A randomized, double-blind, placebo-controlled trial with bifidobacterium longum CECT7894 and pediococcus pentosaceus CECT8330 to treat infant colic.
K. Chen#,*, 1, 2,C. Liu#, 3, H. Li4, Y. Lei4, C. Zeng5, S. Xu6, J. Li2, F. Savino7
1Department of Nutrition, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 1617, Riyue Avenue, Qingyang District, 610031, Chengdu, China; 2Department of Child Health Care, Angel Children’s Hospital, No.46, Section 4, South Renmin Road, 610041, Chengdu, China; 3School of Exercise and Nutritional Sciences, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182, the United States; 4Department of Child Health Care, Qingbaijiang Maternal and Child Health Hospital, No.87, South Qingqiang Road, 610302, Chengdu, China; 5Department of Child Health Care, Chengdu Caojiaxiang Community Healthcare Center, No.173, Section 2, Jiafang Road, 610081, Chengdu, China; 6Department of Child Health Care, Huili Maternity and Child Care Center, 615100, Huili, China; 7Department of Paediatrics, S.S.D. Subintensive Neonatal Care. Children Hospital ‘Regina Margherita’. A.U.O. Città della Salute e della Scienza di Torino, Torino, Italy; #Sharing the first author; *Corresponding author; email@example.com
This randomized, double-blind, placebo-controlled trial was designed to test the hypothesis that oral administration of Bifidobacterium longum CECT7894 and Pediococcus pentosaceus CECT8330 would improve the symptoms of infantile colic. A total of 118 exclusively or predominantly breastfed infants aged less than 3 months and meeting the ROME IV criteria for colic were recruited. The infants were randomized to receive probiotics (IG, n=48) or placebo (PG, n=42), Bifidobacterium longum CECT7894 (KABP042) and Pediococcus pentosaceus CECT8330 (KABP041) (1×109 colony forming units in total) versus placebo, orally administrated daily for 21 days. The primary outcome was daily duration of crying or fussing. Secondary outcomes were number of crying/fussing episodes and family functioning score (paediatric quality of life inventory). Crying/fussing time of infants in the IG on the 7th, 14th and 21st days during the intervention was significantly shorter than those of infants in the PG (p < 0.001). Moreover, infants in the IG had less frequent episodes of crying/fussing per day than infants in the PG (p < 0.001). The IG had a higher proportion of infants responding to the treatment (defined as ≥ 50% reduction in crying and fussing time from baseline) than the PG on the 7th (40% vs. 15%, p < 0.001), 14th (46% vs. 18%, p < 0.001) and 21st (43% vs. 27%, p = 0.004) days. Infants in the IG had less faecal frequency/day when compared with infants in the PG on the 1st, 7th, 14th and 21st days (p < 0.001). However, the faecal consistency score of infants in the IG on the 21st day of intervention was significantly lower than that of infants in the PG (p < 0.001). Daily oral administration of B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041) was an effective treatment of infantile colic. This trial was registered as ISRCTN92431452 (http://www.isrctn.com/ISRCTN92431452).
Keywords: Probiotics, Infant, Colic, Supplementation
Infant colic is a behavioural condition in early infancy that involves long crying bouts and hard-to-soothe behaviour for no apparent cause. It is common and distressing to families and affects up to 20% of infants under three months (Wake et al. 2006).
Although infant colic spontaneously resolves after the first three to four months after birth, it is associated with maternal depression, early breastfeeding cessation, and sometimes with shaken baby syndrome (Landgren et al. 2012). Infant suffering for colic is one of the most common problems to healthcare sectors and is very costly (Akman et al. 2006).
The etiology of infantile colic remains unclear; however, various theories have been proposed such as overproduction of intestinal gas, hypersensitivity to cow’s milk protein, transient lactase deficiency, and gut inflammation (Shenassa and Brown 2004, Eutamène et al. 2017, Savino et al. 2018). The parents and caretakers often seek medical care for colic including the use of drugs, vegetable fibre, lactose, sucrose solution, hypoallergenic diet, and herbal tea. Nevertheless, no single effective, practical, acceptable, and safe intervention or medicine for infant colic exists (Biagioli et al. 2016, Gordon et al. 2018).
