I2: 22.3%), whereas combining 16 effect sizes from cross-sectional studies illustrated a greater reduction in HTN risk . These results varied by studies characteristics, such as the region of study, participants’ sex, study quality, and sample size. Conclusions: An inverse association was found between coffee consumption and hypertension risk in both cross-sectional and cohort studies. However, this association was dependent on studies characteristics. Further studies considering such factors are required to confirm the results of this study.Objectives: The association between coffee intake and hypertension (HTN) risk is controversial. Therefore, this systematic review and meta-analysis aimed at summarizing the current evidence on the association of coffee with hypertension risk in observational studies. Methods: PubMed/Medline and Web of Science were searched for observational studies up to February 2023. Observational studies which assessed the risk of HTN in the highest category of coffee consumption in comparison with the lowest intake were included in the current meta-analysis (registration number: CRD42022371494). The pooled effect of coffee on HTN was evaluated using a random-effects model. Results: Twenty-five studies i.e., thirteen cross-sectional studies and twelve cohorts were identified to be eligible. Combining 13 extracted effect sizes from cohort studies showed that higher coffee consumption was associated with 7% reduction in the risk of HTN (95% CI: 0.88, 0.97;  Hypertension is directly associated with the risk of cardiovascular diseases . The numCoffee is a beverage consumed daily by a large part of the world’s population . TherefoPrevious reviews have indicated that in healthy people, habitual coffee consumption is not associated with an increased risk of hypertension ,10,11,12At present, there is not enough scientific evidence to confirm that consumption of coffee can act in the management of hypertension , especiaSearch Strategy and Study Selection: This meta-analysis was designed, analyzed, and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic search of the available publications was performed using the MEDLINE and Web of Science from inception (1952) to February 2023. Without any restriction on publication date and language, a search strategy applying the key terms of “(coffee OR caffeine) AND (hypertension OR “blood pressure”)” was conducted. No restriction was placed on the article language and publication date. A manual search of recent reviews and relevant original articles was performed for additional relevant studies. The study protocol was registered on the International Prospective Register of Systematic Reviews, PROSPERO (registration number: CRD42022371494). Study selection: Two independent reviewers (FH and PH) screened titles and abstracts for eligible articles. Disagreements were resolved by discussion with C.d.O. and E.S. Then, based on the full text of identified articles, their eligibility for inclusion was assessed according to our inclusion and exclusion criteria. Studies were included if they met the following criteria: (1) original studies on adult population (aged 18 or older), (2) an observational design , (3) reporting the relative risk (RR) or hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI), and (4) assessment of hypertension or elevated blood pressure in subjects with the highest vs. the lowest intake of coffee, irrespective of coffee types and their caffeine content. Studies were excluded if they were not original research or were in vitro or animal model, conducted on adolescents or children, examined gestational or ambulatory or coffee post injection blood pressure or hypertension risk, reported blood pressure mean, assessed blood pressure control over the time, and examined HTN risk for coffee polyphenols. Disagreements were resolved through discussion until agreement was reached. Data extraction and quality assessment: Using a pre-designed extraction form, two independent reviewers (PH and AM) extracted the following information: the author’s first name, country, year, study design, mean age or age range of participants, sample size, follow-up duration for longitudinal studies, instruments used to assess coffee intakes, the method and cut-off point used to HTN diagnosis, main findings (effect and 95% CI), and adjusted confounders. If the results of studies were reported in various groups, the information of all groups was extracted.The quality of included studies in our meta-analysis was assessed using the New Castel Ottawa Scale (NOS) designed for observational studies. In general, this scale consisted of 3 main domains  and 8 questions in total for cohort studies. The minimum score for each domain is zero, while the maximum score varies between domains. The highest scores for participants’ selection, participants’ comparability, and assessment of outcome/exposure domains are 4, 2, and 3, respectively. The overall score ranges from zero to nine. In the adapted version for cross-sectional studies, consisting of 7 questions, the maximum score is 10. In the present study, the quality scores of ≥7 was considered methodologically high, and those with the score of 6 or fewer were considered low methodological quality ,18. I2 values. Heterogeneity was considered substantial when I2 values were greater than 50% [Hypertension risk was reported either as relative risk (RR) or odds ratio (OR). Due to the high prevalence of HTN (32% in women and 34% in men) . To combthan 50% . Heterogthan 50% , study qthan 50% , and folp values < 0.05 were regarded as significant.Publication bias was tested using visual inspection of a funnel plot, Egger’s test, and Begg’s tests ,25. Sensn = 128), 1911 articles were screened for their titles and abstracts, of which 84 articles remained for further evaluation based on their full texts. Finally, 25 articles, published between 2002 and 2023, met our inclusion criteria and were included in the present meta-analysis [The flowchart of study selection process is illustrated in analysis ,48,49,50analysis , or repoanalysis .n = 18) [n = 18) ,48,49,50n = 18) ,41,45,49n = 18) .I2: 22.3%) (p = 0.449) and Begg test (p = 0.714) revealed no evidence of publication bias  . All selion bias . I2 = 0.7%). However, it was not associated in Europe  and Asia . The results of subgroup analysis demonstrated an inverse association in the subgroups of studies with a follow-up duration of at least 10 years , sample size less than median  and cases more than median , and those which were low quality  or conducted in females only , while in the counterpart groups a null association was found. Subgroup analysis based on age showed similar results in both groups  (p for the Egger test = 0.198 and for the Begg test = 0.753). In cross-sectional studies, compared with the lowest amount of coffee consumption, the highest amount was associated with lower risk of HTN . Heterogeneity was considerably high between studies (: 63.2%) . FindingI2 = 0.0%), studies with smaller sample size , and those which defined HTN using the cut-off point of 130/85 mmHg   .The results of the present meta-analysis suggest, overall, a slight reduction in the risk of HTN following coffee consumption. This association was observed in both cohort and cross-sectional studies, and was much stronger in cross-sectional studies. However, this association was influenced by various factors in cohort and cross-sectional studies, such as geographical region, sex, sample size, and study quality.There are several meta-analyses evaluating the relationship between coffee and HTN risk ,51,52. IOverall, this meta-analysis suggested an inverse association between coffee consumption and HTN risk in both cross-sectional and cohort studies with a small heterogeneity in prospective studies. There is a large discrepancy between studies with regard to the association of coffee and HTN risk. While some studies suggested a favorable effect ,28,29,31Our subgroup analyses indicated that the association between coffee and HTN risk differs by countries. Similar to an earlier meta-analysis, we found an in inverse association only in the USA, but not in Europe and Asia in cohort studies. This difference might be explained, at least to some extent, by the amount of coffee consumed. The inverse association between coffee and HTN risk is a non-linear association, and a coffee consumption less than 3 cups/day could not decrease HTN risk . Based oThe characteristics of studies, such as study quality, number of cases, and HTN definition could have affected the association. The results indicated an inverse association between coffee consumption and HTN risk in studies with a larger case number and those which used stage 1 cut-off point for HTN definition. A smaller case number cannot provide enough power to find the expected effect size, which is in concordance with our results as the confidence interval for studies with smaller case number was wider than those with more cases . There was only one study which found a positive direct link between coffee consumption and HTN risk . This stThe main strengths of this meta-analysis are its large population from different countries and ethnicities with a wide age range, a comprehensive literature search to identify relevant articles, and subgroup analysis based on various confounders. Our findings were robust, and no evidence of publication bias was observed. In addition, most cohort studies were long enough to allow investigating incidence of hypertensive cases. We have also investigated a wide range of characteristics of studies which can influence the coffee-HTN association. The first and the main limitation of our study which should be considered for the future studies is the lack of adequate data for determining other plausible heterogeneity sources, such as sodium intake, smoking status, and the type of coffee and its preparing method. For instance, Grosso et al. showed that the association differs by the smoking status of participants. While in the whole population, they reported a null association with a wide confidence interval, in stratified analysis by smoking, they found an inverse association. They found that both non-smoker males and females who drank 3–4 cups coffee/d had lower risk of HTN development, whereas no significant association was found in smokers . FurtherIn conclusion, this meta-analysis showed an inverse association between coffee consumption and hypertension incidence, either cross-sectionally or prospectively. However, this association is dependent on the geographical region of the study, participants’ sex, the number of cases, and study quality. Future studies with an appropriate design which consider the effect of other confounders on HTN risk are warranted to confirm this result.


