PEDIATRICS Vol. 120 No. 2 August 2007, pp. e308-e316 (doi:10.1542/peds.2006-2891)
ARTICLE |
A United Kingdom Population-Based Study of Intellectual Capacities in Children With and Without Soiling, Daytime Wetting, and Bed-wetting
a Departments of Social Medicine
e Community Based Medicine, University of Bristol, Bristol, United Kingdom
b Child and Adolescent Mental Health Services, East Leeds Primary Care Trust, Leeds, United Kingdom
c Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany
d Sheffield Children's National Health Service Trust, Sheffield, United Kingdom
| ABSTRACT |
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OBJECTIVE. The objective of this study was to examine differences in intellectual capacities between children with and without soiling, daytime wetting, and bed-wetting.
METHODS. This study was based on a population of >6000 children (age range: 7 years 6 months to 9 years 3 months; median: 7 years 6 months) from the United Kingdom–based Avon Longitudinal Study of Parents and Children. Data on wetting and soiling were obtained from a questionnaire completed by parents. The Wechsler Intelligence Scale for Children–Third Edition was administered at a research clinic.
RESULTS. Bed-wetting was associated with lower Wechsler Intelligence Scale for Children–Third Edition IQ scores compared with control subjects, particularly performance IQ. This difference remained after exclusion of children with an IQ of <70 and adjustment for gender, stressful life events, and sociodemographic background. There were fewer differences in IQ scores between children with and without soiling or daytime wetting. Co-occurring wetting and soiling were associated with lower IQ scores than isolated soiling, daytime wetting, or bed-wetting, but this was mostly attributable to an overrepresentation of children with an IQ of <70 in the co-occurrence group.
CONCLUSIONS. It is hypothesized that the differences in intellectual capacities between children with and without bed-wetting are associated with maturational deficits of the central nervous system. There was less evidence for differences in intellectual capacities between children with and without soiling and daytime wetting. The central nervous system is involved to a lesser extent in soiling and daytime wetting, because peripheral influences from the bladder and gut play a greater role.
Key Words: soiling bed-wetting daytime wetting intellectual capacities IQ
Abbreviations: CNS—central nervous system WISC-R—Wechsler Intelligence Scale for Children–Revised ALSPAC—Avon Longitudinal Study of Parents and Children WISC-III—Wechsler Intelligence Scale for Children–Third Edition CI—confidence interval OR—odds ratio DSM-IV—Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition
Wetting and soiling problems in children are common conditions that present to many health professionals. Among children aged 7 years, reported rates of bed-wetting are
15% to 22% of boys and 7% to 15% of girls1; daytime wetting has been reported in 2% to 3% of boys and 3% to 4% of girls aged 7 years,2 and rates of soiling in 7-year-olds are
2.3% of boys and 0.7% of girls.3 It is generally accepted that the cause of wetting and soiling problems is multifactorial and likely to involve a complex interrelationship of genetic, environmental, biological, neurologic, and psychological factors.
Nocturnal enuresis is generally considered to be a genetically determined maturational disorder of the central nervous system (CNS) with 2 possible components: either insufficient arousal from bladder stimuli or an inability to suppress the micturition reflex during sleep.4 A number of neurophysiological studies have found evidence for differences in CNS functioning in children with and without nocturnal enuresis, including evidence for an elevated arousal threshold in boys with nocturnal enuresis.5 There is also evidence for a brainstem inhibition deficit in children with nocturnal enuresis, indicated by a reduction in the inhibitory effect of a weak peripheral sensory stimulus presented before a sudden strong stimulus (referred to as prepulse inhibition).4,6,7 This deficiency in inhibitory processing in the brainstem is thought to be analogous to the inability to inhibit micturition during sleep.7 However, another study did not find this deficit.8 Other neurophysiological studies that compared children with and without nocturnal enuresis reported more general deficits in brainstem function,9,10 as well as evidence for functional cortical differences.8,11–15 In addition to the neurophysiological findings, increased rates of neurologic soft signs,15–17 delayed developmental milestones,16,18–20 poorer visuomotor and spatial perception,19 and reading problems21 associated with bed-wetting point toward a complex maturational deficit of the CNS. Despite the increasing evidence for CNS involvement in the cause of bedwetting, there are no detailed studies of the intellectual capacities of children with bed-wetting.
