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Figure.
Flowchart of the Participants’ Progression Through the Study
Flowchart of the Participants’ Progression Through the Study

Data represent children included in the study and the total number evaluated.

Table 1.  
Clinical and Demographic Data at Baseline
Clinical and Demographic Data at Baseline
Table 2.  
Primary Outcome at 1 Month of Life
Primary Outcome at 1 Month of Life
Table 3.  
Primary Outcome at 3 Months of Life
Primary Outcome at 3 Months of Life
Table 4.  
Secondary Outcome at 3 Months of Life
Secondary Outcome at 3 Months of Life
1.
Drossman  DA.  The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130(5):1377-1390.Article
2.
Hyman  PE, Milla  PJ, Benninga  MA, Davidson  GP, Fleisher  DF, Taminiau  J.  Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130(5):1519-1526.
PubMedArticle
3.
Rasquin  A, Di Lorenzo  C, Forbes  D,  et al.  Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527-1537.
PubMedArticle
4.
Iacono  G, Merolla  R, D’Amico  D,  et al; Paediatric Study Group on Gastrointestinal Symptoms in Infancy.  Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005;37(6):432-438.
PubMedArticle
5.
Barreau  F, Ferrier  L, Fioramonti  J, Bueno  L.  New insights in the etiology and pathophysiology of irritable bowel syndrome: contribution of neonatal stress models. Pediatr Res. 2007;62(3):240-245.
PubMedArticle
6.
Romanello  S, Spiri  D, Marcuzzi  E,  et al.  Association between childhood migraine and history of infantile colic. JAMA. 2013;309(15):1607-1612.
PubMedArticle
7.
Brown  M, Heine  RG, Jordan  B.  Health and well-being in school-age children following persistent crying in infancy. J Paediatr Child Health. 2009;45(5):254-262.
PubMedArticle
8.
Di Mauro  A, Neu  J, Riezzo  G,  et al.  Gastrointestinal function development and microbiota. Ital J Pediatr.2013;39(15):1-7. doi:10.1186/1824-7288-39-15.
9.
Szajewska  H, Gyrczuk  E, Horvath  A.  Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162(2):257-262.
PubMedArticle
10.
Indrio  F, Riezzo  G, Raimondi  F,  et al.  Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur J Clin Invest. 2011;41(4):417-422.
PubMedArticle
11.
Coccorullo  P, Strisciuglio  C, Martinelli  M, Miele  E, Greco  L, Staiano  A.  Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr. 2010;157(4):598-602.
PubMedArticle
12.
Savino  F, Pelle  E, Palumeri  E, Oggero  R, Miniero  R.  Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics. 2007;119(1):e124-e130.
PubMedArticle
13.
Indrio  F, Oliva  M, Fontana  C,  et al.  Infantile colic and regurgitation as a early traumatic insult in the development of functional gastrointestinal disorders. Dig Liver Dis. 2010;42:S347.Article
14.
Anand  KJ, Runeson  B, Jacobson  B.  Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J Pediatr. 2004;144(4):449-454.
PubMedArticle
15.
Smith  C, Nordstrom  E, Sengupta  JN, Miranda  A.  Neonatal gastric suctioning results in chronic visceral and somatic hyperalgesia: role of corticotropin releasing factor. Neurogastroenterol Motil. 2007;19(8):692-699.
PubMedArticle
16.
Lin  HC.  Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292(7):852-858.
PubMedArticle
17.
Mayer  EA, Tillisch  K.  The brain-gut axis in abdominal pain syndromes. Annu Rev Med. 2011;62:381-396.
PubMedArticle
18.
de Weerth  C, van Hees  Y, Buitelaar  JK.  Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Hum Dev. 2003;74(2):139-151.
PubMedArticle
19.
van der Wal  MF, van Eijsden  M, Bonsel  GJ.  Stress and emotional problems during pregnancy and excessive infant crying. J Dev Behav Pediatr. 2007;28(6):431-437.
PubMedArticle
20.
Wurmser  H, Rieger  M, Domogalla  C,  et al.  Association between life stress during pregnancy and infant crying in the first six months postpartum: a prospective longitudinal study. Early Hum Dev. 2006;82(5):341-349.
PubMedArticle
21.
de Weerth  C, Fuentes  S, Puylaert  P, de Vos  WM.  Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131(2):e550-e558.
PubMedArticle
22.
Liu  XL, Wong  KK.  Gastroesophageal reflux disease in children. Hong Kong Med J. 2012;18(5):421-428.
PubMed
23.
Kheir  AE.  Infantile colic, facts and fiction. Ital J Pediatr. 2012;38:34. doi:10.1186/1824-7288-38-34.Article
Original Investigation
Journal Club
March 2014

