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Vol. 78. Issue 2.
Pages 82-91 (April 2013)
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Vol. 78. Issue 2.
Pages 82-91 (April 2013)
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Early life events predispose the onset of childhood functional gastrointestinal disorders
Eventos en edad temprana predisponen al desarrollo de trastornos gastrointestinales funcionales
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S.. Bonilla, M.. Saps
Corresponding author
silvanabonilla@hotmail.com

Corresponding author at: Ann & Robert H. Lurie Children's Hospital of Chicago, Box 86, 225 E Chicago Avenue, Chicago, IL 60611, United States. Tel.: +1 312 227 4200. silvanabonilla@hotmail.com
a Division of Pediatric Gastroenterology, Tufts Medical Center, Boston, Massachusetts, United States
b Division of Pediatric Gastroenterology, Ann & Robert H. Lurie Children's Hospital of Chicago, United States
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Background

Functional gastrointestinal disorders (FGIDs) are common digestive conditions characterized by chronic or recurrent symptoms in the absence of a clearly recognized gastrointestinal etiology. The biopsychosocial model, the most accepted concept explaining chronic pain conditions, proposes that the interplay of multiple factors such as genetic susceptibility, early life experiences, sociocultural issues, and coping mechanisms affect children at different stages of their lives leading to the development of different pain phenotypes and pain behaviors. Early life events including gastrointestinal inflammation, trauma, and stress may result in maladaptive responses that could lead to the development of chronic pain conditions such as FGIDs.

Aims

In this review, we discuss novel findings from studies regarding the long-term effect of early life events and their relationship with childhood chronic abdominal pain and FGIDs.

Methods

A bibliographic search of the PubMed database was conducted for articles published over the last 20 years using the keywords: “Functional gastrointestinal disorders”, “chronic abdominal pain”, “chronic pain”, “gastrointestinal inflammation”, and “early life events”. Forty-three articles were chosen for review.

Results

Based on the current evidence, events that take place early in life predispose children to the development of chronic abdominal pain and FGIDs. Conditions that have been studied include cow's milk protein hypersensitivity, pyloric stenosis, gastrointestinal infections, and Henoch–Schonlein purpura, among others.

Conclusions

Early events may play an important role in the complex pathogenesis of functional gastrointestinal conditions. Timely intervention may have a critical impact on the prevention of this group of chronic incapacitating conditions.

Keywords:
Functional gastrointestinal disorders
Chronic pain
Gastrointestinal inflammation
Early life events
Abdominal
Antecedentes

Los trastornos funcionales gastrointestinales (FGID) son condiciones que se caracterizan por la presencia de síntomas crónicos o recurrentes en ausencia de una etiología orgánica. El modelo biopsicosocial utilizado como marco conceptual de las condiciones de dolor crónico propone que la interacción de diferentes factores, como la susceptibilidad genética, los eventos en edad temprana, los factores socioculturales y los mecanismos de adaptación al dolor, afectan a los niños en diferentes estadios de sus vidas y eventualmente resultan en el desarrollo de síndromes de dolor crónico. La inflamación gastrointestinal, el traumatismo y estrés en la edad temprana pueden resultar en una adaptación inadecuada que llevaría al desarrollo de condiciones de dolor crónico tales como los FGID.

Objetivos

En este artículo de revisión se analizan nuevas evidencias de estudios que examinan eventos en edad temprana y sus efectos a largo plazo, así como su relación con el desarrollo de dolor abdominal crónico y FGID.

Materiales y métodos

Búsqueda bibliográfica en la base de datos PubMed en los últimos 20 años usando los términos: «functional gastrointestinal disorders», «chronic abdominal pain», «chronic pain», «gastrointestinal inflammation» and «early life events».

Resultados

Los eventos en la edad temprana predisponen al niño al desarrollo de dolor abdominal crónico y FGID. Entre los desórdenes estudiados tenemos: hipersensibilidad a la proteína de la leche, estenosis pilórica, infecciones gastrointestinales y púrpura de Henoch–Schonlein, entre otros.

Conclusiones

Los eventos en la edad temprana cumplen un papel importante en la compleja patogénesis de los FGID. Una intervención oportuna puede ser de un impacto crítico en la prevención de este grupo de condiciones.

Palabras clave:
Trastornos gastrointestinales funcionales
Dolor crónico
Inflamación gastrointestinal
Trastornos en la edad temprana
Dolor abdominal
Full Text
Introduction

Functional gastrointestinal disorders (FGIDs) are characterized by the presence of chronic or recurrent digestive symptoms without an underlying identifiable structural or biochemical abnormality.1, 2 As such, there are no biological markers to diagnose FGIDs. The diagnosis of FGIDs is based exclusively on the symptoms reported by the child and parents. According to the Rome III criteria,3 the subgroup of FGIDs associated with abdominal pain (abdominal pain-associated FGIDs) is subdivided into four disorders: Irritable Bowel Syndrome (IBS), Functional Dyspepsia, Abdominal Migraine, and Childhood Functional Abdominal Pain (this includes the subgroup of Childhood Functional Abdominal Pain syndrome in children with loss of daily functioning or other somatic complaints) (Table 1). A large proportion of children with complaints of chronic abdominal pain of non-organic origin cannot be diagnosed with a FGID if the Rome criteria are strictly applied. It is unclear whether there is a difference in pathophysiology or impact on quality of life between children who do not meet one or more items of the Rome criteria and children who meet all of them.

Table 1. Rome III classification of functional disorders in children and adolescents.

H1. Vomiting and aerophagia
H1a. Adolescent rumination syndrome
H1b. Cyclic vomiting syndrome
H1c. Aerophagia
 
H2. Abdominal pain-related Functional Gastrointestinal Disorders (FGIDs)
H2a. Functional dyspepsia
H2b. Irritable bowel syndrome
H2c. Abdominal migraine
H2d. Childhood functional abdominal pain
H2d1. Childhood functional abdominal pain syndrome
 
H3. Constipation and incontinence
H3a. Functional constipation
H3b. Non-retentive fecal incontinence

Adapted from Rasquin et al. 3 .

