Although regurgitation from gastroesophageal reflux (GER) is a common problem in infants, the epidemiology of GER remains a neglected field. Until recently, data regarding the natural course of GER during infancy was limited, and no such information about non-Western infants was available.
Epidemiologic studies in adults suggest that the nature of GER may differ among various ethnic groups (1). According to a cross-sectional survey for gastrointestinal symptoms among an Asian population, reflux-type symptoms were reported by only 1.6% of the general population (2), much smaller than Western reports of 19.8% to 32.6% of the population experiencing heartburn at least once in the previous 3 months (3,4). Moreover, in a well-designed study comparing the prevalences of reflux esophagitis between English and Singaporean patients who presented with dyspepsia, Kang et al. (5), using logistic regression analysis, demonstrated that race was a significant risk factor for reflux esophagitis, whereas environmental factors that included smoking, alcohol consumption, and analgesic use were not. Their study found that the prevalence of reflux esophagitis was significantly more common in English dyspeptic patients (25%) than in Singaporean patients (4%). From this evidence, it can be postulated that disorders related to GER are diseases of the West. We believe that the influence of racial factors on the nature of GER, which has been observed in adults, may also be evident in children.
Because there has been no information concerning the nature of GER symptoms in non-Western infants, this cohort study was undertaken with two objectives: 1) to investigate the prevalence of symptoms associated with GER in Thai infants, and 2) to describe the clinical course of reflux regurgitation during the first year of life and to determine the effect of type of milk fed on the prevalence of reflux regurgitation.
SUBJECTS AND METHODS
A cohort study beginning with healthy newborns aged 1 month who attended the well-baby clinic of Songklanagarind Hospital in Southern Thailand was conducted. Newborns with a history of birth asphyxia, prematurity, congenital anomalies, or underlying disease were excluded. All eligible newborns were then evaluated every 2 months at regular well-baby clinic visits for 1 year.
Data collection from each infant at the beginning of the study and during the follow-up period included the following:
- history of reflux symptoms including regurgitation, rumination, hematemesis, chronic cough, recurrent cyanosis or apnea, recurrent pneumonia or pulmonary wheezing, nocturnal irritability, and Sandifer-Sutcliffe syndrome;
- standard deviation scores (Z) of body weight and length for age (in reference to National Center for Health Statistics standard); and
- type of milk fed and daily intake of solid food.
The history of reflux symptoms was obtained by interviewing the parents. To avoid inter-interviewer variation, only one investigator was assigned to interview the parents and to follow all infants during the cohort study. Because regurgitation is the most obvious clinical manifestation of infantile GER, data regarding the frequency of symptoms in terms of days of symptoms per week and the number of reflux episodes per day were collected. In this study, an infant who regurgitated at least 1 day per week was considered to have a symptom of reflux regurgitation. This definition was operational because at the time of our study (1998), there had been no consensus on the diagnostic criteria for infantile reflux regurgitation. The severity of reflux was classified, as in Carre's study (6), into three categories according to the number of days of symptoms per wk: 1 to 3 days per week, 4 to 6 days per week, and daily regurgitation.
For the parent or caretakers of an infant with regurgitation, a diary was provided for recording the occurrence of regurgitation in their infant. Using this diary, objective information about the frequency of regurgitation in the infant was obtained. During the follow-up period, the infants with reflux regurgitations were considered to be free of symptoms when their regurgitations did not occur, as shown in the diary, for at least 4 consecutive weeks. Investigations such as barium-swallow studies or esophageal pH studies were considered only in infants suspected of having pathologic GER on clinical grounds or who had symptoms possibly related to occult GER.
Infants with uncomplicated reflux regurgitation were conservatively treated by reassuring the parents about the physiologic nature of the symptoms and with advice to avoid predisposing factors to regurgitation, such as suddenly changing the position of the infant or abdominal compression after feeding.
