Environmental Risk and Protective Factors During Pregnancy for Cleft Lip and Palate in Turkey: A Preliminary Study

Environmental Risk and Protective Factors During Pregnancy for Cleft Lip and Palate in Turkey: A Preliminary Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Environmental Risk and Protective Factors During Pregnancy for Cleft Lip and Palate in Turkey: A Preliminary Study nur ozel erginbas This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6070727/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hypothesis 1 : There is no significant association between environmental factors (paternal smoking, maternal medication use, and folic acid intake) and the incidence of CL/P in Turkey. Hypothesis 2 : Environmental factors, including paternal smoking, maternal medication use, and folic acid intake, significantly influence the occurrence of CL/P in Turkey. Objective This study aims to identify environmental threats and shields associated with cleft lip or without cleft palate (CL/P) among pregnant women in Turkey. Understanding these factors can contribute to developing preventive measures and improving prenatal care. Methods A case-control study was conducted with 312 patients undergone orthodontic treatment diagnosed with CL/P (CL/P group) and 64 without CL/P (control group). Data on characteristics and surrounding exposures were collected via consent form. Statistical analyses were performed to evaluate possible correlations between surrounding factors and CL/P incidence. Results No significant differences were found between the two groups concerning birth weight, birth order, paternal age, occupation, parental chronic diseases, alcohol consumption, exposure to hazardous materails, maternal smoking, exposure of tobacco passive and vitamin/calcium consumption. Most CL/P cases involved children born at term (≥ 37 weeks, 91.8%) and with a normal birth weight (2.8–3.6 kg, 65.4%), being the first or second child in the family (88.5%). Compared to the control group, CL/P cases had a lower rate of parental folic acid intake (66.2% vs. 22.7%, odds ratio [OR] = 0.134; P < 0.001) and higher rates of parental medication use (4.5% vs. 17.8%, OR = 5.02, P < 0.05) and paternal smoking (37.8% vs. 63.1%, OR = 2.58, P < 0.01). Conclusions : The results of this research could shed light on the link between ecological elements and the risk of CL/P in Turkey. CL/P Environmental factors Folic acid intake Smoking Turkey Introduction Cleft lip and palate (CL/P) are among the most common congenital anomalies worldwide, significantly impacting speech, feeding, and overall quality of life.[ 1 ] The etiology of CL/P is multifactorial, involving genetic and environmental risk factors. [ 2 ] Numerous studies have identified parental smoking, maternal medication use, nutritional deficiencies, and exposure to environmental pollutants as potential contributors to CL/P development.[ 3 , 4 ] While global research has provided insight into these risk factors, limited studies focus on the Turkish population.[ 5 ] Turkey's unique socioeconomic and healthcare landscape presents specific challenges and opportunities for preventing CL/P. Understanding the environmental and lifestyle factors contributing to CL/P within the Turkish population can aid in developing targeted public health interventions and prenatal care strategies.[ 6 , 7 ] This study aims to investigate the impact of environmental risk and protective factors, such as paternal smoking, maternal folic acid intake, and medication use, on the occurrence of CL/P in Turkey. Materials and Methods Study Design and Participants This study was conducted as a case-control design at orthodontic clinics in Izmir Educational Dental Hospital treated between 2009–2019. The sample consisted of 312 patients diagnosed with cleft lip or without cleft palate (CL/P) and 64 control participants without CL/P. Data Collection A structured questionnaire was administered to parents, collecting data on demographic characteristics, environmental exposures, and prenatal risk factors. Questions included details on parental age, occupation, chronic diseases, smoking habits, medication use, vitamin and supplement intake, and exposure to hazardous substances. This study has been approved by Katip Celebi Faculty of Dentistry Ethics Committee with the number 0124. Statistical Analysis Chi-square and Fisher’s exact tests were utilized to assess the relationships between environmental variables and CL/P. Odds ratios (OR) accompanied by 95% confidence intervals (CI) were computed to ascertain risk levels. A significance threshold of P < 0.05 was established. A case control investigation involved 312 orthodontic patients identified with cleft lip and palate (CL/P group) and 64 without CL/P (control group). Information regarding demographic details and environmental factors was gathered through parental surveys. Statistical assessments were conducted to explore possible associations between environmental influences and the occurrence of CL/P. Results revealed no notable disparities between the groups in terms of birth weight, birth order, paternal age, occupation, parental chronic illnesses, alcohol intake, exposure to harmful substances, maternal tobacco use, secondhand smoke exposure, and intake of vitamins/calcium. The majority of CL/P instances were noted in children delivered at term (≥ 37 weeks, 91.8%) and with a standard birth weight (2.8–3.6 kg, 65.4%), predominantly being the first or second offspring in the household. In contrast to the control group, CL/P cases exhibited a diminished rate of maternal folic acid consumption (66.2% vs. 22.7%, odds ratio [OR] = 0.134; P < 0.001) and elevated rates of maternal medication usage (4.5% vs. 17.8%, OR = 5.02, P < 0.05) as well as paternal smoking (37.8% vs. 63.1%, OR = 2.58, P < 0.01). Discussion This study suggests that paternal smoking, maternal medication use, and inadequate folic acid intake are key environmental factors influencing CL/P in Turkey [ 6 , 7 ]. The findings align with international research indicating that genetic and environmental interactions contribute to CL/P development [ 8 ]. Additionally, the findings highlight the importance of socioeconomic factors in the prevalence of CL/P. Families with limited access to healthcare, lower educational levels, and lower socioeconomic status may have reduced awareness of prenatal health practices, including the benefits of folic acid supplementation [ 9 , 10 ]. Future public health interventions should prioritize these vulnerable populations to improve pregnancy outcomes. Another key aspect is the role of epigenetic mechanisms in CL/P development. Previous research suggests that environmental exposures, such as tobacco smoke and inadequate prenatal nutrition, may alter gene expression without changing DNA sequences [ 11 , 12 ]. Understanding these mechanisms could provide new prevention strategies in the future. Moreover, the study underscores the necessity of multidisciplinary healthcare approaches. Collaborative efforts between obstetricians, pediatricians, genetic counselors, and public health officials are essential in reducing the prevalence of CL/P [ 13 ]. Awareness campaigns and educational programs targeting expectant parents should be developed to minimize risk factors [ 14 ]. Furthermore, a growing body of evidence suggests that environmental pollutants, including pesticides and heavy metals, could play a role in congenital anomalies such as CL/P [ 15 , 16 ]. Future research should examine these potential risk factors in the Turkish population, as exposure levels may differ due to geographic and occupational variations [ 17 ]. Another potential area of investigation is maternal stress and its relationship with fetal development. Studies suggest that chronic maternal stress during pregnancy may contribute to congenital anomalies through hormonal and vascular changes affecting placental function [ 18 , 19 ]. Exploring this factor could provide further insights into the complex etiology of CL/P. Future research should also incorporate larger sample sizes and examine additional environmental variables, such as exposure to pesticides, air pollution, and occupational hazards [ 20 , 21 ]. These factors might further clarify the environmental contributions to CL/P incidence in Turkey. Conclusion The influence of environmental elements is crucial in the prevalence of CL/P in Turkey. Enhancing public knowledge regarding prenatal wellness, promoting folic acid consumption, and tackling smoking behaviors may help lower the rates of CL/P. Additional research with more extensive sample sizes and thorough exposure evaluations is advised to improve preventative measures Declarations Acknowledgements I would like to thank Izmir Educational Dental Hospital for for allowing me to conduct a study using patient data Authors’ contributions Dr Nur Ozel Erginbas contributed to data collection, analysis, charts drawing, and critically drafted and revised