Children with functional gastrointestinal disorders with and without co‐existing nausea: A comparison of clinical and psychological characteristics

Nausea co‐existing with functional gastrointestinal disorders (FGIDs) has been suggested to negatively impact physical and psychological factors in children. This study aims to compare clinical and psychological characteristics of a large cohort of pediatric patients with an FGID with and without nausea.


| INTRODUC TI ON
Many children who experience chronic nausea or chronic abdominal pain are diagnosed with a functional gastrointestinal disorder (FGID), meaning that after appropriate medical evaluation their symptoms cannot be explained by another medical condition. 1 FGIDs are highly prevalent in children worldwide. In a representative community sample in the United States, 23.1% of children and adolescents qualified for at least one FGID, and a community survey reported a rate of 15.9% of school-aged children with nausea in Latin America. 2,3 These conditions cause children to suffer from psychosocial and physical distress and increased school absenteeism. [4][5][6] The Rome criteria describe symptom-based FGID subgroups, such as functional nausea and vomiting disorders, and functional abdominal pain disorders (FAPDs). In 2006, the Rome III criteria were launched and revised in 2016, known as the Rome IV criteria. 1,7 Irritable bowel syndrome (IBS) and functional abdominal pain -not otherwise specified (FAP-NOS) are two of the most commonly diagnosed subtypes of FAPDs, characterized by recurrent abdominal pain for more than 2 months and, in the case of IBS, in combination with a change in stool pattern. 1 The term functional abdominal pain (syndrome, FAP (S)) as mentioned in Rome III was changed into FAP-NOS in Rome IV. 1 Another FAPD subtype is functional dyspepsia (FD), characterized by upper gastro-intestinal discomfort such as epigastric pain and early satiation. FD is often accompanied by chronic nausea. According to the Rome IV criteria, chronic nausea can also be an isolated phenomenon and is then defined as functional nausea (FN). It is hypothesized that the etiology of FGIDs is multifactorial including social, biological, and psychological factors.
However, underlying pathophysiological mechanisms are not completely understood. 8,9 The Rome criteria have been designed to assist clinicians and researchers in identifying patients with a homogenous type of presentation. However, many diagnoses frequently have an overlap of symptoms. 10 For example, Rutten et al. showed that pediatric IBS and FAP share many clinical and psychosocial similarities, indicating that IBS and FAP may be different expressions of one underlying FGID. 11 Recently, it was suggested in an adult population that FGIDs might be better characterized as a spectrum rather than discrete entities. 12 On the other hand, therapies do not always show similar efficacy in different FGIDs. Previous studies found that gut-directed hypnotherapy (HT) is an effective treatment for children with either IBS or FAP, with treatment success rates between 85% and 71% and without differences in efficacy between IBS and FAP. 13,14 In children with FN and FD, Browne et al. found a HT treatment success rate of around 60%. After 3 months of HT, treatment seemed more effective in reducing nausea in FN patients than in FD patients. 15 These variances in response to the same treatment suggest that FGIDs and its subgroups FN, FD, IBS, and FAP differ, at least partly, in pathophysiological mechanism and that they should be regarded as different disorders. This observation may also suggest that treatments should not be studied in the context of a Rome-defined disorder, but preferably in relation to the predominant symptom.
Nausea is a prevalent symptom in patients with pain-associated FGIDs, with many children experiencing nausea at least two times a week. 16 However, nausea remains a relatively unexamined symptom in children with FGIDs. 6 In a previous study, nausea co-existing with FAPDS was associated with a higher-intestinal symptom burden, worse quality of life, and impaired functioning in adolescents compared to FAPDs patient without nausea. 17 This study, however, did not include a comparison group comprised of functional nausea patients. One small cohort study retrospectively compared clinical characteristics of adolescents with isolated FN and adolescents with FAPD and comorbid nausea, but did not investigate differences in emotional well-being and quality of life. 18 The aim of the present study was to compare baseline clinical and psychological characteristics in a large population of children diagnosed with functional nausea or FAPDs with co-existing nausea versus children with FAPDs without nausea complaints. For exploratory purposes, we additionally compared characteristics of children with functional nausea versus children with nausea and abdominal pain, and assessed the impact of nausea to the predominant presentation of abdominal pain in IBS and FAP patients. We also examined whether the presence of nausea was associated with a different response to hypnotherapy in patients with IBS and FAP.

