Probiotics for Colic –2018 Update

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.

Key points:

  • “‘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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In Case Someone Asks…Low FODMAP Maternal Diet May Help Colic

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.

Positive Results for Probiotics in Latest Study of Colicy Infants

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.

Key results:

  • 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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Pushback on Probiotics

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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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:

Probiotics for Colic

Another study has shown the potential for probiotics to help colicy infants.  In an editorial, Carlos Lifschitz sums up the paper (The Journal of Pediatrics Volume 163, Issue 5 , Pages 1250-1252, November 2013); here is an excerpt (link from Kipp Ellsworth twitter feed —goo.gl/b3iMFu):

For reasons that are not clear, human infants are born with a well-developed capacity to cry.1 …Unexplained and severe crying affects 3%-28% of breastfed or formula-fed (otherwise-healthy) young infants.2 Although excessive, inconsolable crying and colic are considered to be a benign, self-resolving problem, they can be very distressing and lead to marital conflict and parental exhaustion.3 Infantile colic is defined as paroxysmal, excessive, inconsolable crying without an identifiable cause in an otherwise-healthy infant occurring in the first 3 months of life and lasting a minimum of 3 hours per day, 3 days per week, for 3 weeks…

Enter probiotics. Lactobacillus reuteri DSM 17 938 at a dose of 108 colony-forming units per day in breastfed infants improved symptoms of infantile colic,19 a finding that was further corroborated.20 Despite evidence that altering the microbiota may result in reduced crying, the physiopathology still remains unclear…

In this issue of The Journal, Pärtty et al22 attempt to prevent excessive crying in former premature infants….To determine whether excessive crying is preventable by manipulation of intestinal microbiota, 94 preterm infants, some breast- and formula-fed, with gestational ages ranging from 32 to 36 weeks and birth weights >1500 g, were randomized in the first 3 days of life in a double-blind study to receive for the following 2 months either a mixture of galacto-oligosaccharide and polydextrose (prebiotic group), Lactobacillus rhamnosus GG (probiotic group), or placebo…Follow-up consultations were conducted by the same study nurse at the age of 1, 2, 4, 6, and 12 months…

Significantly less frequent crying was observed in both the pre- and probiotic groups compared with the placebo group (19% vs 19% vs 47%, respectively; P = .02). At 1 month of age, the infants’ fecal microbiota were investigated. The proportion ofLactobacillus-Lactococcus-Enterococcus group to total bacterial count and the proportion of Clostridium histolyticum group to total bacterial count was greater in excessive criers than in contented infants in all 3 study groups (pre-, probiotics, and placebo). The authors concluded that early pre- and probiotic supplementation may alleviate symptoms associated with crying and fussing in preterm infants.

Although in the study the following associations did not reach statistical significance, they are of interest for future investigation: contented infants were more often exclusively breast-fed during the first 2 months (42% vs 22%, respectively, P= .09) and their mothers had received perinatal antibiotics less often (22% vs 41%, respectively, P = .07) than criers… Contrary to this hypothesis, however, is the finding that persistent criers were more often born by vaginal delivery as opposed to cesarean delivery (81% vs 63%, P = .07) than contented babies. This finding is surprising because birth by cesarean delivery and, therefore, lack of exposure to the microbiota of the vaginal canal and perineum, has been associated with abnormal development of intestinal microbiota and several diseases.

Related blog posts:

In a video, Dr. Sanjay Gupta and Dr. John Bachman say ‘we don’t know why babies have colic, but it will end and is not the parent’s fault:’ ow.ly/q4IsW 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

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.
  • -Hochman JA, Simms C: “The role of small bowel bacterial overgrowth in infantile colic“J Pediatr 2005; 147: 410-411 (Letter to Editor).
  • -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.

What to Feed Your Baby

“What to Feed Your Baby” — is the title of a recent, easy-to-read, practical book written by one of my colleagues, Stan Cohen.  I had the opportunity to read it and recommend it as an excellent resource for parents.  This book is not just for selecting formula and introducing foods, but it also reviews gastroesophageal reflux, colic, stooling problems, poor weight gain, overweight issues, prematurity, and allergies.  In addition, the subtitle, “Cost-Conscious Nutrition for Your Infant,” is an important element throughout the book.

The first few chapters highlight the advantages of breastfeeding but acknowledge that formula-feeding is an acceptable alternative.  Specific advantages that are outlined in Table 2.2 include decreased infections, decreased risk for several illnesses like sudden infant death syndrome (along with many others like diabetes and obesity), protection from allergies, and improved intelligence.  Advantages for the mother, like weight loss and better emotional health, are discussed as well.