the manuscript. She reviewed the manuscript and gave final approval and agreed to be accountable for all aspects of the work. Funding This study was no funding Availability of data and materials Consent forms previously filled out by patients who had been treated or visited the hospital in department of orthodontics were used. Ethics approval and consent to participate Ethics committee permission was not obtained for this study. Hospital permission was obtained and a study was conducted based on the consent forms signed by the patients. Consent for publication It is applicable. Competing interests The authors declare no competing interests. References Kang MJ, Li NP, Hong H, Park HS, Park JW, Tolarova MM, Yang IH, Hong M, Baek SH. Preliminary study of environmental risk and protective factors during pregnancy for cleft lip with or without palate in the Korean population.Korean J Orthod. 2024 Nov 25;54(6):411-421. Jamilian A, Sarkarat F, Jafari M, Neshandar M, Amini E, Khosravi S, Ghassemi Family history and risk factors for cleft lip and palate patients and their associated anomalies. A.Stomatologija. 2017;19(3):78-83. Z L Jia 1, B Shi, C H Chen, J Y Shi, J Wu, X Xu Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts Comparative Study Oral Dis. 2011 Sep;17(6):584-9. Michael J Dixon 1, Mary L Marazita, Terri H Beaty, Jeffrey C Murray Cleft lip and palate: understanding genetic and environmental influences Nat Rev Genet. 2011 Mar;12(3):167-78. V. Candotto, L. Oberti, F. Gabrione, G. Greco, D. Rossi, M. Romano, S. Mummolo Current concepts on cleft lip and palate etiology. Journal of Biological Regulators and Homeostatic Agents·2019· J Biol Regul Homeost Agents . 2019 May-Jun;33(3 Suppl. 1):145-151. DENTAL SUPPLEMENT. Karim Ahmed Sakran, Bassam Mutahar Abotaleb, Remsh Khaled Al-Rokhami, T. Hsieh, Mohammed A. Al-Wesabi, Abdo Ahmed Mohammed, H. Al-Sharani, Ping Shi, Dengqi He Analysis of Environmental Exposures for Nonsyndromic Cleft Lip and/or Palate: A Case-Control Study Iranian Journal of Public Health·2022· Iran J Public Health. 2022 Mar;51(3):578-586. R. Molina-Solana, R. Yañez-Vico, A. Iglesias-Linares, A. Mendoza-Mendoza, E. Solano-Reina Current concepts on the effect of environmental factors on cleft lip and palate. International Journal of Oral & Maxillofacial Surgery·2013· Int J Oral Maxillofac Surg . 2013 Feb;42(2):177-84. Y. Lin, S. Shu, Shijie Tang A case-control study of environmental exposures for nonsyndromic cleft of the lip and/or palate in eastern Guangdong, China. International Journal of Pediatric Otorhinolaryngology·2014 Mar;78(3):544-50. I. V. van Rooij, C. 9-Vermeij‐Keers, L. Kluijtmans, M. Ocké, G. Zielhuis, S. Goorhuis‐Brouwer, J. J. van der Biezen, A. Kuijpers-Jagtman, R. Steegers-Theunissen Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? American Journal of Epidemiology· 2003· Apr 1;157(7):583-91. Candice Y Johnson, J. Little Folate intake, markers of folate status and oral clefts: is the evidence converging? International Journal of Epidemiology·2008· Oct;37(5):1041-58 Jose Jesus Ibarra-Lopez, P. Duarte, Verónica Antonio-Véjar, E. Calderón-Aranda, G. Huerta-Beristain, E. Flores-Alfaro, M. E. Moreno-Godinez Maternal C677T MTHFR Polymorphism and Environmental Factors Are Associated With Cleft Lip and Palate in a Mexican Population Journal of Investigative Medicine·2013· Aug;61(6):1030-5 Yu Hong, Xianrong Xu, F. Lian, Rong Chen Environmental Risk Factors for Nonsyndromic Cleft Lip and/or Cleft Palate in Xinjiang Province, China: A Multiethnic Study The Cleft Palate-Craniofacial Journal· 2021 Apr;58(4):489-496.· I. Krapels, G. Zielhuis, F. Vroom, L. de Jong-van den Berg, A. Kuijpers-Jagtman, A. V. D. van der Molen, R. Steegers-Theunissen Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts. Birth defects research. Clinical and molecular teratology·2006· Aug;76(8):613-20 R. Badovinac, M. Werler, Paige L. Williams, K. Kelsey, C. Hayes Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth defects research. Clinical and molecular teratology·2007· Jan;79(1):8-15. L. Nahas, Omar Alzamel, Mammdouh Yassin Dali, Rama Alsawah, A. Hamsho, Rafi Sulman, Mohamad Alzamel, A. Omar ·Distribution and risk factors of cleft lip and palate on patients from a sample of Damascus hospitals - A case-control study Heliyon·2021 Sep 7;7(9):e07957. Lili Ács, Bálint Nemes, Krisztián Nagy, Márton Ács, F. Bánhidy, Noémi Rózsa Maternal factors in the origin of cleft lip/cleft palate: A population-based case-control study. Orthodontics & craniofacial research·2023· Jun:27 Suppl 1:6-13 Fabrizio Bianchi, E. Calzolari, L. Ciulli, Sylvaine Cordier, Francesca Gualandi, A. Pierini, P. Mossey Environment and genetics in the etiology of cleft lip and cleft palate with reference to the role of folic acid. Epidemiologia & Prevenzione·2000· Jan-Feb;24(1):21-7. Da-peng Xu, Wei-dong Qu, Chao Sun, Rong-yu Cao, Dianwei Liu, Pinggong Du A Study on Environmental Factors for Nonsyndromic Cleft Lip and/or Palate The Journal of craniofacial surgery 2018 Mar;29(2):364-367.