Herpes Zoster, commonly known as shingles, is a viral infection that affects a significant portion of the adult population; however, its potential role in the onset or progression of neurodegenerative disorders like dementia remains unclear.We searched the following databases: PubMed, Scopus, Cochrane library, and Web of Science. We included any randomized control trials and controlled observational studies as Cross-sectional, prospective, or retrospective cohort and case-control studies that investigated the prevalence of dementia in Herpes Zoster Virus (HZV)-infected patients and HZV-free control group or if the study investigated the prevalence of HZV in demented patients. Also, if the studies measured the levels of dementia biomarkers in patients with HZV compared with a healthy control group.P = .70). In the outcome of incidences of dementia and Alzheimer’s disease, the pooled analysis showed no statistically significant difference between the HZV group and the incidence of dementia ,  respectively. In the outcome of incidences of Herpes Zoster ophthalmicus (HZO), the generic inverse variance showed a statistically significant association between patients who have HZO and increased incidence of dementia .After the complete screening, 9 studies were included in the meta-analysis. In the outcome of the incidence of HZV, the pooled analysis showed no statistically significant difference between the dementia group and the No dementia group (RR = 1.04% CI = 0.86–1.25, Our study showed no significant association between HZV and the incidence of dementia or Alzheimer’s disease, but it shows a significant association between HZO and the incidence of dementia. More multicenter studies are needed to establish the actual association between the HZV and dementia. At the moment, 5% of those over 65 have dementia, and that percentage rises to about 50% for people over 90. Age is the largest risk factor for dementia because it occurs in more than 90% of cases after the age of 65. As the average population age increases, dementia incidence and prevalence are increasing globally. There are currently 46.8 million dementia sufferers globally, and by the year 2050, that number is expected to rise to 131.5 million, according to the World Alzheimer Report, a detailed meta-analysis of population-based studies. The most common dementia subtypes include Alzheimer’s disease (AD), vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion disorders. AD, by far the most common dementia etiology, accounts for up to 80% of dementia diagnoses. Mortality attributable to AD increased by 89% between 2000 and 2014.Dementias are the primary global cause of dependency and disability among older people, and they also contribute significantly to disease burden in established market economies, according to data from the World Health Organization. It was first postulated in the late twentieth century, following the revelation that chromosome 21 mutations involved defective amyloid precursor protein (APP) metabolism which resulted in hazardous Aβ peptide deposition. In AD, some of the broken protein fragments combine into amyloid, which then accumulates. These hazardous protein aggregates have been shown to alter synapse function, and brain development, limit long-term potentiation (LTP), induce neurodegeneration, and also cause gliosis.–11 Since Schenk et al’s study, numerous research targeting these beta-amyloid proteins have been done. In a recent clinical trial, van Dyck et al, showed that lecanemab reduced amyloid indicators in early AD and resulted in a moderately slower loss in cognition and function assessments than placebo after 18 months, however, it was related to adverse effects. Faced with data that calls the Amyloid hypothesis into question, researchers have reconsidered the role of amylin, also known as islet amyloid polypeptide, in the pathophysiology of AD. Human amylin was discovered in the pancreas, where it is released alongside insulin by pancreatic B cells. According to endocrinology studies, Amylin levels are higher than usual in the early stages of Type II diabetes mellitus. Furthermore, in the absence of a corresponding amount of stabilizing insulin, this protein is prone to misfolding and the formation of oligomers and fibrils.,16 Taking things a step further, research has revealed that type 2 diabetes mellitus is a substantial risk factor for the development of AD. Research has shown that these peptides cause the death of neurons via the induction of proapoptotic genes in a mechanistically similar way to Aβ plaques. These data suggest that amylin, like Aβ peptides, is cytotoxic to neurons and pathogenic, leading to AD.The past decade has experienced tremendous growth in the degree of investigation for AD biomarkers. The amyloid cascade hypothesis is the dominant theory that aims to explain the onset and pathogenesis of AD mechanistically. The virus’s reactivation may encourage neuroinflammation by causing the formation of misfolded oligomers, the buildup of amyloid plaques, and the development of neurofibrillary tangles made of hyper-phosphorylated tau protein.–22 VZV may also directly infect astrocytes to encourage intracellular amyloid formation and extracellular amyloid fibril aggregation. HZ occurs everywhere around the world with no seasonal fluctuations. The prevalence of HZ varies by age, from 1.2 to 3.4 per 1000 individuals per year in younger folks to 3.9 to 11.8 per 1000 individuals per year in patients over the age of 65.Varicella-zoster virus (VZV) is a neurotropic human herpes virus in the alpha herpesviridiae genus. It is a virus that causes both chickenpox/varicella and shingles/Herpes zoster (HZ). The virus is responsible for primary infection which results in varicella while HZ reflects the reactivation of latent infection.,26 Due to the possibility of visual loss, HZO is considered an ophthalmologic emergency. VZV is the only human virus that is capable of replication in cerebral arteries and causes vasculopathy. It primarily affects the elderly as well as those with impaired immune systems.,28 Additionally, via the trigeminal nerve, namely from the ophthalmic branch of trigeminal afferent fibers, the virus travels trans-axonally to cerebral arteries causing additional vascular inflammation and thrombosis that may subsequently damage brain cells.–31 In light of these findings, research by Bennett et al concluded that even in younger patients, those with HZO have a 1.3- to 4-fold higher risk of cerebrovascular events after the disease. Moreover, multiple studies revealed that having a stroke contributes to raising the possibility of dementia.–35 Thus, HZO may be regarded as a common risk factor in the development of dementia and VZV vasculopathy.VZV involvement of the trigeminal nerve’s ocular division (V1) is known as HZO. Ocular symptoms such as conjunctivitis, uveitis, episcleritis, keratitis, or retinitis affect 50% to 85% of HZO cases.–39 On the other hand, 2 studies have contradictorily reported no significant association between HZV infection and increased risk of dementia.,41 Thus, we conducted this meta-analysis to resolve the controversy and evaluate whether HZV infection increases the risk of dementia or not.Finally, on searching the literature we found that several studies reported a possible association between HZV infection and an increased risk of developing dementia.This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.A literature search of the following databases  on the 11th of September 2022, using key terms such as (Herpes zoster OR shingles OR Chickenpox) AND (Dementia OR Alzheimer OR mild cognitive impairment) was performed to identify relevant studies.We screened studies by titles and abstracts according to the following criteria: Any randomized control trials and controlled observational studies as Cross-sectional, prospective, or retrospective cohort and case-control studies that investigated the prevalence of dementia in HZV-infected patients and HZV-free control group or if the study investigated the prevalence of HZV in demented patients. Also, if the studies measured the levels of dementia biomarkers in patients with HZV compared with a healthy control group. No age restriction was implicated.Non-controlled studies, case reports, case series, editorials, animal studies, and brain specimen-based studies of dead patients.Two independent reviewers screened the titles and abstracts of the studies according to our criteria. If an agreement is not achieved, a third opinion was obtained from the first author to resolve the conflict.Some authors were assigned the studies to perform data extraction, where each study was extracted by 2 reviewers independently.The following baseline data were extracted from the included studies: the first author of the study, year of publication, study design, arms of the study, number of participants, age of participants, sex of participants, medical condition, and other baseline medications. And the following outcomes were extracted:Incidences of dementia, Incidences of Alzheimer’s disease (AD), Amylin, Aβ40, Aβ42, Amyloid, Incidence of Herpes Zoster Virus (HZV), and Herpes Zoster ophthalmicus (HZO).The quality was assessed using Newcastle-Ottawa Scale, for evaluating the quality of observational studies. Each study was ranked as good, fair, or poor quality according to its score.P value was less than .05.Data were analyzed using RevMan software, version 5.4. Continuous data were presented as mean difference (MD) with a 95% confidence interval (CI). Dichotomous data were presented as risk ratio (RR) with a 95% CI. If no heterogeneity was observed, results were presented in a fixed effect model and a random effect model was used if significant heterogeneity was observed. Sensitivity analysis (leave-one-out test) will be used to resolve the heterogeneity if detected. Results were considered significant if the After searching the literature, 359 studies resulted, and then became 323 were eligible for the title and abstract screening after duplicate removal. Of the 323, 278 were irrelevant as they didn’t meet the inclusion criteria of our study and finally 46 studies were eligible for full-text screening. Finally, 9 studies were included in the meta-analysis after the full-text screening, as shown in the PRISMA in Fig. .We have compared HZV and no HZV according to the outcomes: incidence of dementia, the incidence of AD, Amylin levels, Aβ40 levels, Aβ42 levels, and Amyloid levels in 3, 2, 2, 3, 3, 2 studies respectively. The incidence of HZV was compared between the dementia group and the no dementia group in 2 studies. The incidence of dementia in patients who have herpes zoster ophthalmicus (HZO) was pooled in 3 studies by generic inverse variance analysis.The overall quality was good in most of the included studies, as shown in Table The total number of patients included in the study is 3090813 patients, 852,837 patients in the HZV group, 1,952,615 in the no HZV control group, also 13816 patients in the dementia group, and 271,545 in no dementia group, other baseline data are shown in Table P = .89). We observed a significant heterogeneity among studies  that wasn’t solved by the leave-one-out test, Figure The pooled analysis showed no statistically significant difference between the HZV group and the incidence of dementia . We observed a significant heterogeneity among studies , Figure The pooled analysis showed no statistically significant difference between the HZV group and the No HZV group . We observed no significant heterogeneity among studies , Figure The pooled analysis showed a statistically significant association between the HZV group and an increased level of Amylin compared with the No HZV group . We observed a significant heterogeneity among studies  that was solved by leave-one-out test by removing Bubak 2020 , and the analysis showed a statistically significant association between the HZV group and decreased levels of Aβ40 compared with No HZV group , Figure The pooled analysis showed no statistically significant difference between the HZV group and the No HZV group . We observed no heterogeneity among