Next Article in Journal
Blood Adhesion Molecules as Biomarkers in Children with Chronic Urticaria
Next Article in Special Issue
Sex Differences in Children with Uncomplicated Attention Deficit/Hyperactivity Disorder and Sleep Problems
Previous Article in Journal
Adaptation and Validation of the MapMe Body Image Scales in Spanish Parents of Schoolchildren
Previous Article in Special Issue
Melatonin Use in Pediatrics: A Clinical Review on Indications, Multisystem Effects, and Toxicity
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Children
Volume 11
Issue 4
10.3390/children11040450
children-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Study on Nocturnal Infant Crying Evaluation (NICE) and Reflux Disease (RED)

by
Greta Carabelli
1,
Ivan Binotto
1,
Chiara Armano
1,
Lorenza Bertù
2,
Chiara Luini
1,
Luana Nosetti
1,
Massimo Agosti
1 and
Silvia Salvatore
1,*
1
Pediatric Department, “F. Del Ponte” Hospital, University of Insubria, 21100 Varese, Italy
2
Research Center Tromboembolic Diseases, University of Insubria, 21100 Varese, Italy
*
Author to whom correspondence should be addressed.
Children 2024, 11(4), 450; https://doi.org/10.3390/children11040450
Submission received: 6 March 2024 / Revised: 31 March 2024 / Accepted: 6 April 2024 / Published: 8 April 2024
(This article belongs to the Special Issue Sleep Disorders in Children: Presentation, Early Identification and Treatment)
Browse Figure
Review Reports Versions Notes

Abstract

:
Background: Nocturnal infant crying is often empirically treated with acid suppressants. The aim of this study was to evaluate the prevalence and characteristics of gastroesophageal reflux (GER) in infants with unexplained persistent crying. Methods: We enrolled all infants (0–12 months) referred for suspected GER disease who underwent esophageal impedance–pH monitoring (MII-pH) for unexplained persistent crying not improved by parental reassurance, dietary modification or alginate. Gastrointestinal malformation/surgery, neurological impairment and infections were exclusion criteria. Demographic and anthropometric parameters, GER symptoms and questionnaires (I-GERQ-R) and MII-pH data were recorded and analyzed. Normal MII-pH was defined when acid exposure was <3%, symptom index was <50% and symptom association probability was <95%. Acid exposure >5% and >10% was also considered. Statistical analysis was performed using Chi-Square and univariate and multivariable regression analysis. Results: We included 50 infants (median age 3.5 months) who fulfilled the study criteria: 30 (60%) had normal MII-pH. I-GERQ-R score was abnormal in 33 (66%) infants, and 21/33 (64%) had normal MII-pH (p = 0.47). In the 26 (52%) infants with nocturnal crying, MII-pH was normal in 16 (54%) (p = 0.82). Associated regurgitation (>3 or >10 episodes/die) did not predict abnormal MII-pH (p = 0.74, p = 0.82, respectively). Univariate and multivariable regression analysis did not identify any clinical variable significantly associated with abnormal MII-pH. Conclusions: Infants with persistent unexplained and nocturnal crying should not be empirically treated with acid inhibitors.

1. Introduction

Distress, colic and nocturnal crying affects 20–40% of infants and is often considered associated with gastroesophageal reflux (GER) [1,2,3,4,5,6]. Reassurance and education of the parents, behavioral advice and infant diet modification are recommended as a first-line approach in this population [1,2,3,4,5]. However, in many cases, complementary medicine and pharmacological treatment are started because of parental distress and sleep disturbances. Despite a lack of evidence of efficacy, empirical acid suppressant drugs continue to be mis- and over-used for infantile distress and persistent crying, especially when episodes of regurgitation are reported [6,7,8,9,10,11,12]. Nonetheless, since acid suppressant drugs may cause adverse events, including an increased rate of respiratory and gastrointestinal infections, fractures, allergies and microbiota alterations, the appropriateness of prescription is of the utmost clinical relevance, particularly in early life [9,10,11,12,13,14,15,16]. Contrarily, the identification of the subgroup of infants with crying associated with GER may alleviate related symptoms and sleep problems and reduce possible esophageal and general complications [1,2,3,4,5,9,17,18,19,20].
In the first months of life, crying is the natural and unspecific response to numerous stimuli, including being hungry or thirsty, hot or cold, tired or distressed, overstimulated or desiring attention, parental stress and anxiety. In addition, infants may also cry because of intestinal fermentation, gastroesophageal reflux, food allergy, infection, inflammation, acute abdomen, neurological problems and pain [21,22]. Persistent infant crying is a frequent cause of pediatric referral and one of the most distressing situations for parents [23]. Alarm symptoms and signs of severe conditions have been identified. However, the distinction between pathological and physiological manifestations and parental reassurance remain challenging in some infants [21,22,23,24,25,26]. Sleep disturbances are also commonly reported in infants, affecting at least 10% of the general population and consisting mostly of night awakenings and short sleep durations [27,28].
Currently, esophageal impedance–pH monitoring (MII-pH) is recognized as the best investigation to detect and quantify acid and non-acid GER episodes, to reveal symptoms temporally associated with reflux and to identify infants to be treated with acid suppressant drugs [2,4,29,30,31].
The aim of this study was to assess and characterize the prevalence of GER disease (GERD) in a population of infants with unexplained nightly and daily persistent crying.

2. Materials and Methods

2.1. Study Design and Population

We consecutively enrolled all infants (0–12 months) referred to our center from January 2008 to May 2023 to perform MII-pH for unexplained inconsolable crying (≥1 h/24 h for ≥1 week) that was persistent despite parental reassurance and education, behavioral and dietary advice (with avoidance of overfeeding), special infant formulas (thickening or protein hydrolyzed formulas for ≥10 days) in formula-fed infants with frequent regurgitation and suspected cow’s milk allergies and maternal cow’s milk elimination diets in breast-fed infants in cases of suspicions of cow’s milk allergies. Information about previous or current diets and eventual pharmacological treatments that can have an effect on GER were also collected. Exclusion criteria were considered as the presence of one of the following: infants aged above 12 months, gastrointestinal malformation/surgery, neurological impairment, naso-gastric tube feeding, current or recent (as occurring in the last two weeks) infections and dietary or pharmacological modifications in the last week. Demographic and anthropometric parameters, GER symptoms, presence of nocturnal crying and failure to thrive, revised infant GER questionnaire (I-GERQ-R) score [19], previous treatments and all MII-pH parameters (including total and nocturnal basal impedance) were recorded and analyzed. Failure to thrive was defined as the presence of subnormal growth, weight for age less than the fifth percentile on WHO growth charts or weight faltering as a decrease in weight percentile of more than two centiles [32,33]. I-GERQ-R is a validated infant questionnaire consisting of 12 questions about the volume and frequency of regurgitations, the occurrence of crying or fussing, eating disturbance, hiccups, arching back, episodes of apnea and cyanosis. Normal values are considered when <16, and higher scores were originally proposed as indicative of GERD [19].
The primary outcome was to assess the prevalence of GERD, detected by MII-pH, in infants with persistent unexplained crying. The secondary outcomes were to evaluate the relation between the MII-pH results and nocturnal crying, regurgitation, failure to thrive and I-GERQ-R score.
This research project obtained approval from the Ethics Committee of the Hospital (ID 24780) and was carried out following the Helsinki Declaration, respecting the human rights of the participants enrolled. Informed consent was obtained from parents of all infants.

