Reference Range of Fetal thorax using Two-dimensional and Three-dimensional Ultrasound VOCAL Technique and Application in Fetal Thoracic Malformations

Reference Range of Fetal thorax using Two-dimensional and Three-dimensional Ultrasound VOCAL Technique and Application in Fetal Thoracic Malformations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Reference Range of Fetal thorax using Two-dimensional and Three-dimensional Ultrasound VOCAL Technique and Application in Fetal Thoracic Malformations Xihua Lian, Zhenhong Xu, Liping Zheng, Zhixing Zhu, Tofunmi Ejiwale, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-127421/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Feb, 2021 Read the published version in BMC Medical Imaging → Version 1 posted 13 You are reading this latest preprint version Abstract Background: To establish the normal reference range of fetal thorax by two-dimensional (2D) and three-dimensional (3D) ultrasound VOCAL technique and evaluate the application in diagnosing fetal thoracic malformations. Methods: A prospective cross-sectional study was undertaken involving 1077 women who have a normal singleton pregnancy at 13-40 weeks gestational age (GA). 2D ultrasound and 3D ultrasound VOCAL technique were utilized to assess fetal thoracic transverse diameter, thoracic anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio. The nomograms of 2D and 3D fetal thoracic measurements were created to GA. 50 cases were randomly selected to calculate intra- and inter-observer reliability and agreement. In addition, the case groups including congenital skeletal dysplasia (SD) (15), congenital diaphragmatic hernia (CDH) (30), pulmonary sequestration (PS) (25) and congenital cystic adenomatoid malformation (CCAM) (36) were assessed by the nomograms and followed up subsequently. Results: Both 2D and 3D fetal thoracic parameters increased with GA using a quadratic regression equation. The intra- and inter-observer reliability and agreement of each thoracic parameter were excellent. 2D fetal thoracic parameters can initially evaluate the fetal thoracic development and diagnose the skeletal thoracic deformity, and lung volume, thoracic volume and lung-to-thorax volume ratio are practical to diagnose and differentiate CDH, PS and CCAM. Conclusion: We have established the normal fetal thoracic reference range at 13-40 weeks, which has a high value in diagnosing congenital thoracic malformations. Nuclear Medicine & Medical Imaging Fetal thorax 3D ultrasound VOCAL Reference range Malformation Figures Figure 1 Figure 1 Figure 2 Figure 2 Figure 3 Figure 3 Figure 4 Figure 4 Background The normal development of the thoracic structure is an essential basis for neonatal spontaneous breathing during the embryonic and fetal period, so the prenatal diagnosis of the fetal thoracic structure and its deformities is critical. Fetal congenital thoracic malformations (CTMs) are diverse, such as congenital skeletal dysplasia (SD), congenital diaphragmatic hernia (CDH), pulmonary sequestration (PS) and congenital cystic adenomatoid malformation (CCAM) [ 1 ]. They can cause various complications, the most serious of which is pulmonary hypoplasia (PH). PH refers to a disease whereby the fetal lung is defectively developed or stunted during the fetal development process. This typically manifest via a reduction number of pulmonary cells, airways and alveoli, thereby reducing lung volume and weight. PH affects fetal lung gas exchange and is responsible for high fetal and neonatal morbidity and mortality [ 2 , 3 ]. Congenital thoracic dysplasia is one of the causes of PH, as abnormal development of the thorax directly affects or restricts the lung development and accompanied by serious consequences [ 4 ]. Thus, early prenatal diagnosis of CMTs is beneficial for timely pregnancy management in fetuses with deadly deformities [ 5 ]. However, few methods are currently available for evaluating fetal thoracic development internationally [ 1 , 5 ]. In addition, there are few studies on the reference range for fetal thorax and the differential diagnosis of normal and abnormal fetus. Therefore, it is imperative to determine a new and dependable method to evaluate the fetal thorax and establish a nomogram of thoracic parameters. Our study aims to: (1) combine two-dimensional (2D) ultrasound and three-dimensional (3D) ultrasound Virtual Organ Computer-aided Analysis (VOCAL) technique to evaluate the normal development of fetal thorax; (2) measure the fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio, and establish a normal reference range of various measurements; (3) further explore its application in the diagnosis of congenital SD, CDH, PS and CCAM. Methods Sample and Protocol This is a prospective cross-sectional study approved by the Research Ethical Committee and undertaken from 1 July 2014 to 1 July 2019. Pregnant women in the normal group and the abnormal groups were randomly selected and recruited into this study and all of them could give informed consents. The inclusion criteria for the normal group included (1) singleton pregnancy, (2) precise gestational age (GA) based on last menstrual period and evaluated via ultrasonography before 20 gestational week, (3) GA is between 13 and 40 weeks, (4) absence of any fetal malformation, and (5) low-risk pregnancy without other maternal or placental complications. Exclusion criteria included (1) multifetal pregnancy, (2) any fetal malformations, (3) poor ultrasound imaging. Abnormal group: All cases were confirmed by postpartum examination or autopsy. To establish the fetal thoracic nomograms, we took measurements from a total of 1077 singleton and healthy pregnant women who met all above inclusion and exclusion criteria. The mean age of them was 27.40 years, the mean GA was 26.35 weeks. Meanwhile, 15 SD fetuses, 30 CDH fetuses, 25 PS fetuses and 36 CCAM fetuses were randomly selected, the mean GA was 19.89 weeks, 25.06 weeks, 25.42 weeks, and 25.84 weeks, respectively. In addition, 50 normal fetuses were randomly selected to analyze the intra- and inter-observer reliability and agreement. The same investigator (X.H.) performed all the thoracic measurements twice to estimate the intra-observer reliability and agreement. Simultaneously, another sonographer (S.L.) conducted an extra measurement to determine the inter-observer reliability and agreement. Both examiners worked independently and were shielded from each other. Measurements All ultrasound parameters were measured by GE E8 or E10 Expert device (General Electric Healthcare, Milwaukee, MI, USA) provided with a 4-8 MHz abdominal curvilinear transducer. A routine standard obstetric ultrasound examination was performed for each fetus to determine the fetal morphology and biometry. To obtain a best acoustic window of the thorax, we scanned fetal thorax on the heart four-chamber view section. From this section, we obtained the fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume and thoracic volume. For the optimization of 3D volume acquisition, we standardized the opening scanning angle between 45° and 85°. The low speed, high quality and harmonic mode was selected respectively. The pregnant women were required to hold their breath for a short time when the fetus was motionless, then we activate the automatic scanning window to involve the entire fetal thorax. All images were saved in the machine and analyzed off line. The 2D measurements were obtained manually from the heart four-chamber view section. The distance between spinal front edge and sternum rear edge was the thoracic anteroposterior diameter; a straight line which was drawn perpendicular to the anteroposterior diameter and between the two thoracic inner edges was the thoracic transverse diameter. A circle was manually traced along the outer and inner edges of the ribs, sternum, and spine to measure the thoracic circumference and thoracic area, respectively. 