studies. , Figure The pooled analysis showed no statistically significant difference between the HZV group and the No HZV group . We observed a significant heterogeneity among studies , Figure The pooled analysis showed no statistically significant difference between the HZV group and the No HZV group . We observed a significant heterogeneity among studies , Figure The pooled analysis showed no statistically significant difference between the dementia group and the No dementia group . We observed a significant heterogeneity among studies , Figure The generic inverse variance showed a statistically significant association between patients who have HZO and an increased incidence of dementia  was related to an elevated risk of a potential dementia diagnosis. Also on limiting exposure to HZO only, they found Comparable outcomes  for dementia. Furthermore, they identified a small apparent protective association between HZ  and dementia which was confined to frail individuals and females and was seen only for mixed or unspecified dementia. Thus, using antiviral drugs did not affect their outcomes. Their findings were backed by a study from the SAIL Databank in wales. In the same study, individuals with treated HZ from Denmark had a 10% lower dementia diagnosis risk, while there was no difference in dementia diagnoses in Germany among those diagnosed and treated for HZ. These findings, however, conflict with 3 studies that used insurance claims data from Taiwan and Korea and found an increase in the risk of dementia following HZ,,43 Nevertheless, only 2 studies,44 found a significant decline in dementia among HZ patients after receiving antiviral treatment. However, they were unable to account for lifestyle factors and did not examine the influence of frailty. Additionally, the dementia outcome in the conflicting studies has varied. Either by requiring multiple instances of a dementia code in outpatient data,44 or 30 days of medication. As a result, ascertainment bias may have occurred because dementia recording may have been more likely among those who sought care frequently. On the other hand, the sample size was unique to Warren et al. They included all patients with a record of HZ in a representative real-world UK population over 17 years, yielding a sample size at least twice as large as all prior research. In contrast to studies with conflicting findings, Warren-Gash et al managed to control for extra confounders. They carefully controlled for confounders and matched patients based on age, sex, practice, and calendar time; even though, they did not observe differences in the rates of dementia diagnoses between those exposed and unexposed to HZ. Finally, Warren-Gash et al also performed a variety of sensitivity assessments which in turn boosted the confidence in their estimations.Previous population-based studies reported both decreased and increased risks of dementia after HZ infection. However, our findings were in line with previous findings from other cohorts, such as Warren-Gash et al study. Data from the Korean National Health Insurance Service, which included information on over 1.14 million individuals, was used in this extensive nationwide cohort study in South Korea. By comparing 11,445 patients aged 60 or older with dementia to 45,780 matched controls without dementia, they discovered reduced odds of past HZ . In addition to basic characteristics like age, sex, income, and location of residence, the control group and the HZI group were matched for risk factors for dementia like hypertension, diabetes, and dyslipidemia. This careful matching offered reliable proof on the absence of a connection between dementia and HZI. Choi et al, have statistical power as they engaged large sample sizes. They employed a population-based data set made up of 1 million patients with a 12-year follow-up period to determine the relationship between HZI and dementia.Another study that reinforced our belief in our estimates is Choi et alTaking into consideration that this study had limitations owing to the use of International classification of disease codes from administrative claims data and the number of visits patients made for dementia and HZI, which may not have been an accurate representation of the patient’s experience with dementia or HZI cases. Additionally, because doctors tend to take care of patients with HZV more frequently, they are more likely to receive outpatient or inpatient care, which increases the likelihood that they may be diagnosed with dementia. This observation can be the result of ascertainment bias. included 2538 age-matched comparison participants and 846 patients with HZ ophthalmicus (HZO), with a mean age of 61.6 years. The comparison patients were chosen by matching them with a given patient with HZO in their consumption of medical services in the same index year. The patients were identified by first-time main diagnosis in clinics or hospitals. Within the 5 years following their index dates, the incidence rates of senile dementia were examined. This retrospective cohort study revealed that patients with HZO had a higher chance of developing dementia than patients without HZO, with 4.61% of patients with HZO receiving a dementia diagnosis over the 5-year follow-up period compared to 1.65% of patients without HZO . In several population-based cohorts, dementia risk has also been attributed to herpes zoster ophthalmicus infections rather than other herpes zoster infections.,40 It has been proposed that in cases of herpes zoster ophthalmicus infections, the virus is more likely to infiltrate the CNS compared to more peripherally located herpes zoster infections.Our meta-analysis reported a statistically significant association between patients who have HZO and an increased incidence of dementia. Thus, our study supports the idea that VZV reactivation rather than VZV primary infection is associated with dementia. Similarly, a study by Tsai et al–31,46,47 Prior research showed that patients with HZO were more likely to experience VZV vasculopathy and stroke than those with other variants of herpes zoster.–48 Consequently, vascular dementia may be primarily linked to the risk of dementia brought on by HZI. Studies have also observed elevations in dementia following a stroke, ranging from 3% to 19% during different follow-up durations (from 3 months to 10 years).–35 In addition, dementia and VZV reactivation may be influenced by aging, psychological stress, a lack of social support, and unfavorable life events.–54 Thus, Tsai et al, tried to investigate the association between cerebrovascular events and increased risk of dementia in the HZO group. A history of stroke was taken into consideration in this study as a covariation factor, however, there was no difference in dementia incidence between the HZI and control groups. To investigate the association between HZO and dementia during the study period, a population-based dataset with a sizable sample size was assumed in this investigation. A significant statistical advantage was provided by the large sample size in terms of identifying actual differences between the 2 cohorts. Additionally, licensed neurologists, infection experts, and dermatologists with extremely good validity in Taiwan performed the HZO and dementia diagnoses. However, several limitations must be taken into consideration when interpreting the study’s findings. The biggest drawback is the lack of information regarding a person’s history of smoking, body mass index, education, or alcohol use, which are risk factors and may affect dementia pathophysiology.Unfortunately, the previous research did not examine the relationship between neuroinflammation and dementia brought on by HZO. The high prevalence of dementia in HZO patients may be attributed to VZV vasculopathy, which may cause dementia by damaging cerebral neural cells as a result of cerebral artery inflammatory and thrombotic mechanisms. Yet, the overall difference in absolute risk was negligible (less than 1%). It was surprising, nevertheless, that the long-term risk of dementia, including Alzheimer’s disease, had slightly decreased. They believed that patients with early-onset dementia or milder degrees of cognitive impairment would overlook, disregard, or misdiagnose milder symptoms of HZ, resulting in misclassification and an apparent non-causal decreased risk of dementia in those with HZ. They think the vast majority of patients received antiviral medications in this setting considering that their cohort was mostly identified based on antiviral prescriptions written at HZ-specific dosages. Since 1 multicenter observational cohort study, and 2 other East Asian studies,44 particularly addressed the impact of antivirals for HZ, they discovered that any antiviral treatment was linked to a reduction in the relative risk of dementia of up to 45%. The recommended treatment may therefore serve to further minimize the risk of dementia. Moreover, Schmidt et al revealed that dementia risk was nearly doubled in the first year following cranial nerve HZ , with the ophthalmic nerve accounting for the majority of cases . These findings are consistent with ours and those of Tsai et al.In a population that was followed for up to 21 years, research by Schmidt et al found a minor relative risk of dementia in a HZ cohort (7%). neuroinflammation and direct cerebral injury may act as a potential mediators in the association between HZ affecting the CNS and dementia. Even though vasculopathy may be implicated, integrating stroke diagnosis into the mediation model failed to lower HRs. Thus, patients with HZ who were diagnosed with stroke after the index date had higher HRs than those who had neither HZ nor stroke at baseline  within the first year. Hence, stroke was not a contributing factor. Even yet, they were unable to rule out the chance of a microinfarction, which is unrelated to clinical stroke. Acute or subacute effects of HZ, misrepresentation of reversible cognitive change brought on by the acute illness, or diagnostic bias resulting from intensive clinical examination in the acute phase may all be responsible for the particularly strong connection in the first year. The latter could explain the short-term elevation in dementia risk among stroke patients who also had HZ diagnoses from hospitals, especially ophthalmic HZ.According to Schmidt et al,,56–58 Ruitenberg et al observed that the incidence of vascular dementia was higher for males than for women in all age ranges in a comprehensive population-based prospective cohort investigation. Contrarily, Schmidt et al, found the lowest HR in men .Some studies have discovered a correlation between gender and dementia, but since they merely focused on vascular dementia, their conclusions can indeed be relied on. These abnormal accumulations lead to the degeneration of synapses and neuronal brain cells (neurodegenerative dementia) and the impairment of cerebral blood flow (vascular dementia) as a result of atherosclerosis or vasculopathy. Amyloid formation is multifactorial and complex, involving interactions between environmental and host factors ; however, infectious agents have been proposed as triggers.,60,61 The systemic inflammation brought on by viral infection causes brain reactions through microglial activation, aggravates the buildup of Ab and tau protein, and accelerates the development of dementia. Except for amylin accumulation, our results reported no significant correlation between HZV and the levels of the different dementia biomarkers we focused on in our study. Research by Buback et al published in 2020 explained the connection between amyloid, VZV, and dementia after investigating the synthesis of amyloid as well as intracellular amyloidogenic proteins between mock- and VZV-infected quiescent primary human spinal astrocytes (qHA-sps), concluding that VZV-infected qHA-sps produced intracellular amyloid and that the extracellular environment of these cells encouraged the formation of amyloid fibrils from cellular peptides, which may have been boosted by VZV gB peptides indicating that cells previously infected with VZV will continue to develop amyloidogenic