Prevalence

Chronic abdominal pain and abdominal pain-associated FGIDs are common in children. Large community-based studies conducted in geographically and socio-culturally diverse areas found a similar prevalence of abdominal pain and FGIDs in children. Thirty-eight percent of American school-age children4 and 35% of Colombian children5 report abdominal pain weekly. A school-based study found FGIDs in 27% of Colombian children. A cross-sectional survey conducted in a semi-urban school in Sri-Lanka found FGIDs in 28.8% of the children6. Eleven percent of 1200 Colombian schoolchildren and 12.5% of 2163 randomly selected Sri-Lankan adolescents were diagnosed with an abdominal pain-associated FGID;7 IBS was the most common abdominal pain-associated FGID in both studies (Colombia 4.2%, Sri-Lanka 4.9%).8

Impact

The socioeconomic burden associated with chronic abdominal pain and abdominal pain-associated FGIDs is substantial.9, 10 Children and adolescents with abdominal pain and abdominal pain-associated FGIDs frequently experience poor quality of life and disability.11, 12 School-aged children with abdominal pain have higher anxiety and depression scores and worse quality of life than their peers.13 Twenty-three percent of children with abdominal pain miss school in a six-month period, and 10% of their parents miss work to care for their sick children.4 Most school-aged children with abdominal pain never seek medical attention for their symptoms.14 The percentage of children who seek medical attention is consistent across studies in areas with different access to medical care and sociocultural background. An American study conducted in a large city (Chicago) and a study conducted in a semirural city in Colombia showed that in both cases only 2–3% of the children who reported abdominal pain sought medical attention. The low ratio of consultation suggests that many children suffer from abdominal pain without receiving professional attention. In those children consulting for abdominal pain, the healthcare costs associated with medical care are considerable. A study conducted in Uruguay showed that the direct healthcare costs associated with a single pediatric consultation for abdominal pain accounted for 4% of the per capita health care spending in one year.15 Costs involved with the care of a child with abdominal pain in the US are also extremely high. The average cost to care for a child with abdominal pain in a tertiary care center in the US exceeds $6000 USD.9 One third of pediatric patients undergo esophagogastroduodenoscopy that rarely changes the patient's management. Despite the presence of common symptoms such as abdominal pain, bloating, distention, diarrhea, and constipation in patients with celiac disease and IBS, celiac disease is rarely found in children presenting with isolated abdominal pain, and celiac disease is infrequent in children with IBS.9 The value of reassuring parents by demonstrating a negative endoscopy is open to question. Children who were told they had a negative endoscopy had the same prognosis as those who were not subjected to endoscopy.16 The cumulative lifetime healthcare costs associated with FGIDs are even more substantial. Almost a third of all the adults that consult for FGIDs began experiencing gastrointestinal symptoms in childhood.17, 18 Long-term follow-up studies have shown that adolescents and young adults with a past history of FGIDs are likely to report other somatic complaints including chronic abdominal pain and headache several years after the initial presentation.19, 20 Direct and indirect costs related to the care of IBS and other somatic complaints frequently present in adults are enormous. The high personal, familiar, and societal burden associated with FGIDs has raised great interest in unveiling the pathogenesis and pathophysiological mechanisms of FGIDs. The biopsychosocial model, the most accepted construct explaining chronic pain conditions21 recognizes the interaction between genetic susceptibility and early life experiences, social and environmental influences, psychological and physiological processes, social and environmental influences, and individual coping mechanisms in the development of FGIDs.22 Several animal and human studies suggest that events occurring early in life may constitute an additional and potentially important contributing factor to the development of FGIDs.23 A better understanding of the various early life events that may contribute to the development of FGIDs could offer a unique opportunity for early intervention to prevent the development of FGIDs and decrease the number of children with FGIDs who continue suffering into adulthood.

FGIDs are more common among members of the same family.24, 25, 26, 27, 28 A parental history of IBS is an independent predictor of the development of IBS in the offspring.29 Children with a maternal history of IBS have a higher frequency of gastrointestinal and non-gastrointestinal symptoms, disability days, and clinical visits compared with those that do not have a similar history.30 Several studies have tried to uncover possible genetic associations that could explain FGIDs. Some of the studies found that distinct gene polymorphisms implicated in 5-HT metabolism were more frequently present in patients with IBS.31 Cytokine gene polymorphisms were also found to be associated with irritable bowel syndrome.32 However, other genetic studies had disappointing results. Guanine nucleotide binding protein (G-protein) beta polypeptide 3 (GNB3) C825T polymorphisms that were presumed to be associated with some FGIDs were found to be equally present in cases and controls.33 Most of the experts believe that the genetic contribution to the development of FGIDs is likely to be modest. None of the genetic findings can solely explain the pathophysiology of FGIDs. Twin and family studies support the coexistence of genetic and environmental contributing factors in the pathogenesis of IBS. Monozygotic twins are more likely to develop FGIDs than dizygotic twins.29 However, the same study showed that having a mother and a father with IBS were independent predictors of IBS, indicating that social learning and parental response to illness had an equal or greater influence than heredity to the development of FGIDs. Chronic abdominal pain is more common in families with higher rates of reported illnesses and anxiety.34, 35 Parental anxiety and preoccupation with physical health may reinforce the child's own concerns about physiological or minor body sensations.30 Studies have demonstrated that some biological factors could also be associated with a greater risk for developing FGIDs. Restricted fetal growth has a significant influence on the development of IBS later in life, with weight below 1500 g influencing age of onset.26 In conclusion, abdominal pain and abdominal pain-related FGIDs are a global health problem that is present across ethnicities, nationalities, and geographic locations and is associated with significant health care expenditure. The pathogenesis of and the individual contributions of the various factors to the development of FGIDs remain unclear despite the increasing body of research focused on elucidating these mechanisms.

