REVIEW The Prevalence of Nocturnal Enuresis among Iranian Children: A Systematic Review and Meta-Analysis Masoud Mohammadi*, Aliakbar Vaisi-Raygani, Rostam Jalali, Akram Ghobadi, Nader Salari Purpose: Nocturnal enuresis is one of the most common diseases in children, which can affect their mental health. The aim of the present study is to determine the prevalence of nocturnal enuresis in Iranian children through sys- tematic review and meta-analysis. Materials and Methods: The present study was conducted through systematic review and meta-analysis of studies during March 2000- July 2018. Articled related to the subject were reviewed by searching the Medline (PubMed), Scopus, ScienceDirect, SID, Magiran, Barakat, and Google Scholar databases where the heterogeneity of studies was investigated using I2 index. The data analysis was then carried out using Comprehensive Meta-Analysis soft- ware. Results: 15 articles with a sample size of 16614 individuals aged 3 to 18 years entered the meta-analysis process. The overall prevalence of nocturnal enuresis in children of Iran was 10.2% (95% CI: 7-14.8%). The highest and lowest prevalence of nocturnal enuresis was seen in children living in Tehran 28.5% (95% CI: 16.1% -45.4) and Tabriz 1.8% (95% CI: 1.2-2.8%), respectively. The findings of the present study revealed that the prevalence of nocturnal enuresis in children decreases with enlargement of the sample size. In addition, the prevalence of noctur- nal enuresis grows with an increase in the years of research, which is statistically significant (P < 0.05). Conclusion: Considering the high prevalence of nocturnal enuresis in the current study, health policy makers need to raise the awareness of families by taking efficient and effective policies. Keywords: nocturnal enuresis; prevalence; children; Iran; meta-analysis INTRODUCTION Children are the architects of the society’s future, so their physical and mental health status is important and their disorders and diseases should be taken care of se- riously(1). Children who are neglected physically and psychologically today and have no access to adequate health and education will be individuals with physical and mental disabilities in the future(2). Nocturnal enu- resis is one of the most commonly reported diseases in children following allergic diseases. This disorder is known as involuntary passage of urine during sleep (3), as well as frequent and unintentional passage of urine in the clothes or bed in children who should have gained control over their bladder considering their age. It is also known in case of absence of certain physical abnormalities(4). The majority of children gain regu- lar daytime urine control by age of 3 to 4, so 5 years old is considered as the best age for the diagnosis and screening of the nocturnal enuresis(5). Nocturnal enure- sis diagnosis is proved when involuntary urination oc- curs in clothes or bed at least twice a week for three consecutive months, or the bedwetting manifests itself as a clinically important concern in the child's life(6). Nocturnal enuresis occurs among 3-15% of 6-year-old children at least one night in a month, and reaches 4 to 16% in 12-year-old children(7). Mental health problems Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Ker- manshah, Iran. *Correspondence: Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran. Tel: +989189057962. E-mail: masoud.mohammadi1989@yahoo.com. Received February 2019 & Accepted August 2019 in children with nocturnal enuresis are 2 to 6 times more prevalent than those of the total population of the world (8). Nocturnal enuresis can cause severe mental stress for families and discomfort for children and adolescents. Parents often feel anxious and angry and may blame, punish, and humiliate children due to lack of awareness of this disorder. They may also create serious mental in- juries for children(8,9). Diagnostic and therapeutic meas- ures, as well as awareness raising plans in families, require access to comprehensive information and statis- tics on the prevalence of nocturnal enuresis in children. Studies in Iran have reported different rates of nocturnal enuresis. In a study in Sanandaj in 2001, the prevalence of nocturnal enuresis was 8.8% (10), 14.3% in Ahwaz in 2013(11), and 11.9% in Birjand in 2005(12), indicating the inconsistency and uncertainty of the nocturnal enuresis among Iranian children. There are still unclear statistics at the national level. The aim of the present study is to determine the overall prevalence of nocturnal enuresis in Iranian children by systematic review and meta-analysis. The results of this study