peptides and amyloid persisted even after receiving acyclovir therapy, imply that VZV infection may contribute to the development of amyloid-associated diseases by increasing the toxic amyloid burden in conjunction with host and other environmental variables. Additionally, Bubak et al published in 2021, reported that zoster plasma includes factor(s) that, taken together, enhanced amyloid fibrillization. The zoster group exhibited considerably higher plasma levels of amyloid than healthy non-zoster controls, although there were no significant differences in the levels of Aβ40, Aβ42, Aβ42/Aβ40 ratios, or amylin. However, additional statistical studies showed that the amylin or Aβ42 levels in the zoster group were positive predictors of total amyloid levels. This shows that zoster plasma may contain a substance or factors that may enhance the amyloid fibrillization of Aβ42 or amylin. The association between Aβ42 and amyloid is positive, as is the correlation between amylin and amyloid. Alternately, or additionally, the zoster plasma may be deficient in one or more inhibitory factors that inhibit Aβ40 or amylin from producing amyloid.Numerous studies have suggested that Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of AD pathology. discovered a significant difference in the distribution of shingles between dementia incident cases and controls. They were able to obtain more thorough data for both dementia outcome and shingles exposure thanks to these data sources. After adjusting for age and sex, their findings revealed that there was a slight but non-significant increase in the risk of dementia in people with shingles diagnosed 3 years or more before dementia diagnosis. This was despite the fact that VZV has been proposed as a direct cause of dementia or that shingles may cause peripheral inflammation that may result in brain inflammation and the potential reactivation of Herpes Simplex Virus 1 (HSV1) or that VZV, like Cytomegalovirus (CMV), causes immune dysregulation, as proposed for the role of CMV in AD, by Stowe et al and Westman et al.In light of the previous assumptions, Lophatananon et al study found that the group with VZV infection had a somewhat higher risk of dementia than the group with HSV infection . In this substantially matched cohort trial, particular antiviral therapy directed against herpesviruses was related to an 11% lower incidence of dementia. However, compared to controls, receiving a herpes diagnosis without antiviral treatment was linked to a 50% increased risk of dementia. These findings are consistent with other register-based studies from Taiwan and South Korea that suggested that antiviral regimens may have a protective effect on dementia as well.,44,66 To potentially lower the long-term risk of dementia, these findings may have possible clinical consequences, prompting doctors to be even more proactive in treating herpes reactivation symptoms with antiviral medications. Further classification of VZV infection into subtypes  may be instructive when interpreting the data. Unfortunately, this subtype classification was not provided in this investigation. However, the control group in this study comprised both seropositive and seronegative status as the seropositivity status of the subjects is unknown, especially because > 95% of the population is projected to be VZV-positive and > 70% of the population is expected to carry HSV1. Because the controls have not been given a herpes diagnosis or have not undergone specialized medical treatment for this, it is plausible to presume that they are more immune resilient to herpes infections and have fewer bouts of symptomatic reactivations. Importantly, herpes diagnoses primarily reflect original infections with overt symptoms or symptomatic reactivation. Thus, the individuals with herpes diagnoses constitute a subgroup of those carrying the pathogen.Furthermore, Lopatko Lindman et al Tsai et al, Lopatko Lindman et al, and Choi et al.The overall quality was good in most of the studies included in our analysis. A good number of studies were subjected to analysis as 9 studies were included. Along with a decent sample size, as 3,090,813 patients were included in our analysis. Moreover, we found that some studies adjusted for some confounding factors for example, Warren et al,Our study shows some limitations. For, example all the studies included were non-randomized observational and hence might be subjected to bias. Prospective multicenter studies are needed to further evaluate the relationship between HZV and dementia development.It is not unexpected that there is no correlation between HZ and an increased risk of dementia, despite epidemiological evidence and biological mechanisms linking HZ to acute cerebrovascular episodes. However, we reported an increase in the prevalence of dementia among HZO groups (reactivation of latent infection). Thus, patients suffering from primary infections should be continuously assessed to prevent the development of HZO and consequently dementia. To further investigate associations, more multicenter randomized Studies are needed to support our findings. Since the middle of the millennium, research has been conducted on how herpes virus infection affects cognitive decline. In order to further investigate associations, future research should combine data from multiple large, prospectively collected datasets from different populations. It is important to minimize biases by, for instance, including laboratory-confirmed infection definitions, repeated regular assessments of the outcome, and thorough confounder control. A deeper comprehension of the intricate relationships between infections, immune system control, and the risk of chronic diseases may make it easier to identify vulnerable people and plan future interventions.Our analysis of 9 studies with 3,090,813 patients revealed no statistically significant difference between the HZV group and no HZV group concerning the incidence of dementia, incidence of AD, and the increased level of Aβ40, Aβ42, and amyloid. However, we found a statistically significant association between HZV group and an increased level of Amylin compared with No HZV group. Also, no statistically significant difference was noticed when analyzing the incidence of HZV in the dementia group compared with no HZV group. On the other hand, our study found a statistically significant association between patients who have HZO and an increased incidence of dementia. Therefore, we concluded that HZO (reactivation of latent infection) increases the prevalence of dementia. To further investigate associations, more multicenter randomized Studies are needed to support our findings.Conceptualization: Rowan H. Elhalag, Karam R. Motawea, Marwan Abowafia.Data curation: Rowan H. Elhalag, Karam R. Motawea, Nesreen Elsayed Talat, Samah S. Rouzan, Sarraa M. Reyad, Soliman M. Elsayed, Pensée Chébl, Jaffer Shah.Formal analysis: Nesreen Elsayed Talat.Investigation: Rowan H. Elhalag, Karam R. Motawea.Methodology: Rowan H. Elhalag, Karam R. Motawea.Project administration: Rowan H. Elhalag, Karam R. Motawea.Supervision: Rowan H. Elhalag, Karam R. Motawea.Validation: Karam R. Motawea.Visualization: Karam R. Motawea, Soliman M. Elsayed, Jaffer Shah.Writing — original draft: Rowan H. Elhalag, Nesreen Elsayed Talat, Samah S. Rouzan, Sarraa M. Reyad, Pensée Chébl.Writing — review & editing: Rowan H. Elhalag, Karam R. Motawea, Marwan Abowafia.


The effect of micronutrients on urologic cancers has been explored in observational studies. We conducted the two-sample mendelian randomization (TSMR) study to investigate whether micronutrients could causally influence the risk of urologic cancers.Summary statistics for four micronutrients and three main urologic cancers outcomes were obtained from genome-wide association studies (GWAS). MR analyses were applied to explore the potential causal association between them. Sensitivity analyses using multiple methods were also conducted.P < 0.001, male; OR = 2.231, 95%CI = 1.524-3.953, P < 0.001, female; OR = 1.595, 95%CI = 1.310–1.758, P = 0.0238, male; OR = 1.484, 95%CI = 1.197–2.337, P = 0.0210, female, respectively) and per SD increase in serum zinc levels was related to decreased risks of RCC . No significant results were observed between micronutrients and the risk of bladder cancer after Bonferroni correction. Additionally, per SD increase in serum zinc level was associated with a 5.8% higher risk of prostate cancer (PCa) .Genetically predicted one SD increase in serum copper and iron concentrations was causally associated with increased risks of renal cell carcinoma (RCC) (OR = 3.021, 95%CI = 2.204–4.687, Micronutrients play a vital role in the development of urological tumors. Future studies are required to replicate the findings, explore the underlying mechanisms, and examine the preventive or therapeutic role of micronutrients in clinical settings. Urologic tumor refers to tumors that affect the organs and structures of the urinary system of both men and women and the reproductive system of men. Three most prevalent types of urologic tumors are: prostate cancer (PCa), renal cell carcinoma (RCC), and bladder cancer (BCa) . The incDietary trace metals, including zinc, copper, iron, and selenium, etc. have been shown to influence the risk of cancer through oxidative stress, DNA injury and repair, regulating cell cycle, and angiogenesis . Some obMendelian randomization (MR) that uses genetic variants as instrumental variables is widely used in epidemiological studies to examine whether a potential factor could casually influence an outcome. Different from traditional observational studies, this method could dramatically lower the effect of confounders and reverse causation . Two-samvia microelement levels. The diagram of the TSMR was shown in The MR analysis was designed to evaluate the associations between microelement levels and risks of urologic tumors . Single nucleotide polymorphisms (SNPs) for common microelements  were selected as instrumental variables from previously published genome-wide association study (GWAS) analyses. Three key assumptions need to be satisfied: (a) the SNPs should have strong associations with microelement levels; (b) the chosen SNPs should be independent of confounders;  the SNPsThe study utilized summarized genetic data from the Genetics of Iron Status (GIS) consortium , ProstatP < 10−5) and have genome-wide statistical significance (P < 5 × 10−8) were proposed as instrumental variables. Phenoscanner website was used to examine the pleiotropic effects of selected IVs and all used IVs were validated in previous studies , iron levels, and blood and toenail Se levels were based on a GWAS with 2,603 adults from Australia and the UK., a GWAS involving 48,972 individuals of European ancestry (GIS Consortium), and the UK Biobank study, respectively , 15, 16. studies , 18. AllRCC, BCa, and PCa were the outcomes. The latest GWAS involving the most complete available data on three types of cancers was selected. The sources were presented in https://shiny.cnsgenomics.com/mRnd/ was used for sample size test. This required four parts data: (a) Proportion of cases in the (intended) study; (b) Total sample size; (c) True odds ratio of the outcome variable per standard deviation of the exposure variable; (d) Proportion of variance in exposure variable explained by SNPs. Results indicated that with all the given sample size, analysis in each subgroup has strong statistical power (via leave-one-out approach and the remaining estimate effect was shown when one SNP was excluded (http://www.rproject.org) with the “TwoSampleMR” package (version 0.5.6). Associations were considered as strong between micronutrients levels and cancer risks if they surpassed a stringent Bonferroni-corrected P-value threshold of 1.67 × 10−3 (0.05/3 cancer outcomes). The reporting of the MR study followed the existed rule  approach was applied for the primary TSMR to quantify the causal associations between micronutrient  concentrations and the risk of three types of cancers . In the al power . All traexcluded . The levted rule .P < 0.001, male; OR = 2.231, 