In this review, we first examine the available evidence on the effects of exposure to pain during the neonatal period. We then discuss novel findings from studies concerning the long-term effect of early life events including cow's milk protein hypersensitivity, pyloric stenosis, and other common pediatric conditions occurring later in childhood, such as gastrointestinal infections and immune conditions that predispose children to chronic abdominal pain and FGIDs (Table 2, Table 3, Table 4).

Table 2. Pain exposure during the neonatal period. Summary of studies in human subjects.

Author Year Country Type of study # of subjects Population Results
Grunau R et al. 2001 Canada Prospective cohort study 136 Preterm neonates Higher frequency of invasive procedures in NICU is associated with immature pain response
Taddio A et al. 2002 Canada Prospective cohort study 21 Full term neonates Neonates exposed to repeated heel lances in the first 24–36 h of life learn to anticipate pain and exhibit more intense pain responses than controls
Grunau R et al. 2004 Canada Prospective cohort study 76 Preterm and term neonates Preterm infants showed significant differences in cortisol levels after stimulation compared with more mature preterm and term infants
Holsti L et al. 2005 Canada Crossover design 54 Preterm infants Prior pain induces heightened bio-behavioral reactivity during subsequent tactile procedures
Grunau R et al. 2005 Canada Prospective cohort study 87 Preterm infants Repeated procedural pain exposure is associated with down-regulation of the hypothalamic-pituitary-adrenal axis
Holsti L et al. 2006 Canada Crossover design 43 Preterm infants Heightened states of arousal and poor ability to modulate heart rate during recovery when an invasive procedure was preceded by routine tactile nursing procedures
Hermann C et al. 2006 Germany Retrospective cohort study 59 School-age children born preterm and full term Altered pain sensitization in those who underwent NICU treatment
Hohmeister J et al. 2009 Germany Retrospective cohort study 59 School-age children born preterm and full term Infants exposed to neonatal pain and prolonged hospitalization exhibit maladaptive pain-related cognitions and foster parental behavior that reinforces the child's pain response
Vederhus BJ et al. 2012 Norway Population-based cohort 59 Adolescents born extremely preterm and full term. Despite reduced tolerance to experimental pain, subjects born preterm scored their pain experiences similarly to those of term controls

NICU: neonatal intensive care unit.

Table 3. Stress and early trauma. Summary of studies in human subjects.

Author Year Country Type of study # of subjects Population Results
Hislop IG et al. 1979 Australia Prospective cohort study 333 Young adults with IBS Common history of an unsatisfactory parental relationship or parental loss through death, divorce, or separation during childhood
Drossman DA et al. 1990 USA Cross-sectional study 206 Young female patients with IBS High prevalence of history of childhood sexual and physical abuse
Talley NJ et al. 1994 USA Cross-sectional study 919 Adult patients 30–49 years of age. Significant association between abuse in childhood and IBS in adulthood
Howell S et al. 2004 Australia Prospective cohort study 980 Adult patients 26 years of age. Childhood social class (affluent) was significantly associated with IBS
Videlock EJ et al. 2009 USA Case–control study 83 Adult patients with IBS and controls Subjects with IBS and a history of early adverse life events have higher cortisol levels in response to a visceral stressor than subjects without such history
Klooker TK et al. 2009 Netherlands Cross-sectional study 816 Adult patients Exposure to severe wartime conditions in early life is associated with an increased risk for developing IBS
Helgeland H et al. 2010 Norway Population-based prospective study 456 Adolescents Maternal psychological distress in early childhood predicts RAP in their offspring 13 years later
Van Tilburg M et al. 2010 USA Prospective cohort study 845 Pediatric patients 4–12 years of age. Positive association between childhood maltreatment and early development of gastrointestinal symptoms
Saps M et al. 2011 USA Case–control study 191 Pediatric patients 4–20 years of age. The presence of pyloric stenosis in infancy and factors involved in its perioperative care represent risk factors in the development of chronic abdominal pain in children at long-term follow-up
Saps M et al. 2012 USA Retrospective cohort study 48 Pediatric patients 2–18 years of age Consultations are more common in children with shorter interval from hematopoietic stem-cell transplant
Bradford et al. 2012 USA Case–control study 731 Adult patients A higher prevalence of early life events (general trauma, physical punishment, emotional abuse and sexual events) is associated with the development of IBS

IBS: irritable bowel syndrome; RAP: recurrent abdominal pain.

Table 4. GI inflammation. Summary of studies in human subjects.

Author Year Country Type of study # of subjects Population Results
Saps M et al. 2008 USA/Italy Case–control study 88 Pediatric patients 3–19 years of age Children with a history of acute bacterial gastroenteritis have a significantly increased incidence and prevalence of FGIDs
Thabane M et al. 2010 Canada Prospective cohort study 467 Pediatric patients under 16 years of age Acute bacterial gastroenteritis is associated with subsequent IBS in children
Saps M et al. 2011 USA Case–control study 105 Pediatric patients 4–18 years of age Cow's milk protein hypersensitivity is a risk factor for the development of chronic abdominal pain and FGIDs in childhood
Saps M et al. 2011 USA Case–control study 76 Pediatric patients 4–18 years of age Patients with Henoch–Schonlein purpura are at an increased risk for developing pain-predominant FGIDs
Saps M et al. 2012 USA Case–control study 97 Pediatric patients between 3 and 22 years of age Children with celiac disease and controls have a similar risk for abdominal pain and pain-predominant FGIDs

FGIDs: functional gastrointestinal disorders; IBS: irritable bowel syndrome.

Methods

A bibliographic search of the PubMed database was conducted for articles published over the last 20 years using the keywords: “Functional gastrointestinal disorders”, “chronic abdominal pain”, “chronic pain”, and “early life events”. Forty-three articles were chosen for the literature review.