3D lung volume and thoracic volume were measured on the three perpendicular planes, VOCAL software (General Electric Medical Systems, KretzTechnik) was used by delimitating the surface with a rotation angle of 15° (12 planes) to acquire the volume automatically on the plane A. Briefly, in terms of lung volume measurement, we draw the lung outline excluding heart, organs in the mediastina, ribs and spine on each rotation plane 12 times. Left and right lung was measured separately, and added together to calculate the overall lung volume. To obtain the thoracic volume, we rotated the z-axis to make sure that the lung apex was above and the diaphragm was below on plane A. The thoracic contour (entire inner margin of thorax and upper margin of the diaphragm) was defined on each plane. After contouring the last plane, the reconstructed lung and thorax 3D images were established (Fig. 1). Statistical Analysis All data were analyzed by SPSS software (version 21.0, IBM Corp., Armonk, NY, USA) and Medcalc software (Mariakerke, Belgium). Continuous variables were stated as mean and standard deviation (SD). We used the quadratic regression model as the best equation for evaluating correlation between each thoracic parameter and GA. Coefficient of determination (R 2 ) was used to calculate the adjustments. According to the best-fit equation, predictive values for mean, SD, 5th, 50th, and 95 percentile ranges of each fetal thoracic parameter were constructed between 13 and 40 weeks. As all thoracic parameters increase with increasing GA, Z score was used to eliminate the effects of GA when comparing the measurements between the abnormal and normal groups. Z score = (measured thoracic value - overall mean thoracic value)/overall standard deviation of thoracic value. The Mann-Whitney U test was performed to compare the data between the abnormal and normal groups. We applied intraclass correlation coefficient (ICC) to calculate the reliability and performed Bland-Altman plots to assess agreement via showing bias between the two values and the limits of agreement (LoA) [6]. The reliability quality could be interpreted excellent if the ICC cutoff value was more than 0.90 [7]. All tests were considered significant with p <0.05. Results Fetal thoracic identification rate and normal ultrasonography There were 1167 pregnant women selected in our study. Of these, 90 fetal images who were affected by thick abdominal fat in pregnant women (n = 25), attenuation of fetal rib (n = 28), fetal position (n = 20) and amniotic fluid volume (n = 17) were excluded. The remaining 1077 women were included in this study, so the identification rate is 92.29%. The fetal thorax is mainly composed of skeletal thoracic frame, which was quasi-circular, and thoracic internal organs, including the heart, large blood vessels, lungs, trachea and thymus. The myocardium and lungs are moderately echogenic, and the cardiac chamber is echoless on four-chamber view section. The three vessels and trachea view section shows that the large vessel wall and tracheal wall are high echo, the lumen are echoless and the thymus is medium-low echo (Fig. 2 ). Normal reference range of fetal thoracic measurements Correlation between fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume, lung-to-thoracic volume ratio and GA had high significance ( P < 0.0001 respectively). Figure 3 represents the correlation and scatterplot of fetal thoracic parameters and GA. Table 1 and Table 2 show the nomograms of thoracic 2D and 3D measurements for each gestational week. Comparison of thoracic parameters between abnormal groups and normal group The comparison of fetal thoracic parameters between the abnormal groups (SD group, CDH group, PS group and CCAM group) and the normal group is shown in Table 3 . All the thoracic parameters in SD group were significantly lower than those in normal group ( P < 0.0001). Similarly, the lung-to-thoracic volume ratio in CDH, PS and CCAM group were lower and had statistical significance ( P < 0.0001). Compared with normal group, the lung volume in CDH, PS and CCAM group were lower ( P 0.05). Intra-observer and inter-observer reliability and agreement The intra- and inter-observer reliability and agreement of fetal thoracic measurements were excellent (ICC > 0.90 and narrow 95% LoA respectively), which are shown in Table 4 and Fig. 4 . Among them, the intra-observer reliability and agreement was the best in measuring the fetal thoracic anteroposterior diameter, with ICC = 0.9992, 95% confidence interval (95%CI) 0.9986 ~ 0.9995 and the mean difference was 0.0048 cm (95% LoA: -0.1039 ~ 0.1135). Discussion Various ultrasound investigations have focused on the fetal lung, such as lung area [ 3 , 8 ] and lung volume [ 9 , 10 ], to evaluate the fetal lung development. In terms of the fetal thorax, some studies mention the usefulness of fetal thoracic area [ 8 ], thoracic circumference [ 2 , 3 ] and thoracic volume [ 10 ] in prenatal diagnosis, but few systematic studies have established the fetal thoracic nomogram and assess the application in diagnosing thoracic malformations. Ultrasound could diagnose congenital thoracic malformations such as congenital pleural effusion, CHD and bronchopulmonary sequestration before 16 gestational weeks, which is beneficial for prenatal counseling and making early decisions concerning deadly fetal malformations [ 5 ]. Suyama et al. [ 8 ] measured thoracic area and used lung-to-thorax transverse area ratio to confirm the lung size after thoracoamniotic shunting, and concluded that the area ratio is connected with the prognosis of fetal primary hydrothorax. Research indicated that the area ratio of liver herniation and thorax is essential for the evaluation of severe degree of liver herniation in CDH individuals [ 11 ]. In terms of thoracic volume measuring method, Miric Tesanic et al [ 10 ] demonstrated that both lung volumes plus heart volume was thoracic volume, which is not completely accurate because they disregard other organs’ volume in the mediastinum, like the thymus. Moreover, they used the 3D multiplane reconstruction mode to measure the fetal lung and heart volume by adding different slices together from the diaphragm to the clavicle. Compared with VOCAL technique, it is difficult to calculate the lower lung volume although there is a similar volume result between multiplane and VOCAL technique [ 12 , 13 ]. Additionally, 3D multiplane reconstruction method is a cumbersome and time-consuming procedure, especially for inexperienced physicians, which limits its clinical application. VOCAL technique is the most popular method for volume measuring method because it is convenient, time-efficient, cost-effective and has high reliability and agreement [ 14 – 17 ]. Additionally, our study shows high reliability with all ICC > 0.90 and excellent agreement with narrow 95% LoA, respectively [ 6 , 7 ]. VOCAL technique can be used to measure regular organs such as bladder and irregular organs such as lung and thymus. In addition, the organ contour in each rotation section can be modified, which makes the volume more accurate. Finally, most previous studies used the VOCAL technique with rotation angle of 30° [ 12 , 14 , 16 , 18 , 19 ], we chose the rotation angle of 15° to make the volume more precise. Consequently, we propose to use 2D ultrasound and 3D ultrasound VOCAL technique to measure fetal thoracic 2D parameters and 3D volumes and establish the reference range for all fetal thoracic parameters. This study results demonstrate that both the 2D and the 3D thoracic parameters increase with the GA. Moreover, the associations between the each thoracic indicator and the GA are high and best illustrated by quadratic equations. Thus, thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thorax volume ratio can be treated as new biometric parameters, which is practical to evaluate the development of fetal thorax. We hypothesize that 2D thoracic parameters can be used to preliminarily assess the basic condition of the fetal thorax, while 3D thoracic parameters further evaluate the fetal lung and thorax, which is beneficial for congenital thoracic malformation diagnosis. Our study results also verified that the thoracic 2D measurements in skeletal dysplasia (SD) group were significantly lower than those in normal group, indicating that SD greatly influences the 2D parameters, and can be diagnosed by 2D ultrasound. Furthermore, both lung volume and thoracic volume were much smaller than the volumes of normal group. This might be because the SD fetus has a narrow skeletal thorax [ 20 , 21 ] and causes the significant diminish of thoracic volume, which results in limited development of the fetal lung which and reduced more significantly. Thus, the lung-to-thorax volume ratio of the SD fetus is decreased markedly compared with the normal group. However, the 2D fetal thoracic parameters in CDH, PS and CCAM group are all within the reference range for the normal group, showing that it is not statistically significant to measure fetal thoracic 2D parameters to diagnose those deformities. On the other hand, there is a statistical difference of lung volume and lung-to-thorax volume ratio between the case and normal groups. For CDH group, due to the diaphragm defect, the abdominal contents herniate into the fetal thorax [ 11 , 22 ], which squeezes the lung tissue and causes the restricted lung development, even resulting in pulmonary dysplasia. Although the thoracic volume of the CDH fetus did not have statistical difference from the normal fetus, it showed a trend to a lower value. We need to increase the CDH sample cases in the future study to confirm whether the CHD fetal thoracic volume is really lower than normal