Signs and symptoms associated with digestive tract development Please cite this article as: Morais MB. Signs and symptoms associated with digestive tract development. J Pediatr (Rio J). 2016;92(3 Suppl 1):S46–56.

Mauro Batista de Morais About the author

ABSTRACT

Objective:

To analyze the development and prevalence of gastrointestinal signs and symptoms associated with the development of the digestive tract, and to assess the measures aimed to reduce their negative impacts.

Source of data:

Considering the scope and comprehensiveness of the subject, a systematic review of the literature was not carried out. The Medline database was used to identify references that would allow the analysis of the study topics.

Synthesis of results:

Infants frequently show several gastrointestinal signs and symptoms. These clinical manifestations can be part of gastrointestinal functional disorders such as infantile colic, infant regurgitation, and functional constipation. Allergy to cow's milk protein and gastroesophageal reflux disease are also causes of these clinical manifestations and represent an important and difficult differential diagnosis. The diseases that course with gastrointestinal signs and symptoms can have an impact on family dynamics and maternal emotional status, and may be associated with future problems in the child's life. Comprehensive pediatric care is essential for diagnosis and treatment. Maternal breastfeeding should always be maintained. Some special formulas can contribute to the control of clinical manifestations depending on the established diagnosis.

Conclusion:

During the normal development of the digestive tract, several gastrointestinal signs and symptoms may occur, usually resulting from functional gastrointestinal disorders, gastroesophageal reflux disease, and allergy to cow's milk protein. Breastfeeding should always be maintained.

KEYWORDS
Gastroesophageal reflux; Constipation; Crying; Milk hypersensitivity; Infant; Infant formula

RESUMO

Objetivo:

Analisar o desenvolvimento e a prevalência de sinais e sintomas gastrintestinais associados com o desenvolvimento do tubo digestivo e as medidas que visam a diminuir suas repercussões negativas.

Fontes dos dados:

Considerando a abrangência e amplitude do tema, não foi feita revisão sistemática da literatura. Usou-se a base de dados do Medline para a identificação de referências bibliográficas que permitissem contemplar os temas de estudo.

Síntese dos resultados:

O lactente apresenta com elevada frequência sinais e sintomas gastrintestinais. Essas manifestações clínicas podem fazer parte de distúrbios funcionais gastrintestinais, como cólica, regurgitação e constipação intestinal funcional. A alergia à proteína do leite de vaca e a doença do refluxo gastroesofágico também são causas dessas manifestações clínicas e representam um importante e difícil diagnóstico diferencial. As doenças que cursam com sintomas e sinais gastrintestinais podem ter consequências na dinâmica familiar e no estado emocional das mães. Podem se associar com problemas na vida futura da criança. A atenção pediátrica completa é fundamental para o diagnóstico e o tratamento. O aleitamento natural deve sempre ser mantido. Algumas fórmulas especiais podem contribuir para o controle das manifestações clínicas na dependência do diagnóstico estabelecido.

Conclusão:

Durante o desenvolvimento normal do tubo digestivo podem ocorrer sinais e sintomas gastrintestinais em geral decorrentes dos distúrbios gastrintestinais funcionais, da doença do refluxo gastroesofágico e da alergia à proteína do leite de vaca. Aleitamento natural deve sempre ser mantido.

PALAVRAS-CHAVE
Refluxo gastroesofágico; Constipação intestinal; Choro; Hipersensibilidade a leite; Lactente; Fórmulas infantis

Introduction

Since the conception, characterized by the moment when the sperm enters the egg, the biological potential for the formation of a new human being develops into a fascinating process of cell multiplication and differentiation. The maturation of the individual occurs during the course of different stages of life. Currently, the first 1000 days, starting at conception, are considered to be a critical period to define the health status of the individual and can have consequences throughout life.11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38.,22 Koletzko B, Brands B, Chourdakis M, Cramer S, Grote V, Hellmuth C, et al. The power of programming and the Early Nutrition project: opportunities for health promotion by nutrition during the first thousand days of life and beyond. Ann Nutr Metab. 2014;64:187-96.

The first two years of life are an important part of this period, which is characterized by accelerated growth rate and development of several organs and systems. Therefore, gastrointestinal signs and symptoms can occur in infants,33 Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29:184-94.,44 Vandenplas Y, Alarcon P, Alliet P, De Greef E, De Ronne N, Hoffman I, et al. Algorithms for managing infant constipation, colic, regurgitation and cow's milk allergy in formula-fed infants. Acta Paediatr. 2015;104:449-57. which may be linked to several anatomical and functional changes observed at this stage of life. In addition to these clinical manifestations, there may be repercussions in the individual's future,55 Vandenplas Y, Abkari A, Bellaiche M, Benninga M, Chouraqui JP, Çokura F, et al. Prevalence and health outcomes of functional gastrointestinal symptoms in infants from birth to 12 months of age. J Pediatr Gastroenterol Nutr. 2015;61:531-7. as well as consequences that will interfere in family dynamics and the parents’ emotional status.

It can be said that the development of the digestive system comprises not only the anatomical and functional aspects of its organs but also local and systemic interactions with the intestinal immune system and the establishment of the gastrointestinal microbiota. The interaction among these three processes has been the object of many basic science and clinical studies searching for alternatives that can provide favorable results during the first 1000 days and several future cycles of life.

This article aimed to analyze the emergence and prevalence of gastrointestinal signs and symptoms associated with the development of the gastrointestinal tract and measures aimed to reduce their negative impacts.

Methods

Considering the scope and comprehensiveness of the subject, a systematic review of the literature was not carried out. The Medline database was used to identify literature references that included the subject of the study. Among others, were used the following terms in the search for information, “digestive,” “tract,” “ontogeny,” “microbiota,” “development,” “premature,” “oral,” and “tolerance”. When necessary, the research was restricted to humans. The author also used his personal experience and trends discussed in national and international scientific events.

Anatomical and functional development of the gastrointestinal tract

The intestine is one of the most complex organs in the human body, both from the anatomical and functional point of view. The intestinal cells and tissues are formed from all three germ layers. Intestinal stem cells derive from the mesoderm, the muscle tissue of the endoderm, and the enteric nervous system of the ectoderm.66 Wells JM, Spence JR. How to make an intestine. Development. 2014;141:752-760. In addition to the digestive and absorptive functions, there are also the intestinal endocrine system (involved in the regulation of systemic levels of nutrients and feeding behavior) and the so-called intestinal barrier, which prevents the passage of the intestinal contents, including microorganisms, into the body.

The epithelial function is carried out by four types of cells: enterocytes, which are responsible for absorption, and three types of secretory cells (mucus-producing goblet cells, antibacterial substance-producing Paneth cells, and several enteroendocrine cells that regulate satiety, intestinal absorption, proliferation of pancreas β-cells, and hormone secretion, among others).66 Wells JM, Spence JR. How to make an intestine. Development. 2014;141:752-760. It is also noteworthy the intense epithelial proliferation of stem cells, which renew the luminal surface of the intestine in a few days, and the complex interaction among the epithelium, smooth muscle, and enteric nervous system, to ensure a unidirectional flow provided by intestinal peristalsis.66 Wells JM, Spence JR. How to make an intestine. Development. 2014;141:752-760.