Effects of exposure to pain during the neonatal period

Clinical and laboratory investigations in neonatal pain have shown that exposure to an early insult – physical and/or psychological – results in maladaptive CNS responses that in turn can lead to the development of chronic pain disorders. Studies conducted in neonatal rat pups showed that exposure to repetitive pain led to altered maturation of the pain system and decreased pain thresholds.36 Preterm neonates that are exposed to acute painful stimuli experience prolonged periods of hyperalgesia.37, 38 Premature babies who had a higher frequency of invasive procedures in the Neonatal Intensive Care Unit (NICU) are less mature in their pain response.39 In preterm infants, prior pain induces an increased bio-behavioral reactivity during subsequent tactile procedures.40 Repeated procedural pain exposure is associated with down-regulation of the hypothalamic-pituitary-adrenal axis as measured by cortisol levels.41 Preterm infants who were born at an extremely low gestational age showed significant differences in cortisol levels after stimulation, compared with more mature preterm and term infants.42 Heightened states of arousal and poor response to invasive procedures have also been described in earlier born preterm infants.43

Newborns exposed to repeated heel lances in the first 24–36 h of life learn to anticipate pain and exhibit more intense pain responses during venipuncture than controls.44 Similar changes have been reported in long-term follow-up studies of ex-preterm neonates who had prolonged stays in the NICU. Altered pain sensitization was also found in school-age children who had undergone NICU treatment.45 Severe inflammatory pain and painful repetitive injections during the first week of life leads to key changes in the developing brain of the neonatal rat.46 The neonatal period is a time of high neural plasticity and insults that occur during this period may alter the development of the Central Nervous System (CNS) and influence future pain responses. However, the mechanisms underlying the long-term adaptations to pain are complex and have yet to be completely elucidated.45, 47, 48 Early life noxious stimuli also affect the gastrointestinal tract. Noxious stimuli in early stages may lead to the development of long-term gastrointestinal hyperalgesia through various putative mechanisms including sensitization of primary sensory or spinal neurons, altered stress response, and/or impaired descending inhibitory control.49 Animal studies have linked gastrointestinal injury to the development of long-term hyperalgesia by demonstrating that neonatal gastrointestinal noxious stimulation can induce long-lasting changes in pain behavior. Neonatal rats infused with iodoacetamide by oral gavage developed chronic gastric hypersensitivity and gastric motor dysfunction as adults in the absence of detectable gastric pathology.50 Neonatal rats subjected to repeated orogastric suctioning develop chronic somatic and visceral hyperalgesia during adulthood.51 Chemically induced mild, transient colitis results in persistent visceral hyperalgesia and referred pain in rats.52 Evidence from animal studies suggests that chemically induced colitis and repeated colorectal distention in neonatal mice leads to chronic visceral hypersensitivity associated with peripheral and central sensitization as adults. The same phenomenon is not present if the noxious stimulus is applied in adulthood.53, 54

Early life psychological stress may also act as a contributing factor toward sensitization to visceral pain. The model of maternal separation allows for the investigation of potential mechanisms involved in stress-related disorders.55, 56 Neonatal maternal separation predisposes rats to develop features that mimic IBS, such as visceral hyperalgesia, increased colonic motility, and reduced somatic analgesia when exposed to an acute psychological stressor.57 Male rat pups that were separated from their mothers have a higher number of bowel movements and higher plasma corticosterone levels in response to stress when compared with controls.58 Stressed pups exhibit increased visceral sensation, changes in fecal microbiota, and a heightened systemic immune response after an in vitro lipopolysaccharide challenge. Using the same model of early psychological stress associated with maternal separation, a group of investigators assessed colorectal balloon distention and its relation to abdominal withdrawal reflex as a surrogate marker of visceral pain.59 The investigators found a significantly higher abdominal withdrawal reflex score in response to colorectal balloon distention in the maternal separation group. The expression of 5-HT, 5-HT3 receptors, and 5-HT transporter in brain and spine tissue was also significantly increased in the maternal separation group, compared with controls. Pain threshold was also significantly lower in the maternal separation group. Only the maternal separation group had a significant increase in 5-HT content in the colon. There is evidence that neonatal maternal separation sensitizes the cingulate cortex and upregulates the activity of the ascending pathway at the spinal level, as well as the thalamo-cortico-amygdala pathway, in response to colorectal distention.60 The authors postulate that the sensitization of these pathways may be responsible for the development of visceral hypersensitivity in IBS. An increased expression of corticotrophin releasing factor (CRF) and CRF type 1 receptor (CRF-R1) was found in the thalamus of neonatal rats exposed to maternal separation.61 Together these results suggest that in line with the biopsychosocial model, animals exposed to early life psychological stress develop brain–gut axis dysfunction.