The interest of using probiotics as a potential treatment to reduce crying in infants with colic has increased lately. Recent studies have reported that gut microbiota in colicky infants is characterized by lower amounts of Lactobacilli and Bifidobacterium and higher amounts of opportunistic proteobacteria (such as Escherichia coli, Enterobacter aerogenes, and Klebsiella) (Rhoads et al. 2018) as compared to the control infants. Thus, several researchers have suggested that probiotics may be useful for treating breastfed colicky infants and reducing their crying time (Savino et al. 2010, Sung et al. 2018).
Among probiotics, Pediococcus pentosaceus CECT8330 (KABP041) is able to induce IL-10 production, and the combination with Bifidobacterium longum CECT7894 (KABP042) has shown a broad spectrum of inhibitory activities against pathogens, both strains having been isolated from gut bacteria of healthy infants (Santas et al. 2015). Remarkably, both strains have exhibited good antagonistic activities against gas-producing enterobacteria. Therefore, in this randomized, double-blind, placebo-controlled trial, we sought to explore the effectiveness of the two-combined probiotic strains in treating infantile colic.
We hypothesize that in comparison to the placebo group, the two-combined probiotic strains, B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041), would reduce mean daily crying or fussing time (primary outcome), decrease daily episodes of crying or fussing, and improve the paediatric quality of life inventory (secondary outcome) after intervention.
Participants & Methods
Subjects & Ethical Approval
This is a randomized, double-blinded, placebo-controlled parallel-group study performed in situations which willing to carry out this research, including Qingbaijing, Jinniu, and Wuhou districts of Chengdu City and Huili County of Xichang City, Sichuan Province, China from June 1st 2018 to June 1st 2019. Infants diagnosed with colic in outpatient care department at Qingbaijiang Maternal and Child Health Hospital, Chengdu Caojiaxiang Community Healthcare Center, Huili Maternity and Child Care Center, and Angel Children’s Hospital Chengdu were recruited. The colic was diagnosed by the paediatrician, and nursing advice was provided by the nurses in each hospital. The enrolment and research plan were reviewed and approved by the institutional ethics committee of Angel Children’s Hospital Chengdu and written informed consent was obtained from parents of each infant. The present study complied with the code of ethics of the World Medical Association (Declaration of Helsinki). There were no important changes to methods after trial commencement.
Inclusion, Exclusion & Withdrawal Criteria
Infant colic is defined as crying or fussing episodes lasting more than 3 hours per day and occurring at least 3 days per week within 7 days prior to enrolment (ROME IV criteria) (Zeevenhooven et al. 2017). Inclusion criteria were: less than 3 months (12 weeks) of age, equal to or greater than 37 weeks of gestation at birth, vaginal delivery, and birth weight of more than 2500g, and provided voluntary written informed consent from parents of the infant. Exclusion Criteria were: average weight gain < 100 grams/week from birth to the last recorded weight, major medical problems (e.g. immunocompromised disease, major developmental or genetic abnormality), gastrointestinal disorder, and taking antibiotics four weeks prior to enrolment, using the same probiotic strains in this study two weeks prior to enrolment, and taking antibiotics during the intervention.
Participation in the study was voluntary, and the parents have the right to withdraw their child from the study without providing a reason and with no loss of benefits to which the child is entitled. If a parent chose to withdraw their child, the study personnel must be informed immediately. The investigator has the right to terminate participation of any child at any time if they deem it the child’s best interest. Examples of possible reasons for withdrawal of a study subject include: child’s parents withdraw consent for personal reasons; child’s general condition contraindicates continuing the study as judged by the study personnel or the medical expert, significant non-compliance with study protocol or lack of cooperation, serious adverse event (SAE), and lost to follow-up.
Determination of Sample Size
A sample size of 40 infants per group was sufficient to detect a 20% difference in treatment success between the intervention and placebo based on a two-sided Z test with pooled variance. The significant level of the test was targeted at 0.05 with a power of 80%. To account for a potential drop-out rate of 40%, a total of 112 subjects were recruited into this study.