Practitioner Points
• Nausea is a prevalent comorbid symptom in patients with functional abdominal pain disorders: 53% have been proven to experience nausea at least two times a week.
• Children with nausea report more feelings of anxiety and depression and lower overall health-related quality of life than children with a functional abdominal pain disorder without nausea.
• Addressing the presence of nausea in children with functional gastrointestinal disorders seems essential to customize their treatment and improve overall quality of life.

| Study design
The present study is an ancillary study to two previously performed randomized controlled trials (RTC). 14,15 The first trial-conducted be- can be found elsewhere. 15,19 In both trials, all children underwent laboratory testing and stool analysis to exclude underlying (organic) diseases before inclusion. Exclusion criteria in both studies were insufficient knowledge of the Dutch language or intellectual disability.

| Patients
Patients in the present study were grouped by the presence of nausea symptoms. Children diagnosed with FN or FD, were clustered in the "nausea" group, as nausea was the main inclusion criteria in that RCT.
In this original RCT the presence of nausea was assessed using a 7-day diary to score the severity, incidence, and frequency of symptoms of nausea. FD patients without nausea were not eligible to participate in the initial trial. To determine if children with IBS and FAP also experienced nausea, two questions from the Children's Somatization Inventory (CSI) were used to determine the presence of nausea. The first question covered symptoms of nausea related to food; "Do you ever feel nauseous because of food (when smelling, thinking, or seeing food)?" In the second question children were asked if they had ever experienced either nausea or an upset stomach: "Do you ever experience nausea or an upset stomach?". Children scored the severity on a 5-point Likert scale (0 = not at all to 4 = a whole lot). If children scored 2 (pretty much) to 4 (a whole lot) on one of the two questions, nausea symptoms were considered to be clinically relevant and children were placed in the "nausea" group. Explorative analyses discriminated all nausea patients into two groups: FN patients who solely experienced nausea versus patients who experienced nausea and abdominal pain. All children diagnosed with IBS, FAP, FD, and accompanying nausea were clustered in the "nausea and abdominal pain" group, as abdominal pain is one of the diagnostic criteria of IBS and FAP and all participating patients with FD experience pain in the upper abdomen.
Moreover, we assessed the impact of nausea to the predominant presentation of abdominal pain in IBS and FAP patients.

| Outcome measures
Outcomes included several clinical and psychological patient characteristics including feelings of anxiety and depression, health-related quality of life (QoL), and somatization scores. Questionnaires were filled out before start of the intervention in both RCTs. Table 1 describes outcome measures and corresponding instruments. Moreover, we compared adequate relief percentages after 3 months of individual hypnotherapy or home-based standardized hypnotherapy between children with IBS/FAP with or without concomitant nausea.

| Statistical analysis
Continuous variables were tested for normality; if normality was confirmed, variables were expressed as mean with standard deviation

Outcome measures Instrument
Anxiety and depression Revised Anxiety and Depression Scale-short version (RCADS-25) 20 Five subscales measuring symptoms of generalized anxiety disorders, separation anxiety disorder, social phobia, panic disorder and major depressive disorder. Each subscale contains five items and scales range from 0 (never) to 3 (always). The total score on anxiety or depression is the sum of the items measuring symptoms of anxiety and depressive symptoms, respectively. Higher scores indicate more symptoms of anxiety or depression.

Somatization
Children's Somatization Inventory (CSI) 21 35 Items on a 5-point Likert scale (0 = not at all to 4 = a whole lot) and children rate the extent to which they experienced somatic symptoms in the previous 2 weeks. The total score is calculated by summing up the 35 items, with higher scores indicating higher intensity of somatic complaints experienced by the child.
Health-related quality of life KIDSCREEN-52 questionnaire 22 Items on ten dimensions related to QoL on a 5-point Likert scale: moods and emotions, self-perception, relations with parents and home life, autonomy, physical well-being, psychological well-being, school environment, social support and peers, social acceptance (bullying) and financial resources. For each individual dimension, Rasch scores are computed from the individual items. These are then transformed into T-values: higher T-values indicate a better health-related QoL and well-being.
(SD). For variables with non-parametric distribution median and the interquartile range (IQR) were reported. Differences between groups were analyzed using independent t-test for continuous vari-

| Ethics
The

| RE SULTS
Baseline data of 355 children were available for the present study.  Table 2.

| Demographics and clinical features
Age of children within the nausea group was significantly higher than children without nausea (U = 8086, z = −5.243, p < 0.001).
Abdominal pain in children without nausea started at a median age of 9.0 years, while children within the nausea group experienced the start of their complaints at a significantly older age (median: 12 years, U = 8408, z = −4.515, p < 0.001). More school absenteeism was reported at baseline within the nausea group compared to children without nausea complaints (76% vs. 65%), but after correcting for multiple testing differences were not significant (χ 2 (1) = 4.460, p = 0.035). Children with nausea experienced significantly more discomfort due to acid reflux. No significant differences were found between the two groups in patients experiencing the following comorbid symptoms: burps, regurgitation, bloated feelings, flatulence, fever, pallor, photophobia, tiredness, and sleep problems. The proportion of patients experiencing associated symptoms is shown in Figure 1.