· A. Czeizel, L. Tı́már, Andrea Sárközi Dose-dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics·1999· Dec;104(6):e66. G. Shaw, S. Carmichael, Cécile Laurent, S. Rasmussen Maternal Nutrient Intakes and Risk of Orofacial Clefts Epidemiology· 2006· May;17(3):285-91. M. Martinelli, L. Scapoli, F. Pezzetti, F. Carinci, P. Carinci, G. Stabellini, L. Bisceglia, Fernando Gombos, M. Tognon C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? American journal of medical genetics·2001· Feb 1;98(4):357-60 Tables Table 1. Distribution of Cleft Type and Sex in the CL/P Group Cleft Type Male (n=172) Female (n=140) Total (n=312) Cleft Lip (CL) 58 (33.7%) 42 (30.0%) 100 (32.1%) Cleft Palate (CP) 42 (24.4%) 38 (27.1%) 80 (25.6%) Cleft Lip and Palate (CLP) 72 (41.9%) 60 (42.9%) 132 (42.3%) Table 2. Demographic Characteristics of Study Participants Characteristic CL/P Group (n=312) Control Group (n=64) P-Value Male (%) 172 (55.1) 34 (53.1) 0.785 Female (%) 140 (44.9) 30 (46.9) 0.785 Term Birth (%) 286 (91.8) 58 (90.6) 0.752 Preterm Birth (%) 26 (8.2) 6 (9.4) 0.752 Table 3. Environmental Exposures and Risk Factors Risk Factor CL/P Group (n=312) Control Group (n=64) OR (95% CI) P-Value Paternal Smoking (%) 197 (63.1) 24 (37.8) 2.58 (1.45–4.61) 0.01 Maternal Smoking (%) 8 (2.6) 1 (1.6) 1.63 (0.18–14.91) 0.56 Folic Acid Intake (%) 71 (22.7) 42 (66.2) 0.134 (0.08–0.23) <0.001 Maternal Medication Use (%) 56 (17.8) 3 (4.5) 5.02 (1.45–17.33) 0.05 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Numerous studies have identified parental smoking, maternal medication use, nutritional deficiencies, and exposure to environmental pollutants as potential contributors to CL/P development.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] While global research has provided insight into these risk factors, limited studies focus on the Turkish population.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eTurkey's unique socioeconomic and healthcare landscape presents specific challenges and opportunities for preventing CL/P. Understanding the environmental and lifestyle factors contributing to CL/P within the Turkish population can aid in developing targeted public health interventions and prenatal care strategies.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] This study aims to investigate the impact of environmental risk and protective factors, such as paternal smoking, maternal folic acid intake, and medication use, on the occurrence of CL/P in Turkey.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e \u003cb\u003eStudy Design and Participants\u003c/b\u003e This study was conducted as a case-control design at orthodontic clinics in Izmir Educational Dental Hospital treated between 2009\u0026ndash;2019. The sample consisted of 312 patients diagnosed with cleft lip or without cleft palate (CL/P) and 64 control participants without CL/P.\u003c/p\u003e \u003cp\u003e\u003cb\u003eData Collection\u003c/b\u003e A structured questionnaire was administered to parents, collecting data on demographic characteristics, environmental exposures, and prenatal risk factors. Questions included details on parental age, occupation, chronic diseases, smoking habits, medication use, vitamin and supplement intake, and exposure to hazardous substances. This study has been approved by Katip Celebi Faculty of Dentistry Ethics Committee with the number 0124.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eChi-square and Fisher\u0026rsquo;s exact tests were utilized to assess the relationships between environmental variables and CL/P. Odds ratios (OR) accompanied by 95% confidence intervals (CI) were computed to ascertain risk levels. A significance threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was established.