fetus. Because of the lung volume decrease and non-obvious thoracic volume change, the lung-to-thorax volume ratio is significantly diminished. Likewise, the lung volumes of the PS fetus and CCAM fetus are also reduced, the reason might be that PS and CCAM are both congenital pulmonary malformations, PS is non-functional sequestered lung tissue which receives blood supply from the circulating arteries, meanwhile, CCAM is characterized by abnormal bronchial airway hyperplasia [ 5 , 23 ], meanwhile, CCAM is characterized by abnormal bronchial airway hyperplasia and lack of normal alveoli [ 5 , 24 ]. Both conditions affect the normal progress of the fetal lung and bring about lower lung volume. Conversely, the abnormal lung mass of PS and CCAM does not affect the development of fetal skeletal thorax and diaphragm, so the difference of thoracic volume between the PS, CCAM group and normal group is not significant. As a result, the lung-to-thorax volume ratio is significantly reduced. Compared with previous studies [ 19 , 25 ], our research has a large sample size including 1077 normal fetuses from 13 gestational weeks to 40 gestational weeks, which makes the reference data more representative and reliable. Moreover, it enriches the normal fetal biostatistics and helps clinicians to evaluate and follow up fetal development comprehensively. Secondly, our study, including both 2D and 3D thoracic parameters, is the first research project to systematically evaluate the development of fetal thorax. This is meaningful and practical to comprehensively distinguish the normal and pathological fetal thoracic state [ 19 ]. In addition, we find that the 2D fetal thoracic parameters can be used to initially evaluate the fetal thoracic development and diagnose skeletal thoracic deformity. Meanwhile, lung volume, thoracic volume and lung-to-thorax volume ratio that reconstructed by 3D VOCAL technique, are useful to diagnose and differentiate CDH fetus, PS fetus and CCAM fetus. Combination of 2D and 3D ultrasound VOCAL technique can guide doctors and pregnant women to carry out early and appropriate measurement to reduce the birth rate of newborns with thoracic malformations. Limitations of this study: firstly, the 3D ultrasound VOCAL technique is susceptible to fetal position, amniotic fluid volume or fat pregnant. Secondly, it is difficult to clearly identify the inferior boundary of fetal lung on some rotation planes, since it is easily affected by the attenuation of the fetal ossific rib or spine, especially in the third trimester of pregnancy. This might reduce the accuracy of volume measurement. Conclusion We establish an integrated nomograms of fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thorax-volume ratio by 2D and 3D ultrasound. All thoracic measurements have high intra- and inter-observer reliability and agreement and increase with the gestational age (GA), the correlation between each measurement and GA is excellent. Meanwhile, we find that combining 2D ultrasound with 3D VOCAL technique has a high value in diagnosing congenital thoracic malformations. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the Second Affiliated Hospital of Fujian Medical University. Written informed consent was obtained from all participants. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was sponsored by the key Clinical Specialty Discipline Construction Program of Fujian, P.R.C [(2017)739], the Research Project of Science and Technology Department of Fujian Province, China (Grant 2018J01288), the Youth Research Project of Health and Family Planning Commission of Fujian Province, China (Grants 2018-1-62 and 2018-2-23), the Quanzhou Science and Technology Project (Grants 2018N012), and the Research Project of Collaborative Innovation Center for Maternal and Infant Health Service Application Technology (Grant XJM1802). The funding bodies provided financial support for the research work but played no role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript. Author’s contributions X L: Study design, study concepts, literature research, data collection and analysis, manuscript writing and post-processing. Z X: Study design, study concepts, data collection and analysis, manuscript writing and post-processing; L Z, Z Z: Literature research, Data collection and analysis, statistical analysis; T E, AK, Y Z: manuscript editing; P C, S H, S L: Data collection; G L: Project administration, manuscript review, supervision. All authors have read and approved the manuscript. Acknowledgement Not applicable. References Rodríguez MR, de Vega VM, Alonso RC, Arranz JC, Ten PM, Pedregosa JP: MR imaging of thoracic abnormalities in the fetus . Radiographics 2012, 32 (7):E305-E321. Britto IS, Tedesco GD, Herbst SR, Bussamra LC, de Andrade FM, Araujo Junior E, Nardozza LM, Ruano R, Moron AF, Aoki T: New anatomical landmarks to study the relationship between fetal lung area and thoracic circumference by three-dimensional ultrasonography . J Matern Fetal Neonatal Med 2012, 25 (10):1927-1932. Triebwasser JE, Treadwell MC: Prenatal prediction of pulmonary hypoplasia . 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Supplementary Files Table14.docx Table14.docx Cite Share Download PDF Status: Published Journal Publication published 22 Feb, 2021 Read the published version in BMC Medical Imaging → Version 1 posted Review # 2 received at journal 29 Dec, 2020 Editorial decision: Minor revision 29 Dec, 2020 Review # 1 received at journal 26 Dec, 2020 Review # 4 received at journal 14 Dec, 2020 Review # 3 received at journal 14 Dec, 2020 Reviewer # 4 agreed at journal 13 Dec, 2020 Reviewer # 3 agreed at journal 09 Dec, 2020 Reviewer # 2 agreed at journal 09 Dec, 2020 Editor assigned by journal 06 Dec, 2020 Reviewers invited by journal 06 Dec, 2020 Reviewer # 1 agreed at journal 06 Dec, 2020 Submission checks completed at journal 06 Dec, 2020 Editor invited by journal 06 Dec, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-127421","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":6348865,"identity":"f45e9cdd-f929-43f4-9b32-b7be0f4f2978","order_by":0,"name":"Xihua Lian","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xihua","middleName":"","lastName":"Lian","suffix":""},{"id":6348866,"identity":"7862ffaf-a2c0-49b4-b752-4d8f6f6753b1","order_by":1,"name":"Zhenhong Xu","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhenhong","middleName":"","lastName":"Xu","suffix":""},{"id":6348867,"identity":"a7b43760-63c4-4188-98da-e9896f061fac","order_by":2,"name":"Liping Zheng","email":"","orcid":"","institution":"Xiamen City Second Hospital: Xiamen Medical College Affiliated Second Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Zheng","suffix":""},{"id":6348868,"identity":"3e83bad1-dd0a-4cc9-8da2-9b39d2a250b3","order_by":3,"name":"Zhixing Zhu","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhixing","middleName":"","lastName":"Zhu","suffix":""},{"id":6348869,"identity":"10a71ae6-d8ab-4f0f-970a-c275692f46ea","order_by":4,"name":"Tofunmi Ejiwale","email":"","orcid":"","institution":"University of Otago Christchurch","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tofunmi","middleName":"","lastName":"Ejiwale","suffix":""},{"id":6348870,"identity":"e9c8b415-e1df-42b3-905c-ea914437f156","order_by":5,"name":"Ayush Kumar","email":"","orcid":"","institution":"University of Otago Christchurch","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayush","middleName":"","lastName":"Kumar","suffix":""},{"id":6348871,"identity":"804e9328-0150-446a-8c48-af640d1f9006","order_by":6,"name":"Peiya Cai","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peiya","middleName":"","lastName":"Cai","suffix":""},{"id":6348872,"identity":"d0fbb4df-bf1d-41b0-9c44-ad9321ad6d82","order_by":7,"name":"Shaozheng He","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shaozheng","middleName":"","lastName":"He","suffix":""},{"id":6348873,"identity":"09567d47-456a-499b-a289-a8e53c667ced","order_by":8,"name":"Shunlan Liu","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shunlan","middleName":"","lastName":"Liu","suffix":""},{"id":6348874,"identity":"18b54817-847b-43eb-a5a3-9ecfe4869fa5","order_by":9,"name":"Ying Zhang","email":"","orcid":"","institution":"Second Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Zhang","suffix":""},{"id":6348875,"identity":"ad1fba23-923b-4817-8cbf-05ea4f401877","order_by":10,"name":"Guorong Lyu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACPhBRAcT8DIwNxGlhAxFngFiygWQtBgeIdRgb/9oHDAcqDtsbnz/c9uAHg52cLiHL2CSeGzAcOHM4cduNxHbDHoZkYzNC1rFJHGNg/th2OMHsBmObBA/DgcRtxGhhOPgP6LD+g22Sf4jSwt8G1NJwmHEDQ2KbNJG2AMPswLH0xBk3gFpkDIjwCz8/0GEHaqzt+fuPP5N8U2EnR1ALg0QC+w8Ez4CQcrA1BA0dBaNgFIyCEQ8ATqk/d27DDo4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3123-1138","institution":"Department of