Prophylactic Use of a Probiotic in the Prevention of Colic, Regurgitation, and Functional ConstipationA Randomized Clinical Trial

Journal Club PowerPoint Slide Download
Author Affiliations
  • 1Department of Pediatrics, Aldo Moro University of Bari, Bari, Italy
  • 2Laboratory of Experimental Physiopathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis,” Castellana Grotte, Italy
  • 3Division of Neonatology, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  • 4Division of Neonatology, Department of Pediatrics, Ospedale S.S. Annunziata, Taranto, Italy
  • 5Division of Neonatology, Department of Pediatrics, S. Orsola-Malpighi University Hospital, Bologna, Italy
  • 6Division of Neonatology, Department of Pediatrics, University of Ferrara, Ferrara, Italy
  • 7Division of Neonatology, Department of Pediatrics, San Giovanni di Dio Hospital, Crotone, Italy
  • 8Department of Pediatrics, Ospedale Fracastoro, San Bonifacio, Italy
  • 9Division of Neonatology, Department of Pediatrics, Ospedale Sesto San Giovanni, Sesto San Giovanni, Italy
  • 10Division of Neonatology, Di Venere Hospital, Bari, Italy
  • 11Department of Biomedical Sciences and Human Oncology, Section of Hygiene, Aldo Moro University of Bari, Bari, Italy
JAMA Pediatr. 2014;168(3):228-233. doi:10.1001/jamapediatrics.2013.4367
Abstract

Importance  Infantile colic, gastroesophageal reflux, and constipation are the most common functional gastrointestinal disorders that lead to referral to a pediatrician during the first 6 months of life and are often responsible for hospitalization, feeding changes, use of drugs, parental anxiety, and loss of parental working days with relevant social consequences.

Objective  To investigate whether oral supplementation with Lactobacillus reuteri DSM 17938 during the first 3 months of life can reduce the onset of colic, gastroesophageal reflux, and constipation in term newborns and thereby reduce the socioeconomic impact of these conditions.

Design  A prospective, multicenter, double-masked, placebo-controlled randomized clinical trial was performed on term newborns (age <1 week) born at 9 different neonatal units in Italy between September 1, 2010, and October 30, 2012.

Setting  Parents were asked to record in a structured diary the number of episodes of regurgitation, duration of inconsolable crying (minutes per day), number of evacuations per day, number of visits to pediatricians, feeding changes, hospitalizations, visits to a pediatric emergency department for a perceived health emergency, pharmacologic interventions, and loss of parental working days.

Participants  In total, 589 infants were randomly allocated to receive L reuteri DSM 17938 or placebo daily for 90 days.

Interventions  Prophylactic use of probiotic.

Main Outcomes and Measures  Reduction of daily crying time, regurgitation, and constipation during the first 3 months of life. Cost-benefit analysis of the probiotic supplementation.

Results  At 3 months of age, the mean duration of crying time (38 vs 71 minutes; P < .01), the mean number of regurgitations per day (2.9 vs 4.6; P < .01), and the mean number of evacuations per day (4.2 vs 3.6; P < .01) for the L reuteri DSM 17938 and placebo groups, respectively, were significantly different. The use of L reuteri DSM 17938 resulted in an estimated mean savings per patient of €88 (US $118.71) for the family and an additional €104 (US $140.30) for the community.

Conclusions and Relevance  Prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the onset of functional gastrointestinal disorders and reduced private and public costs for the management of this condition.