2.2. Procedures

2.2.1. Infant Symptom Recording

At enrollment, we educated parents about the importance of precise reporting of symptoms during the entire pH-MII registration using the internal clock of the device. We gave each parent a routine-use diary to record starting and ending time (hour and minute) of infant feeding and sleeping, crying, fussiness/distress, cough, vomiting, regurgitation or any other symptom occurring during the investigation. All infants participating in this study were hospitalized. A dedicated nurse and doctor were available all day and night in case of any problem or doubt. At the end of the investigation, all symptoms and events were transferred to the MII-pH software (Version 5.0.9) for analysis.

2.2.2. GERD Investigation

In all infants, GERD and symptom–GER association were evaluated and defined based on MII-pH results, as recommended by current pediatric guidelines [1,2,3,4]. MII-pH was performed and analyzed following European and Italian guidelines, consensus and position papers [1,2,29,30,31]. In brief, as previously reported [9,17,18,31], a single-use infant MII-pH catheter (Sleuth®, Diversatek; Milwaukee, WI, USA) was calibrated according to the manufacturer’s instructions. The catheter has a diameter of 2.13 mm (6.4 F) and 7 impedance metallic sensors, positioned every 1.5 cm, corresponding to 6 impedance channels and an antimony electrode sensitive to pH variation placed in the middle of the most distal channel. The catheter was inserted transnasally after a 3 h fasting period and positioned at the level of the second vertebra above the diaphragm, based on Strobel’s formula [34] and X-ray confirmation. The recording lasted 20–24 h, using an exterior MII-pH device (Sleuth-Sandhill—Diversatek); the MII/pH traces were analyzed through a dedicated software (BioView Analysis, Sleuth System, Version 5.0.9) and visual evaluation by a single expert operator (S.S.). An MII-GER event was defined as a ≥50% drop in impedance starting in the most distal channel, extending proximally to at least two consecutive channels, and followed by a return of impedance to the previous baseline value. The pH value of each MII-GER event was defined based on the nadir esophageal pH recorded during the event and was classified as acidic (pH < 4), weakly acidic (pH ≥ 4 and <7), or weakly alkaline (pH ≥ 7), with the last two reported as non-acid GER [29,30,31]. Different MII-pH parameters were recorded: number, duration and type of GER episodes, according to pH, proximal extension of reflux episodes (when reflux reaches the two most proximal channels), bolus clearance time (BCT), reflux index (RI) and bolus exposure index (BEI), defined as percentage of time in which the reflux episodes were acidic and retrograde bolus was present in the esophagus, respectively [29,30,31]. In addition, since low distal, proximal and nocturnal impedance baseline values may provide useful clinical insights and have recently been related to esophagitis, esophageal dysmotility and response to GER treatment, these parameters were also manually calculated and analyzed according to age [30,35,36,37,38,39,40,41,42]. Symptoms were considered temporally associated with GER if they occurred within 2 min of a reflux episode. In agreement with GER guidelines and MII-pH consensus, the association between symptoms and GER was based on symptom index (SI) and symptom association probability (SAP). SI represents the number of temporally associated acid and/or non-acid reflux-related symptoms on the total number of symptoms, considered pathological when ≥50%, whilst SAP is the likelihood that the symptoms were related to reflux, calculated by analyzing consecutive 2 min segments with a Fisher’s table of contingency, considered pathological if ≥95% [1,2,29,30,31].
When parents or clinicians were concerned about infant’s noisy breathing or apnea, laryngoscopy and polysomnography were also performed to detect laryngeal inflammation and or respiratory abnormalities [43,44].

2.2.3. Interpretation of MII-pH Results

Since the cut-off for pathological acid reflux index in neonates and infants is still controversial [1,2,3,4,21,22,23], in accordance with ESPGHAN guidelines for GER [1] and recent Italian Pediatric Consensus on MII-pH [22], we considered completely normal MII-pH when all the following were present: RI < 3%; SI for crying <50%; SAP for crying <95%. In addition, a subgroup analysis based on different thresholds of RI (>5%, >10%) was also performed.

2.2.4. Treatment

Based on MII-pH results, current guidelines and consensus on gastroesophageal reflux [1,2,4,30], acid suppressant drugs were prescribed in case of abnormal acid reflux or positive association between crying and acid SIP or SAP. Alginate was indicated for positive non-acid reflux SI and SAP. Cow’s milk protein elimination diet was started, if not yet reported, in cases of suspected cow’s milk allergy or not responding to other treatment. The effect of treatment on infants’ symptoms was recorded when clinical follow-up of infants was available.

2.3. Statistical Analysis

Data are presented as numbers and percentages for categorical variables. Continuous variables were expressed as mean and standard deviation if normally distributed or as median and interquartile range (IQR) if normality could not be accepted. Statistical analysis was performed using Chi-Square and univariate and multivariate regression analysis (Anova). A p-value < 0.05 was considered statistically significant. Odds ratio (OR) and 95% confidence interval (CI) were calculated for the different variables in the regression analysis. Statistical analyses were performed by an independent statistician (L.B.).

Sample Size

We aimed to include at least 40 infants, as estimated to be a sufficient sample of infants, to assess GERD and associated symptoms by recording MII-pH, as previously reported by our group [18].
All the variables that were analyzed in the present research project are presented in Figure 1.

3. Results

We included 50 infants (median age 3.5 months, 24 male) with persistent unexplained crying who fulfilled the study criteria: 30 (60%) infants had normal MII-pH results. The majority of infants (39/50, 78%) were aged 2–6 months. Failure to thrive was present in 22% (11/50) of our population. More than half of infants (29/50, 58%) were on a cow’s milk-free diet at the time of the investigation.
Demographic and clinical characteristics of the study population are reported in Table 1.
In six infants, acid suppressant agents had been empirically started by the family pediatrician: 1/6 had an abnormal MII-pH with an RI of 11.7%. Alginate treatment had already been attempted in 30/50 (60%) of infants: 9/30 (30%) had an RI > 3%, 6/9 had an RI > 5%, and 4/6 had an RI > 10%.