Almost any question that a new mother would ask about the logistics of breastfeeding are answered in the 3rd chapter: “How long should each feeding be?” “Should I wake the baby?” “Do I need to stop if I have a cold?” “How long can the breastmilk be stored?”  The latter question has its own table 3.1 and the answer depends on the storage temperature.  At room temperature, covered breastmilk should be durable for 6-8 hours.  In addition, Dr. Cohen explains the need for vitamin D supplementation.

Chapters 4 and 5 help parents understand the highly marketed formulas and to understand a rationale for choosing one formula over another, including cost as a factor.  Dr. Cohen provides data on mean docosahexaenoic acid (DHA) content in breastmilk throughout the world.  In the U.S., the level is relatively low at 0.29 (as a percentage of fatty acids).  The breastmilk DHA level is nearly three times higher in Japan and Artic Canada.  These discrepancies account in part why formula companies may choose different target concentrations for some of their components when trying to mimic breastmilk.

While Dr. Cohen explains that some of the differences between formulas are akin to differences between Coke and Pepsi, he expresses a preference for the current Mead Johnson formula Enfamil Premium due to its higher DHA content –“though the research is not thoroughly established.”  However, he states that the differences probably do not justify a much higher cost.  For a generic brand, the Costco brand, “Kirkland Signature…are reasonable and less expensive, FDA-approved options.”

In addition, these chapters question whether infant organic formulas are truly organic (page 55), explain the issue of burping, and discuss the pragmatic advise regarding cleaning nipples/bottles; “kitchen clean” with soap and a washing with hot water should suffice and sterilization is not needed.

The most inciteful comments, in my opinion, are in chapter 5:

  • Lactose-free formulas: “Mead Johnson pulled its product from the market because lactose sensitivity is rare, rare, rare in infants…Abbott, in a shrewd marketing move, renamed its formula, originally called Lactofree, to Similac Sensitive, and that labeling has convinced an enormous number of mothers that this formula makes a difference.”  Similac Sensitive accounts for >10% of formula market.  A similar product is Gerber (previously Nestle) Good Start Soothe.
  • Elemental formulas: “cost as much as a monthly Porsche payment.”  Monthly costs of each type of formula are detailed in Table 5.3.  Routine cow’s milk based formula $149.88, soy-based $153.56, cow’s milk with rice starch $159.39, hydrolyzed (broken down protein) formula (e.g.. Alimentum, Nutramagen) $223.56, and elemental amino acid based $511.83.
  • Among extensively hydrolyzed formulas, Dr. Cohen indicates a preference for Alimentum (from Abbott) over its competitors due to better acceptance by infants.
  • The rationale for not switching from contracted WIC products is explained.  When changing from a contracted product to a non-contract product, the costs are much greater and among the same type of formula there is not a scientific rationale.
  • Reasons why goat’s milk are not a good choice and “dangerous” for infants are detailed.  “The protein content is over three times higher than cow’s milk…additionally, goat’s milk is deficient in folate and vitamin B6.”

As noted above, the book covers a variety of pediatric gastroenterology problems in the newborn.  As part of the chapter on undernutrition, additives to increase calories are detailed (pg 136).  For example, a tablespoon of polycose adds 23 cal, a tablespoon of rice cereal 15 cal, and  a tablespoon of vegetable oil 124 cal.

The last few chapters provide ample advice on transitioning to solid foods, reviews nutrients and mineral oils.  In addition, he provides growth charts (for full term, premature infants, and infants with Down syndrome) as well as tables on infant formula contents.

Take-home message: this is a terrific resource for parents to help understand the what, why and when of feeding their infant.  At the same time, the book provides advice on the most common pediatric gastroenterology problems of infancy like reflux, colic, stooling difficulties, allergies, and poor weight gain.

Book’s website and how to purchase:

http://www.what2feedyourbaby.com

To purchase the book:

Here is the link:

Reviews:

Other favorable reviews (http://what2feedyourbaby.com/reviews/) have come from influential pediatricians like Jay Berkelhammer and pediatric gastroenterologists like Jeff Hyams and Allan Walker.

In this book, Dr. Stanley Cohen, a pediatric gastroenterologist and nutritionist with longstanding interest in infant nutrition, provides a practical and pragmatic approach to a major concern for new mothers, namely What to Feed Your Baby.

— Allan Walker, M.D., director, Division of Nutrition, Conrad Taff professor of pediatrics and nutrition, Harvard Medical School

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