{"paper_id":"4e166708-fb97-4f5c-8df5-7daa6e810b99","body_text":"1\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports\nA systematic review \nand meta‑analysis on alcohol \nconsumption and risk \nof endometriosis: an update \nfrom 2012\nLetizia Li Piani1,2*, Francesca Chiaffarino3, Sonia Cipriani3, Paola Viganò2, \nEdgardo Somigliana1,2 & Fabio Parazzini1\nEndometriosis is a complex and chronic disease, whose multifactorial nature has encouraged a \ndeep investigation on the role of lifestyle factors. A strong association between alcohol intake and \nendometriosis risk has already been shown. We aimed to confirm this association, considering the \nupdated literature. 23 eligible studies were identified through comprehensive literature search of \nPubMed and EMBASE (May 2012–October 2021). A borderline statistical significance was found \ncomparing any alcohol consumption with no consumption (unadjusted OR 1.14; 95% CI: 0.99–1.31, \np = 0.06), in contrast with a previous meta‑analysis. However, we confirmed the significant association \nbetween moderate alcohol intake and endometriosis (unadjusted OR 1.22, 95% CI: 1.03–1.45, \np = 0.02), also performing a sensitivity analysis (unadjusted OR 1.27, 95% CI: 1.04–1.54). Our partly \ndivergent evidence reflects the tough challenge of isolating the impact of specific factors on the \nnatural history of multifactorial diseases. Indeed, on one hand alcohol could be adopted by patients as \na self‑management therapy and on the other, it could favor the disease, promoting positive feedback \nwith inflammatory mediators and oxidative stress. Our study encourages further investigation on the \nrole of modifiable lifestyle factors and highlights the opportunity to adopt them to prevent or at least \nlimit endometriosis progression.\nEndometriosis is a progressive and hormone-related disease that strongly impacts on woman’s physical, mental, \nand social well-being 1. Due to its debilitating nature and difficult clinical management, research has deeply \ninvestigated its possible pathogenesis. Despite decades of research efforts, the comprehension of endometriosis \npathophysiology is still elusive and  inconclusive2–5, but a unique cause seems not plausible. As for other chronic \n illnesses6,7, genetics and inflammation could be a common denominator of different pathogenetic  mechanisms8. \nThe pathway pain-stress-inflammation could play a key role in the development, progression, and exacerbations \nof endometriosis. Indeed, women with endometriosis seem to be caught in a “vicious circle of high stress percep‑\ntion, inflammation and disease progression ”9. Besides, while intrauterine and neonatal exposure to prolonged \nphysical stress stimuli could be linked to the future  development10, in adults chronic stress might directly enhance \nthe  progression11. Inline, increased inflammatory markers have been documented not only in endometriosis \nlesions but also in peritoneal fluid and even in the peripheral blood of patients  affected12–14.\nA consequent important issue is to establish whether and how promoters of inflammation could influence \nendometriosis  risk15,16. It is not surprising that modifiable lifestyle factors, such as diet, caffeine, environment, \nand smoking, all factors possibly associated with inflammation, have been explored in this  regard17–24. Alcohol \nhas already gained a certain attention. A meta-analysis from our group proved a significant correlation between \nalcohol intake and the occurrence of  endometriosis20, based on the published papers until  201225–39. However, \ngiven the preponderance of retrospective studies on the topic, at the time we claimed the need to confirm these \nOPEN\n1Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. 2Infertility \nUnit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via M. Fanti, 6, 20122 Milan, Italy. 3Gynecology \nUnit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.  *email: letizia.lipiani@\nunimi.it\n\n2\nVol:.(1234567890)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nfindings. Therefore, the objective of this study was to verify the correlation between alcohol consumption and \nendometriosis risk, through a state-of-the-art systematic review and a meta-analysis.\nMethods\nInformation sources. This systematic review was designed to meet the PRISMA (Preferred Reporting \nItems for Systematic Reviews and Meta-Analyses)  guidelines40. Systematic research was conducted to search for \nrelevant articles in which the impact of alcohol on endometriosis risk was discussed. The search terms “endome-\ntriosis” and “diet” , “nutrition” , “alcohol” , “vitamin” , “fat” , “vegetable, ” were used as a combination of free text and \nas Medical Subject Heading (MeSH) terms (Pubmed) or Emtree terms (Embase) and temporally limited “from \n2012/05/31 to 2021/10/11” (See search strategy in Supplementary file S1).\nEligibility criteria. Inclusion criteria were:—case–control, cohort or cross-sectional study reporting origi-\nnal data from May 2012 to October 2021;—clinical or histological diagnosis of endometriosis;—presence of \nnumber or percentage of subjects with and without endometriosis according to alcohol intake;—full-length \narticles, published in English.\nSearch strategy and data collection. Data collection for our study followed the methodology of the \nprevious one published in  201319. Our research was registered in PROSPERO (ID: CRD42021282108). Figure 1 \nshows the selection procedure, according to PRISMA  202040. First, two reviewers (LLP and FC) screened PUB-\nMED and EMBASE to identify potential eligible studies. After excluding duplicated reports, they separately \nRecords identified from \ndatabases (n = 2028)\n-P ubmed (n=501)\n- Embase (n=1527)\nRecords removed before \nscreening:\nDuplicate records removed \n(n = 279)\nRecords screened\n(n =1749)\nRecords excluded\n(n = 1733)\nReports sought for retrieval\n(n = 16)\nReports not retrieved\n(n = 1)\nReports assessed for eligibility\n(n = 12) Reports excluded (n=4)\n-I ntrauterine exposure (n=2)\n-Q ualitative data (n=2)\nI\nd\ne\nn\nti\nfi\nc\na\nti\no\nn\nS\nc\nr\ne\ne\nn\ni\nn\ng\nI\nn\nc\nl\nu\nd\ne\nd\nIdentification of new studies via databases and registers\nNew studies included\n(n = 8)\nStudies included in \nprevious version of \nreview (n = 15)\nReports of studies \nincluded in previous \nversion of review (n =0)\nPrevious studies\nTotal studies included in review:  \n(n = 23)\nFigure 1.  