What Is Known
- There are currently no known methods of consistently preventing infant colic.
- One recent study suggests that infant probiotic supplementation with L reuteri DSM 17983 can prophylactically decrease infant crying time; however, it is unclear if this effect can be found with other probiotic supplements, such as Lactobacillus rhamnosus GG.
What Is New
- Based on secondary analysis of data from a randomized controlled trial, we found that there were no differences between the infants exposed to early Lactobacillus rhamnosus GG versus infants exposed to the control intervention.
- In our study, the cumulative incidence of colic (9.8%) was lower than expected.
- Based on this pilot study, early infant supplementation with Lactobacillus rhamnosus GG does not appear to prevent the later development of colic; however, further studies, with greater numbers of infants may be needed.
Few studies examine whether probiotic supplementation from birth can prevent the development of colic, which is an important area of inquiry as there are no known methods of consistently preventing colic. A recent clinical trial documented the effectiveness of a specific probiotic strain, Lactobacillus reuteri DSM 17938 starting within the first week of life for the prevention of infant colic. At 1 month and 3 months of age, the infants randomized to the probiotic supplement had a lower mean duration of crying time/day compared to infants randomized to the control group (1). The use of a probiotic supplement may affect the developing infant gut microbiota and decrease the likelihood of colic (2). Although promising, the effects of probiotic supplementation on infant colic may be strain specific.
We had the opportunity to conduct a secondary analysis of data from the ongoing Trial of Infant Probiotic Supplementation (TIPS) Study as a pilot study to assess the potential effectiveness of Lactobacillus rhamnosus GG (LGG) in preventing the development of colic (3). We previously reported the results of the impact of 6 months of LGG infant supplementation on the incidence of eczema. We now report the results of a secondary, pilot analysis on the development of infant colic in this cohort.
A description of the TIPS Study, including recruitment, randomization and follow-up has been previously published and we briefly highlight the protocol below (4). We recruited pregnant women from the San Francisco, California, metropolitan area to identify potential participants. Eligible newborns had at least 1 biologic parent who reported a history of asthma. Group assignment was based on the output from a computer-generated randomization program. Participants, parents, study staff, and investigators were blinded to group assignment.
The intervention arm received a daily capsule of 10 billion colony-forming units of LGG and 225 mg of inulin for the first 6 months of life (Amerifit Brands, Cromwell, CT). The control arm received a 6-month course of daily capsules that contained 325 mg of inulin. Caregivers were instructed to dissolve the supplement (active or control) in 2 mL of pumped breast milk, infant formula or water and feed to the infant via oral syringe. If families decided to use formula we offered to provide a partially hydrolyzed whey infant formula which did not have a probiotic or prebiotic supplement (Good Start Supreme; Nestlé, Vevey, Switzerland) in order to standardize the type of infant formula exposure and also limit the potential risk of atopic disease (5).
For this secondary analysis, the outcome of interest was the development of colic. We surveyed parents of the participants each month for the first 4 months of life. The presence of colic was determined based on parent report of a diagnosis of colic or parent report of symptoms consistent with a diagnosis of colic. Parent report of a diagnosis of colic was based on a positive answer to the question, “Since we last spoke, has your child been diagnosed with colic?” Parent report of symptoms consistent with a diagnosis of colic was based on a positive answer to the question, “Does your child have episodes of crying lasting longer than 3 hours per day more than 3 days per week with no known cause?” In addition to these questions, we collected demographic, and household data.
The prevalence of colic has been estimated to be as high as 25% by 6 weeks of life based on a recent meta-analysis of published studies (6). Assuming a baseline percentage of colic of 25% and using an alpha (2-sided) of 0.05, with a sample size of 92 patients in each group (total n = 184), our analyses would have 80% power to detect a difference of 16% (risk ratio of 0.344).
We used descriptive statistics to describe the distribution of colic in our study population and χ2 tests to compare the likelihood of a diagnosis of colic before 4 months of age, based on parent-reported symptoms or parent report of a physician diagnosis of colic. For our analyses, we used Stata 13.1 (StataCorp, College Station, TX). The TIPS study protocol was approved by the University of California, San Francisco (UCSF) Committee on Human Research. LGG is currently not approved by the United States Food and Drug Administration for the prevention of colic.
Infant demographics, birth, and feeding characteristics are described in Table 1. One potential confounding factor for the development of colic is diet. In our study population, the rate of breast-feeding was high, but similar in both groups. In addition, all formula-fed infants were offered the same formula.
Out of the 184 infants, 18 (9.8%) had colic based on either parent-reported symptoms only (n = 8) or a parent report of a physician diagnosis (n = 4) or both (n = 6). There were no differences in the 2 groups in the percentage of infants affected by colic, whether this outcome was measured based on symptoms (control 5.4% vs LGG 9.8%; P = 0.19); based on physician diagnosis (control 3.2% vs LGG 7.6%; P = 0.26); or either symptoms or diagnosis combined (control 6.5% vs LGG 13.0%; P = 0.13). Although the percentage of infants affected by colic was higher in the LGG group, the differences were not statistically significant. Finally, for both groups, symptoms seemed to peak during the second month of life (Table 2).
LGG is one of the most commonly used and studied probiotic supplements for children. Although there are dozens of randomized controlled trials examining its effect on common pediatric conditions such as infectious diarrhea and antibiotic associated diarrhea, there are far fewer studies examining the use of LGG for colic (7,8). There is only 1 randomized controlled trial for the use of LGG for the treatment of colic, which showed no difference in infant crying time according to a parental diary at the end of the intervention (9).
