Implementation Protocol for a Treatment Bundle Targeting Modifiable Risk Factors for Preterm Birth: a stepped wedge implementation study.

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Bruna Ribeiro de Andrade Ramos, João José Aguera Oliver Júnior, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5356838/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 Background: Preterm birth (PTB) is the main cause of perinatal and neonatal morbidity and mortality worldwide. Widespread implementation of guidelines for early identification and management of patients at risk for adverse pregnancy outcomes is still feeble. This work aims to implement a simple and low-cost bundle to access and manage major modifiable risk factors for PTB. Methods: We included first trimester pregnant women seen at Health Units from Jaú – SP, where PTB prevalence is 13.4%. The protocol is based on three aspects: a questionnaire to access smoking status and clinical history; Gram staining and of vaginal microbiota evaluation using Nugent’s criteria and evaluation of cervical infections; and transvaginal ultrasound. Pregnant women who smoke and are willing to quit will be treated with auricular acupuncture and referred to a support group if necessary. All patients will be advised on intimate hygiene habits, and those with dysbiosis will be treated. Cervical length will be accessed using transvaginal ultrasound, and those diagnosed with cervical shortening will be treated with vaginal progesterone. Discussion: Prevention of PTB is difficult to achieve. However, a reduction in rate by targeted and tailored interventions for identifiable and modifiable risk factors is achievable. This study highlights the importance of implementing active measures to reduce PTB risk factors in a high prevalence setting. Trial registration: The study protocol was retrospectively registered in the Brazilian Clinical Trial Registry (ReBec) on October 29th, 2024. Preterm Birth Implementation Research Prematurity Prevention Smoking Habits Vaginal Dysbiosis Short Cervix Background Preterm birth (PTB), defined as birth before 37 weeks of gestation, is associated with perinatal morbidity and mortality worldwide. Preterm newborns are more likely to have short- and long-term complications, such as neurological impairment and increased susceptibility to infections, which can lead to irreversible sequelae, reducing the quality of life of the newborn ( 1 ). Worldwide, the prevalence of PTB is approximately 11% ( 1 ), and Brazil in one of the most affected countries, with over 308,700 children born preterm every year, accounting for a preterm birth rate of 11.5%. In São Paulo state, 11.5% of births in 2023 were preterm, and a higher percentage was reported in the municipality of Jaú, where this adverse outcome affected 13.5% of all pregnancies ( 2 ). PTB is a syndrome of multifactorial etiology with significant activation of inflammatory, oxidative stress, and senescence pathways ( 3 ). PTB prevention should be a priority in public health policies; however, despite all the scientific and clinical efforts to fully elucidate and prevent PTB, protocols for early identification and effective management of women at risk have not yet been well-defined or effectively implemented, especially in Brazil. The main barrier to the implementation of such strategies is the gap in knowledge and communication between researchers, health professionals, and policymakers. In this context, three modifiable risk factors stand out for their well-established association with PTB: smoking habit, vaginal dysbiosis, and cervical shortening ( 4 – 9 ). Smoking is a strong predictor of spontaneous preterm labor. Smoking during pregnancy has been associated with numerous adverse outcomes, including low birth weight, intrauterine growth restriction, prematurity, and infant mortality, due to heightened levels of inflammation and oxidative stress ( 4 ). It is important to emphasize that smoking may be considered as a modifiable risk. In an epidemiological study based on national databases in the United States, Soneji et al. ( 4 ) observed that smoking cessation was associated with a relative reduction in the risk of PTB up to 23%, especially if the habit was stopped early in pregnancy. The authors also observed a dose-response effect, with the risk of PTB being directly proportional to the number of cigarettes consumed. There are currently some strategies available to control smoking, such as pharmacological treatment, group support, and acupuncture. Studies suggest that auricular acupuncture can contribute to combating smoking through points that promote a reduction in anxiety and withdrawal symptoms ( 5 ). Healthy vaginal microbiota is mainly colonized by Lactobacillus spp., which synthesizes lactic acid and other products that provide local protection against pathogens ( 6 ). The replacement of the lactobacilli by anaerobic pathogens facilitates its ascent to the amniotic cavity. It triggers an inflammatory response characterized by the production of cytokines and prostaglandins, ultimately inducing the labor-related events of myometrial contractility, cervical effacement, and rupture of the fetal membranes ( 7 ). Although treatment for vaginal dysbiosis has not yet been proven effective in preventing PTB in late pregnancy ( 8 ), the condition is easily diagnosed by bacterioscopy, and the maintenance of eubiosis from the early stages of pregnancy may favor timely, adequate outcomes. Another well-established risk factor for PTB is the length of the uterine cervix. A cervical length of less than 25 mm between the 16th and 24th gestational weeks is a strong independent predictor of spontaneous PTB. The risk of PTB in these cases is estimated at 25–30% in women with no history of PTB and up to 35% in pregnant women who have previously presented PTB ( 9 ). If the length is under 15 mm, the risk of PTB reaches 50%. In