\u003c/p\u003e \u003cp\u003eA case control investigation involved 312 orthodontic patients identified with cleft lip and palate (CL/P group) and 64 without CL/P (control group). Information regarding demographic details and environmental factors was gathered through parental surveys. Statistical assessments were conducted to explore possible associations between environmental influences and the occurrence of CL/P. Results revealed no notable disparities between the groups in terms of birth weight, birth order, paternal age, occupation, parental chronic illnesses, alcohol intake, exposure to harmful substances, maternal tobacco use, secondhand smoke exposure, and intake of vitamins/calcium. The majority of CL/P instances were noted in children delivered at term (\u0026ge;\u0026thinsp;37 weeks, 91.8%) and with a standard birth weight (2.8\u0026ndash;3.6 kg, 65.4%), predominantly being the first or second offspring in the household. In contrast to the control group, CL/P cases exhibited a diminished rate of maternal folic acid consumption (66.2% vs. 22.7%, odds ratio [OR]\u0026thinsp;=\u0026thinsp;0.134; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and elevated rates of maternal medication usage (4.5% vs. 17.8%, OR\u0026thinsp;=\u0026thinsp;5.02, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as well as paternal smoking (37.8% vs. 63.1%, OR\u0026thinsp;=\u0026thinsp;2.58, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study suggests that paternal smoking, maternal medication use, and inadequate folic acid intake are key environmental factors influencing CL/P in Turkey [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The findings align with international research indicating that genetic and environmental interactions contribute to CL/P development [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, the findings highlight the importance of socioeconomic factors in the prevalence of CL/P. Families with limited access to healthcare, lower educational levels, and lower socioeconomic status may have reduced awareness of prenatal health practices, including the benefits of folic acid supplementation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Future public health interventions should prioritize these vulnerable populations to improve pregnancy outcomes.\u003c/p\u003e \u003cp\u003eAnother key aspect is the role of epigenetic mechanisms in CL/P development. Previous research suggests that environmental exposures, such as tobacco smoke and inadequate prenatal nutrition, may alter gene expression without changing DNA sequences [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Understanding these mechanisms could provide new prevention strategies in the future.\u003c/p\u003e \u003cp\u003eMoreover, the study underscores the necessity of multidisciplinary healthcare approaches. Collaborative efforts between obstetricians, pediatricians, genetic counselors, and public health officials are essential in reducing the prevalence of CL/P [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Awareness campaigns and educational programs targeting expectant parents should be developed to minimize risk factors [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, a growing body of evidence suggests that environmental pollutants, including pesticides and heavy metals, could play a role in congenital anomalies such as CL/P [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Future research should examine these potential risk factors in the Turkish population, as exposure levels may differ due to geographic and occupational variations [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother potential area of investigation is maternal stress and its relationship with fetal development. Studies suggest that chronic maternal stress during pregnancy may contribute to congenital anomalies through hormonal and vascular changes affecting placental function [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Exploring this factor could provide further insights into the complex etiology of CL/P.\u003c/p\u003e \u003cp\u003eFuture research should also incorporate larger sample sizes and examine additional environmental variables, such as exposure to pesticides, air pollution, and occupational hazards [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These factors might further clarify the environmental contributions to CL/P incidence in Turkey.