Trial Registration  clinicaltrials.gov Identifier: NCT01235884

Functional gastrointestinal disorders (FGIDs) are defined as a variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities.1

Since FGIDs in childhood are age dependent, the Rome Foundation established 2 different pediatric committees to identify the criteria for FGID diagnosis: the Infant/Toddler Committee (age up to 4 years)2 and the Child/Adolescent Committee (aged 4-18 years).3

Quiz Ref IDInfantile colic, gastroesophageal reflux, and constipation are the most common FGIDs that lead to referral to a pediatrician during the first 6 months of life and are often responsible for hospitalization, feeding changes, use of drugs, parental anxiety, and loss of parental working days with relevant social consequences.4

Although FGIDs have been considered self-limited processes, a low-grade mucosal inflammation and immune or motor alteration has been found in infants affected by colic, regurgitation, and constipation. This early traumatic insult to the intestine may represent a risk factor for the development of irritable bowel syndrome and psychologic problems later in life.57 Recent work indicates a crucial role of the intestinal microbiota in the pathogenesis of gastrointestinal disorders as in FGIDs,8 and many studies target probiotic therapy for specific conditions such as colic,9 regurgitation,10 and constipation.11 The effect of a probiotic could play a crucial role in the modulation of intestinal inflammation.

Quiz Ref IDWe performed a prospective, multicenter, double-masked, placebo-controlled randomized clinical trial to evaluate whether oral supplementation with Lactobacillus reuteri DSM 17938 during the first 3 months of life can reduce the onset of colic, gastroesophageal reflux, and constipation in term newborns and thereby reduce the socioeconomic impact of these conditions.

Methods
Enrollment

The study was carried out between September 1, 2010, and October 30, 2012, in 9 Italian pediatric units. The ethics committees of each participating institution approved the study protocol, and written informed consent was obtained from parents before inclusion of participants.

Eligibility

Inclusion criteria were (1) gestational age more than 37 to less than 41 weeks, (2) age less than 1 week on entry into the study, (3) birth weight adequate for gestational age, (4) Apgar score of more than 8 at 10 minutes, (5) no congenital disorders and/or clinical or physical alterations at clinical examination, and (6) no antibiotic or probiotic administration before inclusion.

Study Design

Quiz Ref IDInfants were randomly allocated to receive either L reuteri DSM 17938 or placebo. The active study product consisted of freeze-dried L reuteri suspended in a mixture of pharmaceutical-grade sunflower and medium-chain triglyceride oils supplied in a dark bottle fitted with a dropper cap. Five drops of the formulation, delivering a dose of 1 × 108 colony-forming units of L reuteri DSM 17938, were administered to the newborns each day for 90 days. Parents were instructed to deliver the drops directly in the mouth of the infants. The placebo consisted of an identical formulation of oils supplied in an identical bottle, except that the live bacteria were excluded. There were no differences in smell or taste between the 2 formulations. Analysis of total Lactobacillus counts was performed in our laboratory on a sample probiotic bottle to ensure the viability of the live bacteria. The investigators assessed compliance through a weekly telephone call to record missed or refused probiotic administration. Both the L reuteri DSM 17938 and placebo study products were manufactured and donated by BioGaia AB.

Sample Size

With an α level of 0.05 and a power of 90% to detect an absolute difference of 15% between the proportion of infants with FGIDs in the placebo (assumed to be 30%) and probiotic groups, a sample size of 460 (230 in each group) was needed.

Randomization

An independent statistician generated the random allocation sequence, which was stratified for sex and gestational age. The study personnel, health care workers, and parents were masked to the study group allocation. Random allocation was performed using Stata 9 software (StataCorp LP).

Masking

Both parents and investigators were masked to the intervention and remained unaware of group assignments during the study.

Symptom and Data Evaluation

Parents were asked to record daily the number of episodes of regurgitation (defined as the passage of refluxed gastric contents into the oral pharynx), periods of inconsolable crying (minutes per day as already described in the literature12), and the number of evacuations. Using a structured diary, parents were asked to record the number of visits to pediatricians, feeding changes, hospitalizations, access to a pediatric emergency department for a perceived health emergency, pharmacologic interventions, and loss of parental working days. The parents recorded the data from recruitment up to age 3 months. Adverse events related to the protocol were monitored by prompted questions on the telephone. To promote uniform documentation by the parents and to confirm that the infants were given the study products correctly, 1 investigator for each center (A. Di Mauro, E.C., C.I., M.B., L.C., E.B., and A. Del Vecchio) was always available by telephone to help parents. All families received a weekly telephone call or personal meeting with one of the investigators, and all infants were observed at visits each month.

Primary and Secondary Outcomes

The primary outcome was to evaluate if L reuteri DSM 17938 supplementation from the first days of life can reduce inconsolable crying, improve regurgitation, and modify bowel movements in neonates during the first 3 months of life.