Early gastrointestinal inflammation, trauma, and stress

For ethical and logistical reasons, most studies on the effect of early life events in gastrointestinal health have been conducted on animals. Lack of human models has limited the progress of research in this area. Gastrointestinal inflammation and physical trauma to the gastrointestinal tract, the most commonly used models in animals, cannot be reproduced in humans for obvious reasons. Recently, our group proposed human models to study the long-term effect of early gastrointestinal inflammation, trauma, and stress. In the first study of our series, we demonstrated that cow's milk protein hypersensitivity – a common transient gastrointestinal inflammatory condition of infancy – was a risk factor for the development of chronic abdominal pain and FGIDs later in childhood.62 This case–control study included 52 subjects between 4 and 18 years of age who were diagnosed with cow's milk protein hypersensitivity within the first year of life. Fifty-three healthy siblings of the same age were selected as controls. Twenty-three of the 52 study subjects (44.2%) reported GI symptoms that included abdominal pain, constipation, or diarrhea compared with 11 of the 53 controls (20.75%) (OR 3.03, p = 0.01). Ten of the 52 subjects (19.2%) met the Rome III criteria for diagnosis of FGIDs (7 IBS, 2 functional dyspepsia, 1 functional abdominal pain), whereas none in the control group did. A second study by our group has shown that a history of pyloric stenosis in infancy is associated with the development of chronic abdominal pain in children at long-term follow-up.63 One hundred cases and 91 controls participated in the study with a mean time to follow-up of 7.22 ± 1.64 years. Chronic abdominal pain was significantly more common in cases (20/100, 20%) versus controls (5/91, 5.8%) (OR 4.3, CI [1.54–11.99] [p = 0.0045]). Seven out of 20 subjects (35%) met the Rome III criteria for diagnosis of an abdominal pain-associated FGID (3 IBS, 2 functional dyspepsia, 2 functional abdominal pain), whereas only 1 patient in the control group did (1 IBS) (OR 6.77, CI [0.82–56.17] [p = 0.043]). This study suggested for the first time that the presence of pyloric stenosis in infancy or factors involved in its perioperative care, such as the use of antibiotics, nasogastric suction, pain related to the surgical incision, and personal and family stressors associated with the surgery, represent risk factors in the development of childhood chronic abdominal pain later in life. An additional benefit derived from this study was the identification of a novel model to study early life events in humans. A limitation of the study was the inability to isolate the single factor or identify the multiple factors explaining the increased risk of pain associated-FGIDs found in this group of children. In light of the biopsychosocial model, several aspects require further study. For example, the relationship between the age at which a patient receives a noxious stimulus and develops the risk for long-term gastrointestinal effects is unclear. The time period of early life events in humans is still undefined. The severity, type, and timing of the noxious stimuli most likely vary from subject to subject. In yet unpublished data, our group has found that surgery in older children also results in an increased risk for developing FGIDs. Pediatric and adult studies have shown that inflammatory conditions that present later in life can also lead to long-term chronic abdominal pain and FGIDs. Studies have found a significant increase in cases of FGIDs following bacterial infections in children outside of the infant period. A study on 44 children with a previous history of acute bacterial gastroenteritis who were contacted at least 6 months after the index episode, showed a significant increase in incidence and prevalence of FGIDs, compared with healthy controls of similar age and sex. Thirty-six percent of exposed patients and 11% of control subjects reported abdominal pain (p < 0.01). Fifty-six percent reported onset of pain following the episode of acute gastroenteritis.64 A recent epidemiologic study conducted in children who experienced acute gastroenteritis as a result of an outbreak of bacterial contamination in the municipal water in Ontario, Canada, confirmed these findings.65 The study included 467 subjects, with 305 subjects who had a history of acute bacterial gastroenteritis and 162 unexposed controls. The cumulative incidence of IBS was significantly increased among exposed subjects vs. controls (10.5% vs. 2.5%; OR 4.6, 95% CI [1.6, 13.3]) and risk factors for the development of IBS were similar to those identified among adults.66, 67, 68 Non-infectious sources of inflammation have also been linked to the development of FGIDs in older children. A follow-up study of children diagnosed with Henoch–Schonlein purpura (HSP) who were contacted several months to years after the acute episode, has shown that HSP predisposes children to the development of FGIDs.69 Possible ongoing inflammation and persistence of symptoms from the time of diagnosis were excluded by review of records, laboratory, and parental interview. Sixty percent of children with a history of HSP and 2.6% of controls reported abdominal pain at follow-up. Children in the HSP group were diagnosed with various FGIDs (IBS in 11%, FAPS in 8%, and FAP in 2.8%). Celiac disease is another model of intestinal inflammation that allows for the investigation of the long-term effects of inflammatory changes in visceral pain. In order to assess whether celiac disease was a risk factor for long-term abdominal pain and FGIDs, our group conducted a case-control study involving 49 cases and 48 controls.70 Twelve children in the celiac disease group (24.5%) and 7 children in the control group (14.6%) had abdominal pain at the time of the study (p = 0.3). Nine children in the celiac disease group (18.3%) and 4 children in the control group (8.3%) met the Rome criteria for an associated FGID (p = 0.23). We found that children with celiac disease and controls have a similar risk for developing abdominal pain and abdominal pain-associated FGIDs. However, larger prospective studies should confirm these findings and investigate whether healthy siblings of celiac disease children have a higher prevalence of FGIDs. Consultation for abdominal pain is frequent in children who had hematopoietic stem-cell transplant. Our group found that consultations are more common in children with a shorter interval from hematopoietic stem-cell transplant. The results of the study suggest that post-hematopoietic stem-cell transplant follows the course of other inflammatory gastrointestinal conditions.71

Psychological stressors have also been shown to predispose to FGIDs in children. Maternal psychological distress during the child's early years is a risk factor for the development of recurrent abdominal pain during adolescence.72 A history of psychological, physical, or sexual abuse in childhood is a strong predictor of the development of gastrointestinal symptoms later in life.73, 74, 75 IBS patients have a higher prevalence of general trauma, physical punishment, emotional abuse, and sexual events than age and sex matched controls.76 This has been confirmed by physiologic studies that have shown that subjects with IBS and a history of early adverse life events have higher cortisol levels in response to a visceral stressor than subjects without a history of early adverse life events.77 Early-life exposure to severe wartime conditions was found to be associated with an increased prevalence of IBS.78 Adults who were less than 2 years of age during a war-related famine have a higher prevalence of IBS than the general population. Possible mechanisms involved include exposure to a stressful environment, severe malnutrition, or increased prevalence of infectious diseases. A history of an unsatisfactory parental relationship or parental loss through death, divorce, or separation during childhood was also found in 31–61% of IBS adult patients.79 Finally, the influence of the childhood socioeconomic environment on the development of adult IBS was studied using information from a New Zealand birth cohort study.80 The authors found that an affluent childhood setting was an independent risk factor for adult IBS.