Flowchart of selection process according to PRISMA 2020 flow-diagram. It showed the study \nselection process. Only case–control, cohort and cross-sectional studies reporting original data were included. \nConversely, case reports, case series and non-English language studies were excluded.\n\n3\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nassessed all articles on title and abstract and selected relevant articles potentially meeting the inclusion criteria. \nThey both read the full text of potentially eligible papers to assess whether they could be included. Full-text arti-\ncles were reviewed, and discrepancies were discussed until consensus was reached among the authors. Exclusion \nreasons for potentially eligible studies were evaluation of intrauterine exposure to maternal alcohol intake or \nqualitative analysis of alcohol intake, in studies aimed to verify other associations.\nFinally, data were extracted into Table 1, where we also considered the previous reports (n = 15). In the table, \nthe following items were described: authors and publication date; country of origin; study design; number and \nage of participants; confounding factors; key findings.\nStatistical analysis. Statistical analyses were performed using Revman (Review Manager [Computer pro-\ngram], version 5.3; The Cochrane Collaboration, 2014) and STATA (STATA, version 10.0; StataCorp LP , Col-\nlege Station, TX, 2012). We pooled the unadjusted odds ratios (OR) by computing the random-effect model \nweighed for the inverse variance. To assess the heterogeneity across studies, we conducted a test based on the \nchi-square distribution. The funnel plot and Egger’s test were used to detect publication  bias41,42. Two sensitivity \nanalyses were also performed. In one, the data by Parazzini et al.35 were excluded because the reference category \nincluded women who consumed less than 0.5 drinks per week and not only the non-consumers. Furthermore, \nthe category of moderate drinkers included women consuming relatively low amount (i.e. 0.5–8 drinks/week) in \ncomparison to other studies. In another sensitivity analysis, the results by Bérubé25 were excluded because heavy \ndrinkers were identified using a cut-off lower than the other studies (i.e., ≥ 9 drinks/month) and because they \nreported the prevalence OR (POR). We performed a further analysis excluding both studies (Bérubé et al. and \nParazzini et al.) in order to evaluate the joint impact of these studies on the overall ORs.\nQuality assessment. The quality of the included studies was evaluated using the Newcastle–Ottawa Scale \n(NOS)43. Studies were evaluated according to three broad categories: selection of study groups, comparability of \nstudy groups, and assessment of outcome (cohort studies) or ascertainment of exposure (case–control or cross-\nsectional studies). The maximum score was 9.\nResults\nSystematic review. Selected articles are shown in Fig. 1. We identified 8 papers from May 2012 up to Sep-\ntember 2021 to be assessed for the systematic review. Considering those selected for our 2013 study (n = 15)20, \nwe counted a total number of 23 studies. In Table 1, we reported the main methodological characteristics of both \nthe previous and the current selected articles, for a more complete information.\nUSA was the country for three  papers44–46, one was conducted in  Brazil49, and the other four were set in \n Europe47,48,50,51. The diagnosis of endometriosis was obtained by a surgical or clinical approach. Only Schink et al. \n50 did not specify the diagnostic method to detect endometriosis. In Table  2, we detailed the cutoffs of alcohol \ndrinking of the selected papers, according to the classification levels used in the previous meta-analysis 20. Few \narticles reported the specific thresholds  used47,48,51. In one study the category of “no alcohol intake” also included \ninfrequent consumption (< 1 glass/week); for this reason, we excluded this study in the meta-analysis48. Moreo-\nver, in two papers, the cut-offs did not allow a precise classification between infrequent and moderate, while in \nanother one between moderate and heavy  consumption48,51,52.\nCross‑sectional studies. Only one of the newly selected articles had a cross-sectional  design51. Saha et al., aimed \nto investigate the relationship between modifiable life-style factors and endometriosis in a cohort of 28,882 \nwomen: while a positive association between smoking or coffee intake with endometriosis was observed, they \ncould not find a similar result considering alcohol consumption. Even taking into consideration the amount of \nalcohol per week, the association was not significant.\nCohort studies. Three cohort studies were identified after the previous  review20. Prescott et  al.45 designed a \nprospective cohort study to evaluate a possible link between endometriosis and infertility. Alcohol, expressed in \nterms of grams/day, was only mentioned as a covariate for their analysis. Hemmert et al.46 work stands out from \nthe others for its nature: it was a multicenter prospective cohort design aimed to evaluate lifestyle exposure prior \nto endometriosis diagnosis. They observed null findings between endometriosis and alcohol intake, considering \n473 women. In contrast, Ek et al.48 observed an inverse association between this habit and endometriosis, based \non 172 women’s reported questionnaires.