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe influence of environmental elements is crucial in the prevalence of CL/P in Turkey. Enhancing public knowledge regarding prenatal wellness, promoting folic acid consumption, and tackling smoking behaviors may help lower the rates of CL/P. Additional research with more extensive sample sizes and thorough exposure evaluations is advised to improve preventative measures\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would like to thank Izmir Educational Dental Hospital for for allowing me to conduct a study using patient data\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Nur Ozel Erginbas contributed to data collection, analysis, charts drawing, and critically\u003c/p\u003e\n\u003cp\u003edrafted and revised the manuscript. She reviewed the manuscript and gave final approval\u003c/p\u003e\n\u003cp\u003eand agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was no funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent forms previously filled out by patients who had been treated or visited the hospital in department of orthodontics were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics committee permission was not obtained for this study. Hospital permission was obtained and a study was conducted based on the consent forms signed by the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt is applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKang MJ, Li NP, Hong H, Park HS, Park JW, Tolarova MM, Yang IH, Hong M, Baek SH. Preliminary study of environmental risk and protective factors during pregnancy for cleft lip with or without palate in the Korean population.Korean J Orthod. 2024 Nov 25;54(6):411-421. \u003c/li\u003e\n\u003cli\u003eJamilian A, Sarkarat F, Jafari M, Neshandar M, Amini E, Khosravi S, Ghassemi Family history and risk factors for cleft lip and palate patients and their associated anomalies. A.Stomatologija. 2017;19(3):78-83.\u003c/li\u003e\n\u003cli\u003eZ L Jia 1, B Shi, C H Chen, J Y Shi, J Wu, X Xu Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts Comparative Study Oral Dis. 2011 Sep;17(6):584-9.\u003c/li\u003e\n\u003cli\u003eMichael J Dixon 1, Mary L Marazita, Terri H Beaty, Jeffrey C Murray Cleft lip and palate: understanding genetic and environmental influences Nat Rev Genet. 2011 Mar;12(3):167-78.\u003c/li\u003e\n\u003cli\u003eV. Candotto, L. Oberti, F. Gabrione, G. Greco, D. Rossi, M. Romano, S. Mummolo Current concepts on cleft lip and palate etiology. Journal of Biological Regulators and Homeostatic Agents\u0026middot;2019\u0026middot; J Biol Regul Homeost Agents . 2019 May-Jun;33(3 Suppl. 1):145-151. DENTAL SUPPLEMENT.\u003c/li\u003e\n\u003cli\u003eKarim Ahmed Sakran, Bassam Mutahar Abotaleb, Remsh Khaled Al-Rokhami, T. Hsieh, Mohammed A. Al-Wesabi, Abdo Ahmed Mohammed, H. Al-Sharani, Ping Shi, Dengqi He Analysis of Environmental Exposures for Nonsyndromic Cleft Lip and/or Palate: A Case-Control Study Iranian Journal of Public Health\u0026middot;2022\u0026middot; Iran J Public Health. 2022 Mar;51(3):578-586.\u003c/li\u003e\n\u003cli\u003eR. Molina-Solana, R. Ya\u0026ntilde;ez-Vico, A. Iglesias-Linares, A. Mendoza-Mendoza, E. Solano-Reina Current concepts on the effect of environmental factors on cleft lip and palate. International Journal of Oral \u0026amp; Maxillofacial Surgery\u0026middot;2013\u0026middot; Int J Oral Maxillofac Surg . 2013 Feb;42(2):177-84.\u003c/li\u003e\n\u003cli\u003eY. Lin, S. Shu, Shijie Tang A case-control study of environmental exposures for nonsyndromic cleft of the lip and/or palate in eastern Guangdong, China. International Journal of Pediatric Otorhinolaryngology\u0026middot;2014 Mar;78(3):544-50. \u003c/li\u003e\n\u003cli\u003eI. V. van Rooij, C. 9-Vermeij‐Keers, L. Kluijtmans, M. Ock\u0026eacute;, G. Zielhuis, S. Goorhuis‐Brouwer, J. J. van der Biezen, A. Kuijpers-Jagtman, R. Steegers-Theunissen Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? American Journal of Epidemiology\u0026middot; 2003\u0026middot; Apr 1;157(7):583-91.\u003c/li\u003e\n\u003cli\u003eCandice Y Johnson, J. Little Folate intake, markers of folate status and oral clefts: is the evidence converging? International Journal of Epidemiology\u0026middot;2008\u0026middot; Oct;37(5):1041-58\u003c/li\u003e\n\u003cli\u003eJose Jesus Ibarra-Lopez, P. Duarte, Ver\u0026oacute;nica Antonio-V\u0026eacute;jar, E. Calder\u0026oacute;n-Aranda, G. Huerta-Beristain, E. Flores-Alfaro, M. E. Moreno-Godinez Maternal C677T MTHFR Polymorphism and Environmental Factors Are Associated With Cleft Lip and Palate in a Mexican Population Journal of Investigative Medicine\u0026middot;2013\u0026middot; Aug;61(6):1030-5\u003c/li\u003e\n\u003cli\u003eYu Hong, Xianrong Xu, F. Lian, Rong Chen Environmental Risk Factors for Nonsyndromic Cleft Lip and/or Cleft Palate in Xinjiang Province, China: A Multiethnic Study The Cleft Palate-Craniofacial Journal\u0026middot; 2021 Apr;58(4):489-496.