Conclusions

Early life events appear to be significant risk factors for the development of an abnormal response to pain later in life. Evidence from experimental and clinical studies suggests that early childhood is a critical time period in which psychological or physical trauma can induce visceral hyperalgesia. Early life events may play an important role in the complex pathogenesis of functional gastrointestinal conditions. Taken together, these findings are of great significance given that some of these events are potentially modifiable. Timely intervention may have a critical impact in the prevention of this group of chronic incapacitating conditions. These findings support the biopsychosocial model as a valid theoretical construct in FGIDs. Future studies are required to further evaluate the relative contribution of each of these factors to the pathogenesis of childhood FGIDs.

Conflict of interest

The authors declare that there is no conflict of interest.

Financial disclosure

No financial support was received in relation to this article.

Received 3 January 2013
Accepted 14 February 2013

Corresponding author at: Ann & Robert H. Lurie Children's Hospital of Chicago, Box 86, 225 E Chicago Avenue, Chicago, IL 60611, United States. Tel.: +1 312 227 4200. silvanabonilla@hotmail.com

Bibliography
[1]
Nurko S, Di Lorenzo C..
Functional abdominal pain: time to get together and move forward..
J Pediatr Gastroenterol Nutr. , 47 (2008), pp. 679-680
[2]
Starfield B, Hoekelman RA, McCormick M, et-al..
Who provides health care to children and adolescents in the United States..
Pediatrics. , 74 (1984), pp. 991-997
[3]
Rasquin A, Di Lorenzo C, Forbes D, et-al..
Childhood functional gastrointestinal disorders: child/adolescent..
Gastroenterology. , 130 (2006), pp. 1527-1537
[4]
Saps M, Seshadri R, Sztainberg M, et-al..
A prospective school-based study of abdominal pain and other common somatic complaints in children..
J Pediatr. , (2008),
[5]
Saps M, Nichols-Vinueza D, Velasco C..
Gastrointestinal symptoms in school-aged Colombian children..
Gastroenterology. , 142 (2012), pp. S381-S382
[6]
Devanarayana NM, Adhikari C, Pannala W, et-al..
Prevalence of functional gastrointestinal diseases in a cohort of Sri Lankan adolescents: comparison between Rome II and Rome III criteria..
J Trop Pediatr. , 57 (2011), pp. 34-39
[7]
Devanarayana NM, Mettananda S, Liyanarachchi C, et-al..
Abdominal pain-predominant functional gastrointestinal diseases in children and adolescents: prevalence, symptomatology, and association with emotional stress..
J Pediatr Gastroenterol Nutr. , 53 (2011), pp. 659-665
[8]
Saps M, Velasco C, Nichols-Vinueza D..
Prevalence of functional gastrointestinal disorders in more than 1000 children and counting..
J Pediatr Gastroenterol Nutr. , 55 (2012), pp. E36
[9]
Dhroove G, Chogle A, Saps M..
A million-dollar work-up for abdominal pain: is it worth it..
J Pediatr Gastroenterol Nutr. , 51 (2010), pp. 579-583
[10]
Levy RL, Von Korff M, Whitehead WE, et-al..
Costs of care for irritable bowel syndrome patients in a health maintenance organization..
Am J Gastroenterol. , 96 (2001), pp. 3122-3129
[11]
Saps M, Sztainberg M, Di Lorenzo C..
A prospective community-based study of gastroenterological symptoms in school-age children..
J Pediatr Gastroenterol Nutr. , 43 (2006), pp. 477-482
[12]
Gatchel RJ, Okifuji A..
Evidence-based scientific data documenting the treatment and cost-effectiveness of comprehensive pain programs for chronic nonmalignant pain..
J Pain. , 7 (2006), pp. 779-793
[13]
Greco LA, Freeman KE, Dufton L..
Overt and relational victimization among children with frequent abdominal pain: links to social skills, academic functioning, and health service use..
J Pediatr Psychol. , 32 (2007), pp. 319-329
[14]
Saps M, Adams P, Bonilla S, et-al..
Parental report of abdominal pain and abdominal pain-related functional gastrointestinal disorders from a community survey..
J Pediatr Gastroenterol Nutr. , 55 (2012), pp. 707-710
[15]
Saps M, Bolioli P, Espana M, et-al..
Cost and consultation patterns of abdominal pain in Uruguayan children..
J Pediatr Gastroenterol Nutr. , 46 (2008), pp. 159-163
[16]
Bonilla S, Deli W, Saps M..
The prognostic value of obtaining a negative endoscopy in children with functional gastrointestinal disorders..
Clin Pediatr (Phila). , 50 (2011), pp. 396-401
[17]
Chitkara DK, Talley NJ, Schleck C, et-al..
Recollection of childhood abdominal pain in adults with functional gastrointestinal disorders..
Scand J Gastroenterol. , 44 (2009), pp. 301-307
[18]
Jarrett M, Heitkemper M, Czyzewski DI, et-al..
Recurrent abdominal pain in children: forerunner to adult irritable bowel syndrome?..
J Special Pediatr Nurs. , 8 (2003), pp. 81-89
[19]
Walker LS, Dengler-Crish CM, Rippel S, et-al..
Functional abdominal pain in childhood and adolescence increases risk for chronic pain in adulthood..
Pain. , 150 (2010), pp. 568-572
[20]
Hotopf M, Carr S, Mayou R, et-al..
Why do children have chronic abdominal pain, and what happens to them when they grow up? Population based cohort study..
BMJ. , 316 (1998), pp. 1196-1200
[21]
Gatchel RJ, Peng YB, Peters ML, et-al..
The biopsychosocial approach to chronic pain: scientific advances and future directions..