The development of the intestine during gestation can be divided into four basic processes: 1. cell differentiation; 2. digestion; 3. absorption; and 4. motility.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73. Table 1 shows the major milestones of intestinal development.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73.

Table 1
Main milestones of intestinal development 77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73.

These physiological properties are very important to understand the feeding process of the newborn, especially those preterm. The transition from parenteral feeding via the umbilical cord and small amounts of swallowed amniotic fluid to obtaining complete nutrients from the colostrum and breast milk occurs at birth.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73. At that time, the intestine undergoes a rapid morphological growth process in terms of length and absorptive surface. It is noteworthy that the intestinal length is estimated at 50 cm in the middle of pregnancy, at approximately 100 cm in the weeks before birth, and 200 cm in the first weeks of life.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73. The colostrum stimulus is important in this process.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73.

Preterm infant feeding is a major challenge due to the immaturity of the digestive system (especially of the swallowing reflex), the lower lactase activity, and the immature pattern of the gastrointestinal tract motility. These facts explain, at least in part, the high prevalence of food intolerance, gastroesophageal reflux, and constipation in preterm infants.77 Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract. 2007;22:159-73.

Colonization of the digestive tract

The development of molecular biology techniques, which do not depend on bacterial isolation through conventional culture methods, has led to extraordinary increase in the knowledge of microorganisms that live in the intestine.88 Neu J, Douglas-Escobar M, Lopez M. Microbes and the developing gastrointestinal tract. Nutr Clin Pract. 2007;22:174-182. More than 1013 microorganisms can be found per gram of intestinal contents in the colon. Knowledge about bacterial diversity has also increased since the identification of new species that comprise the digestive tract microbiota. It is believed that the number of genes in the human microbiota is 100 times higher than in the human body. It is noteworthy that there is a mutual and beneficial interaction between the microbiota and the host. Thus, there are not only nutritional interactions (colonic fermentation with the production of short-chain fatty acids that are absorbed in the colon, and lipid and protein hydrolysis) but also interaction with the intestinal immune system.11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38.,88 Neu J, Douglas-Escobar M, Lopez M. Microbes and the developing gastrointestinal tract. Nutr Clin Pract. 2007;22:174-182.

It should be remembered that the intestinal microbiota is not constituted only of bacteria. Fungi and viruses are also found in the lumen of the gastrointestinal tract. The potential therapeutic use of viruses interfering with the intestinal microbiota composition represents a new challenge in research on the microbiome of humans.99 Mueller NT, Bakacsm E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trend Mol Med. 2015;21:109-117.

The belief that the fetus lives in a sterile environment has been modified in recent years based on evidence of the existence of microorganisms in the amniotic fluid, umbilical cord blood, fetal membranes, and the placenta.1010 Scarpellini E, Ianirob G, Attili F, Bassanellid C, De Santis A, Gasbarrini A. The human gut microbiota and virome: potential therapeutic implications. Dig Liv Dis. 2015;47:1007-12. These findings should be interpreted with caution due to the possibility of contamination of the samples at the time of collection.1010 Scarpellini E, Ianirob G, Attili F, Bassanellid C, De Santis A, Gasbarrini A. The human gut microbiota and virome: potential therapeutic implications. Dig Liv Dis. 2015;47:1007-12. The changes in the mother's vaginal and colonic microbiota during pregnancy are noteworthy, considering that the maternal microbiota influences the formation of the fetus’ and the newborn's microbiota.1010 Scarpellini E, Ianirob G, Attili F, Bassanellid C, De Santis A, Gasbarrini A. The human gut microbiota and virome: potential therapeutic implications. Dig Liv Dis. 2015;47:1007-12.

On the first day of life there is fast newborn intestinal colonization by microorganisms from the maternal and environmental microbiota.88 Neu J, Douglas-Escobar M, Lopez M. Microbes and the developing gastrointestinal tract. Nutr Clin Pract. 2007;22:174-182. The first colonizing agents belong to the genera Escherichia and Enterococcus. Subsequently, anaerobic bacteria of the Bifidobacterium and Bacteroidetes genera appear. That is, the first bacteria are facultative anaerobic (Staphylococcus, Streptococcus, Enterococcus, Enterobacter) that contribute to the development of an anaerobic environment in the intestine, which thus allows the for colonization by obligate anaerobes (Bifidobacterium, Bacteriodetes, Clostridium, Eubacterium).11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38.

With the introduction of complementary foods to breast milk in the infant's diet an important impact is observed on the intestinal microflora, characterized by decreased participation of bifidobacteria (which, however, remains predominant) and increased diversity with greater participation of bacteria from the genera Bacteroides and Clostridium.11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38. A study performed with Brazilian infants receiving exclusive breastfeeding identified six phyla in the fecal microbiota: Bacteroidetes, Firmicutes, Fusobacterium, Proteobacteria, Actinobacteria, and Verrucomicrobia.1111 Taddei CR, Oliveira FF, Duarte RT, Talarico ST, Takagi EH, Ramos Carvalho II, et al. High abundance of Escherichia during the establishment of fecal microbiota in Brazilian children. Microb Ecol. 2014;67:624-34. At three months of life, there was a predominance of Streptococcus and Escherichia; at six months, the predominance of Escherichia was observed.1111 Taddei CR, Oliveira FF, Duarte RT, Talarico ST, Takagi EH, Ramos Carvalho II, et al. High abundance of Escherichia during the establishment of fecal microbiota in Brazilian children. Microb Ecol. 2014;67:624-34.

The colonization of the digestive tract of the newborn and infant depends on several factors, especially the type of delivery and type of feeding. Over the first two years of life, it is observed that the caesarean delivery is associated with greater abundance of Firmicutes and lower of Bacteroidetes. During the first six months of life it is observed that the colonization by Bacteroidetes occurs at a later phase. At the end of two years of life, the relative abundance of microbial constituents is similar in both infants born by vaginal delivery and caesarean section. It was also observed that the circulating levels of cytokines produced by helper T lymphocytes are lower among those born through caesarean section. It should be noted that the fecal microbiota of mothers of children born through caesarean section and vaginal delivery were not different.1212 Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section. Gut. 2014;63:559-66.