Intellectual capacities in children with soiling and daytime wetting have received limited attention. Studies that compared children with and without soiling found no difference in overall IQ3,22 but reported lower scores on Wechsler Intelligence Scale for Children, Revised (WISC-R) subtests (arithmetic, digit span, and coding)22; specific problems with reading, spelling, and arithmetic22,23; and impaired academic performance in children who soil.23 No studies have specifically examined the intellectual capacities of children with daytime wetting, but 1 study reported a delay in developmental milestones and an increased rate of neurologic soft signs in a group of children with daytime/mixed day- and nighttime wetting compared with control subjects.16 However, the generalizability of the findings of these studies is limited because the majority are based on small clinic samples and some did not include a control group.
The aim of this study was to examine the intellectual capacities of children with wetting and soiling problems. The study, based on a United Kingdom population of >6000 children, investigated whether there are differences in IQ scores between children with and without soiling, daytime wetting, and bed-wetting. It was hypothesized that children with soiling, daytime wetting, and bed-wetting would have lower IQ scores compared with control subjects. Because of the high comorbidity of wetting and soiling,3,24–26 this study also examined whether co-occurring wetting and soiling is associated with more impairment in intellectual capacities compared with isolated soiling, daytime wetting, and bed-wetting.
| METHODS |
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Sample and Procedure
The study is based on the ongoing population-based Avon Longitudinal Study of Parents and Children (ALSPAC)27 that investigates a wide range of environmental and other influences on the health and development of children. The study design included all pregnant women who lived in the geographic area of Avon, England, and had an expected date of delivery between April 1, 1991, and December 31, 1992. The average age of the women at delivery was 28 years (range: 14–46 years). Approximately 45% of the women were expecting their first child; 6% of the women had 3 or more children. Information has been collected by questionnaire as well as regular clinic assessments from the age of 7 years. All aspects of the study are reviewed and approved by the ALSPAC Law and Ethics Committee, which is registered as an Institutional Review Board. Approval was also obtained from the Local Research Ethics Committees, which are governed by the Department of Health. More detailed information, including a comparison with the 1991 National Census can been found on the Web site (www.alspac.bris.ac.uk).
Questions about wetting and soiling were included in a self-report questionnaire that was sent to 11021 families, and 8242 questionnaires were returned (in 98% of cases, the respondent was the mother of the study child). The age range was 7 years 6 months to 9 years 3 months with 99% completing the questionnaire by the time their child was 8 years 3 months. IQ testing was conducted at the 8-year clinic to which all children were invited, and 7171 attended. This resulted in a sample of 6063 children who had information on wetting and soiling and who also started the IQ testing session. There was no evidence to suggest that children with wetting or soiling problems were less likely to attend the 8-year clinic.
Measures
Wetting and Soiling
The self-report questionnaire asked how often the child wets or soils during the day or night, with a number of options from "never" to "more than once a day."28 Nocturnal soiling was not considered in the analyses because of small numbers of children with this history. Table 1 shows the rates of wetting and soiling in the sample of 6063 children who started the Wechsler Intelligence Scale for Children–Third Edition (WISC-III)29 clinic session. Table 1 also shows a more detailed breakdown of children with isolated soiling, daytime wetting and bed-wetting, co-occurring wetting/soiling, and a pure control group with no wetting or soiling problems.
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IQ
The WISC-III was administered in a clinic that children attended at 8 years of age. A short form of the test whereby alternative items were used for all subtests, with the exception of the coding subtest, which was administered in full, was used. In addition to the 10 WISC-III subtests, the children were given the digit span task. Raw scores were calculated by summing the individual items within each subtest and multiplying by 2 for picture completion, information, arithmetic, vocabulary, comprehension, and picture arrangement; multiplying by five thirds for similarities; and multiplying by 3 halves for object assembly and block design. This made the raw scores comparable to those that would have been obtained had the full test been administered (the raw score for the coding subtest was calculated in the standard way as the full subtest was administered). With the use of the look-up tables provided in the WISC-III manual, age-scaled scores were obtained from the raw scores for each subtest, and total, performance, and verbal IQ scores were calculated. Prorating (as per the WISC-III manual instructions) was conducted on children who completed 4 of the 5 subtests that comprise verbal and performance IQ; therefore, there are slight differences in sample size for each regression analysis because it was possible to include children who did not complete all subtests.