95%CI = 1.524–3.953, P < 0.001, female; OR = 1.595, 95%CI = 1.310–1.758, P = 0.0238, male; OR = 1.484, 95%CI = 1.197–2.337, P = 0.0210, female, respectively) and per SD increase in serum zinc levels was related to decreased risks of RCC . However, no causal effect was observed in serum selenium and serum and toenail selenium , zinc level , serum selenium , and blood and toenail selenium   , 3. Sens82, IVW) –8.P = 0.0403, IVW). No causal associations were observed between risks of PCa and serum copper level , iron level , serum selenium , and blood and toenail selenium   –6. Consi58, IVW) –14.In the current study, we investigated the causal effects of four micronutrients  on risks of 3 urological tumors. The findings indicated that genetically increased Zinc levels were related to increased risk of PCa, while reduced risk of RCC. Furthermore, increased Copper and iron level were associated with increased risk of RCC. In terms of BCa, no causal effects were observed.Prostate cancer is a common malignancy that affects millions of men globally . Prior oin vivo study that indicated that STEAP3 played a crucial role in the iron dysfunction in ccRCC  is an inherited disorder of copper metabolism, which is caused by homozygous or compound heterozygous mutations  in ATP7B . Copper ATP7B . Few stuATP7B , 39. HaeATP7B . The assOur findings have some clinical and research implications. Firstly, we firstly indicated the genetic associations between micronutrients and three main urologic tumors by using mendelian randomization. Some of the micronutrients we identified in this study can be used as cancer biomarkers for risk prediction. While the prerequisite to achieving this is the clear association between the serum micronutrient level and cancer risks (linear or U-shape or …). Based on this, we can further make a classification strategy, for example, using the median level as the cut-off. Given current evidence, there is still a long way to go. Secondly, appropriate therapy that could adjust micronutrient levels in the blood will contribute to the prevention of urologic tumors and, eventually, of the cancer-associated disease burden and mortality. However, it should be noted that no clear evidence (the number of RCTs is <20) about the micronutrient intervention and cancer risk or cancer progression can be found. While more research is needed to assess whether micronutrients may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of micronutrients. Thirdly, the bias caused by limited numbers of SNPs should be validated in experimental studies. Fourthly, the conflicting findings on the effect of Zinc on PCa and RCC should be examined in experimental studies. According to currently available literature, we supposed that different zinc-related protein expressions in the kidney and the prostate might play a role in the development of the two cancers. Moreover, the balance between the zinc influx protein family and zinc efflux transporters on different organs might make a difference .Our study has some strengths. Firstly, the study was the first MR study to investigate the casual association between micronutrient levels and the risk of urologic tumors. Effects of confounders in observational studies are avoided. Secondly, all the included individuals were of European-descent, which could minimize the potential bias from population stratification. Additionally, four common micronutrients and three main urologic tumors were analyzed, which is comprehensive and informative. Finally, limitations should be pointed out. Firstly, findings achieved from the MR study consisted of European-descent population limited the generativity to other races. Secondly, serum micronutrients might have associations with nutrition status, intelligence, income, and education level, etc . All theIn conclusion, we found that genetically increased Zinc levels were related to increased risk of PCa, while reduced risk of RCC. Furthermore, increased Copper and iron level were associated with increased risk of RCC, no causal effects were observed in BCa. The results indicate that micronutrients play a vital role in urological tumors. Future studies are therefore warranted to validate our findings and examine whether micronutrient concentration surveillance or supplements could be potential interventions for urologic cancer prevention and treatment.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YL, YW, and HL: conception and design. HL: administrative support. YL, HS, and YW: collection and assembly of data. YW and HS: data analysis and interpretation. All author manuscript writing and final approval of manuscript.


Previous studies have shown that ALDH2 and ADH1B genes may be associated with alcohol metabolism and the risk of esophageal squamous cell carcinoma (ESCC), with inconsistent results. This meta‐analysis aimed at comprehensively assessing the associations between ALDH2 and ADH1B polymorphisms and the risk of ESCC to synthesize and clarify the evidence.I2 statistic, and publication bias was assessed by using funnel plots and Begg's test. A Mendelian randomization (MR) analysis was performed to determine the causal association between alcohol intake and esophageal cancer risk. Data from the HaploReg v4.1 and PolyPhen‐2 were analyzed for functional annotations.We calculated summary estimates of the associations between four genetic variants  and the ESCC risk across 23 publications in the additive model and allelic model. Venice criteria, Bayesian false discovery probability (BFDP), and false‐positive reporting probability (FPRP) were used to assess the strength of epidemiological evidence. Heterogeneity among studies was evaluated by using the Higgin's Of the four genetic variants, rs671 of ALDH2 was associated with a significantly reduced risk of ESCC , whereas rs1229984 of ADH1B was associated with a significantly increased risk  in the additive model. In the allelic model, the variant rs1229984 of ADH1B also increased the risk of ESCC . The result for the variant rs671 was considered as strong epidemiological evidence. Functional annotations identified that the four variants were related to the enhancer histone marks and motif changes. The other two variants were not associated with the ESCC risk  in the additive model. The MR analysis did not find a causal effect of alcohol on the esophageal cancer risk.The results showed that ADH1B rs1229984 was significantly associated with an increased the risk of ESCC. Regions with low incidence of ESCC showed stronger association with alcohol consumption than those with high incidence.During the past two decades, studies have been carried out to explore the ALDH2 and ADH1B genetic variants and the risk of ESCC. A previous meta‐analysis that investigated the associations between ALDH2 and ADH1B polymorphisms and ESCC risk was published in 2010.2This systematic review and meta‐analysis was performed according to the PRISMA guidelines.2.1We searched the literature in PubMed and Embase using the terms “ AND (ALDH2)) OR  AND (ADH1B))”. All relevant articles published from database inception to August 2022 were included in the literature search. Included publications conformed to the following criteria: (1) The study design was a case–control study, or a genome‐wide association study (GWAS) conducted among human populations; (2) all ESCC cases were confirmed by pathological diagnosis; (3) the articles provided sufficient data on odds ratios (OR) and 95% confidence intervals (CIs) in additive or allelic model; and (4) it was published in peer‐reviewed journals in English. The exclusion criteria were as follows: (1) duplicate literature; (2) detailed information on gene variants and/or ORs was unavailable; and (3) the study did not assess the association between genetic variants and susceptibility to ESCC.2.2Data were extracted by two researchers (Zhang B. and Luo Y.) using a standard data extraction form. The extracted information included: the first author, publication year, study design, country where the study was conducted, population ethnicity, gene and variant, the number of samples in the case and control groups, the OR and corresponding 95% CI in an allelic model or additive model. All disagreements were discussed, and consensus was obtained.2.3I2 statistic was used to quantitatively assess the level of heterogeneity. An I2 statistic of 0% indicates no observed heterogeneity, whereas I2 statistics less than 25% suggest mild heterogeneity, between 25% and 50% indicating moderate heterogeneity, and greater than 50% demonstrating high heterogeneity.p‐value of Cochran's Q less than 0.1 indicates that the heterogeneity is statistically significant. If the I2 is less than 50%, a fixed‐effect model is applied. A random‐effect model was used, when the I2 is greater than 50%. Stratified analyses and meta‐regression were also performed to explore the potential sources of heterogeneity. Sensitivity analysis was used to assess the stability of results. Funnel plots, Begg's test, and Egger's test were deployed to analyze whether a publication bias was indicated.p < 0.05 indicated statistical significance unless otherwise stated.Stata 12.0 was used to analyze all the data. Meta‐analyses were conducted if at least three studies reported the association between the ALDH2 and ADH1B genetic variants and the ESCC risk in the additive model (AA vs. GG) and allelic model (A vs. G). The additive model is widely used as a conservative choice between the recessive and the dominant model, and most of the included studies in the meta‐analysis provided the data of OR and 95% CI in the additive and allelic models. The summary odds ratios (ORs) or 95% confidence intervals (95% CIs) were calculated. The OR was converted to log (OR). Because the covariates adjusted were different in various studies, we used the crude OR to perform the meta‐analysis. Higgin's 2.4I2 was less than 25%, B means the I2 value is between 25% and 50%, and C represents the I2 greater than 50%. Moreover, a significant association might be obtained due to incorrectly classified genotypes and/or publication bias. Therefore, if there was no observable bias that could affect the results, an A grade was given. The B grade suggests no apparent bias, but there was considerable missing information, and the C grade means there was significant bias that could affect the results. Ultimately, the epidemiological reliability for a significant genetic association was strong when all criterion grades were A and weak if any criterion grade was C. The other combinations indicated that the evidence was moderate.The Venice criteria, proposed by the Human Genome Epidemiology Network (HuGENet) Working Group, were used to assess the strength of epidemiological evidence.The false‐positive reporting probability (FPRP) was calculated to determine whether a significant association could be considered as a false‐positive result. The prior probability was set to 0.05 to detect an OR of 1.5.2.5p < 5 × 10−8); and (2) SNPs are independent of each other (linkage disequilibrium (LD) in the range of 10 Mb r2 < 0.05). In addition, we evaluated the presence of horizontal pleiotropy and heterogeneity using MR‐Egger intercept and Q test.Mendelian randomization analysis was performed by using the inverse variance weighted (IVW) to explore the causal relationship between alcohol (exposure) and esophageal cancer (outcome) through the TwoSampleMR package in R version 4.0.2. Because the IEU Open GWAS only had esophageal cancer data, we analyzed the casual association between alcohol and esophageal cancer risk. The genetic instrument was retrieved from the GWAS data of the UK Biobank study including 456,382 samples. The genetic instrument should meet the following criteria: (1) There was a significant correlation between SNPs and alcohol at genome‐wide significance  out of the eight genetic polymorphisms had been studied in at least three articles, the four genetic variants were evaluated for their associations with the ESCC risk. The meta‐analyses were performed for these four variants to calculate the summary estimates using results from the additive models . However, high heterogeneity was observed for the rs674 (I2 = 69.9), rs1229984 (I2 = 91.3), and rs1042026 (I2 = 96.4) variants  (Table p > 0.1)  Table . For bot1) Table  and S4. 