Study on effectiveness of systematic cardiotocography use in National Maternal and Child Health Center in Cambodia: A study protocol for an explanatory clinical trial

Study on effectiveness of systematic cardiotocography use in National Maternal and Child Health Center in Cambodia: A study protocol for an explanatory clinical trial | 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 Study protocol Study on effectiveness of systematic cardiotocography use in National Maternal and Child Health Center in Cambodia: A study protocol for an explanatory clinical trial Mitsuaki Matsui, Ai Aoki, Nobuya Unno, Hiromi Eto, Rattana Kim, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4148437/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 and objective: An estimated 2 million stillbirths and 2.4 million neonatal deaths occur globally every year, and 98% of these deaths occur in low- and middle-income countries. The main causes of neonatal death are prematurity and intrapartum-related events, and half of stillbirths occur during labor. Although cardiotocography (CTG) is used to detect fetal hypoxia and acidosis in high-income countries, its effectiveness is not shown in resource-limited settings. This study aims to evaluate whether systematic CTG contributes to reducing fetal acidosis, stillbirths and neonatal deaths in a tertiary-level hospital in Cambodia. Methods: Participants will be pregnant women with moderate risk. The study employs pre- and post-comparison design, and consists of three phases: observation (pre), pre-intervention, and intervention (post). Standard care is applied during the observation phase. Training on CTG application using a local guideline is applied in the pre-intervention phase. Systematic CTG use and periodic supervision are key components of the intervention. The observation phase is between January and April 2023, and the intervention phase is between January and April 2024. Primary outcome is fetal acidosis, which manifests as a pH less than 7.20 in the umbilical arterial blood. The results in the observation and intervention phases will be compared using univariate and multivariate logistic regression analyses. Discussion: The novel idea of this study is the systematic use of CTG and the monitoring of hypoxic and acidotic states using blood gas analysis. It is expected that this study will contribute to show effectiveness of CTG use on reduction of fetal acidosis, and eventually on reduction of preventable child deaths in resource-limited settings. Clinical trial registration: UMIN000052815, UMIN Clinical Trials Registry (UMIN-CTR) Stillbirth Neonatal death Asphyxia Hypoxia Acidosis Cardiotocography CTG Figures Figure 1 Figure 2 Figure 3 1. Introduction An estimated 2 million stillbirths and 2.4 million neonatal deaths occur globally every year, and 98% of these deaths occur in low- and middle-income countries (LMICs) [ 1 – 3 ]. Global estimates show that the main causes of neonatal death are prematurity (35%) and intrapartum-related events (23%), and 45% of stillbirths occur during labor [ 4 , 5 ]. Another report showed that half of neonatal deaths occur within the first 2 days of life, and asphyxia in preterm birth is the main cause of death [ 6 ]. Therefore, appropriate monitoring and timely intervention during labor can prevent intrapartum death [ 1 ]. Fetal heart rate (FHR) monitoring is the most common and practical method for confirming fetal well-being during labor. The autonomic nervous system controls FHR, mainly regulated by the tension between oxygen and carbon dioxide in the blood and cerebrospinal fluid, body temperature, and blood pressure [ 7 ]. Therefore, maintenance or disruption of homeostasis in the fetus is observable through changes in the FHR. Two common FHR monitoring methods are intermittent auscultation (IA) and continuous cardiotocography (CTG) monitoring. IA involves listening to an FHR for short periods [ 8 ]. It uses low-cost equipment such as a Pinard stethoscope or a handheld Doppler ultrasound device. Alternatively, CTG simultaneously records FHR with uterine contractions, which enables a visual assessment of the relationship between FHR patterns and uterine contractions. FHR monitoring with uterine contractions provides information on fetal well-being and the ability to detect suspicious patterns of hypo-oxygenation or acidosis. Despite the potential usefulness of CTG, the World Health Organization (WHO) does not recommend its use in healthy pregnant women [ 9 ]. This recommendation is based on evidence published in a Cochrane systematic review, which indicates that CTG use is associated with increased cesarean section and instrumental vaginal deliveries and only makes a small contribution to reduced neonatal morbidity [ 10 ]. However, of the 13 studies included in the review, 12 were published between 1976 and 1994, 11 were conducted in high-income countries (HICs), and only 2 in middle-income countries. Therefore, whether these results can be applied to the current LMIC setting is unclear. Additionally, there is a large gap in the practice of FHR monitoring between HICs and LMICs. CTG use in HICs is a de facto standard despite several recommendations. In 2004, 86% of women in labor were monitored using CTG in the United States [ 11 ]. However, no data on the coverage of intrapartum monitoring in LMICs is available [ 12 ]. Our review showed that CTG use in LMICs has not been standardized [ 13 ]. CTG could serve as a key solution to save millions of babies. However, it is still not appropriately used, perhaps due to insufficient scientific evidence. Therefore, there is an urgent need to determine the effectiveness of CTG in resource-limited settings. 2. Objectives This study aims to evaluate whether systematic cardiotocography (CTG) contributes to reducing fetal acidosis and its consequences, namely stillbirths and neonatal deaths, in a tertiary-level hospital in Cambodia. 3. Materials and Methods 3.1. Study setting This study will be conducted at the National Maternal and Child Health Center in Cambodia (NMCHC). The NMCHC is located in the capital city of Phnom Penh. It is a government-funded hospital specializing in obstetrics, gynecology, and neonatal care. It serves as a referral facility and manages normal births. The clinical activities of the NMCHC are shown in Table S1 (supporting information). 3.2. Participants Pregnant women at moderate risk admitted for delivery to the NMCHC will be recruited. All admitted women will be screened in the triage room using standard initial assessment guidelines and classified into low-, moderate-, or high-risk groups [ 14 ]. The inclusion and exclusion criteria are presented in Table 1 . Table 1 Inclusion and exclusion criteria Conditions Inclusion criteria Exclusion criteria Maternal condition − High blood pressure (systolic 140mmHg or more, or diastolic 90mmHg or more) − Fever (37.5ºC or more) − Anemia (hemoglobin 9.0g/dl or less) − Abnormal amount of amniotic fluid (amniotic fluid index 8 or less, or 25 or more) − Women in severe status (unconsciousness, massive hemorrhage, shock, convulsion, referred to operation theater or intensive care unit directly from the triage room) − less than 18 years old − HIV positive − Obesity (body-mass index 30.0 or more) − Lower body height (less than 140 cm) − Malformation of pelvis Fetal condition − Low estimated body weight (less than 2500g) − High estimated body weight (3500g or more) − Estimated gestational week 27 weeks and 6day or less − Intra-uterine fetal death − Multiple pregnancy − Malformation Progress of labor − Time elapsed from rupture of membrane more than 24 hours − Already in the second stage of labor at the admission 3.3. Study design This study will employ pre- and post- comparison design, and consist of three phases: observation ( pre ), pre-intervention, and intervention ( post ). The systematic use of CTG is a main intervention. To enhance the effective use of CTG by health staff in the NMCHC, we will employ three implementation strategies: distribution of local CTG guidelines, training in the systematic use of CTG during the pre-intervention phase, and supervision of evaluation during the intervention phase. The conceptual framework of the intervention is shown in Fig. 1 . 