3.1. Symptoms and GERD

Nocturnal crying and concurrent sleep disturbance were reported in 26/50 (52%) infants with persistent unexplained crying. In this group, MII-pH was normal in 16/26 (54%) (p = 0.82), 5/26 (19.2%) had an RI > 5%, and 4/5 had an RI > 10%. In 14/50 (28%) infants, MII was abnormal for weakly acidic SI and/or SAP, and only 1/14 also had an RI > 5%. The additional presence of frequent regurgitation (>3 episodes/day or >10/day) did not significantly predict the results of MII-pH (p = 0.74 and p = 0.82, respectively). Likewise, failure to thrive was not significantly associated with abnormal MII-pH. I-GERQ-R score was abnormal in 33/50 (66%) infants, and 21/33 (63.6%) had normal MII-pH (p = 0.47). In 5/17 (29.4%) infants with normal I-GERQ-R, the RI was >5%, and in 3/5, it was >10%.
The univariate analysis of all demographic and clinical variables did not identify any significant correlation, as shown in Table 2. There was also no statistical significance when considering the different cut-offs of RI for 5% and 10%.
In regard to the MII-pH parameters, the number of proximal episodes of reflux did not correlate with the results of the investigation. Abnormal mean distal and nocturnal baseline impedance was significantly (p = 0.02) associated with abnormal MII-pH in univariate but not in multivariable logistic regression (Table 3).

3.2. Results of Laryngoscopy and Polysomnography

Laryngoscopy was performed on 12 infants. Signs of laryngopharyngeal reflux were reported in nine subjects, with pathological acid reflux at MII-pH being reported in two of them and normal acid exposure but positive SI or SAP for non-acid reflux in three infants. It is worth noting that three infants with no signs of laryngitis had positive SI or SAP for non-acid reflux.
Ten infants underwent polysomnography to exclude respiratory abnormalities: obstructive episodes of apnea were reported in five infants, and in two of them, desaturation was also recorded. In six infants, both polysomnography and laryngoscopy were performed, showing arythenoideal edema and/or hyperemia in four subjects, with two also having abnormal acid reflux exposure at MII-pH and one showing normal acid exposure but positive symptom index for non-acid reflux. In one other infant, hyperemia of the petiole of epiglottis was noted, and it was associated with abnormal acid reflux at MII-pH.

3.3. Effect of Treatment and Follow-Up Data

Follow-up data were available in 20/50 (40%) infants: improvement was noted by parents in all subjects within 1–6 months from starting the treatment after MII-pH. Treatment consisted of acid suppressant drugs in 12 infants, alginate in 11 infants (associated with acid suppressant drugs in 7 cases, with cow’s milk protein elimination diet in 5 cases), whilst 2 infants were only on cow’s milk elimination diet.

4. Discussion

In this study, we found that 60% of infants with persistent unexplained crying, not improved with behavior and diet intervention, had normal esophageal MII-pH. Nocturnal crying and awakenings, frequent regurgitation and failure to thrive were not significantly associated with GERD.
Crying and sleep disturbances are frequently reported in infants and are multifactorial manifestations, representing a transient neurodevelopmental phenomenon in most cases. Nevertheless, in selected infants, they may reveal an abnormal condition with a relevant impact on the infant’s and family’s quality of life and possible long-term consequences [45]. Excessive crying affects 20–30% of infants, especially in the first months of life and is a frequent cause of parental distress and health care professional consultation [45,46,47]. Regurgitation and colic are often associated disturbances and are the most common functional gastrointestinal disorders in infants [48,49]. The recommended approach to infant colic, regurgitation and infant distress consists of education and reassurance of parents, as well as behavioral and diet intervention [2,4,5,45,50]. Reassurance and education of parents regarding infant crying and/or sleep problems are recommended worldwide as first-line interventions to be carried out by healthcare providers. However, a standardized model of parental support and counseling is lacking. Different parent training programs have been proposed, including individual or group courses, online or printed materials, direct explanations during the clinic (as in our study) and demonstration of relaxation techniques with heterogeneous modalities and results [1,2,3,4,5,21,22,23,24,25,26,27,28,51].
Though nocturnal awakenings can be regarded as part of the natural development of the sleep–wake cycle of infants, three or more awakenings per night are generally perceived as a sleep problem [52]. Ten percent of parents reported that their infants suffer from disturbed sleep, and this was strictly correlated with the number of nocturnal awakenings and difficulties falling asleep [53]. At 12 months, frequent awakenings were associated with a high number of nocturnal awakenings at 3 months, short daytime sleep, severity of colic, restlessness during sleep, and bottle feeding [52]. Parents of infants suffering from night-waking problems react more rapidly, have a lower tolerance for infant crying and attribute more distress to the crying infants compared to parents in the control groups [54]. GERD can manifest with a wide age-related spectrum of signs and symptoms, including infantile crying and sleep problems [1,2,3,4,55]. It is worth noting that in two recent consensuses on a core outcome set for infant GERD and colic, sleep problems were one of the selected items [56,57]. Despite the relationship between GERD and sleep disturbance is not yet well defined, in infants with crying and concurrent regurgitations and failure to thrive, acid suppressant medications are frequently empirically started [45,46]. However, only a few studies investigated GERD in infants with sleep problems. In 1998, infants with GERD, defined by pathological esophageal pH monitoring, showed a