The study included a baseline day which corresponding to the day when patients were referred to the paediatrician, Day 1, which corresponding to validation of Rome-IV criteria and randomization for baby colic, and Days 7, 14 and 21 all which corresponding to the weekly assessments during the 3-week intervention phase from the Day 1.
A completely randomization schedule that maintains balance between treatment arms was prepared by an independent statistician, not directly involved in the analysis of the study results. The RAND function of Excel (Microsoft, Redmond, WA, USA) was used to generate randomly permutated codes. The physicians responsible for enrollment of patients allocated the next available number on entry into the trial. At enrollment, the parent of the patient received a closed envelope containing a written usage for the oil drops. To minimize potential biases, the study was double-blinded whereby treatment allocation was concealed from all study investigators and participants. All of the care givers have been well trained by using the standardized protocol.
All eligible colic infants were randomized to receive either the probiotics as the intervention group (IG) or a reference product without probiotics as the placebo group (PG). There was no delay between randomization and the initiation of the intervention. The probiotic formula, comprising a sunflower oil suspension of the strains B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041), contains one billion Colony-Forming Units (CFU) in each drop (1:1 for the two strains). Five drops (equal to 1 billion CFU) were taken once daily preferably at the same time of the day, e.g. in the morning. The reference product (placebo) is the identical sunflower oil without probiotics. Both the probiotics and the placebo were produced by AB-Biotics S.A.
Caregivers, who received the standardized operation training from nurses at the time of recruitment, administered five drops of the study product orally to each infant daily for 21 days. The dose was not required to be given at a fixed time or given with feeds. However, for compliance and ease of administration, each family has been recommended to give the dose with the same feed each day. When administration completed, the empty bottle was retrieved to assess the adherence.
The probiotics and the placebo products were similar in smell, taste, and appearance. Both products were labelled with only the randomization number, batch number, expiry date, and the statement ‘For clinical trial use only’. The random allocation sequence was generated by an independent statistician, the nurses enrolled the participants and the pedestrians assigned participants to intervention. Parents and children, the clinical team, statisticians, and representatives from AB-Biotics S.A were blinded during the entire study until the database was unlocked.
Outcome measures were adapted from Sung et al. with minor modification (Sung et al. 2012). A validated measure (Barr et al. 1988) was used to record the infant crying/fussing time (mins/day), number of episodes of crying/fussing/day, number of infants responding to the treatment, stool consistency, and frequency of stool. Stool consistency was scored as 0 for watery stool, 1 for loose stool, 2 for formed stool, and 3 for hard stool. A 15-item validated questionnaire was used to assess family functioning (Varni et al. 2004). Family functional score was evaluated based on the frequency of occurrence of 15 mental status items (0: never happened, 1: almost never happened, 2: happened sometimes, 3: happened often, 4: almost always happened, and 5: always happened). There were not any changes to trial outcomes after the trial commenced.
In addition, demographics information was collected by a questionnaire at baseline. Potential confounders were recorded at baseline [family history of atopic, antenatal or current probiotic/antibiotic use, smoking during pregnancy, and mode of delivery (caesarean versus vaginal)] and during intervention [infant feeding method (breast versus formula); mother’s intake of dairy, probiotics, and medications; infant’s intake of dairy, probiotics, solids, and medications; concurrent illnesses/immunizations]. Compliance was measured by the numbers of days’ study drops missed over the preceding week. Side effect was assessed by stool frequency and consistency. To exclude organic causes of crying, infants were examined by the study paediatrician at the recruitment and during the intervention.
Using the Shapiro-Wilks normality test, the distribution of each set of data was tested for normality prior to analysis. Baseline characteristics and study outcomes were presented as mean and standard deviation (SD) for normally distributed variables or median (P25, P75) for variables with a skewed distribution. Tests of significance are two-tailed and p < 0.05 was considered statistically significant. The Student’s t test was used to compare the mean values of continuous variables approximating a normal distribution in the before–after intervention group for all primary and secondary outcomes. For non-normally distributed variables, the Kruskal-Wallis test was used. The 𝜒2 test was used, as appropriate, to compare proportions. Data were analysed using the SAS for Windows statistical software package (SAS Institute Inc., Cary, NC, USA).