3.3.1 Observation phase No specific interventions will be administered in this phase. Pregnant women with moderate risk will receive standard care during childbirth. Blood from the umbilical cord artery will be collected and analyzed immediately after delivery. The blood sample will be taken using a safePICO aspirator syringe (Radiometer Medical ApS, Brønshøj, Denmark) containing dry, electrolyte-balanced heparin. The analysis will be performed using an epoc® blood analysis system (Siemens Healthineers AG, Forchheim, Germany). The parameters measured will be pH, pCO 2 , pO 2 , lactate, and base excess. 3.3.2 Pre-intervention phase Original guidelines for using CTG and training sessions will be provided to staff members, both medical doctors and midwives working in maternity and delivery wards in the facility. The guidelines comprise a procedure to apply CTG and medical management in cases of abnormal findings, including fetal resuscitation procedures. After completing the training, CTG will be applied for 1 hour to all participants at the admission. We will proceed to the implementation phase after confirming that 80% of the CTG evaluation results correspond between the staff and the researchers. 3.3.3 Intervention phase The CTG will be applied to all participants, and all CTG results will be evaluated using a modified 5-tier system [ 15 ]. The 5-tier system will classify CTG results into five groups: Green – ‘no acidemia’; Blue – ‘no central acidemia’; Yellow – ‘intermittent hypoxia that may lead to acidemia’; Orange – ‘potential for fetal decompensation’; or Red – ‘possible actual or impending fetal asphyxia’ [ 16 , 17 ]. CTG will be applied immediately after admission for 1 hour as an admission test. It will be evaluated every 30 min and classified into one of five colors. CTG will be applied intermittently for Green or Blue cases. For Yellow and Orange cases, CTG will be applied continuously, fetal resuscitation will be applied, and the results will be evaluated every 30 min. For Red cases, fetal resuscitation will be performed, and immediate delivery will be considered. A flowchart of the CTG application is shown in Figs. 2 and 3 . This study will use two types of CTG apparatus: MT-516 (Toitu Co. Ltd., Tokyo, Japan) for the admission test and iCTG (Melody International Ltd., Kagawa, Japan) for further monitoring. Umbilical arterial blood will be collected and measured as it is performed in the observation phase. Supervision sessions will include an independent retrospective evaluation of the CTG and periodic feedback sessions. The researchers will organize all sessions. When researchers find a misinterpretation of CTG results or severe neonatal outcomes, feedback sessions with staff members will be held. 3.3.4 Monitoring This study will not employ monitoring measures. The NMCHC has a designated committee for neonatal death surveillance and response, and the committee independently investigates when neonatal death occurs to confirm the possible causes and establish future prevention measures. 3.4. Assessment of the outcomes 3.4.1 Clinical outcomes The primary endpoint is the detection of fetal acidosis, which manifests as a pH less than 7.20 in the umbilical arterial blood. The secondary outcomes are shown in Table 2 . Table 2 Secondary endpoints, indicators and expected outcomes Endpoint Indicator and expected outcomes Acidosis of umbilical arterial blood pH less than 7.10 will be reduced pH less than 7.00 will be reduced Prognosis of the fetus NCU admission or transfer to other facility will be reduced in the CTG phase Intra-partum stillbirth and early neonatal deaths will be reduced Medical interventions Instrumental deliveries and cesarean sections will be increased to save the fetus lives will be increased 3.4.2 Implementation outcomes The implementation outcomes will be collected: the fidelity of CTG use, the reach of the CTG to pregnant women with moderate risk, and the delivery of implementation strategies to the staff in the NMCHC [ 18 ]. The fidelity of CTG use will be measured using the accuracy of the CTG assessments. 3.5. Data collection period The observation phase was between January and April, and the pre-intervention phase was between May and December 2023. The first case involved in the intervention phase occurred on January 8, 2024. Data is expected to be collected by the end of April 2024. 3.6. Data collection Blood samples from umbilical artery will be collected and measured as it is described in 3.3.1. When the pO 2 level of the blood sample is 100 Torr or higher, the results will be excluded from the analysis. The blood sample is suspected to be contaminated with air, and the pH level may not be reliable. When the data output from the analyzer shows an ‘error,’ the blood sample will be recollected and measured. The blood samples were suspected to be clotted. However, if an erroneous result is repeated in another sample, it will be excluded from the dataset. Stillbirth cases will be confirmed by the research assistants when they collect the blood samples immediately after the birth. Information on neonatal death will be collected via phone call to the mother or family members after one month of the birth. 3.7. Data analysis 3.7.1 Data management Collected paper data will be handled and stored at a research room in the NMCHC. All the information will be put as double-entry file using EpiData software (EpiData Association), converted into Excel file (Microsoft Corp). Blood gas analysis data will be extracted directly from epoc as csv file. Quantitative information will be analyzed using Stata software (version 17, Stata Corp). Only the researchers involved in this study will be able to access the dataset. 3.7.2 Descriptive statistics The participants’ characteristics will be described and compared between the observation and intervention phases. 3.7.3 Clinical outcomes An intention-to-treat analysis will be performed to compare health outcomes between the observation and intervention phases. Subgroup analysis using data from participants who underwent CTG may be considered. However, it will not be applied when the most eligible women are subjected to CTG. Other subgroup analyses will be performed according to parity, body weight at birth, and the types of risk factors. The primary endpoint, a pH level of less than 7.20, will be treated as the proportion of acidosis in the observation and intervention phases. Proportions will be compared using univariate and multivariate logistic regression analyses. The potential confounding factors included in the multivariate model will be age, parity, and body weight at birth. Secondary endpoints will be treated as proportions and analyzed using a logistic regression model. 3.7.4 Implementation outcomes Implementation outcomes are descriptively analyzed. The fidelity of CTG use is the main outcome. It is expected that 90% concordance will be achieved between staff and researchers for the yellow, orange, and red lever FHR patterns. 3.8. Sample size It is expected that fetal acidosis, revealed by a pH less than 7.20 in the umbilical arterial blood sample, will be reduced to 14% after the intervention from 21% before the intervention. The estimated prevalence during the observation phase (21%) is from our preliminary observation conducted in a primary health facility in Cambodia [ 19 ]. With 5% alpha-error and 80% beta-error, one arm will be 462 cases. It was assumed that the dropout rate after obtaining informed consent and mismeasurement of umbilical arterial blood was 10%. Therefore, one arm required 555 patients. 