significantly greater prevalence of nighttime waking >3/night, of parental intervention, of delayed onset of sleeping and of daytime sleep that persisted at 24 months, compared to the population norms [58]. The presence of severe GER (defined as RI > 10% at pH monitoring) was found as a modifier of the sleep pattern in infants, increasing the rate of active sleep, as detected by polysomnography [59]. In one study, sleep disturbances were reported in 49/60 (82%) regurgitating infants [60]. In a cohort of 45 newborns with GER symptoms, a negative significant correlation was found between sleepness periods and the mean reflux duration of both acid and weakly acidic refluxes [61]. In 24 infants (79.2% patients with comorbidities) referred for suspicion of GER-related respiratory symptoms, reflux was a frequent cause of interrupting sleep. Non-acid GER episodes were equally as important as acid GER episodes in causing arousal and awakenings [62]. In another study, 25 infants presenting with brief resolved unexplained events were investigated using MII-pH and 6 h concurrent video-polysomnography. Total wake and sleep duration were similar among the three groups presenting different acid reflux indices (RI < 3% defined as normal, RI ≥ 3% to ≤7% defined as intermediate, and RI > 7% defined as abnormal). Acid reflux episodes were more frequent in the wake state versus the sleep state, whereas the symptom index increased with increasing RI in both the wake and sleep states [63]. Recently, a strong temporal association was documented between sleep irregularities, (i.e., changes in sleep stage) and episodes of GER in 15 infants who underwent MII-pH and synchronized polygraphic recording [64]. Instead, many studies demonstrated a poor correlation between crying and GERD [6,7,8,9,10,16,17,20]. Nonetheless, acid suppressant drugs are frequently empirically prescribed in these infants, although evidence of efficacy is limited, and possible adverse effects have been reported [7,10,11,12,13,14,15,16]. By contrast, correct identification of the subgroup of infants that have GERD may relieve symptoms, reduce complications, parental anxiety and depression [65] and avoid misclassification and overtreatment. In addition, improving infant sleep might play a role in reducing sleep difficulties later on in life [66]. Since the diagnosis of GERD based on clinical presentation is challenging in infants, guidelines and consensus [1,2,3,4] recommend MII-pH to identify reflux and temporal symptom association. Previous studies demonstrated that this investigation significantly increases the diagnostic yield and also has a prognostic value in predicting the duration of GERD symptoms in newborns and infants [2,3,4,17,67,68,69]. According to two pediatric reports, MII-pH can help clinicians in the management of 62–67% of children with suspected GERD [17,70].
Nevertheless, MII-pH is still not frequently used to diagnose GERD in infants, although recently published pediatric age-specific protocols and reference values could make this method more feasible [29,30,31]. To the best of our knowledge, this is the first study that specifically evaluates the relation between nocturnal crying and MII-pH results. We also analyzed concurrent symptoms, previous or current treatments (including cow’s milk-free diet) at the time of investigations and demographic variables without finding any significant association. The diagnostic utility of MII-pH emerged in the positive outcome of all infants on treatment based on MII-pH results, in which follow-up data were available.
However, the present study has several limitations. First, we did not have objective measures of arousal and sleep problems, but only parental reports and symptom diaries. Sleep structures and abnormalities, as well as laryngopharyngeal reflux, were not adequately assessed [71,72,73]. Laryngoscopy and polysomnography were performed only in a subgroup of infants when there were respiratory concerns about noisy breathing or apnea [43,44]. As previously reported by our group [74] and other authors [75,76], there was an inconsistent relationship between the different investigations in our population.
Second, we did not include other possible predictors that could play a role in explaining infant crying and sleep problems, such as social variables, psychometric measures, behavioral characteristics of parents and infants, quality of the mother–child relationship or other factors. Furthermore, this is a monocenter study with a small sample size, limiting the generalization of our results to other infant populations.
In addition, the recruitment of infants who had already been treated for GER could have limited the validity and accuracy of our results. However, our management aligns with the current guidelines on GER [1,2,3,29,30], which recommend conservative treatment, dietary intervention and a short course of alginate and, eventually, in selected infants, acid suppressant drugs before submitting infants to MII-pH. Previous therapies and diets were collected and analyzed, but they did not show a significant predictive value for abnormal MII-pH results.
Finally, although we adopted MII-pH to detect symptom–GER association, only 40% of participants had follow-up data. The improvement of symptoms in infants treated with acid suppressant drugs, alginate or diet, based on MII-pH results, is biased by the limited number of patients with available follow-up. A large multicenter prospective study that can address all the present limitations of this study would help to better understand the contribution of GER and GER treatment on infant crying and sleep patterns in infants.
Currently, our study provides additional insights into the limited relationship between day and night infant crying and GERD. Neither the concomitant presence of regurgitation nor failure to thrive or laryngeal inflammation accurately predicts the results of MII-pH in this age group. As for our results, the empirical use of pharmacological treatment in these infants is not appropriate.

