Exploring clinical and urinary factors in treatment-resistant vs. treatment-responsive childhood enuresis: a comparative study

Abstract

Background

Nocturnal enuresis represents a persistent pediatric health challenge characterized by variable treatment responses. Despite established therapeutic interventions, a substantial proportion of children fail to achieve successful management, highlighting the critical need for a deeper understanding of treatment resistance mechanisms. This study sought to systematically examine the multifaceted factors underlying differential treatment outcomes in childhood enuresis.

Methods

A cross-sectional analytical study was conducted in 2017 at Mohammad Kermanshahi Hospital, Iran. The study included 144 children aged 5–8 years with nocturnal enuresis, divided into treatment-controlled (n = 85) and treatment-resistant (n = 59) groups. Participants received Desmopressin nasal spray (DDAVP) at 10 mcg/spray nightly. Demographics, clinical characteristics, sleep patterns, urination habits, and ultrasound findings were analyzed.

Results

The prevalence of controlled nocturnal enuresis was higher than treatment-resistant cases. Factors, including abnormal residual urine volume (P-value = 0.04), one episode of bedwetting per night (P-value = 0.03) and more than one episode of bedwetting per night (P-value = 0.02) were found to be statistically significant in our findings. Factors more common in the treatment-responsive group included deep sleep (85.9%), daytime urinary control (77.6%). Conversely, treatment-resistant children exhibited higher rates of poor medication adherence (94.9%), high urine volume per episode (86.4%), although these parameters were identified as non-statistically significant in our study.

Conclusion

This study highlights critical factors differentiating treatment-resistant from treatment-responsive nocturnal enuresis in children. Key factors such as deep sleep, daytime urinary control, and effective fluid management were associated with controlled enuresis, while treatment-resistant cases were marked by poor adherence to medication, high urine volume per episode, and frequent enuresis. Future research should explore long-term efficacy and innovative approaches to enhance the management of nocturnal enuresis.

Clinical trial number

Not applicable (This was a cross-sectional analytical study and did not involve a clinical trial).

Introduction

Nocturnal enuresis remains a challenging pediatric condition that significantly impacts children’s psychological and social well-being. Despite its prevalence, treatment outcomes are frequently suboptimal, with up to 50% of children demonstrating resistance to current therapeutic approaches [1]. This variability in treatment response underscores the critical need to understand the underlying factors that differentiate treatment-responsive from treatment-resistant patients.

While existing research has explored various aspects of enuresis, including physiological mechanisms and therapeutic interventions, a comprehensive understanding of the factors influencing treatment outcomes remains elusive. Previous studies have suggested potential contributors to treatment resistance, such as comorbid psychiatric conditions like attention deficit hyperactivity disorder (ADHD) [2], psychological factors including diminished self-esteem [3], and organic pathologies such as constipation [4].

The complex nature of enuresis demands a multifaceted approach to investigation. Current therapeutic strategies, including alarm therapy and pharmacological interventions like desmopressin and anticholinergics, have yielded inconsistent results [5,6,7,8,9,10]. This inconsistency highlights the necessity of a more nuanced understanding of patient characteristics that may predict treatment response.

Accordingly, this study seeks to comprehensively examine the demographic, clinical, ultrasonographic, and psychological variables that distinguish treatment-resistant enuretic children from those who respond positively to pharmacological intervention. By identifying these distinguishing factors, we aim to provide insights that could potentially improve treatment strategies and patient outcomes.

Our investigation represents a critical step towards personalized management of nocturnal enuresis, with the ultimate goal of enhancing therapeutic approaches and improving the quality of life for affected children and their families.

Methods

Study design and participants

This cross-sectional analytical study was conducted in 2017 at the nephrology clinic of Mohammad Kermanshahi Hospital, affiliated with Kermanshah University of Medical Sciences, Iran. The study population comprised 144 children aged 5–8 years diagnosed with nocturnal enuresis. The study was approved by the Ethics Committee of Kermanshah University of Medical Sciences with the ethical code KUMS.REC.1395.739, and informed consent was acquired from the parents or legal guardians of all participants.