can be useful in conducting interventional studies as well as making health policies. MATERIALS AND METHODS This study was a systematic review and meta-analysis Urology Journal/Vol 16 No. 5/ September-October 2019/ pp. 427-432. [DOI: 10.22037/uj.v0i0.5194] and has been the result of findings extracted from the previous studies on the prevalence of nocturnal enure- sis in Iranian children. It includes articles published in domestic and foreign journals, and searches carried out in SID, Magiran, Barakat Knowledge Network system, Medline (PubMed), ScienceDirect, Scopus, and Google Scholar during March 2000 to July 2018. Search strategy The search process was carried out in the above web- sites using the keywords of ‘nocturnal enuresis’, ‘chil- dren’, and their equivalent English words and possible combinations. With regard to the Persian databases, the search was carried out using Farsi keywords of (noctur- nal enuresis), (children) while their equivalent English keywords were used in the English key words of noctur- nal enuresis, children. In addition, both Farsi and Eng- lish words were searched in the Google scholar search engine and the (AND) and (OR) operators were com- bined in order to provide more comprehensive access to all articles. Specifically, OR operators were applied to check the common names for a disorder (Children OR Preschool), (Nocturnal enuresis OR Nighttime Urinary Incontinence). AND word was used in the keywords by matching words in the MeSH browser. Criteria for selecting and evaluating articles First, all articles were collected using selected key- words and a list of abstracts was then prepared after the search process. After hiding the articles’ specifi- cations, including the magazine name and the author's name, the full text of the articles was provided to the reviewers. Each article was read by two reviewers (MM and AVR) independently. If the article was re- jected, the reason should have been mentioned. In case of any disagreement between the two reviewers (MM and AVR), the article was judged by a third reviewer (RJ). The inclusion criteria were Persian and English articles taken from cross-sectional studies on the prev- alence of nocturnal enuresis in Iranian children in age group of 4-15 years. In order to evaluate the articles ob- tained in this study, the PRISMA checklist was used. Other studies, including review, case-control, cohort, and interventional studies were excluded from the list of articles. In this study, searching keywords in Google and reviewing related websites were done to examine gray literature, which is the general name for non-for- mally published scholarly or substantive information. Duplicate publication and multiple publications from the same population would be removed using citation management, software EndNote (version X7, for Win- dows, Thomson Reuters). Quality assessment For quality assessment of cross-sectional studies, the STROBE checklist was used. This checklist contains 22 sections, 18 of which are general and practical for all observational studies, including cohort, case study, and cross-sectional studies. On the other hand, four sections are specific, depending on the type of study as well as various aspects of the methodology including objec- tives of the study, determining the appropriate sample size, type of study (cross sectional, case-control and co- hort), sampling method, research population, data col- lection method, variables definition and sample study method, data collection tools, objectives of the study, statistical test, and study results. Accordingly, the max- imum quality score of 32 was considered, while papers with a score of less than 14 were considered to have low quality, and thus excluded from the study. Statistical analysis In each study, the prevalence of nocturnal enuresis in children was obtained. The heterogeneity of studies was also assessed using the I2 index. Overall, the hetero- Table 1. Specifications of studies included in the study Row Author (Reference) Publication year Area Participants' Age Sample size Prevalence 1 Ghotbi (11) 2001 Sanandaj 9.3±9 681 8.8 2 Zargar (12) 2013 Ahwaz 5-6 807 14.3 3 Khazaei (13) 2005 Birjand 5.5-6.5 455 11.9 4 Haghbin (14) 2003 Yasuj and Gachsaran 7 2846 3.6 5 Mohammadpour (15) 2012 Gonabad 8.6±1.05 250 6.8 6 Emamghoraishi (16) 2004 Jahrom 6-11 1000 16.5 7 Hakim (17) 2015 Ahwaz 8.6±1.8 200 32 8 Naderian (18) 2000 Tehran 4-12 35 28.5 9 Shafipour (19) 2014 Rasht 7-11 768 7.2 10 Ranjbar (20) 2003 Tabriz 5-16 1092 1.8 11 Hashem (21) 2013 Urmia 7-11 918 18.7 12 Safarinejad (22) 2013 Tehran 5-18 7562 6.8 Figure 1. The flowchart for the stages