1) Table . Funnel I2 = 91., and rs1) Figure .3.4Table 3.5Functional annotation was assessed by the Encyclopedia of DNA Elements tool HaploReg v4.1 (Table 3.6p > 0.05). No heterogeneity was observed.The results of the Mendelian randomization analysis showed that there was no causal effect between alcohol and esophageal cancer risk   in drinker population. And the result of the case–control subgroup in the genome‐wide discovery was consistent with result of our meta‐analysis.For alcohol metabolism, a previous study showed that oxidation is catalyzed to produce acetaldehyde primarily by ADHs, and then acetaldehyde is further metabolized to acetate by ALDHs.ADH1B, mapped to 4q23, is about 15 kb in length, and contains nine exons, and can catalyze the rate of ethanol metabolization into acetaldehyde. The rs1229984, a non‐synonymous SNP in exon 3 of ADH1B, encodes lysine‐504 and is prone to T‐to‐C mutations, resulting in an Arg‐to‐His mutation. The genotype of ADH1B rs1229984 carrying allele T encodes a more active protein that can quickly metabolize ethanol into acetaldehyde, while the mutant homozygous CC genotype has very weak activity in metabolizing ethanol. It indicated that mutant homozygous CC genotype could increase ESCC risk. Our study found that this variant was associated with an increased risk of ESCC with moderate evidence. In 2022, a prospective study with 11 years of follow‐up of 9339 Chinese adults also observed that the rs1229984 AA genotype was associated with a lower risk of alcohol‐related cancers than the GG genotype among men.Due to the limited number of studies for ADH1B rs1042026, we only explored the source of the high heterogeneity for ALDH2 rs674 and ADH1B rs1229984. The included studies on these polymorphisms did not provide the ORs and the corresponding 95% CIs in the age and sex subgroups; therefore, the subgroup analyses were stratified on publication year, the number of participants, and study country. However, the high heterogeneity did not reduce dramatically after stratification. We did find that the Japanese population with the ADH1B rs1229984 risk genotype had a greater ESCC risk than the Chinese. Considering the interaction between the genotype and smoking observed in our study, the higher ESCC risk found in the Japanese population could be due to the higher prevalence of smoking in Japan.This study has several limitations. First, most studies included were case–control studies, which are more susceptible to biases such as selection bias and information bias, particularly if the genotypes are associated with ESCC mortality. Secondly, some relevant articles had to be excluded due to missing data and no responses from the corresponding authors. Finally, because of the lack of raw data, we used crude ORs and 95% CIs, which will result in a slight deviation.In summary, after including results from the 11 additional studies published after 2010, this updated meta‐analysis confirmed the associations between the genetic variants of ALDH2 rs671 and ADH1B rs1229984 and the ESCC risk, of which the association between rs671 and the ESCC risk was considered as strong evidence. An interaction between the genetic variant rs1229984 and smoking was also observed. More experiments regarding fundamental research are needed to further elaborate roles of these genetic variants in the development of ESCC in the future work.Biao Zhang: Resources ; software ; visualization . Yu;Hui Peng: Funding acquisition . Yun Luo: Resources ; writing – original draft . Chao Qun Hong: Data curation . Yi Wei Lin: Software . Yuling Zhang: Visualization . Yi Wei Xu: Writing – review and editing . Xuefen Su: Methodology ; writing – review and editing . Fang Cai Wu: Writing – review and editing .This work was supported by the Natural Science Foundation of China [grant number 81972801]; the Guangdong Basic and Applied Basic Research Foundation Enterprise Joint Foundation , the Science and Technology Special Fund of Guangdong Province of China (STKJ202209069), the Guangdong Medical Science and Technology Research Program (A2023414), the Guangdong Esophageal Cancer Institute Science and Technology Program (M202224).All authors declare no conflict of interest.Appendix S1Click here for additional data file.


OR) and 95% confidence interval (95% CI). Meta-regression and subgroup analyses were used to explore potential sources of heterogeneity. Publication bias was detected using the funnel chart and Egger tests. Meta-analysis revealed that there was a significant correlation between C-section and children AR , especially C-section with a family history of allergy . Moreover, elective C-section  had the higher risk of offspring AR  compared with the whole study. Meta-regression demonstrated that sample size explained 38.0% of the variability between studies, and year of publication explained 18.8%. Delivery by C-section, particularly elective C-section and C-section with a family history of allergy can increase the risk of AR in children.Multiple evidence indicates that perinatal factors make impact on immune development and affect offspring allergic rhinitis (AR) risk. In this systematic review and meta-analysis, we examined available published studies to clarify the relationship between cesarean section (C-section) and offspring AR in children. To explore the relationship between C-section, especially the special attention was paid to different cesarean delivery mode, and the risk of AR in children. Articles were searched using PubMed, Web of Science, EMBASE, Cochrane Library, China knowledge Network, Wanfang, and China Science and Technology Journal databases. A meta-analysis of 22 studies published before August 1, 2022, which included 1,464,868 participants, was conducted for statistical analysis with RevMan5.4. The correlation strength between C-section and offspring AR was determined by combining odds ratio ( Studies have reported that the global prevalence of AR is rising2 with a prevalence of 10%–30% in the United States. However, relatively few studies reported the incidence of AR in children. The International Childhood Asthma and Allergy in Childhood (ISAAC)3 estimated the prevalence of allergic diseases in different age groups through a multi-centered global survey, and reported prevalence rates of 8.3% and 15.1% for those aged 6–7 and 13–14 years, respectively. A meta-analysis of all the recent studies conducted under the ISAAC protocol  reported4 an overall AR prevalence of 12.66%. Currently, many regional studies reported the prevalence of childhood AR in China, varying from 12.08 to 30.04% in every city5. It is important to note that AR is more than just sneezing and a nuisance for the children. AR may contribute to sleep loss, learning impairment, decreased overall cognitive functioning, aggravation of underlying asthma, and increased propensity to develop asthma7.Allergic rhinitis (AR)8. However, women's preference for C-section has increased due to concerns of the short- and long-term risks related to vaginal delivery (VD)9. Presently, the C-section rate worldwide continuously exceeds the WHO recommendation10. The national epidemiological survey of the C-section rate in China reported an annual increase in the domestic C-section rate, reaching 34.9%11. C-section can be a life-saving intervention when medically indicated, but this procedure can also lead to short-term and long-term health effects for women and children. C-section is not only associated with an increased risk of uterine rupture, abnormal placentation, ectopic pregnancy, stillbirth, and preterm birth in woman, but also associated with altered immune development in children, like allergy, atopy, and asthma, and reduced intestinal gut microbiome diversity in children12.According to the recommendation of the World Health Organization (WHO), the cesarean section (C-section) rate should be controlled at 10–15%13, which included only seven studies and revealed a positive correlation between C-section and offspring AR. After that, more and more studies still further focus on this topic and have assessed the association between mode of delivery and AR in the following years. Many studies have explored the relationship between C-section and the incidence of AR in children. Because a discrepancy in quantity and degree, the results are not consistent. Some previous studies showed that C-section is not associated with the risk of AR in children16, Others showed that C-section20, especially C-section with a family history of allergy23 could increase the risk of AR in children. More recently, studies linking the risk of AR to mode of delivery have examined the roles of emergency C-section after the onset of labour, versus elective prelabour C-section. Therefore, whether C-section increases the risk of offspring AR remains controversial24. Moreover, the previous meta-analysis13 included people of all ages including adults and children. However, the risk of AR in adults is often related to smoking, long-term exposure to adverse environments, occupational factors and so on26. Our study concentrated on the effects of birth-mode changes on AR in children, and more on early-life observed effects. In line with the ‘hygiene hypothesis’, the intestinal microflora may be modified in those children who are not exposed to the vaginal microbiota, but the effect decreases with the age of the offspring27. The mode of delivery is an important factor affecting the composition of intestinal flora in newborns and infants. Caesarean section may negatively affect the normal development of the microbiota, leading to decreased amounts of lactobacilli and bifidobacteria and increased amounts of Clostridia28. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at children29. To address this problem, we conducted a systematic review and meta-analysis of epidemiological studies to explore the relationship between C-section, especially the special attention was paid to different cesarean delivery method, and the risk of AR in children.Correlation between C-section and AR risk in future generations have attracted much attention. A previous meta-analysis of C-section and offspring AR was conducted in 200930 and Preferred Reporting Items for Systematic Reviews and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines31.This systematic review was registered on PROSPERO (CRD: 42021251713) and conformed to the MOOSEWe searched international online databases, such as PubMed, EMBASE, Web of Science, CNKI, and VIP and Wanfang. In PubMed, the searches were carried out with a combination of subject and free words. The search strategy was designed and set up by an expert in database searches (Yide Yang) and two investigators (Zixin Liu and Junrong Chen).We have arranged the search terms according to PICO model to provide more details to get more accurate search results. According to the search subject of this article. Search terms used were as follows: Patient: pregnant women, pregnant, minors, adolescent, offspring , early life , toddler, child; Intervention: cesarean section, c-section, abdominal deliveries, post-cesarean section; Comparison: natural childbirth, vaginal delivery; Outcome: allergic rhinitis, hay fever, allergic rhinoconjunctivitis, seasonal allergic rhinitis. The titles and abstracts of the studies were screened, and full papers were retrieved if a decision could not be made based on the abstract alone. To identify all potentially eligible studies, the reference lists of all comprised studies were examined. We searched from the beginning of databases up to August 1, 2022.RR), hazard ratio (HR),or odds ratio (OR) and their confidence intervals can be obtained, or enough data to calculate them.The inclusion criteria were as follows: Study population: children aged 0–18 years old. Study types: cohort studies, cross-sectional studies, and case–control studies. Exposure factors: children delivery through C-section; Outcome: offspring diagnosed with AR; and relative risk  independently performed a