\nCase–control studies. Most newly selected papers were case–control  studies44,47,49,50. Both results from Schink \net  al.50 and Da Silva et  al. 49 agreed to deny an association between alcohol and endometriosis; indeed, they \nboth observed that alcohol intake tended to be higher in unaffected patients. In contrast, Ricci et al. found an \nincreased endometriosis risk among alcohol  users47.\nMeta‑analysis. A total of 22 papers were included in the meta-analysis. Figure 2 depicted the study-specific \nand pooled ORs for any versus no alcohol intake. We were not able to find an overall statistically significant \nassociation between any alcohol consumption and endometriosis risk (unadjusted OR 1.14; 95% CI: 0.99–1.31) \nalthough a borderline statistical significance was observed (p = 0.06).\nWe also evaluated the effect of alcohol intake according to the number of drinks (Figs.  3, 4). None of the \nnew papers reported a consumption attributable to the “infrequent” category, as adopted in the meta-analysis of \nParazzini et al.20. For this reason, we did not report the forest plot. Thus, considering “infrequent” vs no alcohol \n\n4\nVol:.(1234567890)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nAuthor, year Country Study design Cases Controls\nSample size\ncases/controls Age (years)\nConfounding \nfactors \nconsidered in \neach  studya Key findings\nGrodstein et al., \n1994 USA, Canada Hospital-based \ncase–control\nWomen with primary \ninfertility due to \nendometriosis\nFertile women 180/3833\nAge, center, \nsmoking habits, \nlifetime n. of \nsexual partner, \ncontraception, \nBMI, exercise, \ncoffee\nCases drank \nmore alcohol \nthan controls \n(40% vs 30%)\nSignorello et al., \n1997 USA Hospital-based \ncase–control\nWomen with infertility \nassociated endome-\ntriosis\n89 fertile women \nand 47 infertile \nwomen both \nwithout endome-\ntriosis\n50/(89 and 47) 23–44\nAge, education, \nheight, weight, \nregularity of \nmenstrual cycle, \nexercise smoking\nConsumption \nof alcoholic \nbeverages had a \nmodest, non sig-\nnificant increase \nin endometriosis \nrisk\nOR 2.0 (95%CI: \n0.6–5.7)\nBerubé et al., \n1998 Canada\nCase–control\non prospective \nstudy\nInfertile women for \nminimal or mild endo-\nmetriosis (laparoscopi-\ncally diagnosed)\nWomen with \nunexplained \ninfertility\n329/262 20–39\n ≥ 9 sd/month: \nOR 1.49 95%CI \n0.93–2.37\nNo dose–\nresponse associa-\ntion\nPauwels et al., \n2001\nBelgium, Neth-\nerlands Case–control Infertile endometriosis \nwomen\nMechanical infer-\ntiles women 42/27 24–42\nAge, BMI, ovula-\ntory disfunc-\ntion, smoking \npattern, caffeine \nconsumption\nSimilar number \nof alcohol con-\nsumers between \ncases and con-\ntrols (3 vs 5)\nEskenazi et al., \n2002 Italy Cohort study\nWomen with endome-\ntriosis confirmed by \nsurgery or ultrasound \nexamination\nWomen without \nendometriosis \nconfirmed by \nsurgery or nega-\ntive ultrasound \nexamination\n19/277  ≤ 30 years old in \n1976\nFinal models \nincluding only \nage because \nstatistically \nsignificant\nLower alcohol \nintake in cases \nthan in controls\nOR 0.39\n(95%CI \n0.11–1.38)\nHemmings et al., \n2004 Canada Hospital-based \ncase–control\nWomen with endo-\nmetriotic lesions at \nthe time of surgery \n(surgery for diagnosis, \nfertility-regulating sur-\ngery, hysterectomy)\nWomen with no \nevidence of endo-\nmetriotic lesion at \nsurgery (surgery \nfor diagnosis, \nfertility-regu-\nlating surgery, \nhysterectomy)\n896/1881 Premenopausal \nage\nNo significant \nassociation \nbetween alcohol \nintake and endo-\nmetriosis\n(≥ 7 sd/wk: \nOR 1.0; 95%CI \n0.5–1.9)\nParazzini et al., \n2004 Italy\nHospital-based \ncase–control \n(from 2 studies)\nWomen with laparo-\nscopically confirmed \nendometriosis\nWomen admitted \nfor acute non-\ngynaecological, \nnon-hormonal, \nnon-neoplastic \nconditions\n504/504 20–65\nAge, calendar \nyear, education, \nparity, BMI, \nstudy\nNo significant \nassociation \nbetween alcohol \nintake and endo-\nmetriosis\n(“heavy intake”: \nOR 0.9; 95%CI \n0.6–1.3)\nTsukino et al., \n2005 Japan Case–control Women with stage \nII-IV endometriosis\nWomen without \nendometriosis or \nstage I endome-\ntriosis\n58/81 20–45\nMenstrual regu-\nlarity, average \ncycle (days)\nAlcohol intake \nin 39.6% of cases \nand in 49.4% of \ncontrols (p 0.45)\nBuck Louis et al., \n2007 USA\nHospital-based \ncase–control in a \ncohort of women \nundergoing \nlaparoscopy\nWomen with \nendometriosis in a \ncohort undergoing \nlaparoscopy for any \ngynecologic indication \nincluding sterilization\nWomen without \nendometriosis \nfrom the same \ncohort of cases\n32/52 18–40\nIn utero expo-\nsure, age, parity, \nsmoking habit, \ncaffeine intake\nNo significant \nassociation \nbetween alcohol \nintake and endo-\nmetriosis risk\n(OR 0.4; 95%CI \n0.07–1.8)\nHeiler et al., 2007 Belgium Matched Case–\ncontrol\nWomen with perito-\nneal endometriosis \n(PE) or deep endome-\ntriotic nodules (DEN)\nWomen with no \nclinical suspicious \nof PE or DEN, \nwithout infertility, \npelvic pain and \ndysmenorrhea \nand with normal \npelvic examina-\ntion, vaginal \nechography \nand serum \nCA-125 < 35U/ml\n88 (PE), 88 \n(DEN)/88 None\nDaily alcohol \nintake associ-\nated with deep \nendometriosis \nnodules (OR \n4.58; 95%CI\n1.80–11.62)\nMatalliotakis \net al., 2008 USA\nCase–control in \na retrospective \nreview\nWomen with pelvic \nendometriosis who \nhad undergone lapa-\nroscopy or laparotomy \nfor pelvic pain or \ninfertility within \n6 years\nInfertile women \n(tubal or male \nfactor infertility)\n535/200 15–56 None\nAlcohol intake \nwas more \nfrequent in cases \n(44%) than in \ncontrols (28%)\n(p: 0.003)\nContinued\n\n5\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nAuthor, year Country Study design Cases Controls\nSample size\ncases/controls Age (years)\nConfounding \nfactors \nconsidered in \neach  studya Key findings\nMarino et al., \n2009 USA Case–control\nWomen