Sampling method and sample size

The study employed a consecutive sampling technique. All eligible patients who visited the clinic during the study period and met the inclusion criteria were invited to participate. The sample size was calculated using the formula for comparing two proportions, with α = 0.05 (two-tailed) and 80% power. Assuming proportions of 0.60 and 0.40 for the controlled and treatment-resistant groups respectively, the calculated sample size was 71 per group. Accounting for a 15% dropout rate, the target sample was 82 per group. The final study sample of 144 children (85 in the controlled group and 59 in the treatment-resistant group) met or approached these requirements.

The minimum sample size was determined based on the study design and a 59.3% prevalence of a positive family history among children with nocturnal enuresis, as reported by prior research (Ashraf Sadat Hakim et al., 2014, Ahvaz). With a 95% confidence level and an 8% margin of error, the sample size calculation, including an additional 10% to account for potential attrition, resulted in a requirement of 160 participants. These participants were selected using a convenience sampling method from among those meeting the study’s inclusion criteria and willing to participate.

The sample size calculation formula used was as follows:

$$\:n=\frac{{\left(1.96\right)}^{2}\left(0.593\right)\left(0.407\right)}{{\left(0.08\right)}^{2}}\cong\:145\:\:\:,\:\:\:145+15\left(10\%\right)=160$$

Inclusion and exclusion criteria

Children aged 5–8 years with a diagnosis of nocturnal enuresis, defined as involuntary urination during sleep at least twice a week for three consecutive months, were included in this study. Both children with primary monosymptomatic nocturnal enuresis and those with potential daytime urinary symptoms were eligible. Exclusion criteria encompassed children with known neurological disorders, urinary tract abnormalities, or other medical conditions that could contribute to enuresis.

Treatment protocol

Children’s enuresis questionnaire

The Children’s Enuresis Questionnaire was a comprehensive, multi-respondent tool developed for this study to gather detailed information on participants’ demographic, clinical, and behavioral characteristics related to nocturnal enuresis. The questionnaire was primarily completed by parents, with certain sections supplemented by clinical assessments from healthcare providers. While most sections were administered before initiating desmopressin treatment, Question 33, which specifically addressed medication adherence, was completed retrospectively after the treatment had begun. The questionnaire encompassed multiple domains, including detailed sleep patterns, fluid intake habits, frequency and volume of bedwetting episodes, family history of enuresis, and daytime urinary control. Parents provided the majority of the information, with healthcare professionals contributing clinical insights to ensure a comprehensive assessment of the child’s enuretic condition and treatment response.

Clinical assessments

Participants underwent a thorough clinical examination, including physical examination, urinalysis, and renal and bladder ultrasonography to assess for anatomical abnormalities and post-void residual urine volume.

Desmopressin treatment

All participants received desmopressin nasal spray (DDAVP) at a dose of 10 mcg/spray nightly. Treatment duration was a minimum of three months. Response to treatment was monitored through reductions in the frequency of wet nights, as reported by parents.

Group classification

Participants were categorized into two groups based on their response to treatment:

• Group 1 (n = 85): Controlled nocturnal enuresis (nocturnal enuresis frequency < 1 episode per week during weeks 11–12 of treatment).

• Group 2 (n = 59): Treatment-resistant nocturnal enuresis (frequency ≥ 1 episode per week during the same period).

Variables assessed

The study examined various factors potentially associated with nocturnal enuresis, including sleep patterns, daytime urination control, fluid intake habits, frequency and volume of bedwetting episodes, family history, urinary urgency and frequency, bladder capacity, bowel habits, and emotional factors.

Definitions of specific terms

• 1. Abnormal Urine Volume:

Abnormal urine volume was defined as urine output per bedwetting episode exceeding the expected bladder capacity for the child’s age. For children aged 5–8 years, this was calculated using the formula:

Bladder capacity (mL) = 30 × (age in years) + 30 [11].

• 2. Abnormal Ultrasound Findings:

Abnormal ultrasound findings included any deviation from normal kidney and bladder anatomy or function. This encompassed findings such as:

• Increased bladder wall thickness.

• Residual urine volume exceeding 20 mL after voiding [12].

• Structural anomalies such as vesicoureteral reflux or hydronephrosis.

These definitions were standardized to ensure consistent assessment and reporting across all study participants.

Statistical analysis

Data were analyzed using SPSS version 22.0 and R (version 4.4.2). Descriptive statistics were calculated for all variables, including frequencies, percentages, means, and standard deviations. The Fisher’s exact test was employed to assess the relationship between various factors and the two study groups. A p-value < 0.05 was considered statistically significant.

