Introduction

Enuresis, or pathological bedwetting, is defined as an intermittent (i.e., not continuous) wetting with any frequency during sleep in children more than or equal to five years old, according to the International Children’s Continence Society (ICCS) [1]. Epidemiological studies have shown that enuresis affects 25–30% of children at age 5 years, and 9.4% at 9.5 years [2,3]; whereas 5% of children at age 5 years and 2% at 10 [4] according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV/5), which requires twice or more in any one week [5,6]. Although the biological basis of enuresis is not fully understood, clinical studies have postulated that there exists neurodevelopmental immaturity, especially in the brainstem and motor cortex circuitry [7,8], as well as urological deficits [9].

Enuresis, especially in clinical situation, is known to be associated with a range of children’s behavioral problems such as emotional problems, peer-relational problems, and conduct problems [10–12]. Hyperactivity-inattention, including attention-deficit hyperactivity disorder (ADHD), which is a pathologic condition on a hyperactivity-inattention spectrum [13], is the most common problem associated with enuresis, a link reported not only in clinical [14, 15], but also in epidemiological studies [16, 17]. A common neural basis is thought to underlie this association, perhaps through inhibitory regulation subserved by the anterior cingulate and the prefrontal cortexes [18], which develops through childhood and adolescence and matures in early adulthood [19, 20]. In clinical situations, these findings have been used for effective treatment of enuresis; the ICCS recommends screening enuretic children for hyperactivity-inattention, since simultaneous treatment for both leads to better outcomes in enuresis [10].

Children in early adolescence, at around 10 years old, perceive enuresis as a highly distressing problem, ranking it eighth among stressful life events [21], and children in eight years of age or older with persistent enuresis have psychosocial difficulties such as decreased self-esteem [22]. Appropriate care for enuresis is therefore very important, even if it does not appear in clinical situations or health professionals have not yet intervened. It is not, however, known whether hyperactivity-inattention may be independently associated with enuresis among general population as well as clinically-diagnosed enuresis [15]. Previous studies on the association have mainly been done in clinical situations, but low consulting rate for medical clinicians for enuresis [23] and restrictive criteria about frequency (twice or more per week according to the DSM-IV/5) [24] have excluded a considerable number of enuretic children from the studies [25].

A few epidemiological studies on early adolescents have suggested an association between enuresis and hyperactivity-inattention among general population. Byrd et al. reported that children with any episodes of enuresis in the previous year showed higher extreme behavior scores, including hyperactivity-inattention, than non-enuretic children [3]. Joinson et al. reported that current enuresis was associated with increased hyperactivity-inattention even after children with frequent enuresis such as twice or more per week were excluded from the analyses [25]. These studies did not, however, examine and separate the overlap of behavioral problems despite their high comorbidity among enuretic children [26].

It therefore remains unclear whether there is an independent association between enuresis and hyperactivity-inattention among general population when other behavioral problems such as emotional and conduct problems are also considered [25]. Our study aimed to examine whether enuresis is independently associated with hyperactivity-inattention in early adolescence even after controlling for the effects of other behavioral problems.

Materials and Methods

Results

Prevalence of enuresis

Enuresis was reported for 407 (9.2%) children out of 4,434 participants (Table 1). Of these, 61 children (1.4% of the total) were placed in the frequent enuresis group. Boys were more likely to show both enuresis (OR = 2.66 [95% CI: 2.12–3.33], p < .001), and frequent enuresis (OR = 2.30 [95% CI: 1.31–4.05], p = .0036).

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Table 1. Demographic data of the participants (Total N = 4,434).

https://doi.org/10.1371/journal.pone.0158786.t001

Differences in behavioral problems and other variables between the enuretic and non-enuretic groups

The enuretic group had a significantly higher hyperactivity-inattention score than the non-enuretic group (enuretic: mean (SD) = 3.8 (2.3), non-enuretic: 3.0 (2.1), p < .001, Table 2). This difference corresponded with Hedge’s g = 0.39. The other SDQ subscale scores were also higher among the enuretic group (g = 0.18 vs. 0.26, p < .001). There were no significant differences in children’s age, estimated IQ, and parental education (p > .20) between the two groups. These results did not change significantly even after excluding the frequent enuresis group (hyperactivity-inattention, enuretic: mean (SD) = 3.8 (2.3), non-enuretic: 3.0 (2.1), g = 0.38, p < .001).

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Table 2. Comparison of behavioral problems in the enuretic and non-enuretic groups.

https://doi.org/10.1371/journal.pone.0158786.t002

Independent association between enuresis and behavioral problems

Enuresis was associated with increased scores in hyperactivity-inattention and all the other SDQ subscales after controlling for demographic variables (hyperactivity-inattention: β = .087 [95% CI:.057–.117], p < .001, other subscales: β = .048–.059, p < .005, Table 3, model 1). In model 2, which additionally adjusted for the other SDQ subscales, enuresis was associated only with increased hyperactivity-inattention (β = .054 [95% CI: .028–.080], p < .001, model 2), but not with the other SDQ subscales (p > .15). Sensitivity analyses, which excluded the frequent enuresis group, showed similar results in both models (hyperactivity-inattention: β = .049 [95% CI: .023–.076], p < .001, other subscales: p > .15, model 2).

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Table 3. Multivariate linear regression analyses predicting behavioral problems from enuresis.

https://doi.org/10.1371/journal.pone.0158786.t003

There were no significant interaction effects between enuresis and sex on the SDQ subscales in these multivariate linear regression analyses (p > .20). Interaction terms were therefore removed from the final analyses shown in Table 3.