Secondary outcomes included a cost-benefit evaluation of the supplementation, calculated with the number of primary care pediatrician visits, feeding changes, hospitalizations, access to a pediatric emergency department, loss of parental working days, and the use of simethicone, cimetropium bromide, and natural or herbal products to control gastrointestinal symptoms.

Statistical Analysis

Quantitative data (daily time crying, bowel movements, and regurgitation) were expressed as mean (SD) differences. The t test for unpaired samples was used to compare groups. For pediatrician visits, feeding changes, hospitalizations, access to a pediatric emergency department, loss of parental working days, and use of drugs, the χ2 test was used to compare the percentages between groups. For all tests, P < .05 was considered significant.

Cost assessment was made by analyzing the costs for the family and community related to the frequency of each parameter in the treated and nontreated groups. Costs were as follows:

  1. Medical examination in the pediatric emergency department (€20.66 [US $27.87] for each examination, as provided by the Italian Ministry of Health)

  2. Work loss days (€43.15 [US $58.21] for each day, as provided by the Italian Ministry of Welfare)

  3. Drugs (at cost, defined in the list from the National Drug Authority)

  4. L reuteri (€60.48 [US $81.59] for the complete treatment)

Community costs were based on factors 1 and 2, while costs for the family were based on factors 3 and 4. This calculation was made since the National Health System in Italy covers all costs for pediatrician visits, and the National Welfare System finances all work loss expenses.

Results

Using the inclusion criteria, 589 newborns were initially included in the study, while 468 completed the 3-month study. Of these, 238 received L reuteri DSM 17938 supplementation and 230 had placebo (Figure). Participants were lost to follow-up because of voluntary withdrawal, withdrawal by the investigator for protocol violation, relocation from the study area, and use of antibiotics, proton-pump inhibitors, or other antacids. Demographic characteristics at baseline are described in Table 1. No clinically relevant differences between the 2 groups were seen at baseline, and the randomization procedure was successful.

After 1 month of intervention, infants receiving L reuteri DSM 17938 displayed a significant decrease in crying time, a significant increase in evacuation frequency, but no significant difference in regurgitation episodes compared with those given the placebo (Table 2). Quiz Ref IDAt the end of the 3-month intervention, significantly decreased crying time and significantly increased evacuation frequency were still evident (Table 3). Furthermore, infants who received L reuteri DSM 17938 showed significantly decreased regurgitation frequency compared with those who received the placebo (Table 3). There were no adverse events reported that were related to the trial.

At the end of the study, there were significantly less pediatric emergency department visits, lost parental working days, and use of agents to promote gastrointestinal comfort in the infants who received L reuteri DSM 17938 (Table 4). The frequency of feeding changes during the study was unaffected by the intervention (Table 4). The mean cost per child for each family related to these parameters was €150 (US $202.35) and €238 (US $321.06) for infants who received L reuteri DSM 17938 and placebo, respectively, while the mean cost per child for the community was €133 (US $179.42) and €237 (US $319.71) for infants who received L reuteri DSM 17938 and placebo, respectively. Thus, the prophylactic use of L reuteri DSM 17938 resulted in an estimated mean savings per participant of €88 (US $118.71) for the family, considering also the cost of the probiotic supplementation (Table 4) and an additional €104 (US $140.30) for the community. The assessment model used is straightforward and conservative and does not take into account indirect costs (such as those related to parental anxiety, exhaustion and stress, and increased number of visits to the family pediatrician), all of which increase the costs in the untreated group, augmenting the expected benefit of treatment.

Discussion

Daily administration of L reuteri DSM 17989 early in life decreased the reported incidence of inconsolable crying, regurgitation, and functional constipation in the first 3 months of life. There were no adverse events, and the supplementation was well tolerated. The socioeconomic impact of supplementation was a savings of €88 (US $118.71) for the family and €104 (US $140.30) for the community. To our knowledge, this is the first randomized clinical trial to address the use of a probiotic to prevent FGIDs in neonates. The study was adequately powered, and to serve as a proof of concept, we chose to perform a multicenter study that included a sufficient number of patients to increase the generalizability of our results.