5. Conclusions

Infants with persistent unexplained and nocturnal crying do not show any distinctive clinical features predictive of GERD as detected by abnormal MII-pH. Empirical PPI should not be started in this population.

Author Contributions

Conceptualization, M.A. and S.S.; Methodology, C.A., L.B., L.N. and S.S.; Formal analysis, L.B. and S.S.; Investigation, C.L., G.C., I.B., C.A., L.N. and S.S.; Data curation, G.C., I.B. and L.B.; Writing—original draft, G.C., I.B., C.A. and S.S.; Writing—review & editing, C.L., L.N., M.A. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This research project obtained approval from the Ethics Committee of the Hospital (ID 24780, 28 February 2017).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available because they belong to children.

Conflicts of Interest

S. Salvatore has participated as a consultant and/or speaker and/or been a part of an advisory board for Aurora Biofarma, Bioprojet, Danone-Mellin, D.M.G. Italia, Humana Italia, Nestlé, Noos. All the above had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The other authors declare no conflicts of interest.

References

  1. Vandenplas, Y.; Rudolph, C.D.; Di Lorenzo, C.; Hassall, E.; Liptak, G.; Mazur, L.; Sondheimer, J.; Staiano, A.; Thomson, M.; Veereman-Wauters, G.; et al. Pediatric gastroesophageal reflux clinical practice guidelines: Joint recommendations of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2009, 49, 498–547. [Google Scholar] [CrossRef]
  2. Rosen, R.; Vandenplas, Y.; Singendonk, M.; Cabana, M.; DiLorenzo, C.; Gottrand, F.; Gupta, S.; Langendam, M.; Staiano, A.; Thapar, N.; et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2018, 66, 516–554. [Google Scholar] [CrossRef]
  3. Sherman, P.M.; Hassall, E.; Fagundes-Neto, U.; Gold, B.D.; Kato, S.; Koletzko, S.; Orenstein, S.; Rudolph, C.; Vakil, N.; Vandenplas, Y. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am. J. Gastroenterol. 2009, 104, 1278–1295. [Google Scholar] [CrossRef]
  4. National Institute for Health and Care Excellence (NICE). GORD: Recognition, Diagnosis and Management in Children and Young People. (Clinical Guideline 193). 2015. Available online: http://www.nice.org.uk/guidance/NG1 (accessed on 30 April 2015).
  5. Salvatore, S.; Abkari, A.; Cai, W.; Catto-Smith, A.; Cruchet, S.; Gottrand, F.; Hegar, B.; Lifschitz, C.; Ludwig, T.; Shah, N.; et al. Review shows that parental reassurance and nutritional advice help to optimise the management of functional gastrointestinal disorders in infants. Acta Paediatr. 2018, 107, 1512–1520. [Google Scholar] [CrossRef]
  6. Heine, R.G.; Jaquiery, A.; Lubitz, L.; Cameron, D.J.; Catto-Smith, A.G. Role of gastro-oesophageal reflux in infant irritability. Arch. Dis. Child. 1995, 73, 121–125. [Google Scholar] [CrossRef]
  7. Tighe, M.P.; Andrews, E.; Liddicoat, I.; Afzal, N.A.; Hayen, A.; Beattie, R.M. Pharmacological treatment of gastro-oesophageal reflux in children. Cochrane Database Syst. Rev. 2023, 8, CD008550. [Google Scholar]
  8. 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, 767–770.e3. [Google Scholar] [CrossRef]
  9. Salvatore, S.; Pagliarin, F.; Huysentruyt, K.; Bosco, A.; Fumagalli, L.; Van De Maele, K.; Agosti, M.; Vandenplas, Y. Distress in Infants and Young Children: Don’t Blame Acid Reflux. J. Pediatr. Gastroenterol. Nutr. 2020, 71, 465–469. [Google Scholar] [CrossRef]
  10. Levy, E.I.; Salvatore, S.; Vandenplas, Y.; de Winter, J.P. Prescription of acid inhibitors in infants: An addiction hard to break. Eur. J. Pediatr. 2020, 179, 1957–1961. [Google Scholar] [CrossRef]
  11. Kołodziej, M.; Gieruszczak-Białek, D.; Pieścik-Lech, M.; Skórka, A.; Vandenplas, Y.; Szajewska, H. Overuse continues despite no new evidence on the efficacy of proton pump inhibitors for crying and irritability in infants. Acta Paediatr. 2022, 111, 682–683. [Google Scholar] [CrossRef]
  12. Malchodi, L.; Wagner, K.; Susi, A.; Gorman, G.; Hisle-Gorman, E. Early Acid Suppression Therapy Exposure and Fracture in Young Children. Pediatrics 2019, 144, e20182625. [Google Scholar] [CrossRef]
  13. Orel, R.; Benninga, M.A.; Broekaert, I.J.; Gottrand, F.; Papadopoulou, A.; Ribes-Koninckx, C.; Thomson, M.; Wilschanski, M.; Thapar, N. Drugs in Focus: Proton Pump Inhibitors. J. Pediatr. Gastroenterol. Nutr. 2021, 72, 645–653. [Google Scholar] [CrossRef]
  14. Dipasquale, V.; Cicala, G.; Spina, E.; Romano, C. A Narrative Review on Efficacy and Safety of Proton Pump Inhibitors in Children. Front. Pharmacol. 2022, 13, 839972. [Google Scholar] [CrossRef]
  15. Wolf, E.R.; Sabo, R.T.; Lavallee, M.; French, E.; Schroeder, A.R.; Huffstetler, A.N.; Schefft, M.; Krist, A.H. Overuse of Reflux Medications in Infants. Pediatrics 2023, 151, e2022058330. [Google Scholar] [CrossRef]
  16. Orenstein, S.R.; 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, 514–520.e4. [Google Scholar] [CrossRef]
  17. Lee, A.L.H.; Varjavandi, V.; Lemberg, D.A.; Ooi, C.Y.; Gupta, N.; Krishnan, U. Does Combined Multichannel Intraluminal Impedance and pH (MII-pH) Testing Improve Clinical Outcomes in Children with Gastroesophageal Reflux Disease? J. Pediatr. Gastroenterol. Nutr. 2020, 71, 596–603. [Google Scholar] [CrossRef]
  18. Salvatore, S.; Ripepi, A.; Huysentruyt, K.; van de Maele, K.; Nosetti, L.; Agosti, M.; Salvatoni, A.; Vandenplas, Y. The Effect of Alginate in Gastroesophageal Reflux in Infants. Paediatr. Drugs. 2018, 20, 575–583. [Google Scholar] [CrossRef]
  19. Kleinman, L.; Rothman, M.; Strauss, R.; Orenstein, S.R.; Nelson, S.; Vandenplas, Y.; Cucchiara, S.; Revicki, D.A. The infant gastroesophageal reflux questionnaire revised: Development and validation as an evaluative instrument. Clin. Gastroenterol. Hepatol. 2006, 4, 588–596. [Google Scholar] [CrossRef]