of including the studies in the systematic review and meta-analysis (PRISMA 2009) Prevalence of Nocturnal Enuresis in Iranian Children-Mohammadi et al. Review 428 Vol 16 No 04 September-October 2019 429 geneity was classified into three categories including I2 value of < 25% (low heterogeneity), 25-75 % (mod- erate heterogeneity), and >75% (high heterogeneity) (10). The data were analyzed using the Comprehensive Meta-analysis (Biostat, Englewood, NJ, USA version 3). The probability of publication bias in results was measured using the funnel plot, the Egger test, and the significance level of 0.05 along with Begg and Mazum- dar's rank correlation and the significance level of 0.1. In addition, the meta-regression test was used in two factors of the sample size and research year to inves- tigate the effects of the potential factors affecting the heterogeneity of the studies. RESULTS Search output According to the review made on the prevalence of nocturnal enuresis among Iranian children and includ- ed articles published in domestic and foreign journals, along with the searches made, 383 articles were ob- tained from the first search, which was ultimately eval- uated based on PRISMA 2009 (Figure 1). Finally, in the final review, relevant articles were introduced into the meta-analysis, in which 12 relevant articles were in- cluded, as reported in Table 1. This table presents the researcher’s name, the article title, the year, and place of the study, sample size, the frequency, and prevalence of nocturnal enuresis in children in the studies(11-22). Heterogeneity and publication bias The heterogeneity of the studies was evaluated using the I2 test, was 97%, showing a high heterogeneity in the studies. Therefore, the random effects model was used to combine the results of the studies. The publi- cation bias of the results was analyzed by a funnel plot and Egger test (Figure 2) at the significance level of 0.05. It indicated that the publication bias was not sta- tistically significant (P = 0.573). Also, considering the high sample size examined in the study, the publication bias was also investigated based on the Begg and Ma- zumdar's rank correlation test at the significance lev- el of 0.1, which was not statistically significant (P = 0.921). The total sample size of the study was 16614 partici- pants aged 3 to 18 years. The overall prevalence of noc- turnal enuresis in Iranian children based on meta-anal- ysis was 10.2% (95% CI: 7-14.8%). The maximum and minimum prevalence of nocturnal enuresis was seen in children living in Tehran 28.5% (95% CI: 16.1% -45.4) (18) and Tabriz 1.8% (95% CI: 1.2-2.8%),(20) respectively (Figure 3). In this figure, the prevalence of nocturnal enuresis in children is shown based on the random ef- fects model, where the black square indicates the prev- alence rate and the length of the line segment, on which the square shows 95% CI of each study. The diamond sign reveals the prevalence rate of nocturnal enuresis in all studies at the national level. Sensitivity analysis A sensitivity analysis was performed to ensure the sta- bility of results, where after removing each study, the results did not change (Figure 4). Meta-regression In order to investigate the effects of factors potentially affecting heterogeneity in the prevalence of nocturnal enuresis in children, a meta-regression was used for two factors of sample size and year of study (Table 2). Based on Figure 2, the prevalence of nocturnal enure- Table 2. Effect of effective factors on heterogeneity (Meta-regression) Point estimate Standard Error Lower limit Upper limit P value Sample Size slope -0.0001 0.00001 -0.0001 -0.00009 0.000 intercept -1.87 0.04 -1.93 -1.76 0.000 Years slope 0.08 0.007 0.06 0.09 0.000 intercept -163.4 14.4 -191.73 -135.11 0.000 Figure 2. Funnel plot for results of prevalence of nocturnal enure- sis in Iranian children Figure 3. Overall prevalence of nocturnal enuresis in children based on random effects model Prevalence of Nocturnal Enuresis in Iranian Children-Mohammadi et al. sis diminishes in children with increasing sample size, which is statically significant (P < 0.05). It was also found that the prevalence of nocturnal enuresis rose in children with an increase in the number of years, which was statistically significant (P < 0.05) (Table 2). DISCUSSION Nocturnal enuresis is one of the most common prob- lems in children, which needs to be treated through counseling and effective measures(23) due to its mental and psychological impacts on the child and the subse- quent problems for the family. Previous studies have stated that nocturnal enuresis is a