with surgically \nconfirmed endo-\nmetriosis from the \nGroup Health (GH) \nCooperative\nWomen without \nendometriosis \nrandomly selected \nfrom a list of GH \nduring the same \nperiod\n341/742 18–49 None\nCases were\nmore likely than \ncontrols to be \nalcohol consum-\ners\n(OR 1.45; 95%CI \n1.07–1.97)\nNagle et al., 2009 Australia Case–control\nWomen with surgically \nconfirmed endome-\ntriosis\nWomen without \nendometriosis 268/244 18–55 None\nSimilar alcohol \nintake between \ncases and \ncontrols\nHuang et al., 2010 Taiwan Case–control Women with endome-\ntriosis\nWomen without \nendometriosis 28/29\nMean age: \ncases = 34.3,con-\ntrols = 36.2\nBackward \nselection of \nconfounders\nSimilar alcohol \nintake between \ncases and \ncontrols\nTrabert et al., \n2011 USA Population-based \ncase–control\nWomen with \nendometriosis \n(ICD9 = 617.0,.5,.8,.9) \nfrom the Group Health \n(GH) Cooperative\nWomen without \nendometriosis \nfrom the GH \nduring the same \nperiod\n284/660 18–49 None\nCases were\nmore likely than \ncontrols to be \nalcohol consum-\ners\nNew contributions\nUpson et al., 2013 USA\nPopulation-based \ncase–control \nstudy of endome-\ntriosis\nWomen with endome-\ntriosis confirmed by \nsurgery\nWomen without \nendometriosis \nassessed by \nsurgery\n92/195 18–49\n57% of cases \nreported current \nalcohol intake vs \n42% controls\nPrescott et al., \n2016 USA Prospective \ncohort study\nWomen with endome-\ntriosis confirmed by \nlaparoscopy\nWomen without \nendometriosis \nassessed by \nsurgery\n658/22,581 24–44\nAlcohol intake \nwas 5.8 g/day and \n6.0 g/day in cases \nand controls\nRicci et al., 2017 Italy\nHospital based \ncase–control \nstudy of endome-\ntriosis\nInfertile women with \nhistologically con-\nfirmed endometriosis\nInfertile women \nwithout endome-\ntriosis, admitted \nto hospital for \nacute conditions\n90/90 17–76\nEducation, BMI, \nphysical activity \nduring adoles-\ncence\nNo significant \nincreased \nendometriosis \nrisk among \nalcohol users: \n(OR 1.48 95%CI: \n0.68–2.79). No \ndifference for the \ntype of alcohol\nSaha et al., 2017 Sweden\nPopulation-based \ncross-sectional \nstudy\nWomen with endome-\ntriosis confirmed by \nmedical records\nWomen without \nendometriosis 1228/27,594 20–65\nAge, age at \nmenarche, BMI, \nparity, OC use, \ninfertility, coffee, \nsmoking\nNo significant \nassociation \nbetween alcohol \nintake and \nendometriosis \nrisk (< 4.5 sd/wk \nOR 0.9, 95%CI \n0.76–1.07)\nEk et al., 2018 Sweden\nHospital-based \ncase cohort study \nbased on a study \nquestionnaire\nWomen with endome-\ntriosis confirmed by \nsurgery\nWomen from \nMalmo Diet and \nCancer cardiovas-\ncular cohort\n172/117 28–52\nAge, education, \noccupation, \nmarital status, \nsmoking, physi-\ncal activity, BMI\nAlcohol intake \nwas inversely \nassociated with \nendometriosis\n(1-4sd: OR \n0.16; 95%CI \n0.09–0.30)\nHemmert et al., \n2019 USA\nMulticentric \ncohort study of \nwomen undergo-\ning laparoscopy, \nregardless clinical \nindications\nWomen with endome-\ntriosis confirmed by \nsurgery\nWomen without \nendometriosis \ndiagnosis after \nsurgery\n190/283 18–44\nAge, marital \nstatus, education, \nrace/ethnicity, \ngravidity, BMI, \nrelevant life-style \nfactors, study site, \npelvic pain\nNo asso-\nciation between \nendometriosis \nand alcohol \nconsumption \n(OR 0.9, 95% CI \n0.7, 1.3)\nSchink et al., 2019 Germany\nRetrospective \ncase–control \nstudy\nWomen with endome-\ntriosis\nWomen without \nendometriosis 156/52 27/43 None\nNo significant \nhigher alcohol \nintake in controls \nthan in cases \n(9.8 ± 16.2 vs \n6.3 ± 8.5 p 0.14)\nDemézio da Silva \net al., 2020 Brazil\nHospital-based \ncase–control \nstudy of endome-\ntriosis\nWomen with endome-\ntriosis confirmed by \nsurgery/MRI\nWomen with \nbenign gyneco-\nlogical disease out \nof endometriosis, \nassessed by \nsurgery\n59/59 29–49 Age, BMI\nCases had lower \nalcohol intake \nthan controls \n(25% vs 51%)\nTable 1.  Main characteristics of considered studies. BMI, body mass index; CA, cancer antigen; DEN, deep \nendometriotic nodules; GH, group health; ICD-9, International Classification of Diseases, Ninth Revision; PE, \nperitoneal endometriosis; SD/WK: standard glass per week. a The confounding factors column refers to the \nconfounding factors considered in each paper. In our meta-analysis, our odd ratios were unadjusted for them.\n\n6\nVol:.(1234567890)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nintake, the OR remained 1.14 (95%CI 0.86–1.52)20. We found out a statistically significant association only when \ncomparing moderate versus no alcohol consumers (p = 0.02) with a summary OR of 1.22 (95% CI, 1.03–1.45). In \ncontrast, in case of heavy alcohol intake, the result was not significant, with an OR of 1.07 (95%CI, 0.90–1.27).\nWe performed two sensitivity analyses. In one, we excluded the data by Parazzini et al.35: the OR for moderate \nversus no alcohol consumption was 1.27 (95% CI, 1.04–1.54). In the second sensitivity analysis, the OR estimate \nfor heavy versus no alcohol consumption was 1.01 (95% CI, 0.85–1.19) when we excluded the study of Bérubé \net al.25. To assess the joint impact of the data by Bérubé et al. and Parazzini et al., we performed further analyses \nby excluding both the studies: the overall ORs were 1.14 (95% CI, 0.97–1.33), 1.22 (95% CI, 1.01–1.49) and 1.03 \n(95% CI, 0.83–1.28) for any, moderate and heavy versus no alcohol consumption, respectively.\nData from Schink et al.50 and Prescott et al.45 could not be included in the meta-analysis as they reported the \nvalue of alcohol intake as means of grams per day. Intriguingly, in both papers, unaffected women were more \nlikely to drink alcohol than affected ones, even if without statistically significance . Data were then analyzed \naccording to the time of alcohol intake (current, former or both). Compared to the previous meta-analysis, \nonly one additional study provided information on this  aspect44 (Table 3). However, compared to our previous \nTable 2.  