Ultrasound Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China. Quanzhou Medical College, Quanzhou, China.","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Guorong","middleName":"","lastName":"Lyu","suffix":""}],"badges":[],"createdAt":"2020-12-12 18:35:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-127421/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-127421/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12880-021-00548-w","type":"published","date":"2021-02-22T15:00:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":4318448,"identity":"0c0bb97f-514a-4fff-aa7d-c4a15d53a978","added_by":"auto","created_at":"2020-12-16 23:27:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16929400,"visible":true,"origin":"","legend":"Ultrasonography and schematic diagram of fetal thoracic measurements. a \u0026 b: Thoracic transverse diameter and thoracic anteroposterior diameter; c \u0026 d: Thoracic circumference; e \u0026 f: Thoracic area; g: lung volume; h: Thoracic volume","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/9fe5217ea16980e44c42e87c.png"},{"id":4318442,"identity":"866c7d88-1f8f-4349-8bc2-4868d8e088af","added_by":"auto","created_at":"2020-12-16 23:27:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16929400,"visible":true,"origin":"","legend":"Ultrasonography and schematic diagram of fetal thoracic measurements. a \u0026 b: Thoracic transverse diameter and thoracic anteroposterior diameter; c \u0026 d: Thoracic circumference; e \u0026 f: Thoracic area; g: lung volume; h: Thoracic volume","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/a8483e513f8f5aea83bdf46c.png"},{"id":4318445,"identity":"21db4df2-eff4-4abd-813e-a834c756182d","added_by":"auto","created_at":"2020-12-16 23:27:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5389898,"visible":true,"origin":"","legend":"Normal ultrasonography of fetal thorax. a: normal ultrasonography of fetal heart four-chamber view section; b: normal ultrasonography of fetal three vessels trachea view section. H: heart, ThAO: thoracic aorta, SP: spine, LL: left lung, RL: right lung, SVC: superior vena cava, MPA: aorta, ARCH: aortic arch, T: trachea, TH: thymus","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/348ea4461986c3090c363cc3.png"},{"id":4318441,"identity":"6a4837f5-02c2-4b6e-84b8-e16d9afe7d9b","added_by":"auto","created_at":"2020-12-16 23:27:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5389898,"visible":true,"origin":"","legend":"Normal ultrasonography of fetal thorax. a: normal ultrasonography of fetal heart four-chamber view section; b: normal ultrasonography of fetal three vessels trachea view section. H: heart, ThAO: thoracic aorta, SP: spine, LL: left lung, RL: right lung, SVC: superior vena cava, MPA: aorta, ARCH: aortic arch, T: trachea, TH: thymus","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/2cc2c9d804b6762f894f6e7b.png"},{"id":4318447,"identity":"e1e34458-6e79-410c-b84c-3cea1d1efb2c","added_by":"auto","created_at":"2020-12-16 23:27:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2914603,"visible":true,"origin":"","legend":"Scatterplot of fetal thoracic parameters and gestational age. a: Transverse diameter; b: Thoracic anteroposterior diameter; c: thoracic circumference; d: thoracic area; e: lung volume; f: thoracic volume; g: lung-to-thoracic volume ratio. The three curves show the 2.5th centile, mean and 97.5th centile, respectively.","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/b32e7001357686ef3a42bb2e.png"},{"id":4318440,"identity":"187e2c4b-f395-4d2d-a065-d81d2f86f3df","added_by":"auto","created_at":"2020-12-16 23:27:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2914603,"visible":true,"origin":"","legend":"Scatterplot of fetal thoracic parameters and gestational age. a: Transverse diameter; b: Thoracic anteroposterior diameter; c: thoracic circumference; d: thoracic area; e: lung volume; f: thoracic volume; g: lung-to-thoracic volume ratio. The three curves show the 2.5th centile, mean and 97.5th centile, respectively.","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/381e2abb141da072ae43ee6a.png"},{"id":4318446,"identity":"f4706dc0-0057-4194-822b-e50737899b14","added_by":"auto","created_at":"2020-12-16 23:27:47","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":948734,"visible":true,"origin":"","legend":"Bland-Altman plots of intra-observer and inter-observer agreement of thoracic measurements. a \u0026 b: Transverse diameter; c \u0026 d: Thoracic anteroposterior diameter; e \u0026 f: Thoracic circumference; g \u0026 h: Thoracic area; i \u0026 j: lung volume; k \u0026 l: thoracic volume. The blue solid curve represents the mean difference, while the red dashed curves show the 95% LoA","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/9ce526725d947213c80fcf84.png"},{"id":4318439,"identity":"806f3ee1-443a-44d9-92a1-35d5d4c6c09a","added_by":"auto","created_at":"2020-12-16 23:27:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":948734,"visible":true,"origin":"","legend":"Bland-Altman plots of intra-observer and inter-observer agreement of thoracic measurements. a \u0026 b: Transverse diameter; c \u0026 d: Thoracic anteroposterior diameter; e \u0026 f: Thoracic circumference; g \u0026 h: Thoracic area; i \u0026 j: lung volume; k \u0026 l: thoracic volume. The blue solid curve represents the mean difference, while the red dashed curves show the 95% LoA","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/f912332150a7d40d88ec8af4.png"},{"id":13634319,"identity":"36fd290b-8edc-49d5-9e60-3b7121d87def","added_by":"auto","created_at":"2021-09-17 08:31:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5331971,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/f208d474-b8d8-494c-9e63-7b18f9e9f870.pdf"},{"id":4318444,"identity":"93cecacc-34f9-4313-a9b7-5418b2a15b30","added_by":"auto","created_at":"2020-12-16 23:27:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45342,"visible":true,"origin":"","legend":"","description":"","filename":"Table14.docx","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/7cf5257a49b0420491dc59c7.docx"},{"id":4318438,"identity":"ee53e05c-e04a-47c8-bf92-53bb596175eb","added_by":"auto","created_at":"2020-12-16 23:27:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45342,"visible":true,"origin":"","legend":"","description":"","filename":"Table14.docx","url":"https://assets-eu.researchsquare.com/files/rs-127421/v1/316a80e06cea9ebe4320f2a4.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eReference Range of Fetal thorax using Two-dimensional and Three-dimensional Ultrasound VOCAL Technique and Application in Fetal Thoracic Malformations\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eThe normal development of the thoracic structure is an essential basis for neonatal spontaneous breathing during the embryonic and fetal period, so the prenatal diagnosis of the fetal thoracic structure and its deformities is critical. Fetal congenital thoracic malformations (CTMs) are diverse, such as congenital skeletal dysplasia (SD), congenital diaphragmatic hernia (CDH), pulmonary sequestration (PS) and congenital cystic adenomatoid malformation (CCAM) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They can cause various complications, the most serious of which is pulmonary hypoplasia (PH). PH refers to a disease whereby the fetal lung is defectively developed or stunted during the fetal development process. This typically manifest via a reduction number of pulmonary cells, airways and alveoli, thereby reducing lung volume and weight. PH affects fetal lung gas exchange and is responsible for high fetal and neonatal morbidity and mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Congenital thoracic dysplasia is one of the causes of PH, as abnormal development of the thorax directly affects or restricts the lung development and accompanied by serious consequences [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thus, early prenatal diagnosis of CMTs is beneficial for timely pregnancy management in fetuses with deadly deformities [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, few methods are currently available for evaluating fetal thoracic development internationally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, there are few studies on the reference range for fetal thorax and the differential diagnosis of normal and abnormal fetus. Therefore, it is imperative to determine a new and dependable method to evaluate the fetal thorax and establish a nomogram of thoracic parameters. Our study aims to: (1) combine two-dimensional (2D) ultrasound and three-dimensional (3D) ultrasound Virtual Organ Computer-aided Analysis (VOCAL) technique to evaluate the normal development of fetal thorax; (2) measure the fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio, and establish a normal reference range of various measurements; (3) further explore its application in the diagnosis of congenital SD, CDH, PS and CCAM.