Results

As shown in Tables 1 and 144 children with nocturnal enuresis were studied within a 3-month period. Among them, 85 children were in the controlled enuresis group (Group 1), while 59 children were in the treatment-resistant enuresis group (Group 2). In Group 1, 57 (67.1%) were boys, and 28 (32.9%) were girls, whereas in Group 2, 25 (42.4%) were boys, and 34 (57.6%) were girls. Moreover, as indicated in Table 1, only gender value was found to be statistically significant (P-value < 0.05) in terms of demographic characteristics. The age distribution was slightly higher in the treatment-resistant group compared to the controlled enuresis group. The educational level of fathers in the treatment-resistant group was higher than in the controlled group, but no significant differences were observed in the mothers’ education levels or the employment status of either parent between the groups.

Table 1 Demographic and parental characteristics of 144 children with nocturnal enuresis by group

In this section, we examined the prevalence of factors influencing nocturnal enuresis in two groups of children: those with controlled nocturnal enuresis and those with treatment-resistant nocturnal enuresis. Factors like deep sleep, daytime urinary control ability, excessive fluid intake before bedtime, a single episode of nocturnal enuresis per night, reduced frequency of nocturnal enuresis with fluid intake management, family history of nocturnal enuresis, prolonged intervals between urination, urinary frequency, post-void residual urine in the bladder, frequent urination with small volumes, and use of alarm systems, were more prevalent in children with controlled nocturnal enuresis compared to those with treatment-resistant enuresis in an identical treatment duration.

Only parameters like abnormal residual urine volume, one episode of bedwetting per night and more than one episode of bedwetting per night were found to be statistically significant in our findings. Likewise, large volume of urine in each bedwetting episode, child’s cooperation in proper medication use and deep sleep have been found as the most prevalent events in both groups.

Additionally, the findings showed minimal differences or comparable percentages between the two groups in factors such as habitual urine retention, snoring, apnea, waking up to drink water, abnormal findings in sonography, spinal examinations, neurological assessments, and genital system evaluations (Table 2).

Table 2 Frequency and percentage of factors influencing nocturnal enuresis in 144 children with enuresis in the two study groups

At the conclusion of the analysis, no statistically significant associations were found at the 5% error level (all P-values > 0.05) between the studied groups and any of the following factors: presence of bowel disorders, habit of holding urine, history of urinary tract infection, occurrence of enuresis every night, ability to control urination during the day, family history of enuresis, use of alarm devices prior to initiating medication, deep sleep, snoring, or sleep apnea (Table 2).

Discussion

The primary objective of this investigation was to elucidate the factors contributing to treatment resistance in childhood primary enuresis. Our findings revealed that among 144 enrolled children, 85 patients demonstrated appropriate response to pharmacologic intervention, while 59 patients exhibited treatment resistance, resulting in therapeutic failure. Although pharmacologic therapy showed efficacy in managing nocturnal enuresis, a substantial proportion of patients demonstrated resistance. This therapeutic challenge is widely recognized in childhood enuresis management, prompting numerous investigations into alternative pharmacological approaches, including the utilization of reboxetine [13] and combination therapy with high-dose oxybutynin and desmopressin [14]. Consequently, the identification of underlying factors and potential contributors to therapeutic resistance remains crucial [15].

Desmopressin, a well-established therapeutic agent in enuresis management, has demonstrated notable efficacy. This medicine is productive in attenuating bedwetting episodes compared to placebo, with most children experiencing fewer wet nights [16, 17]. Furthermore, research suggests that desmopressin, particularly in melt form, can improve sleep patterns and psychological functioning in children with nocturnal enuresis. This result is quite contrast to a Neveus et al. findings. They found that this administration cannot play major role on deep sleep [18]. In another side of the moon, some studies do not recommend the nasal spray formulation of desmopressin for nocturnal enuresis due to risks of hyponatremia and seizures, especially in children [19, 20]. However, a study in 2022 discovered that the risk of hyponatremia can be minimized by using specific dosage of desmopressin intranasal spray [21]. Some of the studies considered alarm therapy as an effective long-term treatment instead of desmopressin [22,23,24].