Although infantile colic is not considered a serious problem, it is the cause of 10% to 20% of all pediatrician visits in the first 4 months of life and can lead to parental anxiety, exhaustion, and stress. Nearly 50% of all healthy infants aged 3 months and younger regurgitate at least once a day, with infant regurgitation representing 25% of pediatric consultations and 3% of gastrointestinal pediatric consultations. Constipation is generally responsible for 3% of all pediatric visits and can have several implications on the quality of life for both the child and the family.4

Functional gastrointestinal disorders in the neonatal period are often considered self-limiting clinical conditions, even though numerous studies in the literature reported these conditions as an early traumatic event predictive of different disease later in life.7,13 Furthermore, a recent study showed a significant association between migraine and history of infantile colic, where for children with migraine, the odds of having had colic as an infant were significantly increased.6

Our group performed a retrospective study of 3000 children diagnosed with irritable bowel syndrome according to Rome III criteria in our pediatric gastroenterology outpatient unit and matched them with healthy controls. The healthy children were evaluated through each child’s personal national health booklet and a parental interview. The results show that children diagnosed with irritable bowel syndrome had a higher percentage of neonatal infantile colic, regurgitation, and constipation than those without irritable bowel syndrome.13

The role of early life events in consequent FGIDs later in life is still controversial, even though some noxious stimulations at birth (ie, gastric suction or alteration of intestinal microbiota) might promote the development of long-term visceral hypersensitivity and cognitive hypervigilance, leading to functional disorders.1416 Early life events could increase visceral sensitivity and mucosal permeability, alter the balance of the enteric microflora, and increase mucosal and neurogenic low-grade inflammation, altering the signal of the gut-brain-microbiota axis.17

In support of this broad concept, several studies have found associations between maternal stress and anxiety during pregnancy and high amounts of infant crying in the weeks after birth.1820

Driving a change of colonization during the first weeks of life through giving lactobacilli may promote an improvement in intestinal permeability; visceral sensitivity and mast cell density and probiotic administration may represent a new strategy for preventing these conditions, at least in predisposed children. A recent article by de Weerth et al21 indicates the presence of microbial signatures in the first weeks of life in infants who later develop colic. These microbial signatures may be used to understand the excessive crying and offer opportunities for early diagnostics as well as for developing specific therapies.

The use of L reuteri DSM 17938 was cost-effective. Symptoms related to FGIDs are common from birth to 6 months of age.10 These conditions often cause numerous visits to the pediatrician, changes in feeding patterns, parental anxiety, and loss of parental working days with important socioeconomic consequences. In our study, daily crying time decreased during the first month of treatment, whereas regurgitation was significantly reduced only after the third month of treatment, possibly explained by the different temporal presentation of these symptoms in infants. Regurgitation actually appears more often in the second and third months of life, while constipation and crying have their peak at 4 to 6 weeks of life.22,23 Finally, a prophylactic approach using L reuteri can save money for both family and society and provide a helpful psychologic effect on the parents. Indeed, it is well known that supporting parents by teaching them to manage the crying and, consequently, acting on parental vulnerability can have a dramatic influence on parent-infant interactions and outcomes in these conditions.

Quiz Ref IDOur study has some limitations. There was a loss to follow-up of 16.8% of the study population, although the numbers lost in each group were similar and therefore should not significantly affect the results. Furthermore, an unselected general population was recruited, and the possible risk of overtreating normal neonates cannot be excluded.

Conclusion

Given the considerable burden of morbidity and the socioeconomic impact of early-life FGIDs, new research should urgently be initiated not only to validate our results but also to tailor optimal schemes of intervention.

Back to top
Article Information

Accepted for Publication: September 19, 2013.

Corresponding Author: Flavia Indrio, MD, Department of Pediatrics, Aldo Moro University of Bari, Policlinico, Piazza G Cesare 11, Bari, Italy (f.indrio@neonatologia.uniba.it).

Published Online: January 13, 2014. doi:10.1001/jamapediatrics.2013.4367.

Author Contributions: Dr Indrio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Indrio, Di Mauro, Riezzo, Corvaglia, Bisceglia, Del Vecchio, Francavilla.

Acquisition of data: Civardi, Intini, Corvaglia, Ballardini, Bisceglia, Cinquetti, Brazzoduro.

Analysis and interpretation of data: Riezzo, Intini, Tafuri.

Drafting of the manuscript: Indrio, Di Mauro, Riezzo, Intini, Ballardini, Bisceglia, Brazzoduro, Del Vecchio.

Critical revision of the manuscript for important intellectual content: Civardi, Corvaglia, Bisceglia, Cinquetti, Del Vecchio, Tafuri, Francavilla.

Statistical analysis: Intini, Tafuri.