A total of 112 infants met the inclusion criteria (56 for each group). Five infants were excluded due to parental rejection. About 15.9% infants (17/107) dropped out during the course of the study. Three of these infants were withdrawn for using other probiotics, seven for loss of data, three for formula-related allergy, and four for diarrhoea. Thus, the primary and secondary outcome measures were obtained from 90 infants (48 and 42 for IG and PG, respectively) (Figure 1). There were no significant differences in the gender, allergy history, age, birth weight, passive smoking exposure, living environment, parents’ educational levels, and feeding method during intervention between the two groups (p > 0.05) (Table 1). All infants were exclusively or predominately breastfed during the intervention period.
(Figure 1). There were no significant differences in the gender, allergy history, age, birth weight, passive smoking exposure, living environment, parents’ educational levels, and feeding method during intervention between the two groups (p > 0.05) (Table 1). All infants were exclusively or predominantly breastfed during the intervention period.
Figure 1 Diagram of patient enrollment and study progress
IG, intervention group; PG, placebo group; †, defined as > 50% breastfeeding.
Effect of intervention on crying/fussing time and frequency
The Shapiro-Wilks normality test showed that crying/fussing time and frequency were both non-normally distributed variables, therefore the Kruskal-Wallis test was used to compare the difference between the two groups at the time points. The result showed that there was no significant difference in crying/fussing time and frequency between IG and PG before the intervention (p > 0.05) (Table 2). The Kruskal-Wallis test showed that the crying/fussing time in the IG was significantly shorter than that in the PG on the 7th, 14th and 21st day of the intervention (p < 0.001). Moreover, the frequency of the crying/fussing episodes in the IG was less than that in the PG (p < 0.001) (Table 2) also on the 7th, 14th and 21st day of the intervention.
Table 2. Effect of intervention on crying/fussing time and frequency [median (25th and 75th percentile)]
A higher proportion of infants in the IG responded to the treatment (defined as a reduction in crying/fussing time of ≥50% from baseline) as compared with the infants in the PG on the 7th (40 vs. 15, p < 0.001), 14th (46 vs. 18, p < 0.001) and 21st (43 vs. 27, p = 0.004) day (Table 3).
Effect of intervention on faecal frequency and consistency
The Shapiro-Wilks normality test showed that faecal frequency and consistency scores were both non-normally distributed variables and the Kruskal-Wallis test was used to compare the difference between the groups. As shown in Table 4, there were no significant differences in faecal frequency and consistency score between IG and PG before the intervention (p > 0.05). The Kruskal-Wallis test indicated that infants in the IG had lower faecal frequency/day than infants in the PG on the 1st, 7th, 14th, and 21st day (p < 0.001) (Table 4). However, the faecal consistency score of infants in the IG was significantly lower than that of infants in the PG on the 21st days of intervention (p < 0.001) (Table 4).
Effect of intervention on PedsQLTM Family Impact Subscale of infants
There was no significant difference in the PedsQLTM Family Impact Subscale between IG and PG before the intervention (p > 0.05) (Table 5). During the intervention, the physical functional score of infants in the IG was marginally improved without reaching significance when compared with infants in the PG on the 21st day (p = 0.0645) and a similar result was found for the social functional score on the 14th day (p = 0.0698) (Table 5).
Administration of B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041) at a dose 109 CFU to exclusively or predominantly breastfed infants is superior to placebo for the management of infantile colic. The use of the two combined strains reduced the crying/fussing time and frequency, decreased the faecal frequency, and improved family functioning. No adverse events and unintended effects were recorded during the intervention. Our results were in agreement with previous studies (Schreck et al. 2017), which reported that the administration of Lactobacillus reuteri DSM 17938 increased the treatment success, although the effectiveness was only seen in breastfed infants and not in formula-fed infants (Sung et al. 2018).