The testers at the clinic made a number of observations about certain behaviors exhibited by children during the IQ testing session that might have affected performance. These included shyness, difficulty paying attention, anxiety, whether the child was noticeably upset, or whether the child gave up too easily on the test. There was no evidence of differences in the rates of these observed behaviors between the wetting/soiling groups and control subjects.
Potential Confounders
Family sociodemographic background was assessed using questions that were administered during the prenatal period, including homeownership status, car ownership, crowding, mother's education, mother's age, birth order, and marital status. Stressful life events were assessed at 7.5 years using the question, "Has anything exceptionally stressful happened to him/her that would really upset almost anyone?" The analyses also adjusted for gender.
Data Analysis
The primary analysis involved 3 sets of comparisons. WISC-III total, performance, and verbal IQ scores and subtest scores of children with soiling were compared with a control group that consisted of the remainder of the sample in a set of multivariable regression analyses that adjusted for the confounders detailed previously. This procedure was repeated using bed-wetting and then daytime wetting as the risk group. In each instance, the control group is slightly different because it consists of all children who were not included in the risk group of interest (eg, the control group in the analysis for soiling will contain some children with bed-wetting and daytime wetting).
On observation, outcome variables were normally distributed apart from picture arrangement, for which there was a secondary peak to the left of the distribution. Results were essentially the same when repeated with and without the cases that formed the peak.
Because it is widely known that children with an IQ <70 are at a higher risk for wetting and soiling,30 it was possible that any observed group differences in the analysis might have been attributable to a higher proportion of children with an IQ <70 in the wetting/soiling groups. For investigation of this possibility, examinations of the differences in intellectual capacities between wetting/soiling children and control subjects were repeated excluding children with an IQ <70.
In a secondary analysis, the population was further subdivided into children with isolated soiling, daytime wetting, and bed-wetting; children with co-occurring wetting/soiling; and a final "pure" control group that consisted of those with no wetting/soiling. Mean scores on total, performance, and verbal IQ scores and subtests were compared with a set of 1-way analyses of variance.
In the multivariable models in the primary analyses, missing data on confounding variables resulted in an additional loss of almost 10% of the sample when the fully adjusted models were derived. For avoidance of any potential bias that might result from incorporating these confounding variables into the model, a missing data imputation technique was used (Missing Imputation for Chained Equations31) using the procedure in Stata known as ice.32 Imputation was restricted to confounding variables (no imputation of the outcome or the wetting variables was performed).
| RESULTS |
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Table 2 shows the IQ score differences and 95% confidence intervals (CIs) for the analyses comparing children with any soiling, daytime wetting, and bed-wetting with control subjects. Differences in intellectual capacities were most evident in the bed-wetting analysis, with lower total, verbal, and performance IQ and subtest scores (comprehension, picture completion, coding, and digit span) in the bed-wetting group. There was some evidence for differences in intellectual capacities in the soiling analysis, with children who soil having lower scores than control subjects for performance IQ and 2 of the subtests (coding and picture arrangement). With the exception of lower scores on 2 of the subtests (comprehension and coding), there was little evidence for differences in IQ scores between children with daytime wetting and control subjects.
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Adjusting for the confounding variables resulted in an increase in the difference in total and verbal IQ scores between children with bed-wetting and control subjects. On additional investigation, this was attributable to adjustment for maternal age and education, both of which were related to wetting and soiling as well as IQ but in opposite directions. Otherwise, adjusting for the confounding variables resulted in a reduction in the score differences between the wetting/soiling groups and control subjects or had little effect.
The rate of children with an IQ <70 in the sample was 1.43% (86 of 5992), and 4 children had IQ <50. Supplementary analyses found that the odds of having an IQ score <70 were considerably greater for children with soiling than bed-wetting or daytime wetting (soiling: odds ratio [OR]: 2.78 [95% CI: 1.55–4.97; P = .001); daytime wetting: OR: 1.95 [95% CI: 1.05–3.62; P = .034]; bedwetting: OR: 1.53 [95% CI: 0.91–2.55; P = .108]). Among children with an IQ <70, there were higher rates of wetting and soiling compared with those with normal intellect (soiling: 16.3% vs 6.5%, P < .001; daytime wetting: 14% vs 7.7%, P = .031; bed-wetting: 22.1% vs 15.7%, P = .105). There was also evidence for a markedly higher risk for co-occurring wetting/soiling among the group of children with an IQ <70 compared with those with normal intellect (14% vs 5.2%); however, there was no difference in rates of isolated bed-wetting and daytime wetting and only a slightly higher risk for isolated soiling in those with an IQ <70 (5.8% vs 3.3%).