4. Ethical considerations 4.1 Recruitment and consent Research assistants employed by this study fund will obtain information on every pregnant woman upon admission from standard initial assessments and medical records. Women with moderate risk who meet the inclusion criteria will be extracted, and the objectives and procedures of this study will be explained to pregnant women or their accompanying members. The contents of the explanation will include voluntary participation in the study, no disadvantages even if the patient refuses to participate, and no specific interventions will be conducted during the observation phase. Women will be involved in the study if they or their representatives provide written informed consent. Written consent will be obtained even during the observation phase to ensure opting-out measures for all participants. An explanation and a consent form is attached as Supporting Information (File S1). 4.2 Disclosure of research information from the NMCHC As this study will collect data from medical records, we will disclose the research outline and collect information on the inpatients for delivery, excluding personal information, by displaying the poster in the triage room for opt-out. We will also explain the purpose and content of this study to hospital staff members before the observation phase. 4.3 Treatment of individual information Personal information, such as participants’ names, addresses, and phone numbers, will be collected to combine data on delivery and neonatal death. The information used to identify participants will be kept strictly at the research office, room 214 in the NMCHC. During the data processing in Excel, participants’ names, addresses, and phone numbers will be deleted from the dataset, hospital ID number will be used as a decoding index, and each piece of information was converted into electronic data and anonymized. 4.4 Ethics review and approval The study protocol was approved by the National Ethics Committee for Health Research, the Ministry of Health in Cambodia (May 02, 2022, 121NECHR), and the Institutional Review Board of Nagasaki University School of Tropical Medicine and Global Health, Japan (June 16, 2022, NU_TMGH_2022_213_1). 4.5 Potential benefits and risks to the study participants 4.5.1 Pregnant women who are targets of clinical research During the observation phase, no potential harm is expected to the pregnant women or their babies. During the intervention phase, the physical burden of wearing the CTG may increase, but we believe that this can be understood by explaining the effects of the CTG. The output from CTG can also provide the benefit of detecting fetal acidosis and the risk of developing medical interventions to respond to abnormalities. We will supervise the intervention period and believe that it can be responded to by ensuring the transparency of the process leading to medical intervention and explaining it to the target women. 4.5.2 Healthcare providers who are targets of implementation research Healthcare providers face no risks in participation in training, supervision, etc., which may limit a certain amount of time. However, it can be acceptable considering the benefits of providing medical care and improving quality. 4.6 Dissemination of the study results As this study is a collaborative work between the NMCHC, two academic societies (Cambodian Society of Gynecology and Obstetrics, and Perinatal Society of Cambodia) and Japanese researchers, relevant information on the results will be disseminated thorough the academic channels in Cambodia and elsewhere in the world. 5. Discussion Although many stillbirths and neonatal deaths are caused by intrauterine hypoxia during the labor period, there is still no effective means of detecting the fetus’s condition in a resource-limited setting. Intermittent auscultation may detect hypoxic or acidotic states. However, there are no specific guidelines for pregnant women at risk [ 20 ]. In addition, IA requires considerable effort from health staff. Listening to the fetal heart rate requires at least a few minutes for healthcare personnel [ 8 ]. As one-to-one care is essential, IA may not be realistic because it increases the workload of the health staff. Therefore, the only possible solution is to introduce CTG [ 20 ]. The novel idea of this study is the systematic use of CTG and the monitoring of hypoxic and acidotic states using blood gas analysis. The Apgar score is a universal indicator for evaluating a baby’s condition after birth. However, as it contains subjective criteria, it may not reflect the hypoxic state of a newborn baby [ 21 ]. This study employed objectively verifiable indicators using the umbilical arterial sample, acidosis level, and the types of acidosis (respiratory, metabolic, or mixed) that can be revealed using pH, lactate, and base excess. As this study will be conducted in cooperation with two Cambodian academic societies, namely gynecology and obstetrics and perinatal care, the results are expected to be used to create national standard guidelines in the future. It is also expected that this study will contribute to other resource-limited settings and will eventually decrease preventable child deaths. This study has some potential limitations. The study will be conducted at a single site; therefore, the implementation process may not directly apply to other facilities. We will systematically exclude women with severe status, multiple pregnancies, and fetuses with malformations, and the effectiveness of CTG in these cases may not be revealed. Declarations Availability of data and materials The data that support the findings of this study will be available from the corresponding author [MM] upon reasonable requests. The data will not be publicly available due to legal restrictions by the Act on the Protection of Personal Information in Japan. Competing interests The principal investigator [MM] and collaborators [AA, HE, NU, RK, KK, SKL, and KT] have no conflicts of interest to declare. Funding The cost of this study will be supported by the Japan Agency for Medical Research and Development (AMED), a research program on the challenges of global health issues, the global clinical research development project－“Clinical research on the effectiveness of introducing Cardiotocography in Cambodia” (grant number JP23jk0110022). The funding organization is not be involved in building research protocols, data collection, or analysis. Protocol registration and checklist The protocol was registered with the UMIN Clinical Trials Registry on November 20, 2023. Its unique ID is UMIN000052815 (available from https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000059930). The protocol version number was set to 1. The SPIRIT 2013 checklist was used to address items in this study protocol and is attached in Table S2. Authors' contributions MM conceived the study design. MM, AA, KT submitted the ethical review and registered the clinical trial. MM, NU and EH created the guidelines, and RK, KK and SKL provides suggestions to adapt the guidelines in the local contexts. AA, KT and MM prepared the figures. MM, AA and KT will perform the data collection. KT and MM will conduct the statistical analyses. AA, KT, and MM will conduct an analysis of implementation processes and outcomes. All the authors were involved in the protocol and manuscript development, and reviewed and approved the final version. Acknowledgements We acknowledge that this protocol has been submitted to and approved by scientific advisory committee in the National Center Consortium in Implementation Science for Health Equity (N-EQUITY) in Japan (approved number N-EQUITY2202) in September 2022. Organization and functions of the N-EQUITY is available from https://www.japanhealth.jp/en/project/2019/Y_Uchitomi_2019.html. References United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). A Neglected Tragedy: The global burden of stillbirths. New York: United Nations Children's Fund; 2020. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels & Trends in Child Mortality: Report 2020, Estimates developed by the United Nations Inter-agency Group for Child Mortality Estimation. New York: United Nations Children's Fund; 2020. McClure EM, Saleem S, Goudar SS, Garces A, Whitworth R, Esamai F, et al. Stillbirth 2010–2018: a prospective, population-based, multi-country study from the Global Network. Reproductive Health. 2020;17(2):146. Oza S, Lawn JE, Hogan DR, Mathers C, Cousens SN. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013. Bull World Health Organ. 2015;93(1):19–28. Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016;388(10063):3027–35. Fottrell E, Osrin D, Alcock G, Azad K, Bapat U, Beard J, et al. Cause-specific neonatal mortality: analysis of 3772 neonatal deaths in Nepal, Bangladesh, Malawi and India. Arch Dis Child Fetal Neonatal Ed. 2015;100(5):F439–47. Ayres-de-Campos D, Arulkumaran S. FIGO consensus guidelines on intrapartum fetal monitoring: Physiology of fetal oxygenation and the main goals of intrapartum fetal monitoring. Int J Gynaecol Obstet. 2015;131(1):5–8. Lewis D, Downe S. FIGO consensus guidelines on intrapartum fetal monitoring: Intermittent auscultation. Int J Gynaecol Obstet. 2015;131(1):9–12. World Health Organization. WHO recommendations: intrapartum care for a positive childbirth experience. Geneva: World Health Organization; 2018. Alfirevic Z, Devane D, Gyte GM, Cuthbert A. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev. 2017;2(2):Cd006066. Caughey AB. Electronic Fetal Monitoring—Imperfect but Opportunities for Improvement. JAMA Netw Open. 2020;3(2):e1921352–e. Wall SN, Lee AC, Carlo W, Goldenberg R, Niermeyer S, Darmstadt GL, et al. Reducing intrapartum-related neonatal deaths in low- and middle-income countries-what works? Semin Perinatol. 2010;34(6):395–407. Takeshita M, Toyomoto R, Marui K, Ito M, Eto H, Takehara K et al. Cardiotocography use for fetal assessment during labor in low- and middle-income countries: A scoping review. Int J Gynecol Obstet. 2024. National Maternal and Child Health. Center and JICA IINeoC project. Guide for Initial Assessment. Phnom Penh: Ministry of Health; 2020. Parer JT, Ikeda T. A framework for standardized management of intrapartum fetal heart rate patterns. Am J Obstet Gynecol. 2007;197(1):e261–6. Okai T, Ikeda T, Kawarabayashi T, Kozuma S, Sugawara J, Chisaka H, et al. Intrapartum management guidelines based on fetal heart rate pattern classification. J Obstet Gynaecol Res. 2010;36(5):925–8. Parer JT. Standardization of fetal heart rate pattern management: Is international consensus possible? Hypertens Res Pregnancy. 2014;2(2):51–8. Glasgow RE, Vogt TM, Boles SM. Evaluating the public health impact of health promotion interventions: the RE-AIM framework. Am J Public Health. 1999;89(9):1322–7. Matsui M, Iwamoto A, Po R, Tung R. Midwifery care, medical interventions during labour and childbirth and neonatal outcomes in the first-line public health facilities in Cambodia. Trop Med Int Health. 2017;22(Suppl 1):338–9. Housseine N, Punt MC, Browne JL, van 't Hooft J, Maaløe N, Meguid T, et al. Delphi consensus statement on intrapartum fetal monitoring in low-resource settings. Int J Gynaecol Obstet. 2019;146(1):8–16. Chauhan S, Singh PK, Gahalaut P, Prasad PL. Correlation of pulse oximetry and apgar scoring in the normal newborns. J Clin Neonatol. 2013;2(1):20–4. Additional Declarations No competing interests reported. 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Center","correspondingAuthor":false,"prefix":"","firstName":"Rattana","middleName":"","lastName":"Kim","suffix":""},{"id":286002677,"identity":"832df11e-0709-4c2b-b0cd-7f0e3bdc910a","order_by":5,"name":"Kanal Koum","email":"","orcid":"","institution":"Cambodian Society of Gynecology and Obstetrics","correspondingAuthor":false,"prefix":"","firstName":"Kanal","middleName":"","lastName":"Koum","suffix":""},{"id":286002683,"identity":"8f23adcd-ac54-4bbf-89af-9abfbf1c9be1","order_by":6,"name":"Sotha Keth Ly","email":"","orcid":"","institution":"Cambodian Society of Gynecology and Obstetrics","correspondingAuthor":false,"prefix":"","firstName":"Sotha","middleName":"Keth","lastName":"Ly","suffix":""},{"id":286002684,"identity":"68f52602-9c6a-4e4c-8b88-3246fb37fe34","order_by":7,"name":"Kenji Takehara","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Takehara","suffix":""}],"badges":[],"createdAt":"2024-03-22 09:03:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4148437/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4148437/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54115610,"identity":"bf56f20c-23cb-47ce-9237-04dec3485c8c","added_by":"auto","created_at":"2024-04-04 19:33:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":109702,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between the intervention and implementation\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/ca17acf5c717ed0af5239fe7.png"},{"id":54116260,"identity":"9dfb4751-1e37-485b-bfc4-588f9847ef0d","added_by":"auto","created_at":"2024-04-04 19:41:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":93113,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEvaluation of CTG using the modified 5-tier system\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/d8dbb6da208d27ae27db7a82.png"},{"id":54116261,"identity":"712fe2e7-d89c-4227-a952-88e0436b3b20","added_by":"auto","created_at":"2024-04-04 19:41:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":185072,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of CTG application\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/5c49e69fd883cb5cddf1e895.png"},{"id":58370584,"identity":"3fc1ab24-13ba-426b-8814-0fcb2a9d86a0","added_by":"auto","created_at":"2024-06-14 13:44:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1019609,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/262ac329-1335-411f-ab0f-8aa56417b138.pdf"},{"id":54115611,"identity":"d61b39e2-da18-47f9-a731-eb4da3e8a5cf","added_by":"auto","created_at":"2024-04-04 19:33:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16167,"visible":true,"origin":"","legend":"","description":"","filename":"SITableS1NMCHCactivities.docx","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/ba398057873a752b63b930bc.docx"},{"id":54115615,"identity":"2af86435-edaf-4901-af61-d1806e7687f6","added_by":"auto","created_at":"2024-04-04 19:33:58","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":126464,"visible":true,"origin":"","legend":"","description":"","filename":"SITableS2SPIRIT2013.doc","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/2144664e2573a8d6b1043181.doc"},{"id":54115613,"identity":"e4c8393d-d4ae-48b6-96df-7243d50ad15b","added_by":"auto","created_at":"2024-04-04 19:33:58","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19776,"visible":true,"origin":"","legend":"","description":"","filename":"SIconsent.docx","url":"https://assets-eu.researchsquare.com/files/rs-4148437/v1/5ec4f8842f01520e735b83e9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Study on effectiveness of systematic cardiotocography use in National Maternal and Child Health Center in Cambodia: A study protocol for an explanatory clinical trial","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAn estimated 2\u0026nbsp;million stillbirths and 2.4\u0026nbsp;million neonatal deaths occur globally every year, and 98% of these deaths occur in low- and middle-income countries (LMICs) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Global estimates show that the main causes of neonatal death are prematurity (35%) and intrapartum-related events (23%), and 45% of stillbirths occur during labor [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Another report showed that half of neonatal deaths occur within the first 2 days of life, and asphyxia in preterm birth is the main cause of death [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, appropriate monitoring and timely intervention during labor can prevent intrapartum death [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFetal heart rate (FHR) monitoring is the most common and practical method for confirming fetal well-being during labor. The autonomic nervous system controls FHR, mainly regulated by the tension between oxygen and carbon dioxide in the blood and cerebrospinal fluid, body temperature, and blood pressure [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, maintenance or disruption of homeostasis in the fetus is observable through changes in the FHR. Two common FHR monitoring methods are intermittent auscultation (IA) and continuous cardiotocography (CTG) monitoring. IA involves listening to an FHR for short periods [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It uses low-cost equipment such as a Pinard stethoscope or a handheld Doppler ultrasound device. Alternatively, CTG simultaneously records FHR with uterine contractions, which enables a visual assessment of the relationship between FHR patterns and uterine contractions. FHR monitoring with uterine contractions provides information on fetal well-being and the ability to detect suspicious patterns of hypo-oxygenation or acidosis.