fact, several authors indicate the need for screening cervical length in this period via transvaginal ultrasound ( 9 – 11 ). The management of cervical shortening (CS) includes the topical administration of progesterone, the use of pessary, and cerclage. A recent meta-analysis detected a significant reduction in the rate of extreme prematurity (< 33 weeks of gestation, < 2,500 grams birth weight) in pregnant women with CS (< 25 mm) who used intravaginal progesterone daily ( 11 ). A common factor for the aforementioned conditions is the possibility of implementing preventive measures. Identifying risk factors for PTB early and before the development of irreversible clinical symptoms (e.g., cervical dilation, intraamniotic infection, oxidative damage associated inflammation) enables a personalized approach to patient care, aiming to reduce the risk of preterm birth and its sequelae. Methods This study aims to implement a bundle comprised of low-cost interventions to treat the main modifiable risk factors for preterm birth in pregnant women from Health Units in the city of Jaú - SP, Brazil. Study design This is the protocol of an ongoing implementation study with a quasi-experimental controlled trial design conducted with pregnant women from primary health care units in the municipality of Jaú. The city of Jaú, located in the central region of the state of São Paulo, has a population of 151,881 inhabitants and 16 Basic Health Units (UBS) and Family Health Units (USF), in addition to a high-risk pregnancy clinic, Gestar, where this project is implemented. The 16 UBS/USF were considered clusters and will be included in the study at different stages, according to the stepped wedge model, in which the clusters are gradually transferred to the intervention group at regular intervals until all have been transferred. This design is particularly useful in situations where the intervention cannot be implemented simultaneously for all units due to time, logistics, or ethical constraints ( 12 ). In the first phase, eight of these clusters were randomly selected using a simple randomization process to receive the intervention, focusing on pregnant women during their first trimester. Over time, the remaining clusters will be randomly assigned to transition into the intervention group at regular intervals, using the same simple randomization method, ensuring that by the end of the study, all clusters will have received the intervention. This approach allows for a structured, phased implementation of the intervention, accommodating logistical and ethical constraints, and enables the comparison between clusters that have and have not yet received the intervention during the initial stages of the study. In the first 14 months, all first-trimester pregnant women from 8 randomized UBS/USF (clusters) are being included. In the next step of the study, 2 UBS/USF per month will be included until all primary care units (clusters) in the municipality are included. All pregnant women of eligible gestational age from the 8 initially randomized health units were systematically invited to participate in the study and referred to Gestar. All participants included in the study will be monitored until the gestational outcome through 3 appointments, one in each gestational trimester. Considering that the intervention can reduce the prematurity rate to 11.5% (rate for the state of SP), with 95% reliability, 5% margin of error and 80% test power, the final minimum sample size calculated is 201 patients. Considering a 20% loss to follow-up, the initial proposed sample size will be 241 patients. The inclusion criteria for the study were singleton pregnancy and gestational age between 11 weeks and 13 weeks and 6 days at the first appointment, defined by ultrasound. Pregnancies with fetal death will be excluded from the study. Interventions The intervention in this study is designed to manage and mitigate modifiable risk factors associated with spontaneous PTB among pregnant women. It is implemented as a bundle of low-cost measures across different stages of pregnancy, with a focus on three key areas: smoking cessation, maintenance of healthy vaginal microbiota, and management of cervical shortening. Below is a detailed description of each component of the intervention: 1. First Trimester (11 to 13 weeks and 6 days): Assessment and Smoking Intervention Sociodemographic and Clinical Assessment : During the first trimester, participants undergo an initial interview to collect personal, social, and clinical information. This includes family and obstetric history, as well as smoking status. Smoking Cessation Support : Pregnant women identified as smokers who are willing to quit are provided with a comprehensive smoking cessation program. This includes referral to the city’s smoking prevention program, which is conducted at the Alcohol and Drug Psychosocial Care Center (CAPS-AD). The smoking intervention involves an initial interview and adjuvant treatment with auricular acupuncture. This technique uses pressure points in the ear to help reduce anxiety and withdrawal symptoms associated with smoking cessation. Acupuncture sessions are conducted every 15 days, where seeds are placed on specific points in the ear to stimulate them. Cotton and 70% alcohol are used to clean the ear, an auricular pressure gauge is used to locate the points, and mustard seeds with micropore are placed for acupressure of the selected points. The patients are instructed to stimulate these points themselves three times daily. If necessary, group sessions with psychological support are provided at CAPS-AD, and pharmacological treatment, such as nicotine patches, may be used for gradual dose reduction to alleviate withdrawal symptoms. 