When the multivariable regression analyses were repeated excluding children with an IQ <70, there was still evidence for differences in WISC-III IQ scores between children with bed-wetting and control subjects (eg, performance IQ: score difference = –1.61 [95% CI: 2.76 to –0.46; P = .006]; coding: score difference = –0.53 [–0.73 to –0.32; P < .001]). After exclusion of children with an IQ <70, the difference in performance IQ scores between children with and without soiling was substantially reduced (score difference = –1.36; 95% CI: –3.01 to 0.29; P = .106), but there was only a small reduction in the difference in subtest scores for soiling and daytime wetting.
A secondary set of analyses examined whether children with co-occurring wetting/soiling had lower WISC-III IQ scores compared with children with isolated soiling, daytime wetting, or bed-wetting and control subjects with no wetting/soiling. Co-occurring wetting and soiling was associated with lower IQ scores than isolated soiling, daytime wetting, or bed-wetting, but this was found to be attributable to an overrepresentation of children with an IQ <70 in the co-occurrence group. The analyses were repeated excluding the children with an IQ <70, resulting in the following 5 groups: control subjects (n = 4559), isolated daytime wetting (n = 208), isolated bed-wetting (n = 699), isolated soiling (n = 197), and co-occurring wetting/soiling (n = 314; 67 [21.3%] daytime wetting and soiling, 114 [36.3%] bed-wetting and daytime wetting, and 60 [19.1%] bed-wetting and soiling; 73 [23.2%] had all 3 problems).
There was some evidence for differences in performance IQ among the 5 groups (score differences compared with control subjects [reference = 1]: daytime wetting –1.26 [95% CI: –1.03 to 3.55]; bedwetting –1.52 [95% CI: –2.83 to –0.20]; soiling –0.88 [95% CI: –3.25 to 1.48]; co-occurring wetting/soiling –1.97 [95% CI: –3.87 to –0.07; P = .032]); however, posthoc tests showed that these differences tended to be between certain groups and the control group (eg, co-occurring wetting/soiling versus control subjects) rather than between the various groups. Examination of the subtest scores (Fig 1) showed that although the children with co-occurring wetting/soiling achieved the lowest score on 3 of the 11 subtests (information, picture completion, and picture arrangement), the differences were not substantial. Children with isolated daytime wetting scored highest in 8 of 11 subtests, especially picture completion, for which the daytime wetting group scored 0.50 points higher than the control group (95% CI: –0.01 to 1.01; P = .053) and between 0.7 and 0.9 points higher than the other wetting/soiling groups. Similarly, with the vocabulary subscale, children with isolated daytime wetting scored 0.65 points higher than control subjects (95% CI: 0.04–1.25; P = .036). Adjustment for gender had little effect on these results.