A sample size of 100 healthy newborns was calculated statistically, based on the 50% prevalence of reflux regurgitation in early infancy from a previous study (P = 0.5) (7) with 95% confidence and 10% precision. However, 200 newborns were included in this study to allow for a 50% dropout rate. Data were analyzed using version 6 of Epi Info statistical package (CDC, Atlanta/WHO, Geneva). Univariate comparisons between data from infants with and without regurgitation were performed using Student t test or χ 2 test, as appropriate. Differences were considered statistically significant if P was less than 0.05.
The ethics committee of the Faculty of Medicine, Prince of Songkla University, approved this study. All parents were fully informed of the nature of the study, and they gave verbal informed consent before participating.
Between March and June 1998, 216 healthy newborns entered this prospective survey. However, 71 infants were withdrawn from the study: 4 were excluded because their parental diaries were missing; 64 were lost to follow-up because their parents moved to other remote provinces, and 3 developed serious diseases during the follow-up period. The remaining 145 infants were eligible for further analysis. These were 81 (55.9%) male and 64 (44.1%) female infants.
Prevalence and Clinical Course of GER Symptoms
No infant with clinical features of pathologic GER or any other GER symptoms apart from regurgitation was encountered in this study. Thus investigations for pathologic GER were not indicated in our studied infants. Of 145 infants who completed the 1-year follow-up, the prevalence of reflux regurgitation peaked at 2 months and decreased significantly at 4, 6, and 8 months (Table 1). At 12 months of age, only 7.6% of infants had reflux regurgitation. The prevalence of daily regurgitation was low in Thai infants. As shown in Table 1, the prevalence of infants who regurgitated daily decreased from 33.1% at 1 month to only 2.1% at 6 months of age. From 6 to 12 months of age, almost all infants with GER regurgitated only 1 to 3 days per week. At each follow-up during this cohort study, approximately 90% of Thai infants with reflux regurgitation had infrequent symptoms of only 1 to 3 episodes per day (Table 1).
The effect of reflux regurgitation on the body weight of the infants was not demonstrated in this study because there was no significant difference in the mean standard deviation scores of body weight for age between infants with and without regurgitation during the 1-year of follow-up (Table 2). Because all 145 regurgitating infants in our study had normal nutritional status and were free of regurgitation-related complications, pathologic GER was excluded in these infants on clinical grounds and their symptoms were treated conservatively.
Type of Milk Fed and Prevalence of Reflux Regurgitation
The influence of the type of milk fed on the prevalence of reflux regurgitation was evaluated in infants younger than 2 months of age, the period of exclusive milk feeding. Dietary history revealed that 27.6% of infants received breast milk, 10.3% received cow milk formula, and 62.1% received breast milk combined with cow milk at 1 month. At 2 months, 26.2% received breast milk, 20.7% received cow milk, and 53.1% received breast milk combined with cow milk. When infants, aged 1 to 2 months, were categorized into three groups according to the type of milk fed, the prevalences of reflux regurgitation among the three groups of infants did not significantly differ (Table 3). Weaning to solid foods was introduced in 90.2% of 4-month-old infants and all infants by 6 months of age. The amount of solid food taken daily by infants with and without regurgitation reflux was comparable (Table 4).
Gastroesophageal reflux is common in infants and usually is associated with regurgitation (8,9). Most infants with reflux regurgitation are healthy and do not experience long-term complications; however, the symptom can result in significant parental anxiety because parents regard their baby's regurgitation as a problem (7). Despite being a common problem, very few data have been published about the prevalence and natural history of GER symptoms during infancy (6,7). Apparently, reports have come only from Western countries. This study is the first known report concerning epidemiology of GER symptoms in Asian infants. We found no pathologic GER or other GER symptoms apart from regurgitation in the infants of this survey study.
At the time of our study (1998) there were no widely accepted diagnostic criteria for infantile regurgitation; however, since then (in 1999) the Rome II criteria have been established (10). Although reflux regurgitation in our studied infants was not defined according to the Rome II criteria, our study does provide information about Thai infants who had symptoms according to the Rome II criteria, which were in fact the subgroup of infants who had daily regurgitation (Table 1). When comparing the natural course of reflux regurgitation in Thai infants with that of Western studies, some interesting points are noted.