\u003c/p\u003e \u003cp\u003eDespite the potential usefulness of CTG, the World Health Organization (WHO) does not recommend its use in healthy pregnant women [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This recommendation is based on evidence published in a Cochrane systematic review, which indicates that CTG use is associated with increased cesarean section and instrumental vaginal deliveries and only makes a small contribution to reduced neonatal morbidity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, of the 13 studies included in the review, 12 were published between 1976 and 1994, 11 were conducted in high-income countries (HICs), and only 2 in middle-income countries. Therefore, whether these results can be applied to the current LMIC setting is unclear. Additionally, there is a large gap in the practice of FHR monitoring between HICs and LMICs. CTG use in HICs is a \u003cem\u003ede facto\u003c/em\u003e standard despite several recommendations. In 2004, 86% of women in labor were monitored using CTG in the United States [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, no data on the coverage of intrapartum monitoring in LMICs is available [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Our review showed that CTG use in LMICs has not been standardized [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCTG could serve as a key solution to save millions of babies. However, it is still not appropriately used, perhaps due to insufficient scientific evidence. Therefore, there is an urgent need to determine the effectiveness of CTG in resource-limited settings.\u003c/p\u003e"},{"header":"2. Objectives","content":"\u003cp\u003eThis study aims to evaluate whether systematic cardiotocography (CTG) contributes to reducing fetal acidosis and its consequences, namely stillbirths and neonatal deaths, in a tertiary-level hospital in Cambodia.\u003c/p\u003e"},{"header":"3. Materials and Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Study setting\u003c/h2\u003e \u003cp\u003eThis study will be conducted at the National Maternal and Child Health Center in Cambodia (NMCHC). The NMCHC is located in the capital city of Phnom Penh. It is a government-funded hospital specializing in obstetrics, gynecology, and neonatal care. It serves as a referral facility and manages normal births. The clinical activities of the NMCHC are shown in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e (supporting information).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Participants\u003c/h2\u003e \u003cp\u003ePregnant women at moderate risk admitted for delivery to the NMCHC will be recruited. All admitted women will be screened in the triage room using standard initial assessment guidelines and classified into low-, moderate-, or high-risk groups [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The inclusion and exclusion criteria are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConditions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInclusion criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExclusion criteria\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus; High blood pressure (systolic 140mmHg or more, or diastolic 90mmHg or more)\u003c/p\u003e \u003cp\u003e\u0026minus; Fever (37.5\u0026ordm;C or more)\u003c/p\u003e \u003cp\u003e\u0026minus; Anemia (hemoglobin 9.0g/dl or less)\u003c/p\u003e \u003cp\u003e\u0026minus; Abnormal amount of amniotic fluid (amniotic fluid index 8 or less, or 25 or more)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus; Women in severe status (unconsciousness, massive hemorrhage, shock, convulsion, referred to operation theater or intensive care unit directly from the triage room)\u003c/p\u003e \u003cp\u003e\u0026minus; less than 18 years old\u003c/p\u003e \u003cp\u003e\u0026minus; HIV positive\u003c/p\u003e \u003cp\u003e\u0026minus; Obesity (body-mass index 30.0 or more)\u003c/p\u003e \u003cp\u003e\u0026minus; Lower body height (less than 140 cm)\u003c/p\u003e \u003cp\u003e\u0026minus; Malformation of pelvis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus; Low estimated body weight (less than 2500g)\u003c/p\u003e \u003cp\u003e\u0026minus; High estimated body weight (3500g or more)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus; Estimated gestational week 27 weeks and 6day or less\u003c/p\u003e \u003cp\u003e\u0026minus; Intra-uterine fetal death\u003c/p\u003e \u003cp\u003e\u0026minus; Multiple pregnancy\u003c/p\u003e \u003cp\u003e\u0026minus; Malformation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgress of labor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus; Time elapsed from rupture of membrane more than 24 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus; Already in the second stage of labor at the admission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Study design\u003c/h2\u003e \u003cp\u003eThis study will employ \u003cem\u003epre-\u003c/em\u003e and \u003cem\u003epost-\u003c/em\u003ecomparison design, and consist of three phases: observation (\u003cem\u003epre\u003c/em\u003e), pre-intervention, and intervention (\u003cem\u003epost\u003c/em\u003e). The systematic use of CTG is a main intervention. To enhance the effective use of CTG by health staff in the NMCHC, we will employ three implementation strategies: distribution of local CTG guidelines, training in the systematic use of CTG during the pre-intervention phase, and supervision of evaluation during the intervention phase. The conceptual framework of the intervention is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1 Observation phase\u003c/h2\u003e \u003cp\u003eNo specific interventions will be administered in this phase. Pregnant women with moderate risk will receive standard care during childbirth. Blood from the umbilical cord artery will be collected and analyzed immediately after delivery. The blood sample will be taken using a safePICO aspirator syringe (Radiometer Medical ApS, Br\u0026oslash;nsh\u0026oslash;j, Denmark) containing dry, electrolyte-balanced heparin. The analysis will be performed using an epoc\u0026reg; blood analysis system (Siemens Healthineers AG, Forchheim, Germany). The parameters measured will be pH, pCO\u003csub\u003e2\u003c/sub\u003e, pO\u003csub\u003e2\u003c/sub\u003e, lactate, and base excess.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2 Pre-intervention phase\u003c/h2\u003e \u003cp\u003e Original guidelines for using CTG and training sessions will be provided to staff members, both medical doctors and midwives working in maternity and delivery wards in the facility. The guidelines comprise a procedure to apply CTG and medical management in cases of abnormal findings, including fetal resuscitation procedures. After completing the training, CTG will be applied for 1 hour to all participants at the admission. We will proceed to the implementation phase after confirming that 80% of the CTG evaluation results correspond between the staff and the researchers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.3.3 Intervention phase\u003c/h2\u003e \u003cp\u003eThe CTG will be applied to all participants, and all CTG results will be evaluated using a modified 5-tier system [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The 5-tier system will classify CTG results into five groups: Green \u0026ndash; \u0026lsquo;no acidemia\u0026rsquo;; Blue \u0026ndash; \u0026lsquo;no central acidemia\u0026rsquo;; Yellow \u0026ndash; \u0026lsquo;intermittent hypoxia that may lead to acidemia\u0026rsquo;; Orange \u0026ndash; \u0026lsquo;potential for fetal decompensation\u0026rsquo;; or Red \u0026ndash; \u0026lsquo;possible actual or impending fetal asphyxia\u0026rsquo; [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. CTG will be applied immediately after admission for 1 hour as an admission test. It will be evaluated every 30 min and classified into one of five colors.