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| DISCUSSION |
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This study found that children who wet the bed are characterized by reduced WISC-III IQ scores compared with control subjects, even when those with an IQ <70 are excluded. Bed-wetting was particularly associated with reduced performance IQ and lower scores on the performance subtests (picture completion, coding, and digit span). Performance IQ represents practical, or "fluid," intelligence and reflects innate intellectual abilities that are thought to be largely influenced by neurologic and biological factors rather than knowledge that is acquired and influenced by education, family, and social context.33 The evidence found in this study for differences in innate intellectual abilities between children with and without bed-wetting is supported by the belief that nocturnal enuresis is a genetically determined maturational disorder of the CNS.4
The 2 proposed mechanisms of maturational delay of the CNS in nocturnal enuresis are the lack of waking when the bladder is full or the lack of inhibition of the micturition reflex during sleep.4 The latter mechanism is supported by experiments showing that prepulse inhibition of the acoustic startle reflex is reduced in children with nocturnal enuresis.4,6,7 This points to a maturational deficit in the basic inhibitory function of the brainstem in children with nocturnal enuresis that manifests as the inability to inhibit the micturition reflex during sleep.7 It is possible that a maturational deficit in basic inhibitory processes is associated with a delay in the development of executive functions in children with nocturnal enuresis. Inhibition, attention, and executive functions are highly interrelated cognitive functions.34 The development of basic inhibitory functions precedes the emergence of more complex functions of selective attention and of executive functions including impulse control, auditory and visual attention, planning, verbal and visual fluency, and the maintenance of information in working memory.34,35 The brain areas that are primarily associated with the performance of executive functions are the prefrontal cortex and the anterior cingulate cortex,36,37 and these areas are reciprocally interconnected with brainstem structures.38 Neurophysiological studies also have linked brainstem deficits to impaired attention, cognition, and executive dysfunction.39,40
In addition to the well-documented brainstem involvement in nocturnal enuresis, there is evidence for functional cortical differences between children with and without nocturnal enuresis. For example, some studies have reported elevated latencies of event-related acoustic evoked potential (P300) in children with nocturnal enuresis compared with control subjects.13,14 P300 latencies have been reported to be associated with specific cognitive impairments. For example, in 1 study, P300 latencies showed a strong inverse correlation with specific WISC-R subtests, including comprehension, picture completion, coding, and digit span, as well as showing an inverse correlation with the total IQ score.41 Additional evidence for cortical involvement comes from studies that reported that bed-wetting is associated with difficulties in motor coordination4,15,16 and visuomotor and spatial perception.19
These studies point toward complex maturational deficits of the CNS in children with nocturnal enuresis. This could explain the differences in intellectual capacities in children with and without bed-wetting reported in this study. Children with isolated bed-wetting scored lowest (or joint lowest with children who had co-occurring wetting and soiling) on a number of the WISC-III subtests, including picture completion, coding, and digit span. These subtests assess a number of executive functions, including attention, visual perception, processing speed, short-term memory, and visual-motor coordination.33 We suggest that the lower IQ scores of children with bed-wetting compared with control subjects are a result of maturational deficits in CNS functioning and that these deficits are also involved in the cause of bed-wetting.
There was some evidence for differences in intellectual capacities between children with and without soiling in this study, with children who soil having lower scores on performance IQ; however, additional analysis revealed that this was largely attributable to the higher rate of children with an IQ <70 in the soiling group. There was evidence that soiling was associated with reduced subtest scores, particularly picture arrangement, after exclusion of children with an IQ <70. The picture arrangement subtest assesses the ability to plan and interpret social situations and to anticipate consequences,33 and reduced scores on this subtest might suggest a deficit in social cognition in children who soil. This clearly requires additional investigation. A "normal range" of IQ scores in children who soil was reported in a previous population-based study, but subtest scores were not reported.3 Only 1 study has found evidence for reduced (WISC-R) IQ subtest scores in children who soil, but this study did not include a control group.22 The overall evidence suggests that although neurologic factors might play a part in the cause of soiling, CNS factors play a lesser role than in bed-wetting. In the majority of cases, the causative basis of soiling is much more likely to be rooted in difficulties with toilet training42 and painful experiences, such as the passage of hard stools, resulting in stool holding and overflow incontinence.43
Children with daytime wetting did not show a general reduction in IQ compared with control subjects, but they did score lower on the comprehension and coding subtests. These differences remained after exclusion of children with an IQ <70. In addition to deficits in perceptual motor speed and working memory speed, attention problems have been found to be associated with impaired performance on the coding subtest.44 An increased rate of attention problems has been reported in children with daytime wetting compared with control subjects,28,45 although the nature of this association remains unclear. Reduced scores on the comprehension subtest are believed to be associated with impaired common sense reasoning and social judgment33 and perhaps reflect a general immaturity in children who experience daytime wetting. An unexpected finding was that children with isolated daytime wetting were found to score highest (relative to those with isolated bed-wetting, soiling, or no wetting/soiling) on the picture completion and vocabulary subscales. It was believed that gender differences in cognitive abilities might have played a part in these findings, because isolated daytime wetting is more common in girls. However, adjustment for gender did not fully explain this finding. The overall evidence suggests a smaller role for the CNS in daytime wetting compared with bed-wetting, because bladder dysfunction plays the major role in its cause.