Classification of dose of alcohol drinking in different studies. wk:week; §  Tertile of intake. Reference \ncategory: < 0.5 drinks/week. A pure alcohol content was assumed in each type of drink (125 ml wine = 333 ml \nbeer = 30 ml spirits). € Categories defined “Infrequent” and “Regular” by the Authors.\nAuthor Infrequent Moderate/regular Heavy\nGrodstein et al., 1994  ≤ 100 g/week =  < 1 drink/day =  < 30 \ndrinks/month\n > 100 g/week =  ≥ 1 drink/day =  ≥ 30 \ndrinks/month\nSignorello et al., 1997  < once/wk =  < 4 drinks/month  ≥ once/wk =  ≥ 4 drinks/month –\nBérubé et al., 1998 1–2 drinks/month 3–8 drinks/month  ≥ 9 drinks/month\nPauwels et al., 2001 – –  ≥ 6 drinks/wk =  ≥ 24 drinks/month\nHemmings et al., 2004 –  < 7 drinks/wk =  < 30 drinks/month  ≥ 7 drinks/wk =  ≥ 30 drinks/month\nParazzini et al., 2004 – 0.5–8 drinks/wk §  ≥ 8 drinks/week §\nTsukino et al., 2005 Weekly Daily\nBuck Louis et al., 2007 1–4 drinks/month  ≥ 5 drinks/month –\nHeilier et al., 2007  < once/wk =  < 4 drinks/month Several times/wk = 4–29 drinks/month Every day =  ≥ 30 drinks/month\nNagle et al., 2009 € €\nNew contributions\nRicci et al., 2017 –  ≤ 7 drinks/wk  > 7 drinks/wk\nSaha et al., 2017 –  ≤ 4.5 drinks/wk  > 4.5 drinks/wk\nEk et al., 2018 –  ≤ 4 drink/wk  > 4 drinks/wk\nHemmert et al., 2019 – 1–2 drinks/wk  ≥ 3 drinks/wk\nFigure 2.  Any versus no alcohol consumption. It presented the summary results of the analyses of any intake \nvs no alcohol intake. In this figure, endometriosis risk due to any alcohol consumption is expressed in terms of \nunadjusted odds ratio (OR).\n\n7\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nFigure 3.  Moderate/regular versus no alcohol consumption. It presented the results of the analyses of moderate \nintake vs no alcohol intake. As in Fig. 2, endometriosis risk due to regular alcohol consumption is expressed in \nterms of unadjusted odds ratio (OR).\nFigure 4.  Heavy versus no alcohol consumption. It presented the results of the analyses of heavy intake vs \nno alcohol intake. As in Fig. 2, endometriosis risk due to heavy alcohol consumption is expressed in terms of \nunadjusted odds ratio (OR).\nTable 3.  Alcohol drinking and risk of endometriosis according to time of intake. OR, Odds ratio; IC, \nconfidence interval. a Reference category.\nAuthor\nNevera Current Former Current/former\nCases/controls\nCases/controls \nOR (95% IC)\nIC)\nCases/controls\nOR (95% IC)\nCases/controls\nOR (95% IC)\nEskenazi et al., 2002 14/171 3/95\n0.39 (0.11–1.38)\n2/11\n2.22 (0.45–11.02) –\nMatalliotakis,2008 193/83 – – 152/32\n2.04 (1.29–3.24)\nMarino, 2009 92/258 159/307\n1.45 (1.07–1.97)\n62/162\n1.07 (0.74–1.57) –\nHuang, 2010 25/26 – – 3/3\nTrabert, 2011 78/228 154/292\n1.54 (1.12–2.13)\n51/140\n1.06 (0.71–1.61) –\nNew contributions\nUpson et al., 2013 29/60 52/90 11/45\nPooled OR 1.39 (1.1–1.7) 1.16 (0.90–1.50) 1.95 (1.26–3.04)\n\n8\nVol:.(1234567890)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\n analysis20, the added data did not significantly change the summary ORs. The updated estimates are reported \nin Table 3.\nFinally, only Ricci et al.47 exploited the effect of different types of beverages, observing a positive, although \nnot significant, association between alcohol intake and endometriosis risk, regardless of wine or beer or spirit.\nSupplementary Figure S1 showed the funnel plot for any versus no alcohol consumption. There was no \nasymmetry in the funnel plot, thus suggesting the absence of publication bias; the Egger test was not significant.\nEvaluation of the study quality according to the Newcastle–Ottawa  Scale43, was reported in Supplementary \nTable S3. Using the NOS tool, high study quality (scale = 7–9) was detected in 16 out of 19 case–control studies \nand in all the cohort and cross-sectional studies.\nDiscussion\nAlcohol consumption in endometriosis has deserved particular attention for many reasons. As summed up by \nParazzini et al., alcohol may interfere with estrogen production, that is critically linked to  endometriosis20,25,52,53. \nMoreover, alcohol could be implied in the vicious circle “pain-stress-inflammation”9,54. In 2021, one of the early \neffects of COVID-19 pandemic was an increase of alcohol consumption for 29.2% endometriosis  patients55. \nNotably, psychiatric disorders (bipolar, depressive, anxiety, and stress-related syndromes) and endometriosis \nmay be  intertwined56–58 so that endometriosis patients may more likely suffer of these  conditions59. However, it \nis not clear whether psychiatric comorbidities burden on endometriosis or whether they are the consequence of \npainful symptoms. Nevertheless, it is not difficult to figure out that chronic pain as well as impaired psychological \nwell-being may encourage alcohol  misuse60,61. Alcohol consumption could be framed as a possible wrong self-\nmedication to cope with either stressful or painful events. Indeed, Gao et al., observed a higher risk of develop-\ning alcohol/drug dependence disorders (HR 1.93; 95%CI, 1.71–2.18) rather than other psychiatric conditions \nin endometriosis population. On the other hand, they also observed the opposite: alcohol/drug dependence \ndisorders were at higher risk for a subsequent endometriosis diagnosis (HR 1.94; 95%CI, 1.84–2.04) 56.\nTo note, alcohol metabolism influences pro-inflammatory pathways and oxidative  stress62–64. Collecting all \nthese premises, alcohol could be involved in endometriosis in two different ways: on one hand, it could be an \neffect of the disease, adopted by patients as a self-management therapy for pain and stressful events or as an \nexpression of psychiatric comorbidity; on the other one, alcohol habit could favor the disease, promoting the \npositive feedback with inflammatory mediators and oxidative stress.