\u003c/p\u003e \u003cp\u003eCTG will be applied intermittently for Green or Blue cases. For Yellow and Orange cases, CTG will be applied continuously, fetal resuscitation will be applied, and the results will be evaluated every 30 min. For Red cases, fetal resuscitation will be performed, and immediate delivery will be considered. A flowchart of the CTG application is shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. This study will use two types of CTG apparatus: MT-516 (Toitu Co. Ltd., Tokyo, Japan) for the admission test and iCTG (Melody International Ltd., Kagawa, Japan) for further monitoring. Umbilical arterial blood will be collected and measured as it is performed in the observation phase.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSupervision sessions will include an independent retrospective evaluation of the CTG and periodic feedback sessions. The researchers will organize all sessions. When researchers find a misinterpretation of CTG results or severe neonatal outcomes, feedback sessions with staff members will be held.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.3.4 Monitoring\u003c/h2\u003e \u003cp\u003eThis study will not employ monitoring measures. The NMCHC has a designated committee for neonatal death surveillance and response, and the committee independently investigates when neonatal death occurs to confirm the possible causes and establish future prevention measures.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Assessment of the outcomes\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1 Clinical outcomes\u003c/h2\u003e \u003cp\u003eThe primary endpoint is the detection of fetal acidosis, which manifests as a pH less than 7.20 in the umbilical arterial blood. The secondary outcomes are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSecondary endpoints, indicators and expected outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndpoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIndicator and expected outcomes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcidosis of umbilical arterial blood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epH less than 7.10 will be reduced\u003c/p\u003e \u003cp\u003epH less than 7.00 will be reduced\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrognosis of the fetus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNCU admission or transfer to other facility will be reduced in the CTG phase\u003c/p\u003e \u003cp\u003eIntra-partum stillbirth and early neonatal deaths will be reduced\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical interventions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInstrumental deliveries and cesarean sections will be increased to save the fetus lives will be increased\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2 Implementation outcomes\u003c/h2\u003e \u003cp\u003eThe implementation outcomes will be collected: the fidelity of CTG use, the reach of the CTG to pregnant women with moderate risk, and the delivery of implementation strategies to the staff in the NMCHC [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The fidelity of CTG use will be measured using the accuracy of the CTG assessments.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Data collection period\u003c/h2\u003e \u003cp\u003eThe observation phase was between January and April, and the pre-intervention phase was between May and December 2023. The first case involved in the intervention phase occurred on January 8, 2024. Data is expected to be collected by the end of April 2024.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Data collection\u003c/h2\u003e \u003cp\u003eBlood samples from umbilical artery will be collected and measured as it is described in 3.3.1. When the pO\u003csub\u003e2\u003c/sub\u003e level of the blood sample is 100 Torr or higher, the results will be excluded from the analysis. The blood sample is suspected to be contaminated with air, and the pH level may not be reliable. When the data output from the analyzer shows an \u0026lsquo;error,\u0026rsquo; the blood sample will be recollected and measured. The blood samples were suspected to be clotted. However, if an erroneous result is repeated in another sample, it will be excluded from the dataset.\u003c/p\u003e \u003cp\u003eStillbirth cases will be confirmed by the research assistants when they collect the blood samples immediately after the birth. Information on neonatal death will be collected via phone call to the mother or family members after one month of the birth.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Data analysis\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.7.1 Data management\u003c/h2\u003e \u003cp\u003eCollected paper data will be handled and stored at a research room in the NMCHC. All the information will be put as double-entry file using EpiData software (EpiData Association), converted into Excel file (Microsoft Corp). Blood gas analysis data will be extracted directly from epoc as csv file. Quantitative information will be analyzed using Stata software (version 17, Stata Corp). Only the researchers involved in this study will be able to access the dataset.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e3.7.2 Descriptive statistics\u003c/h2\u003e \u003cp\u003eThe participants\u0026rsquo; characteristics will be described and compared between the observation and intervention phases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e3.7.3 Clinical outcomes\u003c/h2\u003e \u003cp\u003eAn intention-to-treat analysis will be performed to compare health outcomes between the observation and intervention phases. Subgroup analysis using data from participants who underwent CTG may be considered. However, it will not be applied when the most eligible women are subjected to CTG. Other subgroup analyses will be performed according to parity, body weight at birth, and the types of risk factors.\u003c/p\u003e \u003cp\u003eThe primary endpoint, a pH level of less than 7.20, will be treated as the proportion of acidosis in the observation and intervention phases. Proportions will be compared using univariate and multivariate logistic regression analyses. The potential confounding factors included in the multivariate model will be age, parity, and body weight at birth. Secondary endpoints will be treated as proportions and analyzed using a logistic regression model.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003e3.7.4 Implementation outcomes\u003c/h2\u003e \u003cp\u003eImplementation outcomes are descriptively analyzed. The fidelity of CTG use is the main outcome. It is expected that 90% concordance will be achieved between staff and researchers for the yellow, orange, and red lever FHR patterns.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e3.8. Sample size\u003c/h2\u003e \u003cp\u003eIt is expected that fetal acidosis, revealed by a pH less than 7.20 in the umbilical arterial blood sample, will be reduced to 14% after the intervention from 21% before the intervention. The estimated prevalence during the observation phase (21%) is from our preliminary observation conducted in a primary health facility in Cambodia [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. With 5% alpha-error and 80% beta-error, one arm will be 462 cases. It was assumed that the dropout rate after obtaining informed consent and mismeasurement of umbilical arterial blood was 10%. Therefore, one arm required 555 patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Ethical considerations","content":"\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Recruitment and consent\u003c/h2\u003e \u003cp\u003eResearch assistants employed by this study fund will obtain information on every pregnant woman upon admission from standard initial assessments and medical records. Women with moderate risk who meet the inclusion criteria will be extracted, and the objectives and procedures of this study will be explained to pregnant women or their accompanying members. The contents