Nelson et al. (7) performed a cross-sectional survey for the prevalence of GER symptoms by using standardized questionnaires to interview 948 parents of American infants aged 13 months and younger. They defined reflux symptoms as regurgitation of at least 1 episode daily, which was reported by 50% at 0 to 3 months, 67% at 4 to 6 months, 21% at 7 to 9 months, and 5% at 10 to 12 months. When that study's diagnostic criterion for reflux regurgitation is applied to our infants, these prevalences in American infants are very much higher than in Thai infants. We found that in Thai infants, daily regurgitation occurred in 33.1% at 1 month, 17.9% at 2 months, 8.3% at 4 months, 2.1% at 6 months, 0.7% at 8 months, and 0% at 10 to 12 months (Table 1). Moreover, American infants had more episodes of regurgitation per day. Between the ages of 1 and 6 months, regurgitation of 4 or more episodes per day was constantly reported by 20% of American infants, compared with 14% at 1 month of age in Thai infants and declining to only 3% at 6 months. Almost all Thai infants with GER symptoms regurgitated only one to three times per day.
Our findings that the symptoms of GER in Thai infants improved spontaneously with increasing age support the results of previous Western studies. This phenomenon is attributable to spontaneous improvement in function of the lower esophageal sphincter with maturity. However, in Thai infants, the significant improvement of GER symptoms was evident at the early age of 4 months and improvement was markedly obvious between 4 and 6 months. This observation probably relates to the weaning practice in Thailand, where introduction of solid foods is generally recommended at 4 months of age. Previous studies suggested that increased viscosity of feedings resulted in decreased clinical reflux regurgitation (11,12), and this measure is still recommended for treating uncomplicated infantile GER (13). In our series, introduction of solid foods was initiated in 90% of infants at 4 months; however, this study does not confirm the effect of early weaning because there was no significant difference between the intake of solid food by infants with and without reflux regurgitation (Table 4).
An interesting question is whether GER is more prevalent in formula-fed infants than in breast-fed infants. This question is raised because Heacock et al. (14), in a study examining 24-hour esophageal pH in 74 healthy infants, showed that breast-fed infants had lower esophageal pH reflux indices than did formula-fed infants. Furthermore, slower gastric emptying time was demonstrated in bottle-fed infants (15). As a consequence, the lower esophageal sphincter is more susceptible to transient relaxation induced by increased intragastric pressure. Recently, it has been suggested that GER in infants can be a secondary response to cow milk protein allergy (16). This would indicate that bottle-fed infants are more likely to develop GER. However, the effect of the type of milk on the prevalence of GER symptoms was not demonstrated in our study. This may be because of insufficient size of the study population. To verify such an effect, a population-based study with a large sample size is needed.
Our study indicates that racial differences in the nature of GER symptoms, as has been observed previously in adults, are also evident in infants. Recent evidence indicates that both pediatric- and adult-onset GER have major genetic components (17,18), and a gene on chromosome 13q14 for severe pediatric GER has been recently demonstrated (19). Whether the variation in GER-related genomes plays a major role in the differences in epidemiology among different ethnic groups is therefore an interesting and important subject that needs clarification with further cross-cultural genetic studies.
In summary, our study contributes more data about the epidemiology of infantile GER, particularly in non-Western countries, that will be beneficial for understanding the nature of GER in children in general. The nature of reflux regurgitation in Thai infants differs from that in Western infants, and a practical implication for treating uncomplicated regurgitation in Thai infants is noted. Instead of using Western data, we recommend our results as a reference for Thai pediatricians when providing advice and reassurance to Thai parents about the clinical course of reflux regurgitation. For Thai infants who still have frequent regurgitations beyond 6 months of age, the possibility nonphysiologic GER should be given special attention.
The authors thank Professor Ross W. Shepherd, Department of Pediatric Gastroenterology and Nutrition, Washington University School of Medicine, St. Louis, Missouri, U.S.A., for helpful suggestions.
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Keywords:© 2002 Lippincott Williams & Wilkins, Inc.
Gastroesophageal reflux; Epidemiology; Infant