\u0026middot;\u003c/li\u003e\n\u003cli\u003eI. Krapels, G. Zielhuis, F. Vroom, L. de Jong-van den Berg, A. Kuijpers-Jagtman, A. V. D. van der Molen, R. Steegers-Theunissen Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts. Birth defects research. Clinical and molecular teratology\u0026middot;2006\u0026middot; Aug;76(8):613-20\u003c/li\u003e\n\u003cli\u003eR. Badovinac, M. Werler, Paige L. Williams, K. Kelsey, C. Hayes Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth defects research. Clinical and molecular teratology\u0026middot;2007\u0026middot; Jan;79(1):8-15. \u003c/li\u003e\n\u003cli\u003eL. Nahas, Omar Alzamel, Mammdouh Yassin Dali, Rama Alsawah, A. Hamsho, Rafi Sulman, Mohamad Alzamel, A. Omar \u0026middot;Distribution and risk factors of cleft lip and palate on patients from a sample of Damascus hospitals - A case-control study Heliyon\u0026middot;2021 Sep 7;7(9):e07957.\u003c/li\u003e\n\u003cli\u003eLili \u0026Aacute;cs, B\u0026aacute;lint Nemes, Kriszti\u0026aacute;n Nagy, M\u0026aacute;rton \u0026Aacute;cs, F. B\u0026aacute;nhidy, No\u0026eacute;mi R\u0026oacute;zsa Maternal factors in the origin of cleft lip/cleft palate: A population-based case-control study. Orthodontics \u0026amp; craniofacial research\u0026middot;2023\u0026middot; Jun:27 Suppl 1:6-13\u003c/li\u003e\n\u003cli\u003eFabrizio Bianchi, E. Calzolari, L. Ciulli, Sylvaine Cordier, Francesca Gualandi, A. Pierini, P. Mossey Environment and genetics in the etiology of cleft lip and cleft palate with reference to the role of folic acid. Epidemiologia \u0026amp; Prevenzione\u0026middot;2000\u0026middot; Jan-Feb;24(1):21-7.\u003c/li\u003e\n\u003cli\u003eDa-peng Xu, Wei-dong Qu, Chao Sun, Rong-yu Cao, Dianwei Liu, Pinggong Du A Study on Environmental Factors for Nonsyndromic Cleft Lip and/or Palate The Journal of craniofacial surgery 2018 Mar;29(2):364-367.\u0026middot;\u003c/li\u003e\n\u003cli\u003eA. Czeizel, L. Tı́m\u0026aacute;r, Andrea S\u0026aacute;rk\u0026ouml;zi Dose-dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics\u0026middot;1999\u0026middot; Dec;104(6):e66.\u003c/li\u003e\n\u003cli\u003eG. Shaw, S. Carmichael, C\u0026eacute;cile Laurent, S. Rasmussen Maternal Nutrient Intakes and Risk of Orofacial Clefts Epidemiology\u0026middot; 2006\u0026middot; May;17(3):285-91.\u003c/li\u003e\n\u003cli\u003eM. Martinelli, L. Scapoli, F. Pezzetti, F. Carinci, P. Carinci, G. Stabellini, L. Bisceglia, Fernando Gombos, M. Tognon C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? American journal of medical genetics\u0026middot;2001\u0026middot; Feb 1;98(4):357-60\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Distribution of Cleft Type and Sex in the CL/P Group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCleft Type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMale (n=172)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFemale (n=140)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n=312)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCleft Lip (CL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e58 (33.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100 (32.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCleft Palate (CP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42 (24.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38 (27.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80 (25.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCleft Lip and Palate (CLP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e72 (41.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e132 (42.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Demographic Characteristics of Study Participants\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCL/P Group (n=312)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl Group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e172 (55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34 (53.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e140 (44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 (46.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTerm Birth (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e286 (91.