of the explanation will include voluntary participation in the study, no disadvantages even if the patient refuses to participate, and no specific interventions will be conducted during the observation phase. Women will be involved in the study if they or their representatives provide written informed consent. Written consent will be obtained even during the observation phase to ensure opting-out measures for all participants. An explanation and a consent form is attached as Supporting Information (File S1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Disclosure of research information from the NMCHC\u003c/h2\u003e \u003cp\u003eAs this study will collect data from medical records, we will disclose the research outline and collect information on the inpatients for delivery, excluding personal information, by displaying the poster in the triage room for opt-out. We will also explain the purpose and content of this study to hospital staff members before the observation phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Treatment of individual information\u003c/h2\u003e \u003cp\u003ePersonal information, such as participants\u0026rsquo; names, addresses, and phone numbers, will be collected to combine data on delivery and neonatal death. The information used to identify participants will be kept strictly at the research office, room 214 in the NMCHC. During the data processing in Excel, participants\u0026rsquo; names, addresses, and phone numbers will be deleted from the dataset, hospital ID number will be used as a decoding index, and each piece of information was converted into electronic data and anonymized.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Ethics review and approval\u003c/h2\u003e \u003cp\u003e The study protocol was approved by the National Ethics Committee for Health Research, the Ministry of Health in Cambodia (May 02, 2022, 121NECHR), and the Institutional Review Board of Nagasaki University School of Tropical Medicine and Global Health, Japan (June 16, 2022, NU_TMGH_2022_213_1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Potential benefits and risks to the study participants\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section3\"\u003e \u003ch2\u003e4.5.1 Pregnant women who are targets of clinical research\u003c/h2\u003e \u003cp\u003eDuring the observation phase, no potential harm is expected to the pregnant women or their babies. During the intervention phase, the physical burden of wearing the CTG may increase, but we believe that this can be understood by explaining the effects of the CTG. The output from CTG can also provide the benefit of detecting fetal acidosis and the risk of developing medical interventions to respond to abnormalities. We will supervise the intervention period and believe that it can be responded to by ensuring the transparency of the process leading to medical intervention and explaining it to the target women.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section3\"\u003e \u003ch2\u003e4.5.2 Healthcare providers who are targets of implementation research\u003c/h2\u003e \u003cp\u003eHealthcare providers face no risks in participation in training, supervision, etc., which may limit a certain amount of time. However, it can be acceptable considering the benefits of providing medical care and improving quality.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec30\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Dissemination of the study results\u003c/h2\u003e \u003cp\u003eAs this study is a collaborative work between the NMCHC, two academic societies (Cambodian Society of Gynecology and Obstetrics, and Perinatal Society of Cambodia) and Japanese researchers, relevant information on the results will be disseminated thorough the academic channels in Cambodia and elsewhere in the world.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eAlthough many stillbirths and neonatal deaths are caused by intrauterine hypoxia during the labor period, there is still no effective means of detecting the fetus\u0026rsquo;s condition in a resource-limited setting. Intermittent auscultation may detect hypoxic or acidotic states. However, there are no specific guidelines for pregnant women at risk [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In addition, IA requires considerable effort from health staff. Listening to the fetal heart rate requires at least a few minutes for healthcare personnel [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. As one-to-one care is essential, IA may not be realistic because it increases the workload of the health staff. Therefore, the only possible solution is to introduce CTG [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe novel idea of this study is the systematic use of CTG and the monitoring of hypoxic and acidotic states using blood gas analysis. The Apgar score is a universal indicator for evaluating a baby\u0026rsquo;s condition after birth. However, as it contains subjective criteria, it may not reflect the hypoxic state of a newborn baby [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This study employed objectively verifiable indicators using the umbilical arterial sample, acidosis level, and the types of acidosis (respiratory, metabolic, or mixed) that can be revealed using pH, lactate, and base excess. As this study will be conducted in cooperation with two Cambodian academic societies, namely gynecology and obstetrics and perinatal care, the results are expected to be used to create national standard guidelines in the future. It is also expected that this study will contribute to other resource-limited settings and will eventually decrease preventable child deaths.\u003c/p\u003e \u003cp\u003eThis study has some potential limitations. The study will be conducted at a single site; therefore, the implementation process may not directly apply to other facilities. We will systematically exclude women with severe status, multiple pregnancies, and fetuses with malformations, and the effectiveness of CTG in these cases may not be revealed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study will be available from the corresponding author [MM] upon reasonable requests. The data will not be publicly available due to legal restrictions by the Act on the Protection of Personal Information in Japan.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe principal investigator [MM] and collaborators [AA, HE, NU, RK, KK, SKL,\u0026nbsp;and\u0026nbsp;KT] have no conflicts of interest to declare.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe cost of this study will be supported by the Japan Agency for Medical Research and Development (AMED), a research program on the challenges of global health issues, the global clinical research development project－\u0026ldquo;Clinical research on the effectiveness of introducing Cardiotocography in Cambodia\u0026rdquo; (grant number JP23jk0110022). The funding organization is not be involved in building research protocols, data collection, or analysis.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eProtocol registration and checklist\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe protocol was registered with the UMIN Clinical Trials Registry on November 20, 2023. Its unique ID is UMIN000052815 (available from https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000059930). The protocol version number was set to 1.\u0026nbsp;The\u0026nbsp;SPIRIT 2013 checklist was used to address items in this study protocol and\u0026nbsp;is attached\u0026nbsp;in Table S2.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eMM conceived the study design. MM, AA, KT submitted the ethical review and registered the clinical trial. MM, NU and EH created the guidelines, and RK, KK and SKL provides suggestions to adapt the guidelines in the local contexts. AA, KT and MM prepared the figures. \u0026nbsp;MM, AA and KT will perform the data collection. KT and MM will conduct the statistical analyses. AA, KT, and MM will conduct an analysis of implementation processes and outcomes. All the authors were involved in the protocol and manuscript development, and reviewed and approved the final version.