  20. Salvatore, S.; Hauser, B.; Vandemaele, K.; Novario, R.; Vandenplas, Y. Gastroesophageal reflux disease in infants: How much is predictable with questionnaires, pH-metry, endoscopy and histology? J. Pediatr. Gastroenterol. Nutr. 2005, 40, 210–215. [Google Scholar]
  21. Gatrad, A.R.; Sheikh, A. Persistent crying in babies. BMJ 2004, 328, 330. [Google Scholar] [CrossRef]
  22. Akhnikh, S.; Engelberts, A.C.; van Sleuwen, B.E.; L’Hoir, M.P.; Benninga, M.A. The excessively crying infant: Etiology and treatment. Pediatr. Ann. 2014, 43, e69–e75. [Google Scholar] [CrossRef]
  23. Muller, I.; Ghio, D.; Mobey, J.; Jones, H.; Hornsey, S.; Dobson, A.; Maund, E.; Santer, M. Parental perceptions and experiences of infant crying: A systematic review and synthesis of qualitative research. J. Adv. Nurs. 2023, 79, 403–417. [Google Scholar] [CrossRef]
  24. Whittall, H.; Kahn, M.; Pillion, M.; Gradisar, M. Parents matter: Barriers and solutions when implementing behavioural sleep interventions for infant sleep problems. Sleep Med. 2021, 84, 244–252. [Google Scholar] [CrossRef]
  25. Gordon, M.; Gohil, J.; Banks, S.S. Parent training programmes for managing infantile colic. Cochrane Database Syst. Rev. 2019, 12, CD012459. [Google Scholar] [CrossRef]
  26. Montazeri, R.; Hasanpour, S.; Mirghafourvand, M.; Gharehbaghi, M.M.; Tehrani, M.M.G.; Rezaei, S.M. The effect of behavioral therapy based counseling with anxious mothers on their infants’ colic: A randomized controlled clinical trial. BMC Pediatr. 2022, 22, 645. [Google Scholar] [CrossRef]
  27. Byars, K.C.; Yolton, K.; Rausch, J.; Lanphear, B.; Beebe, D.W. Prevalence, patterns, and persistence of sleep problems in the first 3 years of life. Pediatrics 2012, 129, e276–e284. [Google Scholar] [CrossRef]
  28. Thabet, F.; Tabarki, B. Common sleep disorders in children: Assessment and treatment. Neurosciences 2023, 28, 85–90. [Google Scholar] [CrossRef]
  29. Wenzl, T.G.; Benninga, M.A.; Loots, C.M.; Salvatore, S.; Vandenplas, Y.; ESPGHAN EURO-PIG Working Group. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. J. Pediatr. Gastroenterol. Nutr. 2012, 55, 230–234. [Google Scholar] [CrossRef]
  30. Quitadamo, P.; Tambucci, R.; Mancini, V.; Cristofori, F.; Baldassarre, M.; Pensabene, L.; Francavilla, R.; Di Nardo, G.; Caldaro, T.; Rossi, P.; et al. Esophageal pH-impedance monitoring in children: Position paper on indications, methodology and interpretation by the SIGENP working group. Dig. Liver Dis. 2019, 51, 1522–1536. [Google Scholar] [CrossRef] [PubMed]
  31. Cresi, F.; Cester, E.A.; Salvatore, S.; De Rose, D.U.; Ripepi, A.; Magistà, A.M.; Fontana, C.; Maggiora, E.; Coscia, A.; Francavilla, R.; et al. Multichannel Intraluminal Impedance and pH Monitoring: A Step towards Pediatric Reference Values. J. Neurogastroenterol. Motil. 2020, 26, 370–377. [Google Scholar] [CrossRef] [PubMed]
  32. Olsen, E.M.; Petersen, J.; Skovgaard, A.M.; Weile, B.; Jørgensen, T.; Wright, C.M. Failure to thrive: The prevalence and concurrence of anthropometric criteria in a general infant population. Arch. Dis. Child. 2007, 92, 109–114. [Google Scholar] [CrossRef] [PubMed]
  33. Shields, B.; Wacogne, I.; Wright, C.M. Weight faltering and failure to thrive in infancy and early childhood. BMJ 2012, 345, e5931. [Google Scholar] [CrossRef] [PubMed]
  34. Strobel, C.T.; Byrne, W.J.; Ament, M.E.; Euler, A.R. Correlation of esophageal lengths in children with height: Application to the tuttle test without prior esophageal manometry. J. Pediatr. 1979, 94, 81–84. [Google Scholar] [CrossRef] [PubMed]
  35. Salvatore, S.; Hauser, B.; Devreker, T.; Arrigo, S.; Marino, P.S.; Citro, C.; Salvatoni, A.; Vandenplas, Y. Esophageal Impedance and Esophagitis in Children: Any Correlation? J. Pediatr. Gastroenterol. Nutr. 2009, 49, 566–570. [Google Scholar] [CrossRef] [PubMed]
  36. Pilic, D.; Hankel, S.; Koerner-Rettberg, C.; Hamelmann, E.; Schmidt-Choudhury, A. The role of baseline impedance as a marker of mucosal integrity in children with gastro esophageal reflux disease. Scand. J. Gastroenterol. 2013, 48, 785–793. [Google Scholar] [CrossRef] [PubMed]
  37. Salvatore, S.; Salvatoni, A.; Van Steen, K.; Ummarino, D.; Hauser, B.; Vandenplas, Y. Behind the (impedance) baseline in children. Dis. Esophagus. 2014, 27, 726–731. [Google Scholar] [CrossRef] [PubMed]
  38. Tambucci, R.; Thapar, N.; Saliakellis, E.; Pescarin, M.; Quitadamo, P.; Cristofori, F.; Lindley, K.J.; Borrelli, O. Clinical relevance of esophageal baseline impedance measurement: Just an innocent bystander. J. Pediatr. Gastroenterol. Nutr. 2015, 60, 776–782. [Google Scholar] [CrossRef] [PubMed]
  39. Patel, A.; Wang, D.; Sainani, N.; Sayuk, G.S.; Gyawali, C.P. Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 2016, 44, 890–898. [Google Scholar] [CrossRef] [PubMed]
  40. Rengarajan, A.; Savarino, E.; Della Coletta, M.; Ghisa, M.; Patel, A.; Gyawali, C.P. Mean Nocturnal Baseline Impedance Correlates with Symptom Outcome When Acid Exposure Time Is Inconclusive on Esophageal Reflux Monitoring. Clin. Gastroenterol. Hepatol. 2020, 18, 589–595. [Google Scholar] [CrossRef] [PubMed]
  41. Wu, Y.; Guo, Z.; Zhang, C.; Zhan, Y. Mean nocturnal baseline impedance, a novel metric of multichannel intraluminal impedance-pH monitoring in diagnosing gastroesophageal reflux disease. Therap. Adv. Gastroenterol. 2022, 15, 17562848221105195. [Google Scholar] [CrossRef]
  42. Salvatore, S.; Salvatoni, A.; Van Berkel, M.; Van Steen, K.; Unmarino, D.; Ghanma, A.; Hauser, B.; Vandenplas, Y. Esophageal impedance baseline is age dependent. J. Pediatr. Gastroenterol. Nutr. 2013, 57, 506–513. [Google Scholar] [CrossRef] [PubMed]
  43. Hawkins, D.B.; Clark, R.W. Flexible laryngoscopy in neonates, infants, and young children. Ann. Otol. Rhinol. Laryngol. 1987, 96 Pt 1, 81–85. [Google Scholar] [CrossRef]
  44. Horne, R.S.; Nixon, G.M. The role of physiological studies and apnoea monitoring in infants. Paediatr. Respir. Rev. 2014, 15, 312–318. [Google Scholar] [CrossRef] [PubMed]