Discussion

This study showed that enuresis was independently associated with hyperactivity-inattention in the general population of early adolescents even when considering other behavioral problems such as emotional symptoms, conduct problems, and peer-relationship problems. These results were essentially unchanged even after the frequent enuresis group was excluded.

To the best of our knowledge, this is the first study that has showed the independent association between enuresis and hyperactivity-inattention among a large general population in early adolescence. The result was consistent with a previous case-control clinical study showing independent association of hyperactivity-inattention with enuresis [15]. Our results could have adequate reliability and validity since the prevalence and sex ratio of enuresis is consistent with previous studies [3, 4]. We also observed significant associations between enuresis and other behavioral problems such as emotional and conduct problems in the unadjusted model (model 1), in line with a previous epidemiological study [25]. The sensitivity analyses excluding the frequent enuresis group did not significantly change the results. Therefore, enuresis may not be clearly divided into pathologic/non-pathologic groups according to its frequency, although the DSM-IV/5 defines enuresis based on the frequency [24].

No independent association with enuresis was observed for the other behavioral problems in this study. The clinical case-control study cited above, however, reported that not only hyperactivity-inattention but all the other behavioral problems in the SDQ were also independently associated with enuresis [15]. This difference in the results might be due to the small number of participants recruited from clinical patients in the previous study. Stronger distress associated with enuresis in clinical situation, rather than enuresis without consulting to clinicians, might lead to the association of enuresis with other behavioral problems as well as hyperactivity-inattention [36].

Although the mechanisms for the association between enuresis and hyperactivity-inattention remain unclear, we can propose some possible explanations based on previous studies. From a psychosocial viewpoint, children’s increased hyperactivity-inattention could be a relapse of coping behavior resulted from the psychological burdens of enuresis [9, 36]. These burdens become much stronger in early adolescence, from around 10 years, since enuresis increasingly begins to carry social and peer-relational meanings at that point [21, 37]. From a biological viewpoint, neurophysiological and neuroimaging studies have recently suggested common developmental immaturities in the central nervous system for both enuresis and hyperactivity-inattention [18, 38]. A neurophysiological case-control study showed that deficits in prepulse inhibition were greater in children with clinically-diagnosed enuresis or attention deficit hyperactivity disorder (ADHD) than healthy controls, and greatest in children with both conditions [39]. These results could imply that the two conditions share dysregulation of inhibitory signal processing system in the pons, where exists the pontine micturition center [40], modulated by limbic cortico-striato-pallido-thalamic circuitry and prefrontal neural circuitry [41]. There has been no neuroimaging study focusing on the direct association between enuresis and hyperactivity-inattention. Functional magnetic resonance imaging studies during Go/No-Go tasks, however, have shown impaired activities in the anterior cingulate and the prefrontal cortexes, which are responsible for self-regulatory behavior against emotional reward cues [18–20], in patients with both clinical enuresis [42] and ADHD [43].

The results of this study may provide some clues for appropriate care for children showing enuresis and not consulting to clinicians. In clinical situations, for effective treatment of enuresis, the ICCS recommends screening for psycho-behavioral problems, especially hyperactivity-inattention, among enuretic children and provision of psychosocial care for both issues [10]. This study’s findings suggest that this recommendation could also be applicable to enuresis in non-clinical situations, and that screening for hyperactivity-inattention and psychosocial care for the problem might prove effective care for enuretic children in early adolescence. This implication could be true of not only clinicians and parents but also school teachers and social welfare workers, who often face children with enuresis and hyperactivity-inattention in non-clinical situations (at home, school, and community).

This study has several limitations. First, our survey included no physical examination by medical specialists for urological and neurological disorders. Instead we relied on the parents’ reports. This might not have been sufficient, as physical examinations are recommended in studying incontinence problems [38]. This meant that we were unable to guarantee exclusion of children with urinary disorders other than enuresis. Second, the SDQ scores might be biased towards high scores in the enuretic group, since parents of enuretic children, who perceive higher stress than ones of non-enuretic children [12], could negatively affect their evaluation of children’s behavioral problems [44]. This limitation would, however, not explain the independent association of enuresis with hyperactivity-inattention, and not with other behavioral problems. Third, even though hyperactivity-inattention and ADHD are characterized as a continuous spectrum [13], it requires careful attention that children with high score of hyperactivity-inattention in the SDQ does not necessarily receive a diagnosis of ADHD. Finally, the cross-sectional nature of this study means that we cannot draw conclusions about any causal relationship between children’s enuresis and hyperactivity-inattention. Future studies would benefit from drawing on both prospective and longitudinal viewpoints to clarify the causality. We plan to investigate this in the current longitudinal study.

Conclusion

Enuresis was associated with increased hyperactivity-inattention among the general population of early adolescents even after controlling for other behavioral problems. The lines of evidence on treatments for clinical enuresis, such as screening and psychosocial support for hyperactivity-inattention [10], might therefore also be applicable to early adolescents showing enuresis even if not appearing to clinical situations.

Acknowledgments

The authors are grateful to the participants, recruitment staff, the interviewers, and all of the TTC staff. Sho K was in charge of designing, analyzing and writing the manuscripts, being supervised by Shinsuke K, SA, AN, and KK. SU took charge of supervision of statistical analyses. All the authors critically reviewed the manuscript and approved the final version to be submitted. All of the authors declared that there are no conflicts of interest in relation to this study with respect to the research, authorship, and/or publication.

This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (23118002; Adolescent Mind & Self-Regulation) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.