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eWe acknowledge that this protocol has been submitted to and approved by scientific advisory committee in the National Center Consortium in Implementation Science for Health Equity (N-EQUITY) in Japan (approved number N-EQUITY2202) in September 2022. Organization and functions of the N-EQUITY is available from https://www.japanhealth.jp/en/project/2019/Y_Uchitomi_2019.html.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUnited Nations Inter-agency Group for Child Mortality Estimation (UN IGME). A Neglected Tragedy: The global burden of stillbirths. New York: United Nations Children's Fund; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUnited Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels \u0026amp; Trends in Child Mortality: Report 2020, Estimates developed by the United Nations Inter-agency Group for Child Mortality Estimation. New York: United Nations Children's Fund; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcClure EM, Saleem S, Goudar SS, Garces A, Whitworth R, Esamai F, et al. Stillbirth 2010\u0026ndash;2018: a prospective, population-based, multi-country study from the Global Network. Reproductive Health. 2020;17(2):146.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOza S, Lawn JE, Hogan DR, Mathers C, Cousens SN. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000\u0026ndash;2013. Bull World Health Organ. 2015;93(1):19\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016;388(10063):3027\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFottrell E, Osrin D, Alcock G, Azad K, Bapat U, Beard J, et al. Cause-specific neonatal mortality: analysis of 3772 neonatal deaths in Nepal, Bangladesh, Malawi and India. Arch Dis Child Fetal Neonatal Ed. 2015;100(5):F439\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAyres-de-Campos D, Arulkumaran S. FIGO consensus guidelines on intrapartum fetal monitoring: Physiology of fetal oxygenation and the main goals of intrapartum fetal monitoring. Int J Gynaecol Obstet. 2015;131(1):5\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewis D, Downe S. FIGO consensus guidelines on intrapartum fetal monitoring: Intermittent auscultation. Int J Gynaecol Obstet. 2015;131(1):9\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. WHO recommendations: intrapartum care for a positive childbirth experience. Geneva: World Health Organization; 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlfirevic Z, Devane D, Gyte GM, Cuthbert A. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev. 2017;2(2):Cd006066.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaughey AB. Electronic Fetal Monitoring\u0026mdash;Imperfect but Opportunities for Improvement. JAMA Netw Open. 2020;3(2):e1921352\u0026ndash;e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWall SN, Lee AC, Carlo W, Goldenberg R, Niermeyer S, Darmstadt GL, et al. Reducing intrapartum-related neonatal deaths in low- and middle-income countries-what works? Semin Perinatol. 2010;34(6):395\u0026ndash;407.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeshita M, Toyomoto R, Marui K, Ito M, Eto H, Takehara K et al. Cardiotocography use for fetal assessment during labor in low- and middle-income countries: A scoping review. Int J Gynecol Obstet. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Maternal and Child Health. Center and JICA IINeoC project. Guide for Initial Assessment. Phnom Penh: Ministry of Health; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParer JT, Ikeda T. A framework for standardized management of intrapartum fetal heart rate patterns. Am J Obstet Gynecol. 2007;197(1):e261\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkai T, Ikeda T, Kawarabayashi T, Kozuma S, Sugawara J, Chisaka H, et al. Intrapartum management guidelines based on fetal heart rate pattern classification. J Obstet Gynaecol Res. 2010;36(5):925\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParer JT. Standardization of fetal heart rate pattern management: Is international consensus possible? Hypertens Res Pregnancy. 2014;2(2):51\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlasgow RE, Vogt TM, Boles SM. Evaluating the public health impact of health promotion interventions: the RE-AIM framework. Am J Public Health. 1999;89(9):1322\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsui M, Iwamoto A, Po R, Tung R. Midwifery care, medical interventions during labour and childbirth and neonatal outcomes in the first-line public health facilities in Cambodia. Trop Med Int Health. 2017;22(Suppl 1):338\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHousseine N, Punt MC, Browne JL, van 't Hooft J, Maal\u0026oslash;e N, Meguid T, et al. Delphi consensus statement on intrapartum fetal monitoring in low-resource settings. Int J Gynaecol Obstet. 2019;146(1):8\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChauhan S, Singh PK, Gahalaut P, Prasad PL. Correlation of pulse oximetry and apgar scoring in the normal newborns. J Clin Neonatol. 2013;2(1):20\u0026ndash;4.\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":"Stillbirth, Neonatal death, Asphyxia, Hypoxia, Acidosis, Cardiotocography, CTG","lastPublishedDoi":"10.21203/rs.3.rs-4148437/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4148437/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and objective:\u003c/h2\u003e \u003cp\u003eAn estimated 2\u0026nbsp;million stillbirths and 2.4\u0026nbsp;million neonatal deaths occur globally every year, and 98% of these deaths occur in low- and middle-income countries. The main causes of neonatal death are prematurity and intrapartum-related events, and half of stillbirths occur during labor. Although cardiotocography (CTG) is used to detect fetal hypoxia and acidosis in high-income countries, its effectiveness is not shown in resource-limited settings. This study aims to evaluate whether systematic CTG contributes to reducing fetal acidosis, stillbirths and neonatal deaths in a tertiary-level hospital in Cambodia.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eParticipants will be pregnant women with moderate risk. The study employs pre- and post-comparison design, and consists of three phases: observation (pre), pre-intervention, and intervention (post). Standard care is applied during the observation phase. Training on CTG application using a local guideline is applied in the pre-intervention phase. Systematic CTG use and periodic supervision are key components of the intervention. The observation phase is between January and April 2023, and the intervention phase is between January and April 2024. Primary outcome is fetal acidosis, which manifests as a pH less than 7.20 in the umbilical arterial blood. The results in the observation and intervention phases will be compared using univariate and multivariate logistic regression analyses.\u003c/p\u003e\u003ch2\u003eDiscussion:\u003c/h2\u003e \u003cp\u003eThe novel idea of this study is the systematic use of CTG and the monitoring of hypoxic and acidotic states using blood gas analysis. It is expected that this study will contribute to show effectiveness of CTG use on reduction of fetal acidosis, and eventually on reduction of preventable child deaths in resource-limited settings.\u003c/p\u003e\u003ch2\u003eClinical trial registration:\u003c/h2\u003e \u003cp\u003eUMIN000052815, UMIN Clinical Trials Registry (UMIN-CTR)\u003c/p\u003e","manuscriptTitle":"Study on effectiveness of systematic cardiotocography use in National Maternal and Child Health Center in Cambodia: A study protocol for an explanatory clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-04 19:33:53","doi":"10.21203/rs.3.rs-4148437/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":"0211c2e6-c196-4b10-8ff6-27d95bb64c22","owner":[],"postedDate":"April 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-27T04:44:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-04 19:33:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4148437","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4148437","identity":"rs-4148437","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}