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eSample and Protocol\u003c/h2\u003e\n\u003cp\u003eThis is a prospective cross-sectional study approved by the Research Ethical Committee and undertaken from 1 July 2014 to 1 July 2019. Pregnant women in the normal group and the abnormal groups were randomly selected and recruited into this study and all of them could give informed consents.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria for the normal group included (1) singleton pregnancy, (2) precise gestational age (GA) based on last menstrual period and evaluated via ultrasonography before 20 gestational week, (3) GA is between 13 and 40 weeks, (4) absence of any fetal malformation, and (5) low-risk pregnancy without other maternal or placental complications. Exclusion criteria included (1) multifetal pregnancy, (2) any fetal malformations, (3) poor ultrasound imaging.\u003c/p\u003e\n\u003cp\u003eAbnormal group: All cases were confirmed by postpartum examination or autopsy.\u003c/p\u003e\n\u003cp\u003eTo establish the fetal thoracic nomograms, we took measurements from a total of 1077 singleton and healthy pregnant women who met all above inclusion and exclusion criteria. The mean age of them was 27.40 years, the mean GA was 26.35 weeks. Meanwhile, 15 SD fetuses, 30 CDH fetuses, 25 PS fetuses and 36 CCAM fetuses were randomly selected, the mean GA was 19.89 weeks, 25.06 weeks, 25.42 weeks, and 25.84 weeks, respectively.\u003c/p\u003e\n\u003cp\u003eIn addition, 50 normal fetuses were randomly selected to analyze the intra- and inter-observer reliability and agreement. The same investigator (X.H.) performed all the thoracic measurements twice to estimate the intra-observer reliability and agreement. Simultaneously, another sonographer (S.L.) conducted an extra measurement to determine the inter-observer reliability and agreement. Both examiners worked independently and were shielded from each other.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eMeasurements\u003c/h2\u003e\n\u003cp\u003eAll ultrasound parameters were measured by GE E8 or E10 Expert device (General Electric Healthcare, Milwaukee, MI, USA) provided with a 4-8 MHz abdominal curvilinear transducer.\u003c/p\u003e\n\u003cp\u003eA routine standard obstetric ultrasound examination was performed for each fetus to determine the fetal morphology and biometry. To obtain a best acoustic window of the thorax, we scanned fetal thorax on the heart four-chamber view section. From this section, we obtained the fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume and thoracic volume. For the optimization of 3D volume acquisition, we standardized the opening scanning angle between 45\u0026deg; and 85\u0026deg;. The low speed, high quality and harmonic mode was selected respectively. The pregnant women were required to hold their breath for a short time when the fetus was motionless, then we activate the automatic scanning window to involve the entire fetal thorax. All images were saved in the machine and analyzed off line.\u003c/p\u003e\n\u003cp\u003eThe 2D measurements were obtained manually from the heart four-chamber view section. The distance between spinal front edge and sternum rear edge was the thoracic anteroposterior diameter; a straight line which was drawn perpendicular to the anteroposterior diameter and between the two thoracic inner edges was the thoracic transverse diameter. A circle was manually traced along the outer and inner edges of the ribs, sternum, and spine to measure the thoracic circumference and thoracic area, respectively. 3D lung volume and thoracic volume were measured on the three perpendicular planes, VOCAL software (General Electric Medical Systems, KretzTechnik) was used by delimitating the surface with a rotation angle of 15\u0026deg; (12 planes) to acquire the volume automatically on the plane A. Briefly, in terms of lung volume measurement, we draw the lung outline excluding heart, organs in the mediastina, ribs and spine on each rotation plane 12 times. Left and right lung was measured separately, and added together to calculate the overall lung volume. To obtain the thoracic volume, we rotated the z-axis to make sure that the lung apex was above and the diaphragm was below on plane A. The thoracic contour (entire inner margin of thorax and upper margin of the diaphragm) was defined on each plane. After contouring the last plane, the reconstructed lung and thorax 3D images were established (Fig. 1). \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eAll data were analyzed by SPSS software (version 21.0, IBM Corp., Armonk, NY, USA) and Medcalc software (Mariakerke, Belgium). Continuous variables were stated as mean and standard deviation (SD). We used the quadratic regression model as the best equation for evaluating correlation between each thoracic parameter and GA. Coefficient of determination (R\u003csup\u003e2\u003c/sup\u003e) was used to calculate the adjustments. According to the best-fit equation, predictive values for mean, SD, 5th, 50th, and 95 percentile ranges of each fetal thoracic parameter were constructed between 13 and 40 weeks. As all thoracic parameters increase with increasing GA, Z score was used to eliminate the effects of GA when comparing the measurements between the abnormal and normal groups. Z score = (measured thoracic value - overall mean thoracic value)/overall standard deviation of thoracic value. The \u003cem\u003eMann-Whitney U\u003c/em\u003e test was performed to compare the data between the abnormal and normal groups. We applied intraclass correlation coefficient (ICC) to calculate the reliability and performed Bland-Altman plots to assess agreement via showing bias between the two values and the limits of agreement (LoA) [6]. The reliability quality could be interpreted excellent if the ICC cutoff value was more than 0.90 [7]. All tests were considered significant with\u003cem\u003e p\u003c/em\u003e \u0026lt;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eFetal thoracic identification rate and normal ultrasonography\u003c/h2\u003e\n\u003cp\u003eThere were 1167 pregnant women selected in our study. Of these, 90 fetal images who were affected by thick abdominal fat in pregnant women (n\u0026thinsp;=\u0026thinsp;25), attenuation of fetal rib (n\u0026thinsp;=\u0026thinsp;28), fetal position (n\u0026thinsp;=\u0026thinsp;20) and amniotic fluid volume (n\u0026thinsp;=\u0026thinsp;17) were excluded. The remaining 1077 women were included in this study, so the identification rate is 92.29%.\u003c/p\u003e\n\u003cp\u003eThe fetal thorax is mainly composed of skeletal thoracic frame, which was quasi-circular, and thoracic internal organs, including the heart, large blood vessels, lungs, trachea and thymus. The myocardium and lungs are moderately echogenic, and the cardiac chamber is echoless on four-chamber view section. The three vessels and trachea view section shows that the large vessel wall and tracheal wall are high echo, the lumen are echoless and the thymus is medium-low echo (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eNormal reference range of fetal thoracic measurements\u003c/h2\u003e\n\u003cp\u003eCorrelation between fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume, lung-to-thoracic volume ratio and GA had high significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 respectively). Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e represents the correlation and scatterplot of fetal thoracic parameters and GA. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e show the nomograms of thoracic 2D and 3D measurements for each gestational week.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eComparison of thoracic parameters between abnormal groups and normal group\u003c/h2\u003e\n\u003cp\u003eThe comparison of fetal thoracic parameters between the abnormal groups (SD group, CDH group, PS group and CCAM group) and the normal group is shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. All the thoracic parameters in SD group were significantly lower than those in normal group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Similarly, the lung-to-thoracic volume ratio in CDH, PS and CCAM group were lower and had statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Compared with normal group, the lung volume in CDH, PS and CCAM group were lower (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, all the 2D parameters and thoracic volume had no statistical differences between CDH, PS, CCAM group and normal group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003ch2\u003eIntra-observer and inter-observer reliability and agreement\u003c/h2\u003e\n\u003cp\u003eThe intra- and inter-observer reliability and agreement of fetal thoracic measurements were excellent (ICC\u0026thinsp;\u0026gt;\u0026thinsp;0.90 and narrow 95% LoA respectively), which are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Among them, the intra-observer reliability and agreement was the best in measuring the fetal thoracic anteroposterior diameter, with ICC\u0026thinsp;=\u0026thinsp;0.9992, 95% confidence interval (95%CI) 0.9986\u0026thinsp;~\u0026thinsp;0.9995 and the mean difference was 0.0048\u0026nbsp;cm (95% LoA: -0.1039\u0026thinsp;~\u0026thinsp;0.1135).