multifactorial disorder and cases such as impaired cerebral cortex maturation, rapid eye movement sleep behavior disorder (RBD), disturbed circadian rhythm of ADH secretion, genetic disorders, psychiatric disorders, and kidney problems can contribute to its development(24,25). Many reports have concluded that since the disease prevalence de- creases automatically by 14% with increasing age of the child, the delayed development of the nervous system is one of its major etiologies. Other factors such as the socioeconomic status of the family, previous history of urinary tract infection, family history, parental educa- tion, and mental status can also contribute to the preva- lence of nocturnal enuresis(26,27). Ismail et al.(28) reported, in their study in Egypt, that there are other risk factors for this disorder such as positive family history, deep sleep, low socioeconomic levels, and child punishment. Nocturnal enuresis can also follow a family pattern and can usually affect several members in one family(26). Studies have suggested that the nocturnal enuresis in homozygous twins is more common than in heterozy- gous twins. In the current study and a survey on 16614 children aged 3-18 years, the overall prevalence of noc- turnal enuresis in Iranian children was reported to be 10.2% based on a meta-analysis. Studies in the Middle East and Asian countries have reported different prev- alence rates as follows: Turkey, 16.2% (29), Saudi Ara- bia 15% (30), Taiwan 10% (31), Korea 9.2% (32), India 11.1% (33), China 4.3%(34), Australia 18.9%(35). The same studies in European and African countries reported the following prevalence rates: Italy 3% (36), Burkina Faso (13%)(37), Egypt 10.1% (28), and Nigeria 23.2% (38). Dif- ferences can be attributed to cultural and geographical differences in studies. In most studies, the prevalence of nocturnal enuresis has been greater in boys than in girls(39). For example, the results of a study in Spain showed a boy-girl ratio 5:1(40). The results of a study in Saudi Arabia(30) also revealed a higher prevalence of nocturnal enuresis in boys; researchers justified it by stating that girls usually reach every step of bladder control faster than boys do, which is due to the early de- velopment of bladder control in girls(41). Further studies reported the same prevalence rates for nocturnal enure- sis in both genders(42). However, another study, which reported higher prevalence rates for nocturnal enuresis in girls, attributed such results to the higher risk of uri- nary tract infections (UTIs) in this gender (43). Nocturnal enuresis can be considered as a problem with associated individual, family, social, and emotional dimensions. Considering that this disorder is one of the children's behavioral disorders and various factors are involved in it, the following measures should be considered: increasing family’s level of awareness through coun- seling, adopting health measures as well as appropriate policies to assess the mental health of children, evaluat- ing physical and mental abilities in measurement bases before entering school for early diagnosis and treat- ment, providing guidance to parents and mental health services in schools and establishing psychological counseling centers, and familiarizing parents with the mental health issues of children in order to adequate- ly identify and deal with children's mental disorders(13). The ultimate goal is to prevent social-functional conse- quences in children and enhance their self-confidence and promote their physical and mental health status by treating their disorder. The most important limitation of the present study was the lack of access to the full texts article of some of the old articles and the omission of some of these articles due to their low quality in evaluating the quality of the articles reviewed. CONCLUSIONS Considering the high prevalence of nocturnal enuresis in the current study, it is imperative that health-policy makers take effective and effective measures to raise family awareness, and ensure early diagnosis and treat- ment. ACKNOWLEDGEMENTS The authors thank the faculty members of the Faculty of Nursing and Midwifery, Kermanshah University of Medical Sciences. CONFLICT OF INTEREST There are no conflicts of interest to be disclosed. REFERENCES 1. Branca F, Piwoz E, Schultink W, Sullivan LM. Nutrition and health in women, children, and adolescent girls. BMJ. 2015; 351:h4173. 2. Liu H, Fang H, Zhao Z. Urban-rural disparities of child health and nutritional status in China from 1989 to 2006. Econ Hum Biol. 2013; 11:294-309. 3. 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