| Somatization
As reported in

| Depression and anxiety scores
Median score on depressive symptoms significantly differed be-  Table 1 shows the scores of all 10 subscales of health-related QoL.

| Health-Related quality of life
Higher values indicate a better health-related QoL and well-being.
Median scores on the eight subscales assessing physical well-being, psychological well-being, mood and emotions, self-perception, autonomy, relationship with parents and home life, social supports and peers, and school environment were significantly lower in the group patient experiencing nausea symptoms, indicating a lower health-related QoL in this subgroup. No significant differences were found regarding social acceptance (bullying) and financial resources.

| Explorative analyses-functional nausea versus abdominal pain and nausea
Demographic characteristics and clinical features of nausea patients with and without abdominal pain symptoms are shown in Table 3. Total CSI score was higher in the group of nausea patients with accompanying abdominal pain symptoms, but after correcting for multiple testing, differences were not significant (U = 4735, z = −2.636, p = 0.008). Scores on depressive symptoms, total anxiety, and health-related QoL did not differ between both groups.  Figure S1. IBS and FAP patients with nausea experienced significantly more tiredness (77% vs. 56% IBS and FAP patients without nausea). After correcting for multiple testing, discomfort due to acid reflux did not differ significantly between two groups.

| Explorative analyses-response to hypnotherapy
To investigate whether response to hypnotherapy was lower in patients with IBS and FAP with comorbid nausea compared to IBS and FAP patients without nausea, rates of adequate relief of IBS-related abdominal pain or discomfort were compared. Adequate relief did not significantly differ between the two groups Table 4.

| DISCUSS ION
The present study compared clinical and psychological characteristics in a large population of children with functional nausea and children with FAPD with and without co-existing symptoms of nausea.   An alternative explanation has been proposed by Russel et al., stating that patients with FAPD and comorbid nausea may represent a separate phenotype with a more extensive autonomic nervous system dysfunction, contributing to both nausea and emotional distress. 23 The autonomic nervous system, specifically the parasympathetic nervous system, is involved in, among others, processes of digestion and stress recovery. The vagal nerve represents the main component of the parasympathetic nervous system, the bidirectional link between the GI tract and central nervous system and is considered to be pivotal in the brain-gut axis. 24 Chronic nausea in children and adolescents has been associated with delayed gastric emptying. 25,26 Moreover, in the current study, burps, acid reflux, regurgitation, and a bloated feeling were more prevalent in children with nausea, suggesting that an altered gastric motility indeed plays a role in the pathophysiology of nausea. At the same time, gastric electrical stimulation can improve symptoms in children with severe nausea. 27,28 Since the vagal nerve influences gastric emptying, dysfunction of the parasympathetic nervous system it likely plays a role in the pathogenesis of nausea. 17,29,30 Physiological testing in pediatric patients with chronic unexplained nausea has indeed shown a decreased heart rate variability, suggesting reduced parasympathetic tone and underlying dysfunction. 31 At the same time, it is known that feelings of anxiety and depression are also associated with a lower parasympathetic activity. 32 In light of the gut-brain axis, a vi- Age at symptom onset was significantly higher in the group of patients experiencing nausea. Although not significant, this trend was also seen in the study of Kovacic et al. 18

| CON CLUS ION
The results of the current study show the negative impact of nausea symptoms on psychological and physical distress in children with  in the disease. This knowledge will help to introduce more specific treatments targeting the origin of chronic nausea.

AUTH O R CO NTR I B UTI O N S
CMAB coordinated and participated in data collection, carried out statistical analyses, reviewed the literature, and wrote the manuscript. AG carried out statistical analyses, reviewed the literature, and wrote the manuscript. PB participated in data collection, reviewed and approved the manuscript. MAB participated in patient recruitment, critically revised the protocol, and supervised writing the manuscript. AMV is the principal investigator, designed the study, wrote the protocol, participated in patient recruitment, supervised the study, and writing the manuscript.

ACK N OWLED G M ENTS
We acknowledge the great work and contributions by all clinicians and hypnotherapists who performed the original randomized clinical trials. Finally, we thank all patients who took part in this study.

FU N D I N G I N FO R M ATI O N
No funding.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors have no competing interests.