from each infant. Four were obtained in the first month at day of life 2, 7, 14, and 28 days.  Five were obtained at 3 to 5 months.  All specimens were stored at -20°C until analyzed by the “Human Intestinal Tract Chip (HITChip).” The HITChip microarray was considered satisfactory if 2 independent hybridizations had >95% correlation.  These microarrays “showed a dynamic range of >10,000-fold and >200 independent microarray readouts were used.”

Of 160 healthy term infants, the authors identified colic in 25% who averaged >180 minutes of crying per day over a four-day period.  Then, the authors selected the 12 infants who cried the most and compared them to the 12 infants who cried the least.

Results:

  • In the infants who were highly similar, the “infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.”  Proteobacteria, including Enterobacter aerogenes, Escherichia coli, and Klebsiella pneumoniae, were increased with more than a doubled abundance.  Bifidobacteria and lactobacilli were decreased in colicy infants.
  • At about 3-4 months of age, the colic group had a similar microbiome as the non-colicy group.
  • The authors speculate that proteobacteria might cause inflammation and may displace helpful bacteria.  Certain butyrate-producing bacteria like Butyrivibrio crossotus and Coprococcus estates were more commonly present in the non-colicy group.  The authors note that butyrate reduces the pain sensation in adults.

Bottom-line:

These results could explain why administration of probiotics (and possibly antibiotics) can result in a decrease in colic symptoms.

Related blog entries:

Additional references:

  • -Pediatrics 2010; 126: e526.  Double-blind randomized placebo-controlled trial of Lactobacillus reuteri.
  • -J Pediatr 2009; 155:823. Increased calprotectin in colicy infants. n=36. editorial pg 772.
  • -J Pediatr 2009; 154: 514-20. Colic and reflux. (Orenstein et al), & 475 (editorial -Putnam). PPIs (lansoprazole) do not help colicy Sx in infants c GERD. n=162. Increased resp infections in pts on PPIs. 44% response in Rx & control group.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Pediatrics 2005; 116: e709. Low-allergen maternal diet was helpful.
  • -Arch Pediatr Adol Med 2002; 1183 &1172. lack of sequelae on maternal mental health.
  • -Arch Pediatr Adol Med 2002; 156: 1123-1128. colic 24% of infants, breastfeeding did not help.
  • -Pediatrics 2002; 109: 797-805. carbohydrate malabsorption with breath testing in colicy infants, n=30. 2 hour fasting period.
  • -Arch Dis Child 2001; 84: 138-41. Lack of benefit (vs placebo) of chiropractic manipulation for colic, n=100. 86 completed study. 70% improved vs 60% in placebo.
  • -JPGN 2001; 33:110-111. Lack of assoc c GER
  • -Pediatrics 2000; 106: 1349. Use of hydrolysate decreased crying by 63mins/day
  • -Pediatrics 2001; 108; 878-882. No assoc between colic and markers of atopy/asthma/allergy.

How helpful are probiotics?

Nobody really knows.  Claims about their efficacy are often based on poorly designed studies.  Efficacy of each strain for specific conditions and with specific dosing is often lacking.  One recent negative study demonstrates that probiotics are often not beneficial (J Pediatr 2012; 161: 40-3).

In this randomized, double-blind placebo controlled study of 106 Polish children (1-48 months of age), Lactobacillus reuteri had no effect in preventing nosocomial diarrhea in patients admitted for non-diarrheal illnesses.  While the authors contemplate that this could be due to the strain of probiotic chosen or the dose, it is clear that evidence that probiotics prevent infectious diarrhea “is still scant.”

This conclusion is backed by a large meta-analysis (JAMA 2012; 307: 1959-69).  While the study concludes that the use of probiotics is associated with a lower risk of antibiotic-associate diarrhea (RR 0.58), it predicted that the number to treat for one person to benefit would be 13.  The study was based on a systematic review of 82 randomized clinical studies.  Yet, overall the quality of the research was considered low; the studies were often had shortcomings:

  • 59 studies “lacked adequate information to assess the overall risk of bias”
  • 64 did not indicate if treatment randomization was blinded
  • 31 did not report an intent-to-treat analysis
  • 41 did not include a calculation of the study’s statistical power to detect differences
  • 17 trials were industry-sponsored and 52 did not clarify their funding/potential conflicts of interest
  • 59 did not report on adverse events specifically related to probiotic use; few trials addressed the risk of fungemia or sepsis
  • Trials rarely specified antibiotic agents; thus, it is difficult to know if a particular probiotic would be better with certain types of antibiotic therapy or duration.

Additional references/links:

  • Potential and pitfalls of probiotics with necrotizing enterocolitis
  • -JPGN 2010; 51:24. VSL#3 helpful for IBS, n=509 (4-18yr olds). 1 per day for <11yr, 2/day in 12-18yr olds
  • -Pediatrics 2008; 121:e850. Culturelle, during pregnancy and early infancy, not effective in preventing atopic dermatitis. Did increase wheezing.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, Lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Neurogastroenterol Motili 2007 (Quigley EM, et al), 19: 166-72. Review of probiotics and IBS.
  • -NASPGHAN 2007, author: Brian Dunlap, H. Yu, Y Elitsur. abstract -most commercial yogurts have LOW concentrations of probiotics.
  • -JPGN 2006; 43: 550. Review of probiotics for specific conditions.
  • -J Pediatr 2006; 149: 367. Probiotics reduce risk of antibiotic assoc diarrhea. If 7 pts (on abx) are treated with probiotics, one fewer will develop AAD.
  • -JPGN 2006; 42: 454. Evidenced-based review of probiotics.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -Gastroenterol 2004; 126: 1620-33.  Review of probiotics, prebiotics and antibiotics in IBD.