Regarding the type of feeding, it is well known that the intestinal microbiota of infants who are exclusively breastfed is different from those fed with artificial formula.1313 Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics. 1983;72:317-21.1515 Walker WA. Initial intestinal colonization in the human infant and immune homeostasis. Ann Nutr Metabol. 2013;63:S8-S15. Breast milk is rich in oligosaccharides that influence the composition of the intestinal microbiota.1616 Thurl S, Munzert M, Henker J, Boehm G, Müller-Werner B, Jelinek J, et al. Variation of human milk oligosaccharides in relation to milk groups and lactational periods. Brit J Nutr. 2010;104:1261-1271.,1717 Marx C, Bridge R, Wolf AK, Rich W, Kim JH, Bode L. Human milk oligosaccharide composition differs between donor milk and mother's own milk in the NICU. J Hum Lact. 2014;30:54-61. It is also known that the oligosaccharide profile in breast milk is not the same in all mothers.1818 De Leoz ML, Kalanetra KM, Bokulich NA, Strum JS, Underwood MA, German JB, et al. Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of-concept study. J Proteome Res. 2015;14:491-502.,1919 Wang M, Li M, Wu S, Lebrilla CB, Chapkin RS, Ivanov I, et al. Fecal microbiota composition of breast-fed infants is correlated with human milk oligosaccharides consumed. J Pediatr Gastroenterol Nutr. 2015;60:825-33. The specific effects of these different oligosaccharide profiles on the intestinal microbiota are not yet fully known.1818 De Leoz ML, Kalanetra KM, Bokulich NA, Strum JS, Underwood MA, German JB, et al. Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of-concept study. J Proteome Res. 2015;14:491-502.,1919 Wang M, Li M, Wu S, Lebrilla CB, Chapkin RS, Ivanov I, et al. Fecal microbiota composition of breast-fed infants is correlated with human milk oligosaccharides consumed. J Pediatr Gastroenterol Nutr. 2015;60:825-33. However, breast milk was considered practically sterile until some years ago. Recently a hypothesis was raised that suggests a new way of communication between the mother's and the infant's microbiota.2020 Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. 2013;69:1-10.,2121 Chassard C, de Wouters T, Lacroix C. Probiotics tailored to the infant: a window of opportunity. Curr Opin Biotechnol. 2014;26:141-7. In this context, it is suggested that bacteria from the mother's intestinal microbiota would reach the breast milk by translocation from the intestinal lumen and through bloodstream transportation, featuring an internal enteromammary pathway.2020 Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. 2013;69:1-10.,2121 Chassard C, de Wouters T, Lacroix C. Probiotics tailored to the infant: a window of opportunity. Curr Opin Biotechnol. 2014;26:141-7. This hypothesis was created based on animal studies. These bacteria could influence the infant's colonization process and maturation of the immune system. Another possible pathway is the entry of bacteria from the skin tissue of the mother in the mammary gland through the nipple.2020 Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. 2013;69:1-10.,2121 Chassard C, de Wouters T, Lacroix C. Probiotics tailored to the infant: a window of opportunity. Curr Opin Biotechnol. 2014;26:141-7. Thus, colostrum and human milk are not only sources of oligosaccharides that stimulate the formation of intestinal microflora but also probably a source of bacteria for the infant. It is estimated that 800 mL of breast milk can contain up to 105 to 107 colony-forming units. The bacteria that have been identified in breast milk samples belong mainly to the genera Lactobacillus, Staphylococcus, Enterococcus, and Bifidobacterium.2020 Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. 2013;69:1-10.,2121 Chassard C, de Wouters T, Lacroix C. Probiotics tailored to the infant: a window of opportunity. Curr Opin Biotechnol. 2014;26:141-7.

The intestinal microbiota, through molecular structures that constitute the microbe-associated molecular patterns (MAMPs) interacts with the intestinal immunological system and the intestinal barrier and also interferes with the production of mucus. They stimulate cell proliferation in the crypts and Paneth cells responsible for producing the antimicrobial peptides called defensins. This interaction (“crosstalk”) occurs with specific receptors, such as the toll-like receptors. Pro-inflammatory responses can be neutralized by the specialized regulatory T (Treg) cells through interleukin 10 production.

This mechanism is very important in the development of oral tolerance. Probiotic bacteria such as Lactobacillus GG and Bifidobacterium breve can stimulate the process of immunological tolerance through interleukin-production stimulation.11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38.,2222 Canani RB, Nocerino R, Terrin G, Coruzzo A, Cosenza L, Leone L, et al. Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: a randomized trial. J Allergy Clin Immunol. 2012;129:580-2.,2323 Canani RB, Nocerino R, Terrin G, Frediani T, Lucarelli S, Consenza L, et al. Formula selection for management of children with cow’ milk allergy influences the rate of acquisition of tolerance: a prospective multicenter study. J Pediatr. 2013;163:771-7.

The M cells located next to Peyer's patches are responsible for the presentation of intestinal lumen contents and thus, stimulate the immunological system of the mucosa.11 Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days – Intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25:428-38.

Abnormalities in oral tolerance development in the first months of life can cause non-IgE-mediated allergy to cow's milk protein.2424 Dupont C. Food allergy: recent advances in pathophysiology and diagnosis. Ann Nutr Metab. 2011;59:S8-18.

Gastrointestinal signs and symptoms in infants

The occurrence of digestive symptoms is common in the first months of life, such as regurgitation, vomiting, colic, and constipation. Some clinical manifestations, although they do not constitute a defined disease, may be of concern to parents, such as flatulence, which, incidentally, is hard to quantify to be characterized as excessive or not. Many of these symptoms may be transient and are attributed to immaturity and/or are considered as part of the development of the gastrointestinal tract. Many of these clinical manifestations are included in functional gastrointestinal disorders and their diagnosis can be established by the Rome III criteria.2525 Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-26. The gastroesophageal reflux disease (GERD) and allergy to cow's milk protein are not functional gastrointestinal disorders; however, they can lead to several gastrointestinal signs and symptoms, especially in the first year of life.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229. In pediatric practice, allergy to cow's milk protein and GERD are often part of the differential diagnosis of gastrointestinal functional disorders.2828 Salvatore S, Vandenplas Y. Gastroesophageal reflux and cow’ milk allergy: is there a link? Pediatrics. 2002;110:972-84.,2929 Vandenplas Y, Gottrand F, Veereman-Wauters G, De Greef E, Devreker T, Hauser B, et al. Gastrointestinal manifestations of cow's milk protein allergy and gastrointestinal motility. Acta Paediatr. 2012;101:1105-9.

Therefore, the infant can have different gastrointestinal signs and symptoms, especially in the first six months of life. The physician should recognize the clinical manifestation as isolated and/or transient or as part of a functional gastrointestinal disorder, allergy to cow's milk, or even GERD. Other diseases that are not restricted to the digestive tract are included in the differential diagnosis. Only after careful evaluation and definition of the diagnostic hypothesis it is possible to define the approach to be used. Table 2 presents information that can contribute to the differential diagnosis of gastrointestinal signs and symptoms in infants.2525 Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-26.3232 Vieira MC, Morais MB, Spolidoro JV, Toporovski MS, Cardoso AL, Araujo GT, et al. A survey on clinical presentation and nutritional status of infants with suspected cow’ milk allergy. BMC Pediatrics. 2010;10:25. Cyclic vomiting syndrome and rumination were not included, because they are not as prevalent as other functional gastrointestinal disorders.