Another study (Kianifar et al. 2014) showed that treatment with a combination of L. casei, L. rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, L. acidophilus, B. infantis, L. bulgaricus, and fructooligosaccharides (FOS) reduced the duration of crying by almost 35 min compared to placebo. Moreover, Saavedra et al. (Saavedra et al. 2004) and Ivakhnenko et al. (Ivakhnenko and Nian’kovskiĭ 2013) reported reduced incidence of caregiver-reported colic when supplemented with a combination of B. animalis subsp. lactis, BB-12 and S. thermophilus, although colic was not formally diagnosed by a physician which reduced the strength of the study. The same BB-12 strain in a new study could overcome this shortcoming (Nocerino et al. 2019), as colic was formally diagnosed using Rome-III criteria. However, on the other hand, this new study showed that the response rate was not significantly improved against placebo until day 21, while in our study a significant improvement was already observed on day 7.
However, some studies have produced inconsistent results. One intervention study (Pärtty et al. 2015) reported that the use of L. rhamnosus GG (ATCC53103) had no significant effect on crying of colic infants. In another study (Weizman and Alsheikh 2006), no significant difference in crying and irritability was found between the probiotics and placebo groups when supplemented with either L. reuteri ATCC55730 or B. lactis BB-12.
Possible placebo effect should be recognized (Kirsch 2011). Previous studies have shown that placebo response rates in trials on infantile colic could range from 5% to 83% (Savino et al. 2010, Savino and Tarasco 2010, Szajewska et al. 2013). In the present study, 27 of 42 (64.3%) infants responded to the placebo at day 21. Although a direct placebo effect in young infants is unlikely, an indirect placebo effect (for example, the different degree of tolerance, attention and/or care skills of caregivers to the crying infant) may be possible. Other factor contributing to the placebo effect include the nature regression to mean (subjects are enrolled when most symptomatic and inevitably improve with time owing to the natural variation in symptom severity and irrespective of trial participation) (Bland and Altman 1994, Musial et al. 2007). The exact mechanisms by which B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041) might exert this action have yet to be elucidated. P. pentosaceus has been reported to be a good inducer of the IL-10 anti-inflammatory cytokine (Jonganurakkun et al. 2008). In addition, P. pentosaceus CECT8330 (KABP041) and especially B. longum CECT7894 (KABP042) were able to inhibit the growth of a wide spectrum of opportunistic gas-producing enterobacteria of the Escherichia and Klebsiella genera as well as C. difficile, known to be abnormally abundant in colicky infants (Lehtonen et al. 1994, De Weerth C et al. 2013). This is consistent with the reported capacity of Bifidobacterium strains to modulate the intestinal microbiota (Arboleya et al. 2013) and the antimicrobial activity of P. pentosaceus strains (Borrero et al. 2011, Tokatlı et al. 2015). Additionally, B. longum CECT7894 (KABP042) is effective in inhibiting the growth of E. aerogenes in contrast to L. reuteri DSM 17938, which was significantly higher in colicky infants (De Weerth C et al. 2013).
Strength & Limitation Analysis
The strengths of our study are the adequate sample size, proper blinding maintained throughout the treatment, data management and analyses, and high retention and reported adherence rates, which allowed the achievement of the predetermined statistical power and significance. Moreover, a generally accepted definition of colic was used, and infants were recruited at a similar, early age.
A potential limitation of this study, similar to previous studies mentioned above, is that the measure to assess the duration and frequency of crying and fussing in infants with colic relied solely on the caregivers’ report. This potential shortcoming is not expected to introduce bias in this blinded study. Moreover, the design of our study did not allow for a better description of the crying (e.g., no difference for the food-related crying and typical afternoon crying).
Last limitation of this study is that the compliance with the study products was not objectively assessed. A potential approach to assessing compliance is to weigh the study bottles both before and after dispensing; however, this method has reportedly produced highly variable results (Vitolins et al. 2000).