2. Second Trimester (20 to 23 weeks and 6 days): Cervical Length Monitoring and Infection Treatment Cervical Length Screening : Between 20 and 24 weeks of gestation, all participating women undergo a transvaginal ultrasound to measure cervical length, a critical indicator of the risk for PTB. The measurement is taken with the patient in the lithotomy position, using a transvaginal probe to assess the distance between the internal and external orifices of the cervical canal. Women are instructed to empty their bladder before the ultrasound evaluation. If a cervical length of less than 25 mm is detected, the woman is diagnosed with cervical shortening. Women diagnosed with cervical shortening are prescribed 200 mg of vaginal progesterone daily until 36 weeks of gestation, aiming to reduce the risk of PTB. For these women, the measurement is repeated biweekly for follow-up. For cases of severe cervical shortening, such as lengths below 15 mm, cerclage — a surgical procedure to reinforce the cervix — is considered, depending on the patient’s clinical history and ongoing evaluations. Investigation and Treatment of Infections : During the same trimester, women are also screened for lower genital tract infections using molecular tests for Chlamydia trachomatis and Neisseria gonorrhoeae . These investigations were performed at this time due to the less friable nature of mid-trimester cervices in comparison to the first trimester of pregnancy. The assessment includes a complete gynecological examination with swabs for Gram staining, vaginal pH measurement, and cytobrush sampling collection for PCR analysis of cervical infection using the automated Cobas® 4800 CT/NG v2.0. Identified infections are treated according to the local clinical protocols to ensure the health of both the mother and the fetus. 3. Throughout All Trimesters (11 weeks to Term): Vaginal Microbiota Monitoring and Dysbiosis Management Quarterly Assessment of Vaginal Microbiota : During each trimester, vaginal samples are collected to assess eubiosis (the balance of the vaginal microbiota) using the Gram staining method according to the criteria set by Nugent et al. ( 13 ). The evaluation aims to identify dysbiosis, such as bacterial vaginosis, candidiasis, or other alterations in the vaginal microbiota. Women diagnosed with dysbiosis receive treatment based on the type of condition identified. For bacterial vaginosis, standard antibiotic regimens are administered, while antifungal treatment is provided for candidiasis. Additionally, all participants are educated on proper intimate hygiene practices to help maintain a balanced vaginal environment throughout the pregnancy. The study protocol was registered in the Brazilian Clinical Trial Registry (ReBec) on October 29th, 2024. Analysis The main outcome of interest is gestational age at birth, based on first-trimester ultrasound. Secondary outcomes include the percentage of pregnant women included, the percentage of complete follow-up, adherence to prescribed treatments, and neonatal outcome. Descriptive statistics will be performed to analyze clinical, biological, and sociodemographic data of the studied population. The microbiota status among the trimesters will be compared using the Chi-square test. The level of significance adopted for the tests used will be 5%, using Prism 5.0. Discussion Several factors contribute to prematurity rates at a populational level. Despite ongoing efforts to prevent prematurity, protocols for early identification and management of women at risk are yet to be fully defined and widely implemented. In the context of preterm birth (PTB) prevention, it is crucial to differentiate between merely identifiable risk factors and those that are manageable. Factors such as a personal or family history of PTB are inherently identifiable but cannot be altered ( 14 ). In contrast, modifiable risk factors, including smoking habit, vaginal dysbiosis, and cervical shortening, are more dynamic and can be managed through targeted interventions. These manageable factors are particularly responsive to intervention, meaning that timely and appropriate measures can significantly mitigate their impact on pregnancy outcomes, ultimately reducing the risk of PTB. While individual interventions addressing these risk factors have been applied in some settings, to our knowledge, this is the first study to implement a low-cost bundle that systematically modulates modifiable risk factors for PTB in a high-prevalence population. This bundle is applied at multiple stages of pregnancy to address the specific modifiable risk factors of smoking, cervical shortening, and vaginal dysbiosis. By providing tailored support, the bundle aims to lower the incidence of PTB within this cohort. The approach is practical, scalable, and designed to be low-cost, making it suitable for implementation in resource-limited settings. The implementation of this protocol required overcoming several barriers, such as the slow process of acquiring the ultrasound equipment and strengthening communication between the research team, health professionals, and policymakers. This protocol highlights the importance of implementing active measures to address PTB risk factors in high-prevalence settings and suggests that this strategy could offer meaningful benefits for the prevention of PTB. Conclusion Prevention of syndromes like PTB is difficult to achieve. However, a reduction in rate by targeted and tailored interventions for identifiable and modifiable risk factors is achievable. The effectiveness of such interventions can be twofold: ( 1 ) Addressing an existing risk and minimizing its impact on pregnancy outcome, and ( 2 ) Addressing unchangeable conditions by providing supportive care and stress relief for subjects who are at risk. The latter can also indirectly control stress hormones and endocrinological challenges that can contribute to preterm birth. Current strategies to understand the pathologic mechanisms and develop effective interventions have not met with great success. We strongly urge a simplified approach to screening