Psychol Bull. , 133 (2007), pp. 581-624
[22]
Finestone HM, Alfeeli A, Fisher WA..
Stress-induced physiologic changes as a basis for the biopsychosocial model of chronic musculoskeletal pain: a new theory..
Clin J Pain. , 24 (2008), pp. 767-775
[23]
Chitkara DK, van Tilburg MA, Blois-Martin N, et-al..
Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review..
Am J Gastroenterol. , 103 (2008), pp. 765-774
[24]
Saito YA, Petersen GM, Larson JJ, et-al..
Familial aggregation of irritable bowel syndrome: a family case–control study..
Am J Gastroenterol. , 105 (2010), pp. 833-841
[25]
Buonavolonta R, Coccorullo P, Turco R, et-al..
Familial aggregation in children affected by functional gastrointestinal disorders..
J Pediatr Gastroenterol Nutr. , 50 (2010), pp. 500-505
[26]
Bengtson MB, Ronning T, Vatn MH, et-al..
Irritable bowel syndrome in twins: genes and environment..
Gut. , 55 (2006), pp. 1754-1759
[27]
Morris-Yates A, Talley NJ, Boyce PM, et-al..
Evidence of a genetic contribution to functional bowel disorder..
Am J Gastroenterol. , 93 (1998), pp. 1311-1317
[28]
Mohammed I, Cherkas LF, Riley SA, et-al..
Genetic influences in irritable bowel syndrome: a twin study..
Am J Gastroenterol. , 100 (2005), pp. 1340-1344
[29]
Levy RL, Jones KR, Whitehead WE, et-al..
Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology..
Gastroenterology. , 121 (2001), pp. 799-804
[30]
Levy RL, Whitehead WE, Walker LS, et-al..
Increased somatic complaints and health-care utilization in children: effects of parent IBS status and parent response to gastrointestinal symptoms..
Am J Gastroenterol. , 99 (2004), pp. 2442-2451
[31]
Park JM, Choi MG, Park JA, et-al..
Serotonin transporter gene polymorphism and irritable bowel syndrome..
Neurogastroenterol Motil. , 18 (2006), pp. 995-1000
[32]
Bashashati M, Rezaei N, Bashashati H, et-al..
Cytokine gene polymorphisms are associated with irritable bowel syndrome: a systematic review and meta-analysis..
Neurogastroenterol Motil. , 24 (2012), pp. 1102-1566
[33]
Kim HG, Lee KJ, Lim SG, et-al..
G-protein beta3 subunit C825T polymorphism in patients with overlap syndrome of functional dyspepsia and irritable bowel syndrome..
J Neurogastroenterol Motil. , 18 (2012), pp. 205-210
[34]
Bode G, Brenner H, Adler G, et-al..
Recurrent abdominal pain in children: evidence from a population-based study that social and familial factors play a major role but not Helicobacter pylori infection..
J Psychosom Res. , 54 (2003), pp. 417-421
[35]
Ramchandani PG, Stein A, Hotopf M, et-al..
Early parental and child predictors of recurrent abdominal pain at school age: results of a large population-based study..
J Am Acad Child Adolesc Psychiatry. , 45 (2006), pp. 729-736
[36]
Anand KJ, Coskun V, Thrivikraman KV, et-al..
Long-term behavioral effects of repetitive pain in neonatal rat pups..
Physiol Behav. , 66 (1999), pp. 627-637
[37]
Anand KJ..
Clinical importance of pain and stress in preterm neonates..
Biol Neonate. , 73 (1998), pp. 1-9
[38]
Grunau R..
Early pain in preterm infants. A model of long-term effects..
Clin Perinatol. , 29 (2002), pp. vii-viii
[39]
Grunau RE, Oberlander TF, Whitfield MF, et-al..
Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks’ postconceptional age..
Pediatrics. , 107 (2001), pp. 105-112
[40]
Holsti L, Grunau RE, Oberlander TF, et-al..
Prior pain induces heightened motor responses during clustered care in preterm infants in the NICU..
Early Hum Dev. , 81 (2005), pp. 293-302
[41]
Grunau RE, Holsti L, Haley DW, et-al..
Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU..
Pain. , 113 (2005), pp. 293-300
[42]
Grunau RE, Weinberg J, Whitfield MF..
Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months..
Pediatrics. , 114 (2004), pp. e77-e84
[43]
Holsti L, Grunau RE, Whifield MF, et-al..
Behavioral responses to pain are heightened after clustered care in preterm infants born between 30 and 32 weeks gestational age..
Clin J Pain. , 22 (2006), pp. 757-764
[44]
Taddio A, Shah V, Gilbert-MacLeod C, et-al..
Conditioning and hyperalgesia in newborns exposed to repeated heel lances..
JAMA. , 288 (2002), pp. 857-861
[45]
Hermann C, Hohmeister J, Demirakca S, et-al..
Long-term alteration of pain sensitivity in school-aged children with early pain experiences..
Pain. , 125 (2006), pp. 278-285
[46]
Duhrsen L, Simons SH, Dzietko M, et-al..
Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain..
Neonatology. , 103 (2013), pp. 35-43
[47]
Hohmeister J, Demirakca S, Zohsel K, et-al..
Responses to pain in school-aged children with experience in a neonatal intensive care unit: cognitive aspects and maternal influences..
Eur J Pain (London, England). , 13 (2009), pp. 94-101
[48]
Vederhus BJ, Eide GE, Natvig GK, et-al..
Pain tolerance and pain perception in adolescents born extremely preterm..
J Pain. , 13 (2012), pp. 978-987
[49]
Miranda A..
Early life events and the development of visceral hyperalgesia..
J Pediatr Gastroenterol Nutr. , 47 (2008), pp. 682-684
[50]
Liu LS, Winston JH, Shenoy MM, et-al..
A rat model of chronic gastric sensorimotor dysfunction resulting from transient neonatal gastric irritation..
Gastroenterology. , 134 (2008), pp. 2070-2079