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e58 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.752\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePreterm Birth (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.752\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Environmental Exposures and Risk Factors\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRisk Factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCL/P Group (n=312)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl Group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePaternal Smoking (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e197 (63.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (37.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.58 (1.45\u0026ndash;4.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMaternal Smoking (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.63 (0.18\u0026ndash;14.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFolic Acid Intake (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e71 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42 (66.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.134 (0.08\u0026ndash;0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMaternal Medication Use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.02 (1.45\u0026ndash;17.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"CL/P, Environmental factors, Folic acid intake, Smoking, Turkey","lastPublishedDoi":"10.21203/rs.3.rs-6070727/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6070727/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eHypothesis 1\u003c/b\u003e : There is no significant association between environmental factors (paternal smoking, maternal medication use, and folic acid intake) and the incidence of CL/P in Turkey.\u003c/p\u003e \u003cp\u003e \u003cb\u003eHypothesis 2\u003c/b\u003e: Environmental factors, including paternal smoking, maternal medication use, and folic acid intake, significantly influence the occurrence of CL/P in Turkey.\u003c/p\u003e \u003cp\u003e \u003cb\u003eObjective\u003c/b\u003e This study aims to identify environmental threats and shields associated with cleft lip or without cleft palate (CL/P) among pregnant women in Turkey. Understanding these factors can contribute to developing preventive measures and improving prenatal care.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e A case-control study was conducted with 312 patients undergone orthodontic treatment diagnosed with CL/P (CL/P group) and 64 without CL/P (control group). Data on characteristics and surrounding exposures were collected via consent form. Statistical analyses were performed to evaluate possible correlations between surrounding factors and CL/P incidence.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults\u003c/b\u003e No significant differences were found between the two groups concerning birth weight, birth order, paternal age, occupation, parental chronic diseases, alcohol consumption, exposure to hazardous materails, maternal smoking, exposure of tobacco passive and vitamin/calcium consumption. Most CL/P cases involved children born at term (\u0026ge;\u0026thinsp;37 weeks, 91.8%) and with a normal birth weight (2.8\u0026ndash;3.6 kg, 65.4%), being the first or second child in the family (88.5%).\u003c/p\u003e \u003cp\u003eCompared to the control group, CL/P cases had a lower rate of parental folic acid intake (66.2% vs. 22.7%, odds ratio [OR]\u0026thinsp;=\u0026thinsp;0.134; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and higher rates of parental medication use (4.5% vs. 17.8%, OR\u0026thinsp;=\u0026thinsp;5.02, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and paternal smoking (37.8% vs. 63.1%, OR\u0026thinsp;=\u0026thinsp;2.58, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusions\u003c/b\u003e: The results of this research could shed light on the link between ecological elements and the risk of CL/P in Turkey.\u003c/p\u003e","manuscriptTitle":"Environmental Risk and Protective Factors During Pregnancy for Cleft Lip and Palate in Turkey: A Preliminary Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 15:59:54","doi":"10.21203/rs.3.rs-6070727/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"613016fb-fd67-4b18-9772-5f255cb0d74b","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-29T10:24:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-03 15:59:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6070727","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6070727","identity":"rs-6070727","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}