Table 2
Diagnostic criteria for infant diseases presenting with predominantly gastrointestinal symptoms.

In 2015, a group of specialists from several countries evaluated the available information in the literature on the prevalence of gastrointestinal functional disorders in the first year of life.55 Vandenplas Y, Abkari A, Bellaiche M, Benninga M, Chouraqui JP, Çokura F, et al. Prevalence and health outcomes of functional gastrointestinal symptoms in infants from birth to 12 months of age. J Pediatr Gastroenterol Nutr. 2015;61:531-7. The median prevalence of infantile colic in 30 articles was 18%; however, great variability was observed due, at least in part, to the diversity of diagnostic criteria. It is interesting to mention that, in a study conducted in Brazil that characterized infantile colic according to the Wessel criterion, 16% of the 1086 infants assessed had colic; however, according to their mothers, 80% had colic.3333 Saavedra MA, da Costa JS, Garcias G, Horta BL, Tomasi E, Mendonça R. Incidência de cólica no lactente e fatores associados: um estudo de coorte. J Pediatr (Rio J). 2003;79:115-122. Therefore, there is no full consensus among the different diagnostic criteria used in the studies of prevalence, as well as the opinions and expectations of parents. Regarding the prevalence of infant regurgitation, 13 articles were retrieved, with results ranging from 3% to 87%. The Rome III criteria was used in only two of these 13 articles (two or more regurgitations a day for more than three weeks), with a prevalence of 17% and 26%. It should be noted that, in general, infant regurgitation disappears spontaneously up to 12 months of life.55 Vandenplas Y, Abkari A, Bellaiche M, Benninga M, Chouraqui JP, Çokura F, et al. Prevalence and health outcomes of functional gastrointestinal symptoms in infants from birth to 12 months of age. J Pediatr Gastroenterol Nutr. 2015;61:531-7.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95. In turn, the prevalence of GERD in infants is unknown, but it is accepted that it is much lower than that of infant regurgitation.3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95. The prevalence of functional constipation in the first year of life showed great variation, from less than 1% to 39% in the eight studies retrieved.55 Vandenplas Y, Abkari A, Bellaiche M, Benninga M, Chouraqui JP, Çokura F, et al. Prevalence and health outcomes of functional gastrointestinal symptoms in infants from birth to 12 months of age. J Pediatr Gastroenterol Nutr. 2015;61:531-7. Two cross-sectional studies that used the Rome III criteria found a prevalence of constipation of 0.05–5%.55 Vandenplas Y, Abkari A, Bellaiche M, Benninga M, Chouraqui JP, Çokura F, et al. Prevalence and health outcomes of functional gastrointestinal symptoms in infants from birth to 12 months of age. J Pediatr Gastroenterol Nutr. 2015;61:531-7. In the author's opinion, the Rome III criteria underestimate the diagnosis of intestinal constipation, especially in the first year of life.3636 Hyams J, Colletti R, Faure C, Gabriel-Martinez E, Maffei HV, Morais MB, et al. Functional gastrointestinal disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2002;35:S110-7.,3737 Maffei HV, de Morais MB. Defining constipation in childhood and adolescence: from Rome, via Boston, to Paris and …?. J Pediatr Gastroenterol Nutr. 2005;41:485-6. A recent study compared the prevalence of intestinal constipation in 831 Brazilian infants using the Rome III criteria and another broader criterion (elimination of hard stools with pain/difficulty and/or less frequently than three times a week; or elimination of cylindrical hard stools with cracks or scybalous stools, even if eliminated without pain or difficulty).3838 Morais MB, Souza DS, Aguirre ANC, Tahan S, Vitolo MR, Puccini RF. Critério diagnóstico de Roma III subestima a prevalência de constipação intestinal em lactentes. In: Congreso Ibero Latinoamericano de Gastroenterología, Nutrición y Hepatología Pediátrica. 2015. According to the Rome III criteria, the prevalence of intestinal constipation was 1.1%, whereas the broader criterion identified constipation in 19.6% of the study population.3838 Morais MB, Souza DS, Aguirre ANC, Tahan S, Vitolo MR, Puccini RF. Critério diagnóstico de Roma III subestima a prevalência de constipação intestinal em lactentes. In: Congreso Ibero Latinoamericano de Gastroenterología, Nutrición y Hepatología Pediátrica. 2015.

It is estimated that the prevalence of allergy to cow's milk protein ranges from 2% to 3% in the first year of life.2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229. It must be remembered, however, that clinical manifestations suggestive of allergy to cow's milk are present in a higher percentage of infants, approximately 9% according to a prospective study carried out in the Netherlands.3939 Petrus NC, Schoemaker AF, van Hoek MW, Jansen L, Jansen-van der Weide MC, van Aalderen WM, et al. Remaining symptoms in half the children treated for milk allergy. Eur J Pediatr. 2015;174:759-65. It can be estimated that only a portion of infants (approximately 30–50%) that undergo an elimination diet will show a positive challenge test, confirming the diagnosis.3939 Petrus NC, Schoemaker AF, van Hoek MW, Jansen L, Jansen-van der Weide MC, van Aalderen WM, et al. Remaining symptoms in half the children treated for milk allergy. Eur J Pediatr. 2015;174:759-65.,4040 Lins Md Horowitz MR, Silva GA, Motta ME. Oral food challenge test to confirm the diagnosis of cow's milk allergy. J Pediatr (Rio J). 2010;86:285-9.

Thus, it can be observed that many infants have gastrointestinal signs and symptoms. Some of these infants have more than one symptom.44 Vandenplas Y, Alarcon P, Alliet P, De Greef E, De Ronne N, Hoffman I, et al. Algorithms for managing infant constipation, colic, regurgitation and cow's milk allergy in formula-fed infants. Acta Paediatr. 2015;104:449-57.,4141 Iacono G, Merolla R, D’Amico D, Bonci E, Cavataio F, Di Prima L, et al. Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005;37:432-438. These gastrointestinal manifestations are often reasons for changes in the infants’ diet, mainly changes in the type of infant formula.4242 Forsyth BW, McCarthy PL, Leventhal JM. Problems of early infancy, formula changes, and mothers’ beliefs about their infants. J Pediatr. 1985;106:1012-7.,4343 Polack FP, Khan N, Maisels MJ. Changing partners: the dance of infant formula changes. Clin Pediatr. 1999;38:703-8.

Pediatric care for infants with gastrointestinal clinical manifestations

The first point to be considered is whether the infant's gastrointestinal sign or symptom is actually part of a disease or simply part of the normal digestive physiology or of the development of the gastrointestinal tract in the first year of life.

During pediatric visits, parents often mention that their children pass an excessive volume of gas. An article with suggestions of conduct for frequent gastrointestinal signs in infants discusses this question, associating it with crying and fussiness.33 Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29:184-94. It is noteworthy that the presence of gas in the digestive tract is normal. Excess gas, however, could result from an inappropriate breastfeeding technique, with the occurrence of aerophagia.33 Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29:184-94.