Administrative, technical, or material support: Civardi, Bisceglia.

Study supervision: Indrio, Riezzo, Bisceglia, Del Vecchio, Francavilla.

Funding/Support: This study was supported by BioGaia AB, Sweden, which provided active study product and placebo.

Role of the Sponsors: The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Drossman  DA.  The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130(5):1377-1390.Article
2.
Hyman  PE, Milla  PJ, Benninga  MA, Davidson  GP, Fleisher  DF, Taminiau  J.  Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130(5):1519-1526.
PubMedArticle
3.
Rasquin  A, Di Lorenzo  C, Forbes  D,  et al.  Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527-1537.
PubMedArticle
4.
Iacono  G, Merolla  R, D’Amico  D,  et al; Paediatric Study Group on Gastrointestinal Symptoms in Infancy.  Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005;37(6):432-438.
PubMedArticle
5.
Barreau  F, Ferrier  L, Fioramonti  J, Bueno  L.  New insights in the etiology and pathophysiology of irritable bowel syndrome: contribution of neonatal stress models. Pediatr Res. 2007;62(3):240-245.
PubMedArticle
6.
Romanello  S, Spiri  D, Marcuzzi  E,  et al.  Association between childhood migraine and history of infantile colic. JAMA. 2013;309(15):1607-1612.
PubMedArticle
7.
Brown  M, Heine  RG, Jordan  B.  Health and well-being in school-age children following persistent crying in infancy. J Paediatr Child Health. 2009;45(5):254-262.
PubMedArticle
8.
Di Mauro  A, Neu  J, Riezzo  G,  et al.  Gastrointestinal function development and microbiota. Ital J Pediatr.2013;39(15):1-7. doi:10.1186/1824-7288-39-15.
9.
Szajewska  H, Gyrczuk  E, Horvath  A.  Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162(2):257-262.
PubMedArticle
10.
Indrio  F, Riezzo  G, Raimondi  F,  et al.  Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur J Clin Invest. 2011;41(4):417-422.
PubMedArticle
11.
Coccorullo  P, Strisciuglio  C, Martinelli  M, Miele  E, Greco  L, Staiano  A.  Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr. 2010;157(4):598-602.
PubMedArticle
12.
Savino  F, Pelle  E, Palumeri  E, Oggero  R, Miniero  R.  Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics. 2007;119(1):e124-e130.
PubMedArticle
13.
Indrio  F, Oliva  M, Fontana  C,  et al.  Infantile colic and regurgitation as a early traumatic insult in the development of functional gastrointestinal disorders. Dig Liver Dis. 2010;42:S347.Article
14.
Anand  KJ, Runeson  B, Jacobson  B.  Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J Pediatr. 2004;144(4):449-454.
PubMedArticle
15.
Smith  C, Nordstrom  E, Sengupta  JN, Miranda  A.  Neonatal gastric suctioning results in chronic visceral and somatic hyperalgesia: role of corticotropin releasing factor. Neurogastroenterol Motil. 2007;19(8):692-699.
PubMedArticle
16.
Lin  HC.  Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292(7):852-858.
PubMedArticle
17.
Mayer  EA, Tillisch  K.  The brain-gut axis in abdominal pain syndromes. Annu Rev Med. 2011;62:381-396.
PubMedArticle
18.
de Weerth  C, van Hees  Y, Buitelaar  JK.  Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Hum Dev. 2003;74(2):139-151.
PubMedArticle
19.
van der Wal  MF, van Eijsden  M, Bonsel  GJ.  Stress and emotional problems during pregnancy and excessive infant crying. J Dev Behav Pediatr. 2007;28(6):431-437.
PubMedArticle
20.
Wurmser  H, Rieger  M, Domogalla  C,  et al.  Association between life stress during pregnancy and infant crying in the first six months postpartum: a prospective longitudinal study. Early Hum Dev. 2006;82(5):341-349.
PubMedArticle
21.
de Weerth  C, Fuentes  S, Puylaert  P, de Vos  WM.  Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131(2):e550-e558.
PubMedArticle
22.
Liu  XL, Wong  KK.  Gastroesophageal reflux disease in children. Hong Kong Med J. 2012;18(5):421-428.
PubMed
23.
Kheir  AE.  Infantile colic, facts and fiction. Ital J Pediatr. 2012;38:34. doi:10.1186/1824-7288-38-34.Article
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