high-risk pregnancies focusing on easily identifiable risks and implementing cost-effective interventions that can mitigate PTB. Declarations Ethics approval and consent to participate: This project was approved by the Research Ethics Committee of Unoeste (CAAE 63623922.7.0000.5515). All patients involved will be informed about the research and sign the informed consent form. Consent for publication: Not applicable Availability of data and materials: Not applicable Competing interests: The authors declare that they have no competing interests Funding: São Paulo Western University. The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. Authors' contributions: BRAR contributed to study design, study supervision, discussion, writing of first and subsequent drafts of the paper, and final editing. JJAOJ contributed to study design, clinical evaluations, clinical decisions and discussion. BMB contributed to sample collection/implementation of the protocol and writing of first and subsequent drafts of the paper. GRC and NLV contributed to sample collection/implementation of the protocol, clinical evaluations, and discussion. JNR, KC, BMP, ALCP, IRS, GGH, AAG, NLAN, GFOS, JSBF, EMT, RCV contributed to sample collection/implementation of the protocol. RCP, RM and MGS contributed to study design, discussion, and final editing. Acknowledgements: We acknowledge all the participants in the study. References Harrison MS, Goldenberg RL. Global burden of prematurity. Semin Fetal Neonatal Med. 2016;21(2):74–9. DataSUS tabnet. https://datasus.saude.gov.br/informacoes-de-saude-tabnet/ . Accessed on 12 out 2024. Gravett MG, Menon R, Tribe RM, Hezelgrave NL, Kacerovsky M, Soma-Pillay P, et al. Assessment of current biomarkers and interventions to identify and treat women at risk of preterm birth. Front Med. 2024;11:1414428. Soneji S, Beltrán-Sánchez H. Association of maternal cigarette smoking and smoking cessation with preterm birth. JAMA Netw Open. 2019;2:e192514. Arcanjelo EDV, Lopes SS, Suliano LC. Tratamento do Tabagismo por Acupuntura. Rev Bras Terap e Saúde. 2014;4:15–9. Witkin SS, Moron AF, Ridenhour BJ, Minis E, Hatanaka A, Sarmento SGP, et al. Vaginal biomarkers that predict cervical length and dominant bacteria in the vaginal microbiomes of pregnant women. MBio. 2019;10(5):101128. Jayaram PM, Mohan MK, Konje J. Bacterial vaginosis in pregnancy - a storm in the cup of tea. Eur J Obstet Gynecol Reprod Biol. 2020;253:220–4. Klebanoff MA, Schuit E, Lamont RF, Larsson PG, Odendaal HJ, Ugwumadu A, et al. Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis. Paediatr Perinat Epidemiol. 2023;37(3):239–51. Silva TV, Borovac-Pinheiro A, Cecatti JG, Mol BW, Silva Costa F, França MS, et al. P5 working group. Association between cervical length and gestational age at birth in singleton pregnancies: a multicentric prospective cohort study in the Brazilian population. Reprod Health. 2023;20(1):47. Pacagnella RC, Silva TV, Cecatti JG, Passini R Jr, Fanton TF, Borovac-Pinheiro A, et al. Pessary plus progesterone to prevent preterm birth in women with short cervixes: randomized controlled trial. Obstet Gynecol. 2022;139:41–51. Romero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018;218:161–80. Peters DH, Adam T, Alonge O, Agyepong IA, Tran N. Implementation research: what it is and how to do it. BMJ. 2013;347:f6753. 10.1136/bmj.f6753 . Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol. 1991;29(2):297–301. Ramos BR, Mendes ND, Tanikawa AA, Amador MA, dos Santos NP, dos Santos SE, et al. Ancestry informative markers and selected single nucleotide polymorphisms in immunoregulatory genes on preterm labor and preterm premature rupture of membranes: a case control study. BMC Pregnancy Childbirth. 2016;16:30. 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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associated with perinatal morbidity and mortality worldwide. Preterm newborns are more likely to have short- and long-term complications, such as neurological impairment and increased susceptibility to infections, which can lead to irreversible sequelae, reducing the quality of life of the newborn (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWorldwide, the prevalence of PTB is approximately 11% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), and Brazil in one of the most affected countries, with over 308,700 children born preterm every year, accounting for a preterm birth rate of 11.5%. In S\u0026atilde;o Paulo state, 11.5% of births in 2023 were preterm, and a higher percentage was reported in the municipality of Ja\u0026uacute;, where this adverse outcome affected 13.5% of all pregnancies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePTB is a syndrome of multifactorial etiology with significant activation of inflammatory, oxidative stress, and senescence pathways (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). PTB prevention should be a priority in public health policies; however, despite all the scientific and clinical efforts to fully elucidate and prevent PTB, protocols for early identification and effective management of women at risk have not yet been well-defined or effectively implemented, especially in Brazil. The main barrier to the implementation of such strategies is the gap in knowledge and communication between researchers, health professionals, and policymakers. In this context, three modifiable risk factors stand out for their well-established association with PTB: smoking habit, vaginal dysbiosis, and cervical shortening (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSmoking is a strong predictor of spontaneous preterm labor. Smoking during pregnancy has been associated with numerous adverse outcomes, including low birth weight, intrauterine growth restriction, prematurity, and infant mortality, due to heightened levels of inflammation and oxidative stress (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It is important to emphasize that smoking may be considered as a modifiable risk. In an epidemiological study based on national databases in the United States, Soneji et al. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) observed that smoking cessation was associated with a relative reduction in the risk of PTB up to 23%, especially if the habit was stopped early in pregnancy. The authors also observed a dose-response effect, with the risk of PTB being directly proportional to the number of cigarettes consumed. There are currently some strategies available to control smoking, such as pharmacological treatment, group support, and acupuncture. Studies suggest that auricular acupuncture can contribute to combating smoking through points that promote a reduction in anxiety and withdrawal symptoms (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHealthy vaginal microbiota is mainly colonized by \u003cem\u003eLactobacillus\u003c/em\u003e spp., which synthesizes lactic acid and other products that provide local protection against pathogens (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The replacement of the lactobacilli by anaerobic pathogens facilitates its ascent to the amniotic cavity. It triggers an inflammatory response characterized by the production of cytokines and prostaglandins, ultimately inducing the labor-related events of myometrial contractility, cervical effacement, and rupture of the fetal membranes (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Although treatment for vaginal dysbiosis has not yet been proven effective in preventing PTB in late pregnancy (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), the condition is easily diagnosed by bacterioscopy, and the maintenance of eubiosis from the early stages of pregnancy may favor timely, adequate outcomes.\u003c/p\u003e \u003cp\u003eAnother well-established risk factor for PTB is the length of the uterine cervix. A cervical length of less than 25 mm between the 16th and 24th gestational weeks is a strong independent predictor of spontaneous PTB. The risk of PTB in these cases is estimated at 25\u0026ndash;30% in women with no history of PTB and up to 35% in pregnant women who have previously presented PTB (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). If the length is under 15 mm, the risk of PTB reaches 50%. In fact, several authors indicate the need for screening cervical length in this period via transvaginal ultrasound (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The management of cervical shortening (CS) includes the topical administration of progesterone, the use of pessary, and cerclage. A recent meta-analysis detected a significant reduction in the rate of extreme prematurity (\u0026lt;\u0026thinsp;33 weeks of gestation, \u0026lt; 2,500 grams birth weight) in pregnant women with CS (\u0026lt;\u0026thinsp;25 mm) who used intravaginal progesterone daily (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA common factor for the aforementioned conditions is the possibility of implementing preventive measures. Identifying risk factors for PTB early and before the development of irreversible clinical symptoms (e.g., cervical dilation, intraamniotic infection, oxidative damage associated inflammation) enables a personalized approach to patient care, aiming to reduce the risk of preterm birth and its sequelae.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study aims to implement a bundle comprised of low-cost interventions to treat the main modifiable risk factors for preterm birth in pregnant women from Health Units in the city of Ja\u0026uacute; - SP, Brazil.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is the protocol of an ongoing implementation study with a quasi-experimental controlled trial design conducted with pregnant women from primary health care units in the municipality of Ja\u0026uacute;. The city of Ja\u0026uacute;, located in the central region of the state of S\u0026atilde;o Paulo, has a population of 151,881 inhabitants and 16 Basic Health Units (UBS) and Family Health Units (USF), in addition to a high-risk pregnancy clinic, Gestar, where this project is implemented.\u003c/p\u003e \u003cp\u003eThe 16 UBS/USF were considered clusters and will be included in the study at different stages, according to the stepped wedge model, in which the clusters are gradually transferred to the intervention group at regular intervals until all have been transferred. This design is particularly useful in situations where the intervention cannot be implemented simultaneously for all units due to time, logistics, or ethical constraints (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In the first phase, eight of these clusters were randomly selected using a simple randomization process to receive the intervention, focusing on pregnant women during their first trimester. Over time, the remaining clusters will be randomly assigned to transition into the intervention group at regular intervals, using the same simple randomization method, ensuring that by the end of the study, all clusters will have received the intervention. This approach allows for a structured, phased implementation of the intervention, accommodating logistical and ethical constraints, and enables the comparison between clusters that have and have not yet received the intervention during the initial stages of the study.\u003c/p\u003e \u003cp\u003eIn the first 14 months, all first-trimester pregnant women from 8 randomized UBS/USF (clusters) are being included. In the next step of the study, 2 UBS/USF per month will be included until all primary care units (clusters) in the municipality are included.