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eVarious ultrasound investigations have focused on the fetal lung, such as lung area [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and lung volume [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], to evaluate the fetal lung development. In terms of the fetal thorax, some studies mention the usefulness of fetal thoracic area [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], thoracic circumference [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and thoracic volume [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] in prenatal diagnosis, but few systematic studies have established the fetal thoracic nomogram and assess the application in diagnosing thoracic malformations. Ultrasound could diagnose congenital thoracic malformations such as congenital pleural effusion, CHD and bronchopulmonary sequestration before 16 gestational weeks, which is beneficial for prenatal counseling and making early decisions concerning deadly fetal malformations [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Suyama et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] measured thoracic area and used lung-to-thorax transverse area ratio to confirm the lung size after thoracoamniotic shunting, and concluded that the area ratio is connected with the prognosis of fetal primary hydrothorax. Research indicated that the area ratio of liver herniation and thorax is essential for the evaluation of severe degree of liver herniation in CDH individuals [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In terms of thoracic volume measuring method, Miric Tesanic et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated that both lung volumes plus heart volume was thoracic volume, which is not completely accurate because they disregard other organs\u0026rsquo; volume in the mediastinum, like the thymus. Moreover, they used the 3D multiplane reconstruction mode to measure the fetal lung and heart volume by adding different slices together from the diaphragm to the clavicle. Compared with VOCAL technique, it is difficult to calculate the lower lung volume although there is a similar volume result between multiplane and VOCAL technique [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, 3D multiplane reconstruction method is a cumbersome and time-consuming procedure, especially for inexperienced physicians, which limits its clinical application. VOCAL technique is the most popular method for volume measuring method because it is convenient, time-efficient, cost-effective and has high reliability and agreement [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, our study shows high reliability with all ICC\u0026thinsp;\u0026gt;\u0026thinsp;0.90 and excellent agreement with narrow 95% LoA, respectively [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. VOCAL technique can be used to measure regular organs such as bladder and irregular organs such as lung and thymus. In addition, the organ contour in each rotation section can be modified, which makes the volume more accurate. Finally, most previous studies used the VOCAL technique with rotation angle of 30\u0026deg; [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], we chose the rotation angle of 15\u0026deg; to make the volume more precise.\u003c/p\u003e \u003cp\u003eConsequently, we propose to use 2D ultrasound and 3D ultrasound VOCAL technique to measure fetal thoracic 2D parameters and 3D volumes and establish the reference range for all fetal thoracic parameters. This study results demonstrate that both the 2D and the 3D thoracic parameters increase with the GA. Moreover, the associations between the each thoracic indicator and the GA are high and best illustrated by quadratic equations. Thus, thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thorax volume ratio can be treated as new biometric parameters, which is practical to evaluate the development of fetal thorax.\u003c/p\u003e \u003cp\u003eWe hypothesize that 2D thoracic parameters can be used to preliminarily assess the basic condition of the fetal thorax, while 3D thoracic parameters further evaluate the fetal lung and thorax, which is beneficial for congenital thoracic malformation diagnosis. Our study results also verified that the thoracic 2D measurements in skeletal dysplasia (SD) group were significantly lower than those in normal group, indicating that SD greatly influences the 2D parameters, and can be diagnosed by 2D ultrasound. Furthermore, both lung volume and thoracic volume were much smaller than the volumes of normal group. This might be because the SD fetus has a narrow skeletal thorax [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and causes the significant diminish of thoracic volume, which results in limited development of the fetal lung which and reduced more significantly. Thus, the lung-to-thorax volume ratio of the SD fetus is decreased markedly compared with the normal group. However, the 2D fetal thoracic parameters in CDH, PS and CCAM group are all within the reference range for the normal group, showing that it is not statistically significant to measure fetal thoracic 2D parameters to diagnose those deformities. On the other hand, there is a statistical difference of lung volume and lung-to-thorax volume ratio between the case and normal groups. For CDH group, due to the diaphragm defect, the abdominal contents herniate into the fetal thorax [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], which squeezes the lung tissue and causes the restricted lung development, even resulting in pulmonary dysplasia. Although the thoracic volume of the CDH fetus did not have statistical difference from the normal fetus, it showed a trend to a lower value. We need to increase the CDH sample cases in the future study to confirm whether the CHD fetal thoracic volume is really lower than normal fetus. Because of the lung volume decrease and non-obvious thoracic volume change, the lung-to-thorax volume ratio is significantly diminished. Likewise, the lung volumes of the PS fetus and CCAM fetus are also reduced, the reason might be that PS and CCAM are both congenital pulmonary malformations, PS is non-functional sequestered lung tissue which receives blood supply from the circulating arteries, meanwhile, CCAM is characterized by abnormal bronchial airway hyperplasia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], meanwhile, CCAM is characterized by abnormal bronchial airway hyperplasia and lack of normal alveoli [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Both conditions affect the normal progress of the fetal lung and bring about lower lung volume. Conversely, the abnormal lung mass of PS and CCAM does not affect the development of fetal skeletal thorax and diaphragm, so the difference of thoracic volume between the PS, CCAM group and normal group is not significant. As a result, the lung-to-thorax volume ratio is significantly reduced.\u003c/p\u003e \u003cp\u003eCompared with previous studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], our research has a large sample size including 1077 normal fetuses from 13 gestational weeks to 40 gestational weeks, which makes the reference data more representative and reliable. Moreover, it enriches the normal fetal biostatistics and helps clinicians to evaluate and follow up fetal development comprehensively. Secondly, our study, including both 2D and 3D thoracic parameters, is the first research project to systematically evaluate the development of fetal thorax. This is meaningful and practical to comprehensively distinguish the normal and pathological fetal thoracic state [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition, we find that the 2D fetal thoracic parameters can be used to initially evaluate the fetal thoracic development and diagnose skeletal thoracic deformity. Meanwhile, lung volume, thoracic volume and lung-to-thorax volume ratio that reconstructed by 3D VOCAL technique, are useful to diagnose and differentiate CDH fetus, PS fetus and CCAM fetus. Combination of 2D and 3D ultrasound VOCAL technique can guide doctors and pregnant women to carry out early and appropriate measurement to reduce the birth rate of newborns with thoracic malformations.