Excessive crying and fussiness are often considered as gastrointestinal manifestations.4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75. In 1954, Wessel defined infantile colic as episodes of irritability, agitation, or intense crying for at least three hours, three days a week and lasting more than three weeks (“rule of three”).4646 Wessel MA, Cobb JC, Jackson EB, Harris GS Jr, Detwiler AC. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics. 1954;14:421-34. In general, it disappears at approximately four months of life.4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75. In 2006, infantile colic was included in the Rome III criteria (Table 2), which aims to standardize the diagnosis of functional gastrointestinal disorders.2525 Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-26. In practice, both for health professionals and parents, these criteria do not always have to be fully met for infantile colic to be considered a concern and a serious problem.

A study conducted in the pediatric emergency department of the Netherlands has shown that, in the care of infants with crying as the main cause of consultation, approximately 6% of parents acknowledged the practice of actions that could pose a serious health hazard to infants, such as shaking (which can be a cause of the “shaken baby syndrome”) and attempts at suffocation.4747 Reijneveld SA, van der Wal MF, Brugman E, Sing RA, Verloove-Vanhorick SP. Infant crying and abuse. Lancet. 2004;364:1340-2. Alarming results were found in another study carried out in Japan.4848 Yamada F, Fujiwara T. Prevalence of self-reported shaking and smothering and their associations with co-sleeping among 4-month-old infants in Japan. Int J Environ Res Public Health. 2014;11:6485-93.

Mothers of infants with colic may have decreased quality of life, especially in the areas of physical and social performance, and increased risk of depression,4949 Abaci FB, Gökçe S, Tuygun N, Karacan CD, Öner Ö. Psychosocial status and quality of life in mothers of infants with colic. Turk J Pediatr. 2013;55:391-5.,5050 Vik T, Grote V, Escribano J, Socha J, Verduci E, Fritsch M, et al. Infantile colic, prolonged crying, and maternal postnatal depression. Acta Paediatr. 2009;98:1344-8. which may decrease with the control of colic.5151 Mi GL, Zhao L, Qiao DD, Kang WQ, Tang MQ, Xu JK. Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial. Antonie Van Leeuwenhoek. 2015;107:1547-53. Thus, infantile colic, expressed as intense and inconsolable crying, constitutes an important health problem in the first four months of life. In addition to the infant's suffering, it can be the cause of a great deal of anxiety in parents and reduce the family's quality of life.4949 Abaci FB, Gökçe S, Tuygun N, Karacan CD, Öner Ö. Psychosocial status and quality of life in mothers of infants with colic. Turk J Pediatr. 2013;55:391-5. It should be emphasized that pediatric assessment of crying infants should be detailed and careful, aiming to identify causes that require specific therapy. A retrospective study conducted in Toronto highlights the importance of clinical history, physical examination, and urinalysis in the evaluation of febrile infants with crying, irritability, and fussiness.5252 Freedman SB, Al-Harthy N, Thull-Freedman J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics. 2009;123:841-8. It is important to remember that infantile colic occurs equally in the presence of natural and artificial feeding.4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75.

In general, regurgitation as an isolated manifestation in infants reflects the occurrence of physiological reflux (infant regurgitation according to the Rome III criteria, Table 2). In GERD other signs are observed associated with regurgitation and vomiting, including weight gain deficit and clinical manifestations attributed to probable reflux esophagitis, such as irritability, excessive crying, and difficulty feeding.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95. The diagnosis of GERD is essentially clinical. Infants with mild symptoms and no warning signs are called “happy vomiters” and there is no need for medication.3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.

There are questionnaires developed to help differentiate between infantile regurgitation and GERD. In the analysis of a questionnaire for this purpose, the clinical evaluation by an experienced specialist was used as reference, supplemented or not with other exams.5353 Deal L, Gold BD, Gremse DA, Winter HS, Peters SB, Fraga PD, et al. Age specific questionnaires distinguish Gerd symptom frequency and severity in infants and young children: development and initial validation. J Pediatr Gastroenterol Nutr. 2005;41:178-185. Ultrasonography has no value in differentiating infantile regurgitation from GERD2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95. and thus, it should not be indicated for assessment of the infant with suspected GERD. It is very useful when there is suspicion of hypertrophic pyloric stenosis. Contrast radiography of the esophagus, stomach, and duodenum may be indicated when anatomical abnormalities of the upper gastrointestinal tract are suspected.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95.

Two articles have been recently published on the practice of Brazilian pediatricians regarding the evaluation of infants with excessive crying or suspected GERD.5454 Marcon AC, Vieria MC, Morais MB. Conhecimentos do pediatra sobre o manejo do lactente que chora excessivamente nos primeiros meses de vida. Rev Paul Pediatr. 2014;32:187-92.,5555 Soares AC, Freitas CL, Morais MB. Conhecimento e prática de pediatras brasileiros sobre a doença do refluxo gastroesofágico em lactentes. Rev Paul Pediatr. 2015;33:12-8. In the first study, 132 pediatricians were asked to analyze a case of an exclusively breastfed infant with excessive crying, regurgitation, and fully satisfactory weight gain. The diagnostic hypothesis of GERD was suggested by 63% of respondents, while 24% considered the possibility of infantile colic.5454 Marcon AC, Vieria MC, Morais MB. Conhecimentos do pediatra sobre o manejo do lactente que chora excessivamente nos primeiros meses de vida. Rev Paul Pediatr. 2014;32:187-92. This result suggests that there is an overestimation of the possibility of GERD in the clinical context. The second study involved 140 professionals who analyzed two typical clinical cases, one of infantile regurgitation (physiological reflux) and another with GERD.5353 Deal L, Gold BD, Gremse DA, Winter HS, Peters SB, Fraga PD, et al. Age specific questionnaires distinguish Gerd symptom frequency and severity in infants and young children: development and initial validation. J Pediatr Gastroenterol Nutr. 2005;41:178-185. Based on the answers about the approach to be adopted, the authors concluded that most pediatricians correctly differentiated physiological reflux from GERD.5555 Soares AC, Freitas CL, Morais MB. Conhecimento e prática de pediatras brasileiros sobre a doença do refluxo gastroesofágico em lactentes. Rev Paul Pediatr. 2015;33:12-8.

Regarding the intestinal habits, it should be noted that, in general, the passage of first meconium occurs within the first 24 h of life. Preterm newborns with less than 1500 g of birth weight may have the passage of first meconium after 48 h.5656 den Hertog J, Leengoed EV, Kolk F, van den Broek L, Kramer E, Bakker EJ. The defecation pattern of healthy term infants up to the age of three months. Arch Dis Child Fetal Neonatal Ed. 2012;97:F465-70.