  45. Douglas, P.; Hill, P. Managing infants who cry excessively in the first few months of life. BMJ 2011, 343, d7772. [Google Scholar] [CrossRef] [PubMed]
  46. Douglas, P.S. Excessive crying and gastro-oesophageal reflux disease in infants: Misalignment of biology and culture. Med. Hypotheses. 2005, 64, 887–898. [Google Scholar] [CrossRef] [PubMed]
  47. Sung, V. Infantile colic. Aust. Prescr. 2018, 41, 105–110. [Google Scholar] [CrossRef] [PubMed]
  48. Steutel, N.F.; Zeevenhooven, J.; Scarpato, E.; Vandenplas, Y.; Tabbers, M.M.; Staiano, A.; Benninga, M.A. Prevalence of Functional Gastrointestinal Disorders in European Infants and Toddlers. J. Pediatr. 2020, 221, 107–114. [Google Scholar] [CrossRef] [PubMed]
  49. Beser, O.F.; Cullu Cokugras, F.; Dogan, G.; Akgun, O.; Elevli, M.; Yilmazbas, P.; Ocal, M.; Bayrak, N.A.; Sezer Yamanel, R.G.; Bozaykut, A.; et al. The frequency of and factors affecting functional gastrointestinal disorders in infants that presented to tertiary care hospitals. Eur. J. Pediatr. 2021, 180, 2443–2452. [Google Scholar] [CrossRef] [PubMed]
  50. Vandenplas, Y.; Benninga, M.; Broekaert, I.; Falconer, J.; Gottrand, F.; Guarino, A.; Lifschitz, C.; Lionetti, P.; Orel, R.; Papadopoulou, A.; et al. Functional gastro-intestinal disorder algorithms focus on early recognition, parental reassurance and nutritional strategies. Acta Paediatr. 2016, 105, 244–252. [Google Scholar] [CrossRef]
  51. Reuter, A.; Silfverdal, S.A.; Lindblom, K.; Hjern, A. A systematic review of prevention and treatment of infant behavioural sleep problems. Acta Paediatr. 2020, 109, 1717–1732. [Google Scholar] [CrossRef]
  52. Sette, S.; Baumgartner, E.; Ferri, R.; Bruni, O. Predictors of sleep disturbances in the first year of life: A longitudinal study. Sleep Med. 2017, 36, 78–85. [Google Scholar] [CrossRef]
  53. Bruni, O.; Baumgartner, E.; Sette, S.; Ancona, M.; Caso, G.; Di Cosimo, M.E.; Mannini, A.; Ometto, M.; Pasquini, A.; Ulliana, A.; et al. Longitudinal study of sleep behavior in normal infants during the first year of life. J. Clin. Sleep Med. 2014, 10, 1119–1127. [Google Scholar] [CrossRef] [PubMed]
  54. Sadeh, A.; Juda-Hanael, M.; Livne-Karp, E.; Kahn, M.; Tikotzky, L.; Anders, T.F.; Calkins, S.; Sivan, Y. Low parental tolerance for infant crying: An underlying factor in infant sleep problems? J. Sleep Res. 2016, 25, 501–507. [Google Scholar] [CrossRef]
  55. Salvatore, S.; Hauser, B.; Vandenplas, Y. The natural course of gastro-oesophageal reflux. Acta Paediatr. 2004, 93, 1063–1069. [Google Scholar] [CrossRef]
  56. Singendonk, M.M.J.; Rexwinkel, R.; Steutel, N.F.; Gottrand, F.; McCall, L.; Orsagh-Yentis, D.K.; Rosen, R.; Strisciuglio, C.; Thapar, N.; Vandenplas, Y.; et al. Development of a Core Outcome Set for Infant Gastroesophageal Reflux Disease. J. Pediatr. Gastroenterol. Nutr. 2019, 68, 655–661. [Google Scholar] [CrossRef]
  57. Steutel, N.F.; Benninga, M.A.; Langendam, M.W.; Korterink, J.J.; Indrio, F.; Szajewska, H.; Tabbers, M.M. Developing a core outcome set for infant colic for primary, secondary and tertiary care settings: A prospective study. BMJ Open 2017, 7, e015418. [Google Scholar] [CrossRef]
  58. Ghaem, M.; Armstrong, K.L.; Trocki, O.; Cleghorn, G.J.; Patrick, M.K.; Shepherd, R.W. The sleep patterns of infants and young children with gastro-oesophageal reflux. J. Paediatr. Child Health 1998, 34, 160–163. [Google Scholar] [CrossRef] [PubMed]
  59. Harris, P.; Brockmann, P.; Muñoz, C.; Mobarec, S.; Mesa, T.; Sánchez, I. Alteraciones polisomnográficas en lactantes con reflujo gastroesofágico [Polysomnographic abnormalities in infants with gastroesophageal reflux]. Rev. Med. Chil. 2003, 131, 1143–1150. [Google Scholar] [CrossRef]
  60. Hegar, B.; Rantos, R.; Firmansyah, A.; De Schepper, J.; Vandenplas, Y. Natural evolution of infantile regurgitation versus the efficacy of thickened formula. J. Pediatr. Gastroenterol. Nutr. 2008, 47, 26–30. [Google Scholar] [CrossRef] [PubMed]
  61. Cresi, F.; Locatelli, E.; Maggiora, E.; Di Nicola, P.; Cester, E.; Sabatino, G.; Martano, C.; Giuliani, F.; Bertino, E. Relationship between sleep/wakefulness and gastroesophageal reflux in symptomatic newborns. J. Biol. Regul. Homeost. Agents 2012, 26 (Suppl. S3), 83–85. [Google Scholar]
  62. Machado, R.; Woodley, F.W.; Skaggs, B.; Di Lorenzo, C.; Splaingard, M.; Mousa, H. Gastroesophageal reflux causing sleep interruptions in infants. J. Pediatr. Gastroenterol. Nutr. 2013, 56, 431–435. [Google Scholar] [CrossRef] [PubMed]
  63. Sankaran, J.; Qureshi, A.H.; Woodley, F.; Splaingard, M.; Jadcherla, S.R. Effect of Severity of Esophageal Acidification on Sleep vs. Wake Periods in Infants Presenting with Brief Resolved Unexplained Events. J. Pediatr. 2016, 179, 42–48.e1. [Google Scholar] [CrossRef] [PubMed]
  64. Pappa, A.; Muschaweck, M.; Wenzl, T.G. Change of Sleep Stage during Gastroesophageal Reflux in Infants. Children 2023, 10, 836. [Google Scholar] [CrossRef] [PubMed]
  65. Aizlewood, E.G.; Jones, F.W.; Whatmough, R.M. Paediatric gastroesophageal reflux disease and parental mental health: Prevalence and predictors. Clin. Child Psychol. Psychiatry. 2023, 28, 1024–1037. [Google Scholar] [CrossRef] [PubMed]
  66. Tikotzky, L.; Shaashua, L. Infant sleep and early parental sleep-related cognitions predict sleep in pre-school children. Sleep Med. 2012, 13, 185–192. [Google Scholar] [CrossRef] [PubMed]
  67. Francavilla, R.; Magistà, A.M.; Bucci, N.; Villirillo, A.; Boscarelli, G.; Mappa, L.; Leone, G.; Fico, S.; Castellaneta, S.; Indrio, F.; et al. Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux. J. Pediatr. Gastroenterol. Nutr. 2010, 50, 154–160. [Google Scholar] [CrossRef] [PubMed]