thorough title and abstract screening. Articles were added to this shortlist of studies through reference cross-checking. Disagreements were resolved by a consensus discussion in a meeting with the senior author (Jian Li). After agreement between the two investigators, studies were merged into a final list for full-text analysis and data extraction. Both investigators agreed on the final shortlist for data analysis and extraction.OR] and their 95% confidence interval [95% CI], or enough data to compute them). If studies reported relative risks (RR) or hazard ratios (HR) as the effect size, Hazard ratios were directly considered as RR32. RR (95% CI) were converted to OR (95% CI) by using the following formula: OR = [(1-P0) * RR/ (1-RR * P0)], where P0 indicates the incidence of the outcome of interest in the non-exposed/reference group. The standard error of the resulting converted relative risk was then determined with this formula: SElog (RR) = SElog (OR)*log (RR)/log (OR)33. This meta-analysis used OR as the effect size because some research reports only provided OR and did not include HR or RR. In such situations, using OR as the effect size allowed for better utilization of the data for comprehensive analysis. Adopting a unified algorithm and interpretation method could simplify the process of data integration and comparison, and improve the reliability and interpretability of the results. When several estimates were reported within the same study, the most adjusted model was used for the pooled analysis.Two researchers  independently examined the literature and extracted the data. In the case of disagreement, a third researcher (Jian Li) was consulted if necessary. The final determination of the extracted literature was the result of a consensus reached by three individuals. If there were significant doubts regarding the data from a particular study, the corresponding authors were contacted for confirmation of the extracted data. Information extracted from the tables in the literature was as follows: study details ; study methodology and characteristics; study design ; participant information ; follow-up or study duration, relevant independent, and dependent variables; data analysis methods; adjustment for confounding factors; and effects obtained from study results  and cohort studies . Those with scores of ≤ 5 and ≥ 6 were classified as low- and high-quality studies, respectively. For cross-sectional studies, 11 checklists recommended by the Agency for Healthcare Research and Quality35 were used to evaluate the studies37. A higher total score of each item corresponded to a higher-quality document; if the answer was "no" or "unclear,” the item score was "0," and if the answer was "yes," the item score was "1," of which the fifth was a reverse score. The evaluation of literature quality was as follows: low quality = 0–3, medium quality = 4–7, and high quality = 8–1138. The studies were independently evaluated by two researchers (Zixin Liu and Junrong Chen). In case of differences, a third experienced investigator (Jian Li) was consulted until a consensus was reached.For cohort and case–control studies, the Newcastle–Ottawa Scale (NOS)OR was used as the effect index. The correlation strength between C-section and offspring AR was determined by combining OR and 95% CI. Cochran’s Q test and I2 index were used to evaluate the heterogeneity of the studies39. Regarding the heterogeneity test, a P-value of ≥ 0.1 and I2 of ≤ 50% suggested homogeneity among the studies, and a fixed effects model was used for merging; a P-value of ≤ 0.1 and I2 of ≥ 50% suggested heterogeneity among the studies, and a random effects model was used to estimate the combined effect. Prediction intervals were calculated in meta-analyses40 with at least four studies41 to take the large between-study heterogeneity into account. Meta-regression was used to investigate potential sources of heterogeneity between the studies. For analytical purposes, the studies’ characteristics were grouped as follows: study design; study areas; year of publication; sample size; age; diagnostic mode and follow-up period. According to the included studies, a subgroup analysis was also performed on type of C-section and C-section with or without history of atopy. Publication bias was assessed using funnel plot and Egger’s test correlation. Sensitivity analysis was performed by excluding the study one by one. P < 0.05 was deemed statistically significant.RevMan5.4 and STATA16.0 was used for statistical analysis, and 53. The screening process and results are shown in Fig. Two reviewers independently screened the studies included in the meta-analysis. We calculated the percentage agreement to evaluate the consistency of the two reviewers in the search process for the meta-analysis. The first round of percentage agreement was 86.7%. After discussing with a third experienced expert, the second round of percentage agreement improved to 100%. We retrieved 379 citations from multiple electronic databases. After excluding 158 repetitive studies, and reading titles and abstracts, 155 studies were excluded because they were systematic reviews, reviews, letters, case reports, and study factors were not relevant. After evaluating 66 full-text articles, studies with an outcome index of > 18 years (n = 9), lack of focus on the between C-section and childhood AR (n = 30), those that could not obtain specific data (n = 3), and low quality studies (n = 2) were excluded. Finally, 22 articles were included in this study51, 2 case–control studies49, and 9 cross-sectional studies53. For study areas, 6 were conducted in Europe44, 9 in Asia52, 5 in North America53, and 2 in South America22. In previous studies, Richards51 used RR as the effect value, Mitselou18 used HR. We ensured the comprehensiveness of analysis and the maximization of statistical ability by calculating OR54 as the combination effect value55.This study included 22 studies involving 1,464,868 participants. Regarding research methods, there were 11 cohort studies53 studies were conducted based on the ISAAC questionnaire. Clinical diagnosis was based on the physician's judgment based on the clinical history, using International Classification of Disease (ICD) diagnosis codes or Positive Skin Prick Test (SPT) reaction from the electronic health records.The diagnosis of AR included the questionnaire survey and clinical diagnosis. In the questionnaire survey, 523 examined the relation between mode of delivery and the development of AR with a parental history of atopy, 345 studies used stratified analysis of C-section according to family history of allergies,351 studies reported the effect of different types of C-section on AR in children. The most adjusted covariates included age, preterm birth or neonatal complications, educational level, income, and birth order. The general characteristics and quality evaluation results were shown in Table Cohort studies were mainly from Europe and North America, while cross-sectional and case–control studies were concentrated in Asia. Pistiner 's study2 = 68%, P < 0.001). A random effects model was used to demonstrate the results of the meta-analysis, and revealed that there was a significant correlation between C-section and children AR . The results were shown in Fig. In this meta-analysis, the rate of heterogeneity was high , study areas (Europe/Asia/North America/South America), age , diagnostic mode , and follow-up period . However, meta-regressions confirmed the year of publication , and sample size  may have been the possible causes of heterogeneity.P = 0.031). A larger effect size of studies with sample sizes less than 10,000 (1.75 [1.42–2.15] and 1.30 [1.18–1.43]) was found in comparison with studies model assessment of sample size greater than 10,000 (1.10 [1.03–1.17]), and the difference was also significant (P = 0.001). Subgroup analysis indicated that for most of the variables evaluated, the association measurement continued to be associated with AR. Subgroup analysis and meta-regression results were shown in Table In the meta-regression analysis, sample size (38.0%) and year of publication (18.8%) explained the variability between studies. Subgroup analysis showed that, a greater effect size was observed for articles published before 2020 (1.32[1.09–1.60] and 1.24 [1.12–1.37]) compared with the whole study [1.19(1.12–1.27)], and the difference was statistically significant in the meta-regression . A fixed effects model was used to estimate the combined effect. The meta-analysis demonstrated that C-section with parental history of allergy had a higher risk of offspring AR  compared with C-section with No parental history of allergy  and the whole analysis  as shown in Fig. Four studies were incorporated. The result demonstrated that the heterogeneity was low . So meta-analysis was conducted and showed that elective C-section  had the higher risk of offspring AR  compared with the whole analysis . In our research, no association between emergency cesarean  delivery and AR in children was found . The results were shown in Fig. Emergent C-section, means a period of vaginal delivery and with genital tract microbe exposure but terminated because iatrogenic reason, was showed significantly higher risk for children AR than elective C-section in Mitselou’sOR of AR in the overall C-section (Egger’s test: p = 0.137), cohort study (Egger’s test: p = 0.390), cross-sectional study (Egger’s test: p = 0.675) and case–control study (Egger’s test: p = 0.752). Indicating no publication bias in this meta-analysis. Removing the included literatures one by one did not affect the results of this study, which means that the above results are stable and reliable.The funnel chart was drawn using Stata16.0, and the trim-and-fill method was used to calculate the combined estimate after adjusting for publication bias. The resulting estimate did not change significantly. The statistical tests of publication bias were not significant for the 95% CI: 1.12–1.27, P < 0.001).This is the first meta-analysis evaluating the effects of C-section on the AR risk of offspring in child. Our systematic review revealed 22 studies reporting on cesarean delivery and offspring AR risk. Findings suggest that the overall pooled OR for AR in children was 1.19. There are several possible explanations for this finding. Firstly, it is possible that earlier literature relied more on self-made questionnaires for the assessment of AR. This could have led to the inclusion of children who had not yet developed AR, thus affecting the consistency of the results. With the passage of time, the diagnosis and assessment methods for allergic rhinitis have continuously improved and been standardized. This was also explained in our subgroup analysis of the diagnostic mode for AR. Additionally, it is likely that the heterogeneity in the results is also influenced by the advancements in research methods and medical technologies in different time periods. These changes may include more accurate and standardized data collection methods, as well as the utilization of more advanced medical technologies and treatment methods. These factors could contribute to increased heterogeneity in the results across different time periods. In conclusion, after incorporating the adjusted effect size finding. We had gotten a conclusion that the overall risk of AR in children delivered after C-section increased by 19% and increased by 82% after C-section with parental history of allergy. In addition, elective C-section had a higher risk of AR compared with the whole study.Results from the meta-regression analysis revealed that sample size and publication year affected the association between C-section and AR, which explained nearly 38% and 19% of the variability between studies. We observed larger effects of studies with sample sizes smaller than 10,000. The current analysis finds evidence of a negative correlation between sample size and effect size in studies that get included in meta-analyses61. In our subgroup analysis with a family history of allergies, we found that C-section in families with a history of allergies increased the