There are few studies in the literature that evaluated intestinal habits of infants.5656 den Hertog J, Leengoed EV, Kolk F, van den Broek L, Kramer E, Bakker EJ. The defecation pattern of healthy term infants up to the age of three months. Arch Dis Child Fetal Neonatal Ed. 2012;97:F465-70.6262 Çamurdan AD, Beyazova U, Özkan S, Tunç VT. Defecation patterns of the infants mainly breastfed from birth till the 12th month: prospective cohort study. Turk J Gastroenterol. 2014;25:S1-5. Considering the information in these articles, it can be said that, in the first month of life, most infants have four to six bowel movements a day. This number decreases after the second month of life. The number of stools and stool consistency is associated with the type of feeding. It is well established that breastfed infants have more bowel movements when compared with formula-fed infants.5858 Weaver LT, Ewing G, Taylor LC. The bowel habit of milk-fed infants. J Pediatr Gastroenterol Nutr. 1998;7:568-71.,6060 Tunc VT, Camurdan AD, Ilhan MN, Sahin F, Beyazova U. Factors associated with defecation patterns in 0-24 month-old children. Eur J Pediatr. 2008;167:1357-1362. The stool of breastfed infants is softer than those who receive infant formula.5656 den Hertog J, Leengoed EV, Kolk F, van den Broek L, Kramer E, Bakker EJ. The defecation pattern of healthy term infants up to the age of three months. Arch Dis Child Fetal Neonatal Ed. 2012;97:F465-70.,5858 Weaver LT, Ewing G, Taylor LC. The bowel habit of milk-fed infants. J Pediatr Gastroenterol Nutr. 1998;7:568-71. The type of infant formula can also influence the consistency of stools and stool frequency. Infants fed conventional or soy infant formula had half the frequency of bowel movements and harder stool consistency compared to breastfed infants.6363 Hyams JS, Treem WR, Etienne NL, Weinerman H, MacGilpin D, Hine P, et al. Effect of infant formula on stool characteristics of young infants. Pediatrics. 1995;95:50-4. In comparison, those receiving extensively hydrolyzed protein formula have an increased frequency of bowel movements and softer stool consistency.6363 Hyams JS, Treem WR, Etienne NL, Weinerman H, MacGilpin D, Hine P, et al. Effect of infant formula on stool characteristics of young infants. Pediatrics. 1995;95:50-4.

The main changes in the infant's intestinal habits are diarrhea and constipation. Generally, diarrhea is defined as the occurrence of three or more loose stools in the preceding 24 h.6464 World Health Organization. The treatment of diarrhoea – A manual for physicians and other senior health workers (WHO/CAH/03.7). Geneva: World Health Organization; 2005.,6565 World Health Organization. Diarrhoea. Diarrhoea. Why children are still dying and what can be done? UNICEF/WHO; 2009. It is a broad definition that includes bacterial and viral infections of the digestive tract (acute and persistent diarrhea), which can cause dehydration and malnutrition, and are not included in the scope of this article. Nonetheless, it is worth mentioning that some parents mistakenly consider the frequency and consistency of stools in the first month of life as “diarrhea”, which actually constitutes normal bowel habits. Conversely, intestinal constipation usually starts with the elimination of hard, scybalous stools, with pain or difficulty.6666 Aguirre AN, Vitolo MR, Puccini RF, Morais MB. Constipação em lactentes: influência do tipo de aleitamento e da ingestão de fibra alimentar. J Pediatr (Rio J). 2002;78:202-8. However, the Rome III criteria2525 Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-26. does not take into account the shape and consistency of stools to characterize intestinal constipation in infants, which can delay the diagnosis.

Principles and perspectives for the control of gastrointestinal signs and symptoms in infants

For infants with colic and regurgitation, the most important procedure is elucidating parents about the benign and transitory characteristic of these manifestations.33 Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29:184-94.,44 Vandenplas Y, Alarcon P, Alliet P, De Greef E, De Ronne N, Hoffman I, et al. Algorithms for managing infant constipation, colic, regurgitation and cow's milk allergy in formula-fed infants. Acta Paediatr. 2015;104:449-57.,2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75. In this context, parents should be sure that additional exams are not required and that their children are not at immediate or future risks. It is advisable to check the sources that parents are possibly accessing to obtain information about the health of their children and, when necessary, appropriate and corrective pediatric guidelines should be offered.

It is important to avoid prescribing unnecessary medications. A common approach is to conduct unjustified and often prolonged empiric treatment for probable esophagitis due to gastroesophageal reflux in infants with excessive crying and irritability.

In this context, it is important to mention the abusive use of proton-pump inhibitors in infants.6767 Chen IL, Gao WY, Johnson AP, Niak A, Troiani J, Korvick J, et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012;54:8-14. According to clinical trials6868 Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:219-23.,6969 Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154:514-20. and a meta-analysis,7070 Gieruszczak-Białek D, Konarska Z, Skórka A, Vandenplas Y, Szajewska H. No effect of proton pump inhibitors on crying and irritability in infants: systematic review of randomized controlled trials. J Pediatr. 2015;166:767-70. proton-pump inhibitors provide no reduction in the daily duration of infantile crying and can also cause adverse affects.6767 Chen IL, Gao WY, Johnson AP, Niak A, Troiani J, Korvick J, et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012;54:8-14. A study carried out in Brazil showed that prokinetics, such as domperidone and bromopride, are considered in the treatment of infants with infantile regurgitation and GERD,5555 Soares AC, Freitas CL, Morais MB. Conhecimento e prática de pediatras brasileiros sobre a doença do refluxo gastroesofágico em lactentes. Rev Paul Pediatr. 2015;33:12-8. which goes against the most recent recommendations.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95.

A study carried out in 11 European countries7171 Quitadamo P, Papadopoulou A, Wenzl T, Urbonas V, Kneepkens CM, Roman E, et al. European pediatricians’ approach to children with gastroesophageal reflux symptoms: survey on the implementation of 2009 Naspghan-Espghan Guidelines. J Pediatr Gastroenterol Nutr. 2014;58:505-509. with 567 pediatricians showed that few follow the NASPGHAN/ESPGHAN (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) guideline, published in 2009.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547. The reasons for the lack of adherence to the care protocols should be the subject of future studies. It should be noted that there is no evidence that dimethicone is effective in the treatment of infantile colic.4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75.

Regarding the feeding regimen, exclusive breastfeeding should always be maintained. No gastrointestinal signs or symptoms should be understood as reason for breastfeeding interruption, as shown in the reviews3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,4545 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75. and guidelines2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229.,3030 Tabbers MM, DiLorenzo C, Berger MY, Faure C, Langendam MW, Nurko S, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from Espghan and Naspghan. J Pediatr Gastroenterol Nutr. 2014;58:258-74.,3131 Sociedade Brasileira de Pediatria e Associação Brasileira de Alergia e Imunopatologia. Consenso brasileiro sobre alergia alimentar: 2007. Rev Bras Alerg Imunopatol. 2008;31:64-89.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95.,3636 Hyams J, Colletti R, Faure C, Gabriel-Martinez E, Maffei HV, Morais MB, et al. Functional gastrointestinal disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2002;35:S110-7. for the treatment of gastrointestinal functional disorders.