[51]
Smith C, Nordstrom E, Sengupta JN, et-al..
Neonatal gastric suctioning results in chronic visceral and somatic hyperalgesia: role of corticotropin releasing factor..
Neurogastroenterol Motil. , 19 (2007), pp. 692-699
[52]
Traub RJ, Tang B, Ji Y, et-al..
A rat model of chronic postinflammatory visceral pain induced by deoxycholic acid..
Gastroenterology. , 135 (2008), pp. 2075-2083
[53]
Al-Chaer ED, Kawasaki M, Pasricha PJ..
A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development..
Gastroenterology. , 119 (2000), pp. 1276-1285
[54]
Lin C, Al-Chaer ED..
Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain..
Brain Res. , 971 (2003), pp. 73-82
[55]
O‘Mahony SM, Hyland NP, Dinan TG, et-al..
Maternal separation as a model of brain–gut axis dysfunction..
Psychopharmacology (Berl). , 214 (2011), pp. 71-88
[56]
Moloney RD, O‘Leary OF, Felice D, et-al..
Early-life stress induces visceral hypersensitivity in mice..
Neurosci Lett. , 512 (2012), pp. 99-102
[57]
Coutinho SV, Plotsky PM, Sablad M, et-al..
Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat..
Am J Physiol. , 282 (2002), pp. G307-G316
[58]
O‘Mahony SM, Marchesi JR, Scully P, et-al..
Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses..
Biol Psychiatry. , 65 (2009), pp. 263-267
[59]
Ren TH, Wu J, Yew D, et-al..
Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome..
Am J Physiol. , 292 (2007), pp. G849-G856
[60]
Chung EK, Zhang X, Li Z, et-al..
Neonatal–maternal separation enhances central sensitivity to noxious colorectal distention in rat..
Brain Res. , 1153 (2007), pp. 68-77
[61]
Tjong YW, Ip SP, Lao L, et-al..
Neonatal maternal separation elevates thalamic corticotrophin releasing factor type 1 receptor expression response to colonic distension in rat..
Neuroendocrinol Lett. , 31 (2010), pp. 215-220
[62]
Saps M, Lu P, Bonilla S..
Cow's-milk allergy is a risk factor for the development of FGIDs in children..
J Pediatr Gastroenterol Nutr. , 52 (2011), pp. 166-169
[63]
Saps M, Bonilla S..
Early life events: infants with pyloric stenosis have a higher risk of developing chronic abdominal pain in childhood..
J Pediatr. , 159 (2011), pp. 551-554
[64]
Saps M, Pensabene L, Di Martino L, et-al..
Post-infectious functional gastrointestinal disorders in children..
J Pediatr. , 152 (2008), pp. 812-816
[65]
Thabane M, Simunovic M, Akhtar-Danesh N, et-al..
An outbreak of acute bacterial gastroenteritis is associated with an increased incidence of irritable bowel syndrome in children..
Am J Gastroenterol. , 105 (2010), pp. 933-939
[66]
Mearin F, Perez-Oliveras M, Perello A, et-al..
Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study..
Gastroenterology. , 129 (2005), pp. 98-104
[67]
Mearin F, Perello A, Balboa A, et-al..
Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis..
Scand J Gastroenterol. , 44 (2009), pp. 1173-1185
[68]
Thabane M, Kottachchi DT, Marshall JK..
Systematic review and meta-analysis: the incidence and prognosis of post-infectious irritable bowel syndrome..
Aliment Pharmacol Ther. , 26 (2007), pp. 535-544
[69]
Saps M, Dhroove G, Chogle A..
Henoch–Schonlein purpura leads to functional gastrointestinal disorders..
Dig Dis Sci. , 56 (2011), pp. 1789-1793
[70]
Saps M, Adams P, Bonilla S, et-al..
Abdominal pain and functional gastrointestinal disorders in children with celiac disease..
J Pediatr. , (2012),
[71]
Saps M, Broglie L, Danner-Koptik K, et-al..
Prevalence of abdominal pain related functional gastrointestinal disorders in pediatric recipients of hematopoietic stem cell transplant..
Gastroenterology. , 142 (2012), pp. S381-S382
[72]
Helgeland H, Sandvik L, Mathiesen KS, et-al..
Childhood predictors of recurrent abdominal pain in adolescence: a 13-year population-based prospective study..
J Psychosom Res. , 68 (2010), pp. 359-367
[73]
van Tilburg MA, Runyan DK, Zolotor AJ, et-al..
Unexplained gastrointestinal symptoms after abuse in a prospective study of children at risk for abuse and neglect..
Ann Fam Med. , 8 (2010), pp. 134-140
[74]
Drossman DA, Leserman J, Nachman G, et-al..
Sexual and physical abuse in women with functional or organic gastrointestinal disorders..
Ann Intern Med. , 113 (1990), pp. 828-833
[75]
Talley NJ, Fett SL, Zinsmeister AR, et-al..
Gastrointestinal tract symptoms and self-reported abuse: a population-based study..
Gastroenterology. , 107 (1994), pp. 1040-1049
[76]
Bradford K, Shih W, Videlock EJ, et-al..
Association between early adverse life events and irritable bowel syndrome..
Clin Gastroenterol Hepatol. , 10 (2012), pp. 385-390
[77]
Videlock EJ, Adeyemo M, Licudine A, et-al..
Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome..
Gastroenterology. , 137 (2009), pp. 1954-1962
[78]
Klooker TK, Braak B, Painter RC, et-al..
Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study..
Am J Gastroenterol. , 104 (2009), pp. 2250-2256
[79]
Hislop IG..
Childhood deprivation: an antecedent of the irritable bowel syndrome..
Med J Aust. , 1 (1979), pp. 372-374
[80]
Howell S, Talley NJ, Quine S, et-al..
The irritable bowel syndrome has origins in the childhood socioeconomic environment..
Am J Gastroenterol. , 99 (2004), pp. 1572-1578
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