risk of children developing AR, with heterogeneity reduced to 0%. One possible explanation for the reduced heterogeneity within this subgroup is the shared genetic predisposition to allergies among family members. This shared genetic background could contribute to a more consistent pattern of allergic reactions and therefore a lower heterogeneity in the subgroup. In addition to genetic factors, families often share similar living conditions, dietary habits, and exposure to potential allergens environmental influences within families which could contribute to the reduced heterogeneity. A family history of allergy is a common risk factor for allergic diseases in offspring. C-sections with a family history of allergy have a higher risk of AR in children than overall C-sections. This demonstrates that the interaction between genes and the environment plays an important role in the development of such diseases62.We had observed that the overall risk of AR in children delivered through C-section increased. This is consistent with the results of previous studies on C-section and allergic diseases. Previous studies have shown that C-section increase the risk of asthma, food allergies, and allergic dermatitis in children of offspring63. In Behzad Darabi’s meta-analysis. They also found that children delivered by elective C-section have a higher risk of asthma than children delivered by emergency C-section64.Many studies have shown that delivery by C-section is associated with an increased risk of disease associated with allergic disease in the offspring, but these studies have generally not discriminated between the effect of acute and elective C-section. In our study, we observed that children who were born by elective C-section had a higher chance of developing AR. Similar results were found in other studies. A cohort study conducted in the Denmark included over 750,569 participants and showed that elective C-section was higher than the effect of emergency C-section on the risk of asthma65. In a cohort study of allergic diseases in South Africa66, the incidence of AR in urban children  was significantly higher than that in rural children . The rate of C-section in urban areas was twice as high as that in rural areas. This may be because the antenatal and childhood contact with farm animals in a rural environment resulted in low prevalence of AR in children owing to multiple exposures that mediate strong protective epigenetic modification through the microflora diversity69. Healthy or ‘tolerant’ individuals often produce high amounts of allergen-specific IgG4 and/or IgA, and IgA-deficient individuals are at risk of developing an allergy70. Generally, the exposure to microorganisms results in lipopolysaccharide stimulation of Toll-like receptors to produce interleukin 12 (IL-12) and interferon λ (IFN-λ), which promote the development of the Thnaive cells into Th1 effector cells. An impaired regulation of this immune pathway to children born by C-section71. Factors that alter the composition and diversity of the microbiome, such as the mode of infant delivery have a strong effect on immune responses, altering the immune response from one what is consistent with a state of tolerance to a dysfunctional hyper-responsive state that is associated with allergic diseases. However, conflicting results have been observed in recent epidemiological investigations. First, the incidence of AR began to decline in some Western European countries, but there was no obvious evidence that it was due to the decline in sanitary condition or increase in the number of family members72. Second, in a cohort study by Weber73, on personal and family cleanliness and allergic disease, which included 399 participants, dust parameters in the household objectively reflected personal cleanliness, including hand washing and household cleanliness, although personal cleaning or household cleanliness was not associated with the risk of allergy. Other microbial components in the indoor dust that were not affected by personal hygiene might play an important role. Considering the reasons for the increasing prevalence of AR in children based on the hygiene hypothesis, further studies are needed to determine the underlying genetic and epigenetic mechanisms, focusing on the role of early allergens and differences in epidemiological studies74.The etiology behind C-section leading to AR in children is not fully understood until now. Based on the hygiene hypothesis, the rapid progression of the epidemic was attributed to a reduced diversity of early environmental microbe exposure, which decreased the occurrence of allergic diseases, including eczema, AR, and asthma75. Conversely, the microbiome of infants born via C-section shows an increased prevalence of either skin flora or potentially pathogenic microbial communities such as Klebsiella, Enterococcus, and Clostridium76. There are several explanations for this mechanism. Firstly, Shohei Akagawa77 points out that children born by C-section have characteristics such as reduced Bacteroides and decreased butyric acid concentration in the gut. The decrease in butyric acid concentration inhibits the differentiation of immature T cells into Tregs, which are crucial for suppressing excessive immune responses. This impairment of the immune system's ability to suppress excessive immune responses can lead to the development of allergic diseases. Secondly, there was evidence that low α-diversity and relative abundance of particular gut-commensal bacteria genera are associated with childhood respiratory diseases. However, the higher relative abundance of Bacteroidaceae, Clostridiaceae, and Enterobacteriaceae, and the lower relative abundance of Bifidobacteriaceae and Lactobacillaceae were associated with the development of allergies78. In addition, our study has shown that elective C-section is associated with a higher risk of AR. This might be because the newborns in contact with C-section related contaminants were exposed to the maternal genital tract microbiome due to factors, such as premature rupture of membranes, resulting in partial restoration of the newborn’s bacterial community to levels similar to those of babies born through VD79. In conclusion, the mode of delivery is a significance factor affecting the composition of intestinal flora in newborns and infants, which plays an important role in the development of the immune system.At the same time, some studies have also shown that differences in the colonization of neonatal intestinal flora caused by caesarean section are also related to allergic diseases in offspring. The developmental starting point of the infant gut microbiota is still unknown, but undoubtedly, the process of delivery seems to be a key point in the development of the neonatal microbiota. Babies born via C-section miss out on this initial exposure to the mother's microbiota. Instead, they are colonized primarily by the skin and environmental microorganisms present in the operating room. The intestinal microflora of infants born through VD had a higher abundance of Bifidobacterium, Lactobacillus, Escherichia coli, and Bacteroides; demonstrating greater intestinal microbial diversity81, which would cause the failure of immune tolerance and increase the risk of AR. In response to their preventive measures, Lunjani82 suggested that microbial exposure was the most effective way to prevent atopic diseases within 1–2 years after birth. For example, the orderly combination of infant intestinal microbial ecosystem was formed by an exposure to the maternal microflora, breastfeeding, and early exposure to various food, and environmental microorganisms during the prenatal period, childbirth, and delivery83. However, in a cohort study of 335 children by Jelding-Dannemand84, exclusive breastfeeding was observed to be ineffective in reducing early childhood sensitization or high-risk childhood related diseases at the age of 7 years. We found that most of the literature has corrected for breastfeeding, whether breastfeeding reduce the risk of C-section-related AR in our study remains unelucidated. However, the early introduction of supplementary foods, especially cereals, fish, and eggs, appeared to prevent asthma and allergies, and the introduction of supplementary foods as early as possible while continuing breastfeeding might be a more important strategy to prevent allergies in children85. These included studies did not specifically investigate and adjust the diet of mothers during pregnancy and children. It is necessary to study these factors in future research to explore whether diet can reduce the risk of AR in children born by C-section.A large number of studies have consistently observed that C-section could lead to an increased incidence of AR in children, therefore, most of the experiments were observational studies on the effects of C-section on allergic diseases in children. Several societal factors that may contribute to the rise in C-section rates include fear of VD among pregnant women, doctors' desire to avoid unknown medical risks, and cultural and religious differences in certain regions. Therefore, in order to reduce the C-section rate, it is recommended to consider the individual circumstances and medical indications for each delivery, including but not limited to strictly defining the indications for cesarean section, promoting VD, widespread adoption of painless delivery techniques, and encouraging women who have had a cesarean section to attempt vaginal birth after cesarean. Factors other than C-section might also affect the development of allergic diseases in children, including race, birth season, geographical location, social class or income level, tobacco exposure during pregnancy, changes in an indoor environment, adverse pregnancy outcomes, dietary changes, and antibiotic use81 may affect the development of children's immune system, but some studies are aimed at term pregnancy, normal birth weight newborns as inclusion criteria, and the specific reasons for choosing C-section have not been described in the article, such as fetal distress, placenta previa, umbilical cord prolapse. Second, moderate-high heterogeneity across studies was detected for C-section and AR. Different issues could generate this heterogeneity, including different study population, study location, sample size, duration of follow-up, outcome diagnosis, publication areas, number of years, and treatment of confounding factors. Subgroup analysis and meta-regression were run to deal with the heterogeneity by using random-effect models. Third, this study included few small-scale studies and self-reported AR for the diagnosis, self-report or information from parental interviews may be liable to recall bias, which might have caused the actual prevalence to be higher than the present results, thereby reducing the universality of our findings, any deviations or inaccuracies in individual studies could have also influenced our analysis.This study has several limitations. First, in the subgroup analysis regarding different types of C-section, we identified higher heterogeneity. Most of the studies investigating the relationship between C-section and AR in children were retrospective and did not include specific clinical indications for mothers choosing elective or emergency C-sections. Preterm delivery and low birth weightTherefore, C-section increase the risk of AR in children compared with VD. In the case of a high C-section rate worldwide, formulating specific clinical guidelines and implementing appropriate management plans helping reduce the AR risk in children after C-section need to be strengthened.In conclusion, our study identifies and characterizes that C-section is associated with subsequent childhood AR. However, the confounding effects of delivery mode and Indications for C-section remain to be studied in more detail. Future well-designed studies are warranted to validate the findings of the current analysis. When the C-section rate remains high, it is suggested that the formulation of specific clinical guidelines and implementation of appropriate management plans can reduce the risk of AR.