Regarding infants with suspected allergy to cow's milk while receiving exclusive breastfeeding, the mother should eliminate cow's milk proteins from her diet.2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229.,3131 Sociedade Brasileira de Pediatria e Associação Brasileira de Alergia e Imunopatologia. Consenso brasileiro sobre alergia alimentar: 2007. Rev Bras Alerg Imunopatol. 2008;31:64-89. Infants with food allergies during breastfeeding and with severe clinical manifestations, with stunting and/or iron deficiency anemia, for instance, should be individually assessed by specialists. Specialized assessment should also be carried out in infants with suspected disease such as galactosemia and congenital glucose–galactose malabsorption, among others.

For infants who no longer receive breast milk and when relactation cannot be achieved, there are several formulas that have been developed to contribute for the control of gastrointestinal signs and symptoms in infants, including: 1. thickened formulas, 2. soy formulas, 3. formulas with partially hydrolyzed proteins and lower lactose content, 4. formulas with prebiotics, 5. formulas with extensively hydrolyzed proteins, with and without lactose, and 6. amino acid formulas.

Thickened formulas provide a decrease in the frequency and volume of regurgitation. Thus, they can decrease the parents’ anxiety. It should be noted that they are formulas that reduce regurgitation, but not the total time of exposure of the esophagus to gastric acid.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95.

Another situation that constitutes a major healthcare problem is that of infants with regurgitation, vomiting, irritability, and excessive crying, associated or not with other clinical manifestations. Diagnostic hypotheses of GERD and allergy to cow's milk protein are often considered. The ESPGHAN/NASPGHAN guideline for infants with frequent regurgitation and irritability, associated or not with decreased weight gain, recommends the exclusion of cow's milk protein from the diet for two to four weeks.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547. The guideline suggests formulas with extensively hydrolyzed proteins or amino acid formulas as substitutes.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547. Thus, in case of patient improvement after this period of elimination diet, a challenge test should be planned to confirm the diagnosis.2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229. However, many physicians that recommend cow's milk elimination from the diet do not perform the challenge test to ascertain the diagnosis of allergy to cow's milk.7272 Sladkevicius E, Nagy E, Lack G, Guest JF. Resource implications and budget impact of managing cow’ milk allergy in the UK. J Med Econ. 2010;13:119-28.,7373 Taylor RR, Sladkevicius E, Panca M, Lack G, Guest JF. Cost-effectiveness of using an extensively hydrolysed formula compared to an amino acid formula as first-line treatment for cow’ milk allergy in the UK. Pediatr Allergy Immunol. 2012;23:240-9. This procedure maintains a substantial proportion of infants3939 Petrus NC, Schoemaker AF, van Hoek MW, Jansen L, Jansen-van der Weide MC, van Aalderen WM, et al. Remaining symptoms in half the children treated for milk allergy. Eur J Pediatr. 2015;174:759-65.,4040 Lins Md Horowitz MR, Silva GA, Motta ME. Oral food challenge test to confirm the diagnosis of cow's milk allergy. J Pediatr (Rio J). 2010;86:285-9. that are not allergic to cow's milk (but who casually had a reduction in clinical manifestations) on a replacement diet, which is more expensive, for a period longer than necessary. Although not indicated for infants younger than six months, about one-third of pediatricians would prescribe soy formula to infants with suspected gastroesophageal reflux secondary to allergy to cow's milk protein.5555 Soares AC, Freitas CL, Morais MB. Conhecimento e prática de pediatras brasileiros sobre a doença do refluxo gastroesofágico em lactentes. Rev Paul Pediatr. 2015;33:12-8. It should be noted that soy formulas are not indicated for the treatment of infantile colic,33 Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29:184-94.,44 Vandenplas Y, Alarcon P, Alliet P, De Greef E, De Ronne N, Hoffman I, et al. Algorithms for managing infant constipation, colic, regurgitation and cow's milk allergy in formula-fed infants. Acta Paediatr. 2015;104:449-57.,4444 Savino F. Focus on infantile colic. Acta Paediatr. 2007;96:1259-64.,45 45 Akhnikh S, Engelberts AC, van Sleuwen BE, L’Hoir MP, Benninga MA. The excessively crying infant: etiology and treatment. Pediatr Ann. 2014;43:e60-75. allergy to cow's milk protein in the first six months of life,2727 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’ milk protein allergy in infants and children: Espghan GI Committee Practical Guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-229.,3131 Sociedade Brasileira de Pediatria e Associação Brasileira de Alergia e Imunopatologia. Consenso brasileiro sobre alergia alimentar: 2007. Rev Bras Alerg Imunopatol. 2008;31:64-89. infant regurgitation, or GERD.2626 Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Naspghan) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Espghan). J Pediatr Gastroenterol Nutr. 2009;49:498-547.,3434 Ferreira CT, Carvalho E, Sdepanian VL, Morais MB, Vieira MC, Silva LR. Gastroesophageal reflux disease: exaggerations, evidence and clinical practice. J Pediatr (Rio J). 2014;90:105-18.,3535 Lightdale JR, Gremse DA. Section on gastroenterology hepatology, and nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131:e1684-95.

Formulas with partially hydrolyzed proteins and low lactose content have been used in infants with gastrointestinal manifestations such as colic, regurgitation, flatulence, and hardened stools, based on open clinical trials.7474 Savino F, Cresi F, Maccario S, Cavallo F, Dalmasso P, Fanaro S, et al. Minor feeding problems during the first months of life: effect of a partially hydrolysed milk formula containing fructo- and galacto-oligosaccharides. Acta Paediatr Suppl. 2003;91:86-90.7777 Vandenplas Y, Cruchet S, Faure C, Lee HC, Di Lorenzo C, Staiano A, et al. When should we use partially hydrolysed formulae for frequent gastrointestinal symptoms and allergy prevention? Acta Paediatr. 2014;103:689-95. It can be hypothesized that their effectiveness in these circumstances is related to the following mechanisms: 1. increased rate of gastric emptying7878 Billeaud C, Guillet J, Sandler B. Gastric emptying in infants with or without gastro-oesophageal reflux according to the type of milk. Eur J Clin Nutr. 1990;44:577-83.,7979 Garzi A, Messina M, Frati F, Carfagna L, Zagordo L, Belcastro M, et al. An extensively hydrolysed cow’ milk formula improves clinical symptoms of gastroesophageal reflux and reduces the gastric emptying time in infants. Allergol Immunopathol (Madr). 2002;30:36-41. and 2. decrease in the effects of excessive fermentation of carbohydrates in the intestinal lumen, considering that in patients with infantile colic, a greater production of hydrogen in the expired air has been demonstrated in the hydrogen breath test.8080 Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colic and noncolic infants. J Pediatr. 1988;113:979.8282 Infante D, Segarra O, Luyer BL. Dietary treatment of colic caused by excess gas in infants: biochemical evidence. World J Gastroenterol. 2011;17:2014-8. It should be noted that no formula with partially hydrolyzed proteins, with normal or low content of lactose, should be used in the treatment of infants with suspected allergy to cow's milk protein.7777 Vandenplas Y, Cruchet S, Faure C, Lee HC, Di Lorenzo C, Staiano A, et al. When should we use partially hydrolysed formulae for frequent gastrointestinal symptoms and allergy prevention? Acta Paediatr. 2014;103:689-95.