\nAs already mentioned, our group previously found a significant positive association between alcohol con-\nsumption and endometriosis  risk20. Our goal was to corroborate this result, updating data with the recent \nliterature.\nExcluding the two papers where alcohol was expressed in  grams44,45, among the newly selected papers we \ncould observe contrasting results. While Ricci et al. 47 reported an increased, although not significant, endo -\nmetriosis risk according to alcohol intake (OR 1.48, 95%CI 0.68–2.79), Ek et al. 48, Schink aet al. 49 and da Silva \net al.50 agreed that unaffected patients tended to be more likely alcohol users. Hemmert et al.46 and Saha et al.51 \nfound no association between this habit and endometriosis risk.\nOverall, in our meta-analysis considering aggregated data to date, although an increased risk of endometriosis \nwas confirmed among any alcohol users, the finding was only of borderline statistical significance and the OR \nestimate was lower than in our previous analysis.\nTo explain these not totally consistent findings, some differences with the previous results should be consid-\nered. In the present meta-analysis, a higher number of prospective studies have been included. Only one of the \nselected recent papers was a cross-sectional  study51. Thus, the possible bias derived by ascertaining exposure \nand outcome at the same time was reduced. In the previous review, the higher proportion of retrospective \ncase–control studies could favor the introduction of selection and recall bias. Collecting lifestyle information \nbefore outcome assessment could limit recall bias. Hemmert et al. 46 used this approach, denying any associa-\ntion between alcohol and endometriosis occurrence. Indeed, going deeper into the concept of exposure, Wolff  \net al. assessed in utero exposures and the risk of endometriosis diagnosis. Intriguingly, though not significantly, \naffected women were less likely to have been exposed to alcohol during  pregnancy10.\nInterestingly, we confirmed a significant relation between a moderate/regular alcohol intake and endome-\ntriosis, with a significant OR of 1.22 (95% CI: 1.03–1.45, p = 0.02). This finding could be in line with the possible \ndouble role of alcohol in the natural history of the disease, as described before. Furthermore, it is reasonable to \ninfer that this result is still related to results from the studies included in the previous meta-analysis20. Indeed, we \nhave added only 3 papers to the other 11 previous works reporting data for the subgroup of “moderate intake” . \nIn other words, findings reported before 2012 could have been robust enough to provide still significant results \nfor the subgroup of “moderate intake” , while they could have been diluted in the overall group of “any intake” by \nthe addition of the more recent findings.\nWe recognize that our study has some limitations that must be addressed. In some papers, endometriosis \ndiagnosis was not confirmed by surgery. This choice may have allowed the inclusion of affected women in the \ncontrol group; however, the general prevalence of the disease is less than 5%2 and this ascertainment bias cannot \nbe expected to have mainly distorted the results. Moreover, self-reported alcohol intake may have introduced a \nfurther bias, especially in the evaluation of number of usual drinks. On the other hand, the funnel plot and the \nEgger test for funnel plot asymmetry did not show evidence of publication bias.\nThe difficulty in establishing whether alcohol exposure precedes endometriosis represents the biggest limita-\ntion for drawing definitive conclusions and still constitutes the real challenge. This issue was similarly reported \nin several works, concerning other modifiable factors. In two independent reviews, both Parazzini et al. 19 and \nlater Osmanlioglu et al. 22 agreed that evidence supporting a significant association between diet and endo-\nmetriosis is equivocal. Polak et al. 21 could not take out any significant conclusions about the relation between \n\n9\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nenvironment and endometriosis risk. On the other hand, higher concentrations of trans-nonachlor, and dioxin-\nlike toxic equivalents, together with an increased inflammatory profile have been associated with higher risk of \n endometrioma65. Environmental exposure remains a major and unsolved  issue66.\nIn line with these papers, our work reflects the tough challenge of isolating the role of specific factors in the \nnatural history of multifactorial diseases, such as endometriosis. Nevertheless, never as now the investigation of \nmodifiable lifestyle factors is urgent for a new integrated therapeutic approach.\nFrom our meta-analysis, we could confirm a significant association between moderate alcohol intake and \nendometriosis but the strength of our previous results could not be proved considering the other categories. \nDespite this could be due to some methodological differences (i.e. the nature of published studies), establishing \nthe role of alcohol in the pathogenesis and progression of disease remains an undisputed need.\nData availability\nAll data generated or analyzed during this study are included in this published article and in its supplementary \ninformation file.\nReceived: 15 March 2022; Accepted: 23 September 2022\nReferences\n 1. Kennedy, S. et al. ESHRE special interest group for endometriosis and endometrium guideline development group. ESHRE guide-\nline for the diagnosis and treatment of endometriosis. Hum. Reprod. 20(10), 2698–704 (2005).\n 2. Vercellini, P ., Viganò, P ., Somigliana, E. & Fedele, L. Endometriosis: Pathogenesis and treatment. Nat. Rev. Endocrinol. 10(5), \n261–275 (2014).\n 3. Laganà, A. S. et al. The pathogenesis of endometriosis: Molecular and cell biology insights. Int. J. Mol. Sci. 20(22), 5615 (2019).\n 4. Ottolina, J. et al. Early-life factors, in-utero exposures and endometriosis risk: A meta-analysis. Reprod. Biomed. Online. 