  68. Loots, C.M.; Benninga, M.A.; Davidson, G.P.; Omari, T.I. Addition of pH-impedance monitoring to standard pH monitoring increases the yield of symptom association analysis in infants and children with gastroesophageal reflux. J. Pediatr. 2009, 154, 248–252. [Google Scholar] [CrossRef] [PubMed]
  69. Cresi, F.; Locatelli, E.; Marinaccio, C.; Grasso, G.; Coscia, A.; Bertino, E. Prognostic values of multichannel intraluminal impedance and pH monitoring in newborns with symptoms of gastroesophageal reflux disease. J. Pediatr. 2013, 162, 770–775. [Google Scholar] [CrossRef] [PubMed]
  70. Rosen, R.; Hart, K.; Nurko, S. Does reflux monitoring with multichannel intraluminal impedance change clinical decision making? J. Pediatr. Gastroenterol. Nutr. 2011, 52, 404–407. [Google Scholar] [CrossRef] [PubMed]
  71. Kaditis, A.; Gozal, D. Sleep Studies for Clinical Indications during the First Year of Life: Infants Are Not Small Children. Children 2022, 9, 523. [Google Scholar] [CrossRef]
  72. Wise, M.S.; Nichols, C.D.; Grigg-Damberger, M.M.; Marcus, C.L.; Witmans, M.B.; Kirk, V.G.; D’Andrea, L.A.; Hoban, T.F. Executive summary of respiratory indications for polysomnography in children: An evidence-based review. Sleep 2011, 34, 389–398AW. [Google Scholar] [CrossRef] [PubMed]
  73. Lechien, J.R. Pediatric Laryngopharyngeal Reflux: An Evidence-Based Review. Children 2023, 10, 583. [Google Scholar] [CrossRef] [PubMed]
  74. Mantegazza, C.; Mallardo, S.; Rossano, M.; Meneghin, F.; Ricci, M.; Rossi, P.; Capra, G.; Latorre, P.; Schindler, A.; Isoldi, S.; et al. Laryngeal signs and pH-multichannel intraluminal impedance in infants and children: The missing ring: LPR and MII-pH in children. Dig. Liver Dis. 2020, 52, 1011–1016. [Google Scholar] [CrossRef] [PubMed]
  75. Singendonk, M.M.; Pullens, B.; van Heteren, J.A.; de Gier, H.H.; Hoeve, H.L.; König, A.M.; van der Schroeff, M.P.; Hoekstra, C.E.; Veder, L.L.; van der Pol, R.J.; et al. Reliability of the reflux finding score for infants in flexible versus rigid laryngoscopy. Int. J. Pediatr. Otorhinolaryngol. 2016, 86, 37–42. [Google Scholar] [CrossRef]
  76. Rosen, R.; Mitchell, P.D.; Amirault, J.; Amin, M.; Watters, K.; Rahbar, R. The Edematous and Erythematous Airway Does Not Denote Pathologic Gastroesophageal Reflux. J. Pediatr. 2017, 183, 127–131. [Google Scholar] [CrossRef]
Children 11 00450 g001
Figure 1. Variables analyzed in the NICE RED study.
Figure 1. Variables analyzed in the NICE RED study.
Children 11 00450 g001
Table 1. Demographic and clinical characteristics of the study population.
Table 1. Demographic and clinical characteristics of the study population.
MII-pH
TotalAbnormalNormal
Total number (n) of infants 502030
Sex, n (% of infants)Female26 (52.0)8 (40.0)18 (60.0)
Male24 (48.0)12 (60.0)12 (40.0)
Age (months)Mean (SD)4.0 (2.4)3.6 (2.7)4.2 (2.2)
Median (IQR)3.5 (2.0–6.0)2.0 (2.0–5.0)4.0 (3.0–6.0)
Min-max1.0–11.01.0–11.01.0–10.0
Class of age, n (%)0–1 month5 (10.0)2 (40.0)3 (60.0)
2–6 months39 (78.0)16 (41.0)23 (59.0)
>6 months6 (12.0)2 (33.3)4 (66.7)
Failure to thrive, n (%) 11 (22.0)3 (27.3)8 (72.7)
Regurgitation, episodes n/day (%)0–234 (68.0)13 (38.2)21 (61.7)
3–109 (18.0)4 (44.4)5 (55.6)
>107 (14.0)3 (42.9)4 (57.1)
Nocturnal crying/sleep disturbance, n (%) 26 (52.0)10 (38.5)16 (61.5)
Abnormal I-GERQ-R, n (%) 33 (66.0)12 (36.4)21 (63.6)
Cow’s milk-free diet, n (%) 29 (58.0)10 (34.5)19 (65.5)
Table 2. Univariate logistic regression results of the association between abnormal MII-pH and demographics or clinical features.
Table 2. Univariate logistic regression results of the association between abnormal MII-pH and demographics or clinical features.
Variable OR95%CIp-Value
SexFemale1Reference
Male2.250.71–7.140.17
Age (continuous) 0.890.69–1.140.63
Class of age0–1 month0.960.14–6.400.97
2–6 months1Reference
>6 months0.720.12–4.410.72
Failure to thrive, n (%)No1Reference
Yes0.490.11–2.110.34
Regurgitation, n of episodes (% of infants)01Reference
3–101.290.29–5.710.74
>101.210.23–6.300.82
Nocturnal crying/sleep disturbance, n (%)No1Reference
Yes0.880.28–2.720.82
I-GERQ-R scoreNormal1Reference
Abnormal0.640.20–2.110.47
Cow’s milk-free diet, n (%)No1Reference
Yes0.580.18–1.830.35
Table 3. Association between abnormal MII-pH and baseline impedance according to univariate and multivariable logistic regression.
Table 3. Association between abnormal MII-pH and baseline impedance according to univariate and multivariable logistic regression.
Abnormal MII-pHOR95% CIp-Value
Univariate Logistic Regression
Distal Baseline ImpedanceNormal1.0Reference
Abnormal13.381.46–122.680.02
Nocturnal Distal BaselineNormal1.0Reference
Abnormal3.651.06–12.560.04
Multivariable Logistic Regression
Distal Baseline ImpedanceNormal1.0Reference
Abnormal8.200.84–80.510.07
Nocturnal Distal BaselineNormal1.0Reference
Abnormal2.620.67–10.250.17
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Carabelli, G.; Binotto, I.; Armano, C.; Bertù, L.; Luini, C.; Nosetti, L.; Agosti, M.; Salvatore, S. Study on Nocturnal Infant Crying Evaluation (NICE) and Reflux Disease (RED). Children 2024, 11, 450. https://doi.org/10.3390/children11040450

AMA Style

Carabelli G, Binotto I, Armano C, Bertù L, Luini C, Nosetti L, Agosti M, Salvatore S. Study on Nocturnal Infant Crying Evaluation (NICE) and Reflux Disease (RED). Children. 2024; 11(4):450. https://doi.org/10.3390/children11040450

Chicago/Turabian Style

Carabelli, Greta, Ivan Binotto, Chiara Armano, Lorenza Bertù, Chiara Luini, Luana Nosetti, Massimo Agosti, and Silvia Salvatore. 2024. "Study on Nocturnal Infant Crying Evaluation (NICE) and Reflux Disease (RED)" Children 11, no. 4: 450. https://doi.org/10.3390/children11040450

APA Style

Carabelli, G., Binotto, I., Armano, C., Bertù, L., Luini, C., Nosetti, L., Agosti, M., & Salvatore, S. (2024). Study on Nocturnal Infant Crying Evaluation (NICE) and Reflux Disease (RED). Children, 11(4), 450. https://doi.org/10.3390/children11040450

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop