This study represents the first investigation specifically targeting the impact of constipation on treatment outcomes in NMNE patients. Among NMNE patients, those with constipation had a higher proportion of daytime LUTS such as daytime incontinence, holding maneuver and urgency. Analysis of voiding diaries showed no significant effect of constipation on voiding frequency and maximum voided volume. Although the group without constipation showed a relatively higher maximal flow rate, there was no significant difference observed in the PVR or uroflow pattern between the two groups. Regarding treatment response, there was no notable discrepancy in the time required to achieve partial or complete response between patients with and without constipation. The use of laxatives in the constipated group did not significantly improve enuresis treatment.

Currently, research on the relationship between constipation and enuresis is scarce, often involving both MNE and NMNE cases [13, 16]. In contrast to previous studies, this research exclusively enrolled patients with NMNE, providing greater certainty regarding whether constipation affects the treatment outcomes in this group. Furthermore, we considered the time required to achieve the response, rather than solely focusing on the results at a single time point. This information not only helps inform patients and their families during consultations about the expected duration for achieving treatment effectiveness but also offers a more comprehensive evaluation of the treatment’s efficacy in enuresis.

This study employs combination therapy in the treatment of enuresis for cases where single treatment responses are inadequate. In contrast, past research on constipation and enuresis used only desmopressin as the primary treatment [16]. Combination therapy has been shown to yield superior treatment outcomes compared to single therapy [18]. Relying solely on a single medication may not align with real-world practices, making it challenging to ascertain whether constipation genuinely affects enuresis treatment. Therefore, the results of this study enable us to understand whether constipation affects the effectiveness of using multiple drugs to treat NMNE in real-world scenarios.

Consistent with previous research findings [7], we observed an association between constipation and LUTS. In the general pediatric population, children with constipation are more prone to have infrequent voiding and holding maneuver. In contrast, among the NMNE patients with constipation, daytime incontinence, urgency, and holding maneuver are more frequently observed. Although we found that treating constipation may not improve enuresis, it may still play a crucial role in the management of daytime incontinence. Borch et al. demonstrated that treating constipation could lead to over 50% improvement in daytime incontinence in 68% of children, while only 17% of children experienced over 50% improvement in enuresis [8]. Similarly, Loening-Baucke et al. found that treating constipation resulted in more significant improvement in daytime incontinence compared to enuresis [19]. Therefore, in children with NMNE, addressing constipation remains important.

Because rectal distention caused by constipation can induce DO, constipated children might have higher urinary frequency and smaller voided volume compared to those without constipation [6]. However, in this study, constipation did not lead to higher urinary frequency or smaller maximal voided volume in NMNE patients. Other studies have also shown no differences between constipated and non-constipated groups in terms of voiding frequency and bladder capacity [13, 20]. This study found that constipated children were more prone to the presence of holding maneuver. It is possible that holding maneuver counteract the effect of DO on urinary frequency and bladder capacity. Therefore, we did not observe significant difference of these parameters between constipated and non-constipated group.

Non-constipated NMNE patients had a higher maximum flow rate than those with constipation, but the incidence of abnormal flow rate was comparable between the constipation and non-constipation groups. A study on the results of healthy children’s uroflowmetry found that voided volume and maximum flow rate increase with age [21]. In our study, the non-constipation group was slightly older than the constipation group, potentially explaining the higher maximum flow rate in the non-constipation group. In healthy children, constipation leads to decreased voiding efficiency and increased PVR [22]. For children with nocturnal enuresis, higher PVR affects the chances of achieving a complete response [15]. However, among our NMNE cohort, constipation does not result in an increase in PVR, leading to similar timelines in achieving a complete response between the two groups.

In this study, NMNE patients with constipation had a worse baseline enuresis severity compared to those without constipation, which was consistent with previous findings [16]. However, other studies have indicated that constipation may not result in more severe enuresis. In a study that employed the Rome criteria to define constipation, the frequency and amount of enuresis in the constipated group were comparable to the non-constipated group [11]. Another study, which used rectal diameter greater than 3 cm as definition of constipation, found that constipation did not lead to more enuresis volume [20]. While constipation does not necessarily escalate enuresis severity, this study still identified that the constipated group more frequently required a combination of two or more medications for effective treatment. Furthermore, the longer follow-up duration in the constipation group suggests that they require a longer tapering-off period for medications. These suggest that constipation increases the difficulty of enuresis management.

We found that the constipation group have comparable time to attain complete response to that of the non-constipation group. This corresponds with earlier investigations, which found no correlation between constipation and the achievement of complete response [14, 15]. The median time to achieve complete response was approximately 6 months, which was consistent with the results of a study that employed a multi-drug combination approach for NMNE treatment [23]. Conversely, another study focused on NMNE treatment demonstrated that less than half of the patients achieved complete response at 12 months [14]. The differences may be due to the later initiation of drug treatment and combined regimen in that study. Therefore, a longer time may be required to reach a certain proportion of complete response. This underscores the importance of early initiation of drug therapy with a combination of medications for NMNE patients to overcome enuresis in a shorter time frame. Furthermore, since constipation itself or the use of laxatives has limited impact on enuresis improvement, treatment of enuresis should be initiated at the time of diagnosis rather than addressing constipation as an initial step.

This study still has several limitations. First, it is a retrospective study, which inherently comes with limitations such as data missing. Second, since constipation accounts for approximately 14–35% of the population with enuresis [13, 15, 16], out of 128 children with NMNE, only 23 had constipation, resulting in a significant imbalance in the number of cases between the two groups. Additionally, the smaller number of children with constipation may have limited our ability to statistically observe any differences in treatment response between those who received treatment for constipation and those who did not. Third, it is possible that children with constipation who did not receive laxative treatment may have managed to improve their constipation through non-pharmacological means, which could explain why the use of laxatives did not contribute to treatment response. However, we did not track the improvement of constipation in these children. Fourth, as bedwetting alarms are not covered by Taiwan’s health insurance, our analysis focused on children primarily treated with medication, and the use of bedwetting alarms could potentially yield different results. Lastly, the median follow-up duration in this study was 8.6 months (IQR: 3.5–15.6 months), and there was no longer-term follow-up after achieving complete response, making it difficult to determine the recurrence rate after complete response. Future studies with a prospective design and longer follow-up periods are needed to specifically investigate the relationship between treating constipation and the improvement of NE in children with NMNE. Additionally, since our findings suggest that children with constipation require more medications to achieve a treatment response, future research should explore whether effective treatment of constipation could reduce the number of medications needed to achieve a treatment response in children with NMNE.