In summary, exclusively or predominantly breastfed infants with colic benefited from the treatment with B. longum CECT7894 (KABP042) and P. pentosaceus CECT8330 (KABP041) mix compared with placebo. The necessity of treating this self-limiting condition may be questioned. However, if one wants to modify the natural history of infantile colic to improve the family functioning, the treatment could be discussed with caregivers. The lack of an effective therapy for infantile colic and the generally good safety profile of probiotics in otherwise healthy populations are in favour of such treatment. Future studies should clarify the mechanism of the probiotics in the management of infantile colic.
We thank all the parents or main caregivers and their children for their participation in the study and thank the health care workers in field trial whose name are not mentioned above for their diligent assistance. We also thank the foundation from Maternal and Infant Health and Care Science Laboratory, Shanghai, China (MIHC/2017/10/AKO2018).
Akman I, Kuşçu K, Ozdemir N, Yurdakul Z, Solakoglu M, et al. 2006. Mothers’ postpartum psychological adjustment and infantile colic. Arch. Dis. Child. 91:417-19
Arboleya S, Salazar N, Solís G, Fernández N, Hernández-Barranco AM, et al. 2013.
Assessment of intestinal microbiota modulation ability of Bifidobacterium strains in in vitro fecal batch cultures from preterm neonates. Anaerobe 19:9-16
Barr RG, Kramer MS, Boisjoly C, McVey-White L, Pless IB. 1988. Parental diary of infant cry and fuss behaviour. Arch. Dis. Child. 63:380-87
Biagioli E, Tarasco V, Lingua C, Moja L, Savino F. 2016. Pain-relieving agents for infantile colic. Cochrane Database Syst Rev 9:CD009999
Bland JM, Altman DG. 1994. Some examples of regression towards the mean. BMJ 309:780 Borrero J, Jiménez JJ, Gútiez L, Herranz C, Cintas LM, Hernández PE. 2011. Protein expression vector and secretion signal peptide optimization to drive the production, secretion, and functional expression of the bacteriocin enterocin A in lactic acid bacteria. J. Biotechnol. 156:76-86
De Weerth C, Fuentes S, Puylaert P, de Vos WM. 2013. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics 131:e550-58
Eutamène H, Garcia-Rodenas CL, Yvon S, d’Aldebert E, Foata F, et al. 2017. Luminal contents from the gut of colicky infants induce visceral hypersensitivity in mice. Neurogastroenterol. Motil. 29
Gordon M, Biagioli E, Sorrenti M, Lingua C, Moja L, et al. 2018. Dietary modifications for infantile colic. Cochrane Database Syst Rev 10:CD011029
Ivakhnenko ES, Nian’kovskiĭ SL. 2013. Effect of probiotics on the dynamics of gastrointestinal symptoms of food allergy to cow’s milk protein in infants. Georgian Med News: 46-52
Jonganurakkun B, Wang Q, Xu SH, Tada Y, Minamida K, et al. 2008. Pediococcus pentosaceus NB-17 for probiotic use. J. Biosci. Bioeng. 106:69-73
Kianifar H, Ahanchian H, Grover Z, Jafari S, Noorbakhsh Z, et al. 2014. Synbiotic in the management of infantile colic: a randomised controlled trial. J Paediatr Child Health 50:801-05
Kirsch I. 2011. Role of placebo in irritable bowel syndrome. J. Pediatr. Gastroenterol. Nutr. 53 Suppl 2:S42-43
Landgren K, Lundqvist A, Hallström I. 2012. Remembering the Chaos – But Life Went on and the Wound Healed. A Four Year Follow Up with Parents having had a Baby with Infantile Colic. Open Nurs J 6:53-61
Lehtonen L, Korvenranta H, Eerola E. 1994. Intestinal microflora in colicky and noncolicky infants: bacterial cultures and gas-liquid chromatography. J. Pediatr. Gastroenterol. Nutr. 19:310-14
Musial F, Klosterhalfen S, Enck P. 2007. Placebo responses in patients with gastrointestinal disorders. World J. Gastroenterol. 13:3425-29
Nocerino R, De Filippis F, Cecere G, Marino A, Micillo M, et al. 2019. The therapeutic
efficacy of Bifidobacterium animalis subsp. lactis BB-12 ® in infant colic: A randomized, double blind, placebo-controlled trial. Aliment. Pharmacol. Ther. Osmanagaoglu O, Kiran F, Yagci FC and Gursel I, Immunomodulatory function and in vivo properties of Pediococcus pentosaceus OZF, a promising probiotic strain. Ann Microbiol 63:1311-1318, (2013).