Our analysis focused on early supplementation of LGG for prevention (not treatment) of colic. We found that LGG does not seem to be effective in preventing colic. There was no difference in the incidence of colic or the month of life when colic symptoms peaked. Furthermore, although not statistically significant, it is not clear why a higher percentage of infants consuming LGG developed colic compared to the control group. When the outcome of interest is infrequent, there is greater possibility of a random uneven distribution among the 2 groups. Although this study is a prevention study, the negative outcome of this study is consistent with a previous treatment study by Partty et al, who reported that LGG was not effective for colic (9). Although early probiotic supplementation with a different probiotic (L reuteri DSM 17938) has been reported as successful in the primary prevention of colic (1), the effects of probiotic supplementation are generally strain-specific and not generalizable to other probiotic supplements (10).
In our study we report a cumulative incidence of colic of 9.8% which lower than other studies, but within the wide range of values (2%–34%) previously reported (6). Differences in incidence by country may represent cultural differences in infant care or genetic differences. Another reason may due to data collection methods, as many colic studies ask parents to collect data on a daily basis using a Barr Diary (11). In our study, we asked parents about symptoms over the last month. With a long 1-month recall window, compared to a shorter daily recall window with a Barr Diary, parents may have underestimated the actual crying time. In addition, the primary outcome of the TIPS trial was not colic or crying times, but wheezing and asthma. Parents may have focused more on the primary outcome and under-reported crying times. Although the differences in data collection and study focus could have led to potential measurement error, it is, however, unlikely to have led to a bias in the analysis, as all parents and the investigators were blinding to treatment group assignment.
Our study has several limitations. First, the outcomes were based on parent report of a health care provider's diagnosis and parent report of the duration of crying. We did not conduct evaluations to rule out another cause when the parent reported the symptoms or diagnosis. It is possible that there may have been an underlying pathology for the crying; however, we did ask parents specifically if their child received any other diagnosis. Second, although the TIPS sample of infants was drawn from an ethnically and racially diverse population, reflecting a large, urban population in the United States, the infants’ mothers were older and the families were more affluent than the typical US population (3). In our sample, there were high rates of breast-feeding. It is possible that high rates of breast-feeding may blunt or mask any response to the administered probiotic.
Finally, this analysis illustrates the difficulty in designing randomized controlled trials for the prevention of an outcome, such as colic, that demonstrates a wide variance in cumulative incidence in the literature (6). As the incidence of colic decreases in the control group, there is less of a “margin” for the intervention to show a decrease. The frequency of colic in the control group (7%) was much less than other commonly reported frequencies of colic (6). If the incidence of colic was 25% in the control group, our sample size of 92 patients in each group (total n = 184), would have 80% power to detect a difference of 16% (risk ratio of 0.344). With an incidence of 7% in the control, we would, however, have needed twice the number of patients (total n = 368) to have 80% power to detect a difference of 6%. The results from this analysis may, however, be useful for the design of future preventive studies for colic.
Notwithstanding these limitations, there are potential clinical implications. This pilot analysis suggests that early LGG supplementation beginning in the first 4 days of life does not appear to have a preventative effect on the development of colic. This is important information for clinicians counseling parents who are interested in giving probiotics to their infants. The lay literature on probiotics often fails to present information on specific strains used in published studies or to clarify that effects documented with 1 strain may not be seen with other strains. With the proliferation of probiotic products on the market, it is critical that both clinicians and parents be given accurate and specific information regarding the potential effects of different strains on pediatric conditions. Given the low frequency of colic in our study population, larger studies are needed to better assess potentially smaller clinical effects on colic associated with early LGG supplementation.
1. Indrio F, Demure A, Riezzo G, et al. Prophylactic use of a probiotic in the prevention
, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr
2. deWeerth C, Fuentes S, Puylaert P, et al. Intestinal microbiota of infants with colic
: development and specific signatures. Pediatrics
3. Cabana MD, McKean M, Caughey AB, et al. Early probiotic supplementation for eczema and asthma prevention
: a randomized controlled trial. Pediatrics
2017; 140:pii: e20163000.
4. Cabana MD, McKean M, Wong AR, et al. Examining the hygiene hypothesis: the Trial of Infant Probiotic Supplementation. Paediatr Perinat Epid
2007; 21: s23–8.
5. vonBerg A, Filipiak-Pittroff B, Krämer U, et al. GINIplus study group. Allergies in high-risk school children after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol
6. Wolke D, Bilgin A, Samara M. Systematic review and meta-analysis: fussing and crying durations and prevalence of colic
in infants. J Pediatr
7. Guarino A, Guandalini S, Lo Vecchio A. Probiotics
and treatment of diarrhea. J Clin Gastroenterol
8. Szajewska H, Kołodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus
GG in the prevention
of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther
9. Pärtty A, Lehtonen L, Kalliomäkii M, et al. Probiotic Lactobacillus rhamnosus
GG therapy and microbiological programming in infantile colic
: a randomized, controlled trial. Pediatr Res
10. Wallace TC, Guarner F, Madsen K, et al. Human gut microbiota and its relationship to health and disease. Nutr Rev
11. Barr RG, Kramer MS, Boisjoly C, et al. Parental diary of infant cry and fuss behaviour. Arch Dis Child