Diffusion tensor MR imaging of the normal fetal lung: a preliminary report

Diffusion tensor MR imaging of the normal fetal lung: a preliminary report | 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 Diffusion tensor MR imaging of the normal fetal lung: a preliminary report Qiang Liu, Feng Jin, Min Wang, Yun Chen, Hui Ting Cao, Wen Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7743702/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Fetal lung development is a complex and continuous process involving the progressive maturation of multiple structural and functional aspects. From early embryonic stages to birth, the fetal lung transforms primitive alveoli into mature lung tissue, encompassing four main stages: the canalicular, saccular, canalicular, and alveolar stages. Accurate assessment of fetal lung development stages is essential for the health management of the fetus. Objective this study aims to evaluate the feasibility of magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) to assess the normal fetal lung and prospectively determine whether DTI measurements can be used as markers of fetal lung development. Materials and methods Diffusion tensor imaging of normal fetal lungs was performed on 84 pregnant women at a gestational age (GA) of 18–36 weeks. Regions of interest (ROI) for both liver and lung were drawn on the b = 0 images to obtain the lung-to-liver signal intensity ratio (LLSIR), and the 3D segmentation measured the fetal lung volume (FLV). At the same time, DTI-related indices, fractional anisotropy (FA), and mean diffusivity (MD) were derived. Using regression analysis,DTI measurements, LLSIR, and FLV were correlated with gestational age. Results Thirty-two patients were excluded due to fetal motion artifacts during DTI imaging. The remaining 52 patients (61.9%) were analyzed for DTI indices. FA (r = -0.697; r = -0.711; r = -0.711; all P < 0.001), MD (r = 0.582; r = 0.492; r = 0.567, all P < 0.001), LLSIR (r = 0.608; r = 0.634; r = 0.637, all P < 0.001) and FLV (r = 0.838, r = 0.888, r = 0.874, all P < 0.001) were significantly correlated with gestational age. FA decreased dramatically before 29 weeks (slope = -0.020; -0.023; -0.022) but remained stable after 29 weeks (slope = 0.003; 0.003; 0.002). Conclusions DTI measurements coincided with the microstructural changes of the developing fetal lung. In particular, a dramatic decrease in the FA value may correspond to development from the canalicular to the saccular stage. Magnetic resonance imaging diffusion tensor imaging fetus lung Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Pulmonary disease remains the leading cause of morbidity and mortality among preterm neonates[ 1 – 3 ] due to their inability to oxygenate adequately[ 4 ]. When faced with iatrogenic preterm delivery or spontaneous preterm delivery, knowledge of fetal lung maturity status is valuable for delivery decision-making, such as timing or the use of corticosteroids[ 5 , 6 ]. Thus, an accurate assessment of fetal lung development before delivery may reduce the risk of adverse neonatal outcomes. Fetal lung maturation traditionally has been measured by lecithin/sphingomyelin (L/S) ratios and surfactant levels in the amniotic fluid; however, the invasiveness of the amniocentesis procedure increases the risks of rupture of membranes, bleeding, injury to the fetus, and isoimmunization [ 7 – 9 ]. Non-invasive measures of normal and pathological fetal lung development have relied mainly on biometric measurements of lung size, including two‐dimensional lung-to-head circumference ratios using ultrasound[ 10 – 14 ] or three‐dimensional (3D) volume measurements of the fetal lung using ultrasound[ 15 – 17 ] or magnetic resonance imaging (MRI)[ 18 – 20 ]. However, neither biometric measure provides information regarding histological or functional changes during fetal lung development. Several studies employ relative signal intensity from T2-weighted MRI (T2WI) of the fetal lung to assess fetal lung development [ 21 – 24 ]; however, T2WI only provides information about the fluid content of the fetal organ. By contrast, the apparent diffusion coefficient (ADC) value, calculated from diffusion-weighted MRI (DWI), is highly correlated with gestational age and can reflect the developmental process of vascularization[ 25 , 26