41(2), \n279–289 (2020).\n 5. Somigliana, E. et al. Natural pregnancy seeking in subfertile women with endometriosis. Reprod. Sci. 27(1), 389–394 (2020).\n 6. Ma, H. & Li, J. The ginger extract could improve diabetic retinopathy by inhibiting the expression of e/iNOS and G6PDH, apoptosis, \ninflammation, and angiogenesis. J. Food Biochem. 20, e14084 (2022).\n 7. Hua, F ., Shi, L. & Zhou, P . Phenols and terpenoids: Natural products as inhibitors of NLRP3 inflammasome in cardiovascular \ndiseases. Inflammopharmacology 1, 137–147 (2022).\n 8. Giacomini, E. et al. Genetics and inflammation in endometriosis: Improving knowledge for development of new pharmacological \nstrategies. Int. J. Mol. Sci. 22(16), 9033 (2021).\n 9. Toth, B. Stress, inflammation and endometriosis: Are patients stuck between a rock and a hard place?. J. Mol. Med. (Berl.) 88(3), \n223–225 (2010).\n 10. Wolff, E. F . et al. In utero exposures and endometriosis: The endometriosis, natural history, disease, outcome (ENDO) study. Fertil. \nSteril. 99(3), 790–795 (2013).\n 11. Reis, F . M., Coutinho, L. M., Vannuccini, S., Luisi, S. & Petraglia, F . Is stress a cause or a consequence of endometriosis?. Reprod. \nSci. 27(1), 39–45 (2020).\n 12. Cuevas, M. et al. Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model. Reprod. Sci. \n19(8), 851–862 (2012).\n 13. Kokot, I., Piwowar, A., Jędryka, M., Sołkiewicz, K. & Kratz, E. M. Diagnostic significance of selected serum inflammatory markers \nin women with advanced endometriosis. Int. J. Mol. Sci. 22, 2295 (2021).\n 14. Fan, Y . Y . et al. Expression of inflammatory cytokines in serum and peritoneal fluid from patients with different stages of endo-\nmetriosis. Gynecol. Endocrinol. 34(6), 507–512 (2018).\n 15. Zhou, J. et al. Peritoneal fluid cytokines reveal new insights of endometriosis subphenotypes. Int. J. Mol. Sci. 21(10), 3515 (2020).\n 16. Missmer, S. A. et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. \nAm. J. Epidemiol. 160(8), 784–796 (2004).\n 17. Sasamoto, N. et al. In utero and early life exposures in relation to endometriosis in adolescents and young adults. Eur. J. Obstet. \nGynecol. Reprod. Biol. 252, 393–398 (2020).\n 18. Afrin, S. et al. Diet and nutrition in gynecological disorders: A focus on clinical studies. Nutrients 13(6), 1747 (2021).\n 19. Parazzini, F ., Viganò, P ., Candiani, M. & Fedele, L. Diet and endometriosis risk: A literature review. Reprod. Biomed. Online 26(4), \n323–336 (2013).\n 20. Parazzini, F . et al. A metaanalysis on alcohol consumption and risk of endometriosis. Am. J. Obstet. Gynecol. 209(2), 106 (2013).\n 21. Polak, G., Banaszewska, B., Filip, M., Radwan, M. & Wdowiak, A. Environmental factors and endometriosis. Int. J. Environ. Res. \nPublic Health 18(21), 11025 (2021).\n 22. Osmanlıoğlu, Ş & Sanlier, N. The relationship between endometriosis and diet. Hum. Fertil. (Camb.) 27, 1–16 (2021).\n 23. Chiaffarino, F . et al. Coffee and caffeine intake and risk of endometriosis: A meta-analysis. Eur. J. Nutr. 53(7), 1573–1579 (2014).\n 24. Sahin Ersoy, G. et al. Cigarette smoking affects uterine receptivity markers. Reprod. Sci. 24(7), 989–995 (2017).\n 25. Berube, S., Marcoux, S. & Maheux, R. Characteristics related to the prevalence of minimal or mild endometriosis in infertile \nwomen: Canadian collaborative group on endometriosis. Epidemiology 9, 504–510 (1998).\n 26. Buck Louis, G. M., Hediger, M. L. & Pena, J. B. Intrauterine exposures and risk of endometriosis. Hum. Reprod. 22, 3232–3236 \n(2007).\n 27. Eskenazi, B. et al. Serum dioxin concentrations and endometriosis: A cohort study in Seveso, Italy. Environ. Health Perspect. 110, \n629–634 (2002).\n 28. Grodstein, F . et al. Relation of female infertility to consumption of caffeinated beverages. Am. J. Epidemiol. 137, 1353–1360 (1993).\n 29. Heilier, J. F . et al. Environmental and host-associated risk factors in endometriosis and deep endometriotic nodules: A matched \ncase-control study. Environ. Res. 103, 121 (2007).\n 30. Hemmings, R. et al. Evaluation of risk factors associated with endometriosis. Fertil. Steril. 81, 1513–1521 (2004).\n 31. Huang, P . C. et al. Association between phthalate exposure and glutathione S-transferase M1 polymorphism in adenomyosis, \nleiomyoma and endometriosis. Hum. Reprod. 25, 986–994 (2010).\n 32. Marino, J. L., Holt, V . L., Chen, C. & Davis, S. Lifetime occupational history and risk of endometriosis. Scand. J. Work Environ. \nHealth 35, 233–240 (2009).\n 33. Matalliotakis, I. M. et al. Epidemiological characteristics in women with and without endometriosis in the Y ale series. Arch. Gynecol. \nObstet. 277, 389–393 (2008).\n 34. Nagle, C. M. et al. Relative weight at ages 10 and 16 years and risk of endometriosis: A case-control analysis. Hum. Reprod. 24, \n1501–1506 (2009).\n\n10\nVol:.(1234567890)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\n 35. Parazzini, F . et al. Selected food intake and risk of endometriosis. Hum. Reprod. 19, 1755–1759 (2004).\n 36. Pauwels, A. et al. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: A casecontrol study of infertile \nwomen. Hum. Reprod. 16, 2050–2055 (2001).\n 37. Signorello, L. B. et al. Epidemiologic determinants of endometriosis: A hospital-based case-control study. Ann. Epidemiol. 7, \n267–741 (1997).\n 38. Trabert, B. et al. Diet and risk of endometriosis in a population-based case-control study. Br. J. Nutr. 105, 459–467 (2011).\n 39. Tsukino, H. et al. Associations between serum levels of selected organochlorine compounds and endometriosis in infertile Japanese \nwomen. Environ. Res. 99, 118–125 (2005).\n 40. Page, M. J. et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 372, n71 (2021).\n 41. Egger, M., Davey Smith, G., Schneider, M. & Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109), \n629–634 (1997).\n 42. Thornton, A. & Lee, P . Publication bias in meta-analysis: Its causes and consequences. J Clin Epidemiol. 