Pärtty A, Lehtonen L, Kalliomäki M, Salminen S, Isolauri E. 2015. Probiotic Lactobacillus rhamnosus GG therapy and microbiological programming in infantile colic: a randomized, controlled trial. Pediatr. Res. 78:470-75
Rhoads JM, Collins J, Fatheree NY, Hashmi SS, Taylor CM, et al. 2018. Infant Colic
Represents Gut Inflammation and Dysbiosis. J. Pediatr. 203:55-61.e3
Ryu EH and Chang HC, In vitro study of potentially probiotic lactic acid bacteria strains isolated from kimchi. Ann Microbiol 63:1387-1395, (2013).
Saavedra JM, Abi-Hanna A, Moore N, Yolken RH. 2004. Long-term consumption of infant formulas containing live probiotic bacteria: tolerance and safety. Am. J. Clin. Nutr. 79:261-67
Santas J, Fuentes M.C, Tormo R, Guayta-Escolies R, Lázaro E, Jordi C. Pediococcus
pentosaceus CECT 8330 and bifidobacterium longum CECT 7894 show a trend towards lowering infantile excessive crying syndrome in a pilot clinical trial. 2015. Int J Pharm Bio Sci. 6:458 – 466
Savino F, Cordisco L, Tarasco V, Palumeri E, Calabrese R, et al. 2010. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics 126:e526-33
Savino F, Garro M, Montanari P, Galliano I, Bergallo M. 2018. Crying Time and RORγ
/FOXP3 Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial. J. Pediatr. 192:171-77.e1
Savino F, Tarasco V. 2010. New treatments for infant colic. Curr. Opin. Pediatr. 22:791-97 Schreck BA, Gregory PJ, Jalloh MA, Risoldi CZ, Hein DJ. 2017. Probiotics for the Treatment of Infantile Colic: A Systematic Review. J Pharm Pract 30:366-74
Shenassa ED, Brown MJ. 2004. Maternal smoking and infantile gastrointestinal dysregulation: the case of colic. Pediatrics 114:e497-505
Sung V, D’Amico F, Cabana MD, Chau K, Koren G, et al. 2018. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics 141
Sung V, Hiscock H, Tang M, Mensah FK, Heine RG, et al. 2012. Probiotics to improve
outcomes of colic in the community: protocol for the Baby Biotics randomized controlled trial. BMC Pediatr 12:135
Szajewska H, Gyrczuk E, Horvath A. 2013. Lactobacillus reuteri DSM 17938 for the
management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J. Pediatr. 162:257-62
Tokatlı M, Gökşen G, Bağder ES, Arslankoz İN, Özçelik F. 2015. In Vitro Properties of
Potential Probiotic Indigenous Lactic Acid Bacteria Originating from Traditional Pickles. Biomed Res Int 2015:315819
Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. 2004. The PedsQL Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes 2:55 Vitolins MZ, Rand CS, Rapp SR, Ribisl PM, Sevick MA. 2000. Measuring adherence to behavioral and medical interventions. Control Clin Trials 21:188S-94S
Wake M, Morton-Allen E, Poulakis Z, Hiscock H, Gallagher S, Oberklaid F. 2006.
Prevalence, stability, and outcomes of cry-fuss and sleep problems in the first 2 years of life: prospective community-based study. Pediatrics 117:836-42
Weizman Z, Alsheikh A. 2006. Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study. J Am Coll Nutr 25:415-19
Zeevenhooven J, Koppen IJ, Benninga MA. 2017. The New Rome IV Criteria for Functional Gastrointestinal Disorders in Infants and Toddlers. Pediatr Gastroenterol Hepatol Nutr 20:1-13