We discovered that a large volume of urine in each bedwetting episode is one of the most prevalent influential factors in both groups. Jørgensen et al. revealed that decreasing maximum voided volume can potentially lead to approximately a 50% improvement in response to desmopressin treatment [25]. Although the rate of treatment enhancement is remarkable, but the issue remains with a notable incidence rate. In this regard, according to an updated document from the International Children’s Continence Society, if the desmopressin treatment does not provide relief, especially in monosymptomatic enuresis, anticholinergic therapy and antidepressant treatment can be considered as the second- and later-line treatment options, respectively [26].

In our study, 41% of cases demonstrated treatment resistance after less than 3 months of desmopressin nasal spray treatment. Falak-ul-Aflaki et al. reported treatment success rates aligned with our findings, documenting complete improvement in 44.4% of subjects and partial improvement in 38.1% [27]. However, contrasting results were observed in Landmark’s comparative analysis of pharmacological and non-pharmacological interventions, where less than half of the patients receiving pharmacologic therapy showed improvement [7]. This discrepancy may be attributed to variations in patient characteristics, dosage regimens, and treatment duration.

Our analysis revealed that 85.9% of treatment-resistant patients exhibited deep sleep patterns, as reported by parents. It is important to note that the study relied on parental reporting for the assessment of deep sleep, which limits the accuracy of this finding. Objective measures, such as validated sleep scores or sleep studies, were not employed due to resource constraints. This limitation should be addressed in future studies to provide a more accurate understanding of the role of sleep patterns in nocturnal enuresis.

Notably, factors more prevalent among treatment responders included daytime urinary control, urinary frequency regulation, and participation in alarm training. This observation aligns with Özgür et al.‘s findings regarding the potential efficacy of alarm intervention in enuresis management [28].

In a similar study performed in Sweden, age was discovered as a strong predictor of non-response. Also, they found daytime incontinence unrelated to the outcomes and enuresis alarm therapy success [29]. Similarly in our study, the ability to control urination during the day did not influence in nocturnal enuresis in both groups.

We also found urinary frequency at night, including one or more than one episode of bedwetting per night, and abnormal residual volume as potential risk factors for enuresis, which are similar to the results of a study performed by Li et al. [30]. Similarly, intestinal disorders was found to be non-statistical significant in influencing enuresis. However, they did not investigate other factors affecting enuresis on our study. Besides, we discovered that the treatment-resistant enuresis group had more cases with abnormal post-void residual volume compared to the controlled enuresis group, which is quite different to findings of Hagstroem et al. which individuals with abnormal post-void residual volume were equal between two groups [31].

Besides, while our findings showed no significant difference in bowel movement disorders between groups, other studies have demonstrated a substantial relationship between constipation and nocturnal enuresis, with constipation management yielding significant enuresis improvement [32].

Limitations

This study has a limitation that should be considered when interpreting the findings. The relatively brief treatment duration and the cross-sectional design of this study restrict the ability to assess the prolonged efficacy of treatment strategies and the progression of treatment-resistant cases. Longitudinal studies with extended follow-up periods are essential to evaluate sustained treatment responses and identify additional factors contributing to resistance.

Despite this limitation, the study provides valuable insights into factors differentiating treatment-resistant from treatment-responsive nocturnal enuresis and highlights critical areas for future investigation.

Conclusion

This study provides critical insights into the factors differentiating treatment-resistant from treatment-responsive nocturnal enuresis in children. The findings revealed that the prevalence of controlled nocturnal enuresis was higher than treatment-resistant cases. Factors such as deep sleep, daytime urinary control, and fluid management were more prevalent in children with controlled enuresis. In contrast, treatment-resistant cases were characterized by poor medication adherence, high urine volume per episode, and frequent enuresis.

Furthermore, large volume of urine in each bedwetting episode, child’s cooperation in proper medication use and deep sleep had the highest prevalence in both groups. Also, abnormal residual urine volume, one and more than one episode of bedwetting per night were found to be statistically significant in affecting the nocturnal enuresis.

These findings underscore the importance of individualized management strategies that address specific clinical and behavioral factors in treatment-resistant cases, potentially improving therapeutic outcomes. Longitudinal research is needed to assess long-term treatment efficacy and explore new therapeutic approaches, with a focus on improving outcomes for children with nocturnal enuresis.