53(2), 207–216 (2000).\n 43. Wells, G.A. et al. In Newcastle‑Ottawa Scale for Assessing the Quality of Nonrandomized STUDIES in Meta‑Analysis (2019)\n 44. Upson, K. et al. Phthalates and risk of endometriosis. Environ. Res. 126, 91–97 (2013).\n 45. Prescott, J. et al. A prospective cohort study of endometriosis and subsequent risk of infertility. Hum. Reprod. 31(7), 1475–1482 \n(2016).\n 46. Hemmert, R. et al. Modifiable life-style factors and risk for incident endometriosis. Paediatr. Perinat. Epidemiol.  33(1), 19–25 \n(2019).\n 47. Ricci, E. et al. Wine, spirits and beer intake and endometriosis risk among infertile women: Results from a case-control study. Clin. \nExp. Obstet. Gynecol. XLIV, 547–550 (2017).\n 48. Ek, M., Roth, B., Nilsson, P . M. & Ohlsson, B. Characteristics of endometriosis: A case-cohort study showing elevated IgG titers \nagainst the TSH receptor (TRAb) and mental comorbidity. Eur. J. Obstet. Gynecol. Reprod. Biol. 231, 8–14 (2018).\n 49. Demézio-da-Silva, C. V . et al. Dietary inflammatory index score and risk of developing endometriosis: A case–control study. J.. \nEndometriosis Pelvic Pain Disord. 13(1), 32–39 (2021).\n 50. Schink, M. et al. Different nutrient intake and prevalence of gastrointestinal comorbidities in women with endometriosis. J. Physiol. \nPharmacol. 70, 2 (2019).\n 51. Saha, R., Kuja-Halkola, R., Tornvall, P . & Marions, L. Reproductive and lifestyle factors associated with endometriosis in a large \ncross-sectional population sample. J. Womens Health (Larchmt.) 26(2), 152–158 (2017).\n 52. Hankinson, S. E. et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J. \nNatl. Cancer Inst. 87(17), 1297–1302 (1995).\n 53. Fernandez, S. V . Estrogen, alcohol consumption, and breast cancer. Alcohol Clin. Exp. Res. 35(3), 389–391 (2011).\n 54. Jiang, L., Y an, Y ., Liu, Z. & Wang, Y . Inflammation and endometriosis. Front. Biosci. (Landmark Ed). 21, 941–948 (2016).\n 55. Ramos-Echevarría, P . M. et al. Impact of the early COVID-19 era on endometriosis patients: Symptoms, stress, and access to care. \nJ. Endometriosis Pelvic Pain Disord. 13(2), 111–121 (2021).\n 56. Gao, M. et al. Psychiatric comorbidity among women with endometriosis: Nationwide cohort study in Sweden. Am. J. Obstet. \nGynecol. 223(3), 415.e1-415.e16 (2020).\n 57. Chen, L. C. et al.  Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal \nfollow-up study. J. Affect. Disord. 190, 282–285 (2016).\n 58. Ek, M. et al. Gastrointestinal symptoms among endometriosis patients—a case-cohort study. BMC Womens Health. 15, 59 (2015).\n 59. Lagan, A. S. et al. Analysis of psychopathological comorbidity behind the common symptoms and signs of endometriosis. Eur. J. \nObstet. Gynecol. Reprod. Biol. 194, 30–33 (2015).\n 60. Pope, C. J., Sharma, V ., Sharma, S. & Mazmanian, D. A systematic review of the association between psychiatric disturbances and \nendometriosis. J. Obstet. Gynaecol. Can. 37(11), 1006–1015 (2015).\n 61. Maleki, N. & Oscar-Berman, M. Chronic pain in relation to depressive disorders and alcohol abuse. Brain Sci. 10(11), 826 (2020).\n 62. Crews, F . T. et al. Cytokines and alcohol. Alcohol Clin. Exp. Res. 30(4), 720–730 (2006).\n 63. Kawaratani, H. et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm. 2013, 495156 (2013).\n 64. Van-de-Loo, A. J. A. E. et al. The inflammatory response to alcohol consumption and its role in the pathology of alcohol hangover. \nJ. Clin. Med. 9(7), 2081 (2020).\n 65. Matta, K. et al. Associations between persistent organic pollutants and endometriosis: A multiblock approach integrating metabolic \nand cytokine profiling. Environ. Int. 158, 106926 (2021).\n 66. Caporossi, L., Capanna, S., Viganò, P ., Alteri, A. & Papaleo, B. From environmental to possible occupational exposure to risk fac-\ntors: What role do they play in the etiology of endometriosis?. Int. J. Environ. Res. Public Health. 18(2), 532 (2021).\nAuthor contributions\nF .P . designed the study, L.L.P . and F .C. collected the data, F .C. and S.C. performed the analysis and prepared \nFigs. 2, 3 and 4, L.L.P wrote the first draft of the manuscript and prepared Fig. 1, Tables 1, 2 and 3, supplemen-\ntary files. P .V . and E.S. revised and corrected the manuscript. All the authors revised the final version of the \nmanuscript.\nFunding\nThis study was (partially) funded by Italian Ministry of Health- Current research IRCCS.\nCompeting interests \nE. Somigliana receveid personal honoraria to give talks at international meetings from Theramex and Merck-\nSerono, received a donation (US machine) from Merck-Serono for the ART unit and handled grants of research \nfrom Ferring and Theramex. The remaining authors report no financial or commercial conflicts of interest.\nAdditional information\nSupplementary Information The online version contains supplementary material available at https:// doi. org/ \n10. 1038/ s41598- 022- 21173-9.\nCorrespondence and requests for materials should be addressed to L.L.P .\nReprints and permissions information is available at www.nature.com/reprints.\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and \ninstitutional affiliations.\n\n11\nVol.:(0123456789)Scientific Reports |        (2022) 12:19122  | https://doi.org/10.1038/s41598-022-21173-9\nwww.nature.com/scientificreports/\nOpen Access  This article is licensed under a Creative Commons Attribution 4.0 International \nLicense, which permits use, sharing, adaptation, distribution and reproduction in any medium or \nformat, as long as you give appropriate credit to the original author(s) and the source, provide a link to the \nCreative Commons licence, and indicate if changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the \nmaterial. If material is not included in the article’s Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from \nthe copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\n© The Author(s) 2022","source_license":"CC0","license_restricted":false}