The co-occurrence of wetting and soiling problems is common in childhood and is associated with a higher rate of psychological problems compared with children with wetting problems alone.26 Children with co-occurring wetting and soiling had lower IQ scores than those with a single continence problem (data not shown), but this was mostly explained by an overrepresentation of children with an IQ <70 in the co-occurrence group. In the analysis that excluded children with an IQ <70, those with co-occurring wetting and soiling had the lowest performance IQ score and the lowest scores on 3 of the subtests, although the differences between the groups were not substantial. This suggests that, among children with an IQ of
70, those with co-occurring wetting and soiling have only a slightly greater risk for lower IQ scores than those with isolated wetting or soiling.
The effect sizes found in this study are small, but this is not surprising in a large population-based sample. This might be because the wetting and soiling groups were not restricted to the most severe cases that are likely to present to clinics but also comprised children with soiling, daytime wetting, and bed-wetting that did not meet Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) criteria. It could be argued that these children are not representative of children with wetting and soiling problems and their inclusion will weaken the findings. However, previous studies of children with bed-wetting have found evidence for neurologic impairments16 and behavior problems46 in children whose bed-wetting does not meet DSM-IV criteria. Additional investigation revealed that restricting the analysis to children who met DSM-IV criteria for wetting/soiling increased the difference in IQ scores between the groups. However, the purpose of this study was to examine differences in cognitive functioning across the whole range of wetting/soiling problems in a sample from the general population.
Multiple testing is also an issue in this study. Because of the variety of outcomes and exposure variables considered in this study, the number of statistical tests was considerable. Traditional corrections such as Bonferroni are inappropriate because of the strong dependence between WISC-III subtests and also among the various wetting/soiling problems. Findings should be considered in light of these possible limitations. Although it is unlikely that new findings from our primary analysis could be replicated, our findings are consistent and in line with current theory, giving credence to the overall message of this article.
A shortened form of the WISC-III, whereby alternative items (always starting with item 1 in the standard form) were used for all subtests (with the exception of the coding subtest, which was administered in its full form), was used in this study. This was done for practical reasons relating to the large number of children being tested and to reduce the length of the session so that children were less likely to tire. Although shortening the WISC-III could result in loss of reliability in the derived IQ measures, shortened versions have been used successfully in other studies, and it has been argued that they are a valid substitute.47,48
Another potential limitation is that there was differential attrition in the cohort, with the subsample of the ALSPAC families who responded to the questionnaire and the subsample of children who attended the clinic for IQ testing being more socially advantaged than those who defaulted. However, there does not seem to be a relationship between dropout and wetting or soiling, so we are confident that these results are not overly biased.
| CONCLUSIONS |
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Although the causative basis of bed-wetting is likely to be multifactorial, our results along with the findings of previous studies underline the importance of neurologic factors. The specific factors relating to the CNS include polyuria,49 lack of arousal,5 and failure to inhibit the micturition reflex during sleep (ie, to stop the bladder from emptying).7,50 The last 2 mechanisms are mediated by the brainstem, the first by the antidiuretic hormone, which is secreted from the CNS. In daytime wetting and soiling, the CNS is involved to a lesser extent, because peripheral influences from bladder and gut play a greater role. These findings are especially interesting in that children with bed-wetting (with the greatest CNS involvement) show the most evidence for cognitive differences compared with control subjects. More detailed neuropsychological testing of children with bed-wetting is required to define carefully the cognitive profile that is associated with bed-wetting and to determine whether it is associated with learning problems and academic achievement.
| ACKNOWLEDGMENTS |
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A grant to support this research was given by the Big Lottery Fund to the charity Education and Resources for Improving Childhood Continence, and the study was conducted in collaboration with ALSPAC.
We are extremely grateful to all of the families who took part in this study; the midwives for help in recruiting them; and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The United Kingdom Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC.
| FOOTNOTES |
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Accepted Jan 25, 2007.
Address correspondence to Carol Joinson, PhD, Avon Longitudinal Study of Parents and Children, Department of Social Medicine, 24 Tyndall Ave, Bristol, BS8 1TQ, United Kingdom. E-mail: carol.joinson{at}bristol.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
This article is the work of the authors, who also serve as guarantors for its contents.
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