Breastfed infants have low risk for constipation. This may be a consequence of the oligosaccharide content in human milk, which increases the frequency of bowel movements and decreases stool consistency.8383 Scholtens PA, Goossens DA, Staiano A. Stool characteristics of infants receiving short-chain galactooligosaccharides and long-chain fructo-oligosaccharides: a review. World J Gastroenterol. 2014;20:13446-13452. Several mechanisms may account for this effect:8181 Miller JJ, McVeagh P, Fleet GH, Petocz P, Brand JC. Breath hydrogen excretion in infants with colic. Arch Dis Child. 1989;64:725-9. 1. increased microbial mass (including probiotic bacteria) due to the availability of oligosaccharides to be fermented; 2. selective growth of Bifidobacterium and Lactobacillus bacteria that ferment the oligosaccharides and produce short-chain fatty acids that increase the water content in the stool.8383 Scholtens PA, Goossens DA, Staiano A. Stool characteristics of infants receiving short-chain galactooligosaccharides and long-chain fructo-oligosaccharides: a review. World J Gastroenterol. 2014;20:13446-13452. In turn, the short-chain fatty acids can stimulate intestinal motility, as they are used as an energy source by colonocytes and induce tonic and phasic contractions in the circular muscles of the colon; and 3. oligosaccharides play the role of soluble fibers and, thus, increase the water content of the stool.8383 Scholtens PA, Goossens DA, Staiano A. Stool characteristics of infants receiving short-chain galactooligosaccharides and long-chain fructo-oligosaccharides: a review. World J Gastroenterol. 2014;20:13446-13452.

The same effect on intestinal habit and stool consistency can be obtained by adding prebiotics to infant formula.8484 Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B, et al. Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants. J Pediatr Gastroenterol Nutr. 2002;34:291-5.8787 Scalabrini DM, Mitmesser SH, Welling GW, Harris CL, Marunyez JD, Walker DC, et al. New prebiotic blend of polydextrose and galacto-oligossaccharides has a bifidogenic effect in young infants. J Pediatr Gastroenterol Nutr. 2012;54:343-52. Thus, more frequent bowel movements with softer consistency can be obtained with the use of infant formula with added prebiotic, which can potentially reduce the likelihood of constipation onset. The NASPGHAN/ESPGHAN guideline offers a specific algorithm for constipation before six months of age.3030 Tabbers MM, DiLorenzo C, Berger MY, Faure C, Langendam MW, Nurko S, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from Espghan and Naspghan. J Pediatr Gastroenterol Nutr. 2014;58:258-74.

Probiotics are live microorganisms that, when consumed in adequate amounts, provide a beneficial effect to the host's health.8888 Joint FAO/WHO Working Group on Drafting Guidelines forthe Evaluation of Probiotics in Food. Guidelines for the evaluation of probiotics in food: report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food. 2002. Available at: http://www.who.int/foodsafety/fs management/en/probiotic_guidelines.pdf [accessed 09 March 2016].
http://www.who.int/foodsafety/fs managem...
,8989 Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506-14. Infants with colic9090 de Weerth C, Fuentes S, Puylaert P, de Vos WM. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131:e550-8. or allergy to cow's milk protein9191 Thompson-Chagoyan OC, Fallani M, Maldonado J, Vieites JM, Khanna S, Edwards C, et al. Faecal microbiota and short-chain fatty acid levels in faeces from infants with cow’ milk protein allergy. Int Arch Allergy Immunol. 2011;156:325-32. may show alterations in the intestinal microbiota, as observed in functional gastrointestinal disorders and other allergic diseases.9292 Melli LC, do Carmo-Rodrigues MS, Araújo-Filho HB, Solé D, de Morais MB. Intestinal microbiota and allergic diseases: a systematic review. Allergol Immunopathol (Madr). 2016;44:177-88. Thus, the role of probiotics in controlling these diseases in infants has been the subject of several studies.

Clinical trials5151 Mi GL, Zhao L, Qiao DD, Kang WQ, Tang MQ, Xu JK. Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial. Antonie Van Leeuwenhoek. 2015;107:1547-53.,9393 Savino F, Cordisco L, Tarasco V, Palumeri E, Calabrese R, Oggero R, et al. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics. 2010;126:e526-33.9595 Chau K, Lau E, Greenberg S, Jacobson S, Yazdani-Brojeni P, Verma N, et al. Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938. J Pediatr. 2015;166:74-78. and a meta-analysis9696 Collett S, de Gooyer T, Hiscock H, Tang M, Wake M. Probiotics to prevent or treat excessive infant crying: systematic review and meta-analysis. JAMA Pediatr. 2013;167:1150-7. showed that Lactobacillus reuteri DSM 17938 provides a reduction in daily crying time in patients with infantile colic. In turn, Lactobacillus GG can accelerate the acquisition of tolerance by infants with allergy to cow's milk protein.2222 Canani RB, Nocerino R, Terrin G, Coruzzo A, Cosenza L, Leone L, et al. Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: a randomized trial. J Allergy Clin Immunol. 2012;129:580-2.,2323 Canani RB, Nocerino R, Terrin G, Frediani T, Lucarelli S, Consenza L, et al. Formula selection for management of children with cow’ milk allergy influences the rate of acquisition of tolerance: a prospective multicenter study. J Pediatr. 2013;163:771-7. From a clinical point of view, it is important to emphasize that the effect of a particular probiotic is specific to a particular strain. A clinical trial showed that administration of Lactobacillus reuteri DSM 17938 can reduce the frequency of gastrointestinal symptoms in the first months of life.9797 Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014;168:228-33. These data show how the development of research in the field of prebiotics and probiotics for the prevention and control of gastrointestinal signs and symptoms in infants is promising.

In conclusion, the prevalence of gastrointestinal signs and symptoms in infants is very high. The diagnosis is usually based on information from parents and the clinical examination of the child, including weight assessment. The lack of specific and precise tests may hinder the differential diagnosis. Offering recommendations and support to parents is crucial, regardless of the diagnosis. Exclusive breastfeeding should always be stimulated and maintained.

  • Please cite this article as: Morais MB. Signs and symptoms associated with digestive tract development. J Pediatr (Rio J). 2016;92(3 Suppl 1):S46–56.

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Publication Dates

  • Publication in this collection
    May-Jun 2016

History

  • Received
    1 Feb 2016
  • Accepted
    20 Feb 2016
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