\u003c/p\u003e \u003cp\u003eLimitations of this study: firstly, the 3D ultrasound VOCAL technique is susceptible to fetal position, amniotic fluid volume or fat pregnant. Secondly, it is difficult to clearly identify the inferior boundary of fetal lung on some rotation planes, since it is easily affected by the attenuation of the fetal ossific rib or spine, especially in the third trimester of pregnancy. This might reduce the accuracy of volume measurement.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eWe establish an integrated nomograms of fetal thoracic transverse and anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thorax-volume ratio by 2D and 3D ultrasound. All thoracic measurements have high intra- and inter-observer reliability and agreement and increase with the gestational age (GA), the correlation between each measurement and GA is excellent. Meanwhile, we find that combining 2D ultrasound with 3D VOCAL technique has a high value in diagnosing congenital thoracic malformations.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of the Second Affiliated Hospital of Fujian Medical University. Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was sponsored by the key Clinical Specialty Discipline Construction Program of Fujian, P.R.C [(2017)739], the Research Project of Science and Technology Department of Fujian Province, China (Grant 2018J01288), the Youth Research Project of Health and Family Planning Commission of Fujian Province, China (Grants 2018-1-62 and 2018-2-23), the Quanzhou Science and Technology Project (Grants 2018N012), and the Research Project of Collaborative Innovation Center for Maternal and Infant Health Service Application Technology (Grant XJM1802). The funding bodies provided financial support for the research work but played no role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.\u003c/p\u003e\n\u003ch2\u003eAuthor\u0026rsquo;s contributions\u003c/h2\u003e\n\u003cp\u003eX L: Study design, study concepts, literature research, data collection and analysis, manuscript writing and post-processing. Z X: Study design, study concepts, data collection and analysis, manuscript writing and post-processing; L Z, Z Z: Literature research, Data collection and analysis, statistical analysis; T E, AK, Y Z: manuscript editing; P C, S H, S L: Data collection; G L: Project administration, manuscript review, supervision. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRodr\u0026iacute;guez MR, de Vega VM, Alonso RC, Arranz JC, Ten PM, Pedregosa JP: \u003cstrong\u003eMR imaging of thoracic abnormalities in the fetus\u003c/strong\u003e. \u003cem\u003eRadiographics \u003c/em\u003e2012, \u003cstrong\u003e32\u003c/strong\u003e(7):E305-E321.\u003c/li\u003e\n\u003cli\u003eBritto IS, Tedesco GD, Herbst SR, Bussamra LC, de Andrade FM, Araujo Junior E, Nardozza LM, Ruano R, Moron AF, Aoki T: \u003cstrong\u003eNew anatomical landmarks to study the relationship between fetal lung area and thoracic circumference by three-dimensional ultrasonography\u003c/strong\u003e. \u003cem\u003eJ Matern Fetal Neonatal Med \u003c/em\u003e2012, \u003cstrong\u003e25\u003c/strong\u003e(10):1927-1932.\u003c/li\u003e\n\u003cli\u003eTriebwasser JE, Treadwell MC: 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Obstet \u003c/em\u003e2009, \u003cstrong\u003e280\u003c/strong\u003e(3):363-368.\u003c/li\u003e\n\u003cli\u003eMiric Tesanic D, Merz E, Wellek S: \u003cstrong\u003eFetal lung volume measurements using 3D ultrasonography\u003c/strong\u003e. \u003cem\u003eUltraschall Med \u003c/em\u003e2011, \u003cstrong\u003e32\u003c/strong\u003e(4):373-380.\u003c/li\u003e\n\u003cli\u003eWerneck Britto IS, Olutoye OO, Cass DL, Zamora IJ, Lee TC, Cassady CI, Mehollin-Ray A, Welty S, Fernandes C, Belfort MA\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eQuantification of liver herniation in fetuses with isolated congenital diaphragmatic hernia using two-dimensional ultrasonography\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2015, \u003cstrong\u003e46\u003c/strong\u003e(2):150-154.\u003c/li\u003e\n\u003cli\u003ePeralta CF, Cavoretto P, Csapo B, Falcon O, Nicolaides KH: \u003cstrong\u003eLung and heart volumes by three-dimensional ultrasound in normal fetuses at 12-32 weeks' gestation\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2006, \u003cstrong\u003e27\u003c/strong\u003e(2):128-133.\u003c/li\u003e\n\u003cli\u003eMoeglin D, Talmant C, Duyme M, Lopez AC, Cfef: \u003cstrong\u003eFetal lung volumetry using two- and three-dimensional ultrasound\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2005, \u003cstrong\u003e25\u003c/strong\u003e(2):119-127.\u003c/li\u003e\n\u003cli\u003eBarra DA, Lima JC, Mauad Filho F, Araujo Junior E, Martins WP: \u003cstrong\u003eMeasuring fetal volume during late first trimester by three-dimensional ultrasonography using virtual organ computer-aided analysis\u003c/strong\u003e. \u003cem\u003eUltrasound Med Biol \u003c/em\u003e2013, \u003cstrong\u003e39\u003c/strong\u003e(9):1552-1559.\u003c/li\u003e\n\u003cli\u003eBecsek A, Tzanidakis N, Blanco M, Bollwein H: \u003cstrong\u003eTransrectal three-dimensional fetal volumetry and crown-rump length measurement during early gestation in mares: Intra- and inter-observer reliability and agreement\u003c/strong\u003e. \u003cem\u003eTheriogenology \u003c/em\u003e2019, \u003cstrong\u003e126\u003c/strong\u003e:266-271.\u003c/li\u003e\n\u003cli\u003eKusanovic JP, Nien JK, Goncalves LF, Espinoza J, Lee W, Balasubramaniam M, Soto E, Erez O, Romero R: \u003cstrong\u003eThe use of inversion mode and 3D manual segmentation in volume measurement of fetal fluid-filled structures: comparison with Virtual Organ Computer-aided AnaLysis (VOCAL)\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2008, \u003cstrong\u003e31\u003c/strong\u003e(2):177-186.\u003c/li\u003e\n\u003cli\u003eDuin LK, Willekes C, Vossen M, Beckers M, Offermans J, Nijhuis JG: \u003cstrong\u003eReproducibility of fetal renal pelvis volume measurement using three-dimensional ultrasound\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2008, \u003cstrong\u003e31\u003c/strong\u003e(6):657-661.\u003c/li\u003e\n\u003cli\u003eTonni G, Rosignoli L, Cariati E, Martins WP, Miyague AH, Bruns RF, Araujo Junior E: \u003cstrong\u003eFetal thymus: visualization rate and volume by integrating 2D- and 3D-ultrasound during 2nd trimester echocardiography\u003c/strong\u003e. \u003cem\u003eJ Matern Fetal Neonatal Med \u003c/em\u003e2016, \u003cstrong\u003e29\u003c/strong\u003e(14):2223-2228.\u003c/li\u003e\n\u003cli\u003eRuano R, Martinovic J, Dommergues M, Aubry MC, Dumez Y, Benachi A: \u003cstrong\u003eAccuracy of fetal lung volume assessed by three-dimensional sonography\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2005, \u003cstrong\u003e26\u003c/strong\u003e(7):725-730.\u003c/li\u003e\n\u003cli\u003eSchramm T, Mommsen H: \u003cstrong\u003eFetal Skeletal Disorders\u003c/strong\u003e. \u003cem\u003eUltraschall Med \u003c/em\u003e2018, \u003cstrong\u003e39\u003c/strong\u003e(6):610-634.\u003c/li\u003e\n\u003cli\u003eLiu Y, Wang L, Yang YK, Liang Y, Zhang TJ, Liang N, Yang LM, Li SJ, Shan D, Wu QQ: \u003cstrong\u003ePrenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases\u003c/strong\u003e. \u003cem\u003eDiagn Pathol \u003c/em\u003e2019, \u003cstrong\u003e14\u003c/strong\u003e(1):76.\u003c/li\u003e\n\u003cli\u003eChatterjee D, Ing RJ, Gien J: \u003cstrong\u003eUpdate on congenital diaphragmatic hernia\u003c/strong\u003e. \u003cem\u003eAnesth Analg \u003c/em\u003e2019.\u003c/li\u003e\n\u003cli\u003eZhang N, Zeng Q, Chen C, Yu J, Zhang X: \u003cstrong\u003eDistribution, diagnosis, and treatment of pulmonary sequestration: Report of 208 cases\u003c/strong\u003e. \u003cem\u003eJ Pediatr Surg \u003c/em\u003e2019, \u003cstrong\u003e54\u003c/strong\u003e(7):1286-1292.\u003c/li\u003e\n\u003cli\u003eDelacourt C, Bertille N, Salomon LJ, Benachi A, Henry E, Massardier J, Mottet N, Rosenblatt J, Sartor A, Thong‐Vanh C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrenatal natural history of congenital pulmonary malformations: MALFPULM population‐based cohort study\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2019, \u003cstrong\u003e54\u003c/strong\u003e(3):381-388.\u003c/li\u003e\n\u003cli\u003eGerards FA, Engels MA, Twisk JW, van Vugt JM: \u003cstrong\u003eNormal fetal lung volume measured with three-dimensional ultrasound\u003c/strong\u003e. \u003cem\u003eUltrasound Obstet Gynecol \u003c/em\u003e2006, \u003cstrong\u003e27\u003c/strong\u003e(2):134-144.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, tables are only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Fetal thorax, 3D ultrasound, VOCAL, Reference range, Malformation","lastPublishedDoi":"10.21203/rs.3.rs-127421/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-127421/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e To establish the normal reference range of fetal thorax by two-dimensional (2D) and three-dimensional (3D) ultrasound VOCAL technique and evaluate the application in diagnosing fetal thoracic malformations. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A prospective cross-sectional study was undertaken involving 1077 women who have a normal singleton pregnancy at 13-40 weeks gestational age (GA). 2D ultrasound and 3D ultrasound VOCAL technique were utilized to assess fetal thoracic transverse diameter, thoracic anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio. The nomograms of 2D and 3D fetal thoracic measurements were created to GA. 50 cases were randomly selected to calculate intra- and inter-observer reliability and agreement. In addition, the case groups including congenital skeletal dysplasia (SD) (15), congenital diaphragmatic hernia (CDH) (30), pulmonary sequestration (PS) (25) and congenital cystic adenomatoid malformation (CCAM) (36) were assessed by the nomograms and followed up subsequently.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBoth 2D and 3D fetal thoracic parameters increased with GA using a quadratic regression equation. The intra- and inter-observer reliability and agreement of each thoracic parameter were excellent. 2D fetal thoracic parameters can initially evaluate the fetal thoracic development and diagnose the skeletal thoracic deformity, and lung volume, thoracic volume and lung-to-thorax volume ratio are practical to diagnose and differentiate CDH, PS and CCAM.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWe have established the normal fetal thoracic reference range at 13-40 weeks, which has a high value in diagnosing congenital thoracic malformations.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Reference Range of Fetal thorax using Two-dimensional and Three-dimensional Ultrasound VOCAL Technique and Application in Fetal Thoracic Malformations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-16 23:27:38","doi":"10.21203/rs.3.rs-127421/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-12-30T00:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.\n\nMinor corrections as highlighted to be considered please:\n\n1. Annotations on figure 2a and 2b are barely visible. Could you please improve the figure 2ab so that the reader could identify all the structures. For example; arrows and subsequent explanations in the legend may be helpful and would increase the teaching value.\nPlease note that white font on more hyperechoic structures is difficult to read, perhaps try to change some annotations to black.\n2. Please kindly provide higher resolution for figures 2 and 3.\n3. Line 10-11, page 8; Do you mean BMI of the patient, pregnancy weight gain? There seems to be minor \"typo\" mistake as highlighted, please kindly check.\n4. Line 4, page 8; Part of the sentence \"to reduce the birth rate\" may appear controversial in some countries. Please kindly consider modification of the sentence so that your valuable research appears as neutral as possible for many international readers. Alternatively, please kindly explain your message in more detail.\n5. Page 5; I would suggest to rewrite first sentence from discussion part and provide more details regarding references 3, 8, 9, 10.\n\n5.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Minor revision","date":"2020-12-30T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-12-27T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nFetal congenital thoracic malformations (CTMs) are diverse, such as congenital skeletal dysplasia (SD), congenital diaphragmatic hernia (CDH), pulmonary sequestration (PS) and congenital cystic adenomatoid malformation (CCAM).It is critical for the prenatal diagnosis of the normal fetal thoracic structure and its deformities.Early prenatal diagnosis of CTMs is beneficial for timely pregnancy management in fetuses with deadly deformities.Currently, the most frequently used method to obtain volume measuremnts form 3D volume datasets is VOCAL(Virtual Organ Computer-aided Aaalysis), with high reliability, validity, and good intra-and interobserver agreement.As for this manuscript,there are some questions for the authors to addressed.\n1.Is it a single-center or a mult-center retrospective cross-sectional study? as for the subjects included in this study, it is ongly one simple big sample or one complex big sample?\n2.Page2,line 11-13, the author mentioned that In addition, there are few studies on the reference range for fetal thorax and the differential diagnosis of normal and abnormal fetus. Could the authors listed or simply evaluated this sort of studies on the reference range for fetal thorax and the differential diagnosis of normal and abnormal fetus?\n3.3D lung volume and thoracic volume were measured on the three perpendicular planes, VOCAL software (General Electric Medical Systems, KretzTechnik) was used by delimitating the surface with a rotation angle of 15° (12 planes) to acquire the volume automatically on the plane A. How much time spend for one case by using VOCAL with a rotation angle of 15° (12 planes)?\n4.For Abstract and Methods section, Method section is simple and Result section is simple and unadequate, the protocol for measurements is so simple, some detailed information obscure. Figures' notations also is not clear specified.\n5.Page2,line6, CMTs or CTMs?\nThank you.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-12-15T00:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-12-15T00:00:00+00:00","index":3,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\n\nThe authors defined their aims to be (1) feasibility of VOCAL technique to evaluate the normal development of fetal thorax, (2) quantitative measurement of various parameters, and (3) the application in the diagnosis of congenital skeletal dysplasia, congenital diaphragmatic hernia, pulmonary sequestration, and congenital cystic adenomatoid malformation. Although this approach might be interesting, this scientific report lacks satisfactory analyses, and the conclusion is not clear.\n\nMajor issues:\n#1 Tables 1 and 2\nThese data are original raw data. The authors should analyze these data statistically and make graphs to summarize these data. If the authors wish to publish these raw data with the manuscript, these data should be included in the supplemental section.\n\n#2 Specify the focus of this study.\nThe authors should describe what they wanted to do and what they did in the materials and methods section and the result section.\n\n#3 The quality of the manuscript\nThis manuscript is not suitable for publication, and not of the quality to go to the review process. The authors should carefully revise their manuscript before submitting their manuscript. As stated above, it was hard to understand what the authors aimed to do and how they did what they did, and analyses were not satisfactory. There are other issues as well. For example, p3L21-26 and p3L38 show almost the same explanation. Also, some technical words lack the explanations.\n\n#4 Area and volume measurements: quantitative analysis\nQuantitative analyses are the most important points in this study. Therefore, parameters need formulas that are used to calculate these values. Even if they employed the specific software like VOCAL, the formula should be noted in the manuscript.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-12-14T00:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-10T01:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-10T00:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-07T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-12-07T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-07T00:00:00+00:00","index":1,"fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-06T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-06T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d5363187-e091-4442-b1a7-db6f45695745","owner":[],"postedDate":"December 16th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1504921,"name":"Nuclear Medicine \u0026 Medical Imaging"}],"tags":[],"updatedAt":"2021-02-28T15:00:43+00:00","versionOfRecord":{"articleIdentity":"rs-127421","link":"https://doi.org/10.1186/s12880-021-00548-w","journal":{"identity":"bmc-medical-imaging","isVorOnly":false,"title":"BMC Medical Imaging"},"publishedOn":"2021-02-22 15:00:29","publishedOnDateReadable":"February 22nd, 2021"},"versionCreatedAt":"2020-12-16 23:27:38","video":"","vorDoi":"10.1186/s12880-021-00548-w","vorDoiUrl":"https://doi.org/10.1186/s12880-021-00548-w","workflowStages":[]},"version":"v1","identity":"rs-127421","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-127421","identity":"rs-127421","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}