\u003c/p\u003e \u003cp\u003eAll pregnant women of eligible gestational age from the 8 initially randomized health units were systematically invited to participate in the study and referred to Gestar. All participants included in the study will be monitored until the gestational outcome through 3 appointments, one in each gestational trimester. Considering that the intervention can reduce the prematurity rate to 11.5% (rate for the state of SP), with 95% reliability, 5% margin of error and 80% test power, the final minimum sample size calculated is 201 patients. Considering a 20% loss to follow-up, the initial proposed sample size will be 241 patients. The inclusion criteria for the study were singleton pregnancy and gestational age between 11 weeks and 13 weeks and 6 days at the first appointment, defined by ultrasound. Pregnancies with fetal death will be excluded from the study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eThe intervention in this study is designed to manage and mitigate modifiable risk factors associated with spontaneous PTB among pregnant women. It is implemented as a bundle of low-cost measures across different stages of pregnancy, with a focus on three key areas: smoking cessation, maintenance of healthy vaginal microbiota, and management of cervical shortening.\u003c/p\u003e \u003cp\u003eBelow is a detailed description of each component of the intervention:\u003c/p\u003e\n\u003ch3\u003e1. First Trimester (11 to 13 weeks and 6 days): Assessment and Smoking Intervention\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSociodemographic and Clinical Assessment\u003c/b\u003e: During the first trimester, participants undergo an initial interview to collect personal, social, and clinical information. This includes family and obstetric history, as well as smoking status.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSmoking Cessation Support\u003c/b\u003e: Pregnant women identified as smokers who are willing to quit are provided with a comprehensive smoking cessation program. This includes referral to the city\u0026rsquo;s smoking prevention program, which is conducted at the Alcohol and Drug Psychosocial Care Center (CAPS-AD).\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eThe smoking intervention involves an initial interview and adjuvant treatment with auricular acupuncture. This technique uses pressure points in the ear to help reduce anxiety and withdrawal symptoms associated with smoking cessation.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAcupuncture sessions are conducted every 15 days, where seeds are placed on specific points in the ear to stimulate them. Cotton and 70% alcohol are used to clean the ear, an auricular pressure gauge is used to locate the points, and mustard seeds with micropore are placed for acupressure of the selected points. The patients are instructed to stimulate these points themselves three times daily.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e If necessary, group sessions with psychological support are provided at CAPS-AD, and pharmacological treatment, such as nicotine patches, may be used for gradual dose reduction to alleviate withdrawal symptoms.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003e2. Second Trimester (20 to 23 weeks and 6 days): Cervical Length Monitoring and Infection Treatment\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eCervical Length Screening\u003c/b\u003e: Between 20 and 24 weeks of gestation, all participating women undergo a transvaginal ultrasound to measure cervical length, a critical indicator of the risk for PTB.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe measurement is taken with the patient in the lithotomy position, using a transvaginal probe to assess the distance between the internal and external orifices of the cervical canal. Women are instructed to empty their bladder before the ultrasound evaluation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf a cervical length of less than 25 mm is detected, the woman is diagnosed with cervical shortening.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWomen diagnosed with cervical shortening are prescribed 200 mg of vaginal progesterone daily until 36 weeks of gestation, aiming to reduce the risk of PTB. For these women, the measurement is repeated biweekly for follow-up.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor cases of severe cervical shortening, such as lengths below 15 mm, cerclage \u0026mdash; a surgical procedure to reinforce the cervix \u0026mdash; is considered, depending on the patient\u0026rsquo;s clinical history and ongoing evaluations.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eInvestigation and Treatment of Infections\u003c/b\u003e: During the same trimester, women are also screened for lower genital tract infections using molecular tests for \u003cem\u003eChlamydia trachomatis\u003c/em\u003e and \u003cem\u003eNeisseria gonorrhoeae\u003c/em\u003e. These investigations were performed at this time due to the less friable nature of mid-trimester cervices in comparison to the first trimester of pregnancy.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe assessment includes a complete gynecological examination with swabs for Gram staining, vaginal pH measurement, and cytobrush sampling collection for PCR analysis of cervical infection using the automated Cobas\u0026reg; 4800 CT/NG v2.0.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIdentified infections are treated according to the local clinical protocols to ensure the health of both the mother and the fetus.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e\n\u003ch3\u003e3. Throughout All Trimesters (11 weeks to Term): Vaginal Microbiota Monitoring and Dysbiosis Management\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eQuarterly Assessment of Vaginal Microbiota\u003c/b\u003e: During each trimester, vaginal samples are collected to assess eubiosis (the balance of the vaginal microbiota) using the Gram staining method according to the criteria set by Nugent et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe evaluation aims to identify dysbiosis, such as bacterial vaginosis, candidiasis, or other alterations in the vaginal microbiota.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWomen diagnosed with dysbiosis receive treatment based on the type of condition identified. For bacterial vaginosis, standard antibiotic regimens are administered, while antifungal treatment is provided for candidiasis.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAdditionally, all participants are educated on proper intimate hygiene practices to help maintain a balanced vaginal environment throughout the pregnancy.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe study protocol was registered in the Brazilian Clinical Trial Registry (ReBec) on October 29th, 2024.\u003c/p\u003e\n\u003ch3\u003eAnalysis\u003c/h3\u003e\n\u003cp\u003eThe main outcome of interest is gestational age at birth, based on first-trimester ultrasound. Secondary outcomes include the percentage of pregnant women included, the percentage of complete follow-up, adherence to prescribed treatments, and neonatal outcome. Descriptive statistics will be performed to analyze clinical, biological, and sociodemographic data of the studied population. The microbiota status among the trimesters will be compared using the Chi-square test. The level of significance adopted for the tests used will be 5%, using \u003cem\u003ePrism\u003c/em\u003e 5.0.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral factors contribute to prematurity rates at a populational level. Despite ongoing efforts to prevent prematurity, protocols for early identification and management of women at risk are yet to be fully defined and widely implemented. In the context of preterm birth (PTB) prevention, it is crucial to differentiate between merely identifiable risk factors and those that are manageable. Factors such as a personal or family history of PTB are inherently identifiable but cannot be altered (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In contrast, modifiable risk factors, including smoking habit, vaginal dysbiosis, and cervical shortening, are more dynamic and can be managed through targeted interventions. These manageable factors are particularly responsive to intervention, meaning that timely and appropriate measures can significantly mitigate their impact on pregnancy outcomes, ultimately reducing the risk of PTB.\u003c/p\u003e \u003cp\u003eWhile individual interventions addressing these risk factors have been applied in some settings, to our knowledge, this is the first study to implement a low-cost bundle that systematically modulates modifiable risk factors for PTB in a high-prevalence population. This bundle is applied at multiple stages of pregnancy to address the specific modifiable risk factors of smoking, cervical shortening, and vaginal dysbiosis. By providing tailored support, the bundle aims to lower the incidence of PTB within this cohort. The approach is practical, scalable, and designed to be low-cost, making it suitable for implementation in resource-limited settings.\u003c/p\u003e \u003cp\u003eThe implementation of this protocol required overcoming several barriers, such as the slow process of acquiring the ultrasound equipment and strengthening communication between the research team, health professionals, and policymakers. This protocol highlights the importance of implementing active measures to address PTB risk factors in high-prevalence settings and suggests that this strategy could offer meaningful benefits for the prevention of PTB.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePrevention of syndromes like PTB is difficult to achieve. However, a reduction in rate by targeted and tailored interventions for identifiable and modifiable risk factors is achievable. The effectiveness of such interventions can be twofold: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Addressing an existing risk and minimizing its impact on pregnancy outcome, and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Addressing unchangeable conditions by providing supportive care and stress relief for subjects who are at risk. The latter can also indirectly control stress hormones and endocrinological challenges that can contribute to preterm birth. Current strategies to understand the pathologic mechanisms and develop effective interventions have not met with great success. We strongly urge a simplified approach to screening high-risk pregnancies focusing on easily identifiable risks and implementing cost-effective interventions that can mitigate PTB.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis project was approved by the Research Ethics Committee of Unoeste (CAAE 63623922.7.0000.5515). All patients involved will be informed about the research and sign the informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e S\u0026atilde;o Paulo Western University. The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e BRAR contributed to study design, study supervision, discussion, writing of first and subsequent drafts of the paper, and final editing. JJAOJ contributed to study design, clinical evaluations, clinical decisions and discussion. BMB contributed to sample collection/implementation of the protocol and writing of first and subsequent drafts of the paper. GRC and NLV contributed to sample collection/implementation of the protocol, clinical evaluations, and discussion. JNR, KC, BMP, ALCP, IRS, GGH, AAG, NLAN, GFOS, JSBF, EMT, RCV contributed to sample collection/implementation of the protocol. RCP, RM and MGS contributed to study design, discussion, and final editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We acknowledge all the participants in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHarrison MS, Goldenberg RL. Global burden of prematurity. Semin Fetal Neonatal Med. 2016;21(2):74\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDataSUS tabnet. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://datasus.saude.gov.br/informacoes-de-saude-tabnet/\u003c/span\u003e\u003cspan address=\"https://datasus.saude.gov.br/informacoes-de-saude-tabnet/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed on 12 out 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGravett MG, Menon R, Tribe RM, Hezelgrave NL, Kacerovsky M, Soma-Pillay P, et al. Assessment of current biomarkers and interventions to identify and treat women at risk of preterm birth. Front Med. 2024;11:1414428.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoneji S, Beltr\u0026aacute;n-S\u0026aacute;nchez H. Association of maternal cigarette smoking and smoking cessation with preterm birth. JAMA Netw Open. 2019;2:e192514.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArcanjelo EDV, Lopes SS, Suliano LC. Tratamento do Tabagismo por Acupuntura. Rev Bras Terap e Sa\u0026uacute;de. 2014;4:15\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitkin SS, Moron AF, Ridenhour BJ, Minis E, Hatanaka A, Sarmento SGP, et al. Vaginal biomarkers that predict cervical length and dominant bacteria in the vaginal microbiomes of pregnant women. MBio. 2019;10(5):101128.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJayaram PM, Mohan MK, Konje J. Bacterial vaginosis in pregnancy - a storm in the cup of tea. Eur J Obstet Gynecol Reprod Biol. 2020;253:220\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlebanoff MA, Schuit E, Lamont RF, Larsson PG, Odendaal HJ, Ugwumadu A, et al. Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis. Paediatr Perinat Epidemiol. 2023;37(3):239\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilva TV, Borovac-Pinheiro A, Cecatti JG, Mol BW, Silva Costa F, Fran\u0026ccedil;a MS, et al. P5 working group. Association between cervical length and gestational age at birth in singleton pregnancies: a multicentric prospective cohort study in the Brazilian population. Reprod Health. 2023;20(1):47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePacagnella RC, Silva TV, Cecatti JG, Passini R Jr, Fanton TF, Borovac-Pinheiro A, et al. Pessary plus progesterone to prevent preterm birth in women with short cervixes: randomized controlled trial. Obstet Gynecol. 2022;139:41\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRomero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018;218:161\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters DH, Adam T, Alonge O, Agyepong IA, Tran N. Implementation research: what it is and how to do it. BMJ. 2013;347:f6753. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.f6753\u003c/span\u003e\u003cspan address=\"10.1136/bmj.f6753\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol. 1991;29(2):297\u0026ndash;301.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamos BR, Mendes ND, Tanikawa AA, Amador MA, dos Santos NP, dos Santos SE, et al. Ancestry informative markers and selected single nucleotide polymorphisms in immunoregulatory genes on preterm labor and preterm premature rupture of membranes: a case control study. BMC Pregnancy Childbirth. 2016;16:30.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"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":"Preterm Birth, Implementation Research, Prematurity Prevention, Smoking Habits, Vaginal Dysbiosis, Short Cervix","lastPublishedDoi":"10.21203/rs.3.rs-5356838/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5356838/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Preterm birth (PTB) is the main cause of perinatal and neonatal morbidity and mortality worldwide. Widespread implementation of guidelines for early identification and management of patients at risk for adverse pregnancy outcomes is still feeble.\u003cstrong\u003e \u003c/strong\u003eThis work aims to implement a simple and low-cost bundle to access and manage major modifiable risk factors for PTB.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We included first trimester pregnant women seen at Health Units from Jaú – SP, where PTB prevalence is 13.4%. The protocol is based on three aspects: a questionnaire to access smoking status and clinical history; Gram staining and of vaginal microbiota evaluation using Nugent’s criteria and evaluation of cervical infections; and transvaginal ultrasound. Pregnant women who smoke and are willing to quit will be treated with auricular acupuncture and referred to a support group if necessary. All patients will be advised on intimate hygiene habits, and those with dysbiosis will be treated. Cervical length will be accessed using transvaginal ultrasound, and those diagnosed with cervical shortening will be treated with vaginal progesterone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e Prevention of PTB is difficult to achieve. However, a reduction in rate by targeted and tailored interventions for identifiable and modifiable risk factors is achievable. This study highlights the importance of implementing active measures to reduce PTB risk factors in a high prevalence setting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e The study protocol was retrospectively registered in the Brazilian Clinical Trial Registry (ReBec) on October 29th, 2024.\u003c/p\u003e","manuscriptTitle":"Implementation Protocol for a Treatment Bundle Targeting Modifiable Risk Factors for Preterm Birth: a stepped wedge implementation study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-11 09:25:04","doi":"10.21203/rs.3.rs-5356838/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":"912228ff-8f98-4421-a241-4f43981b6ed6","owner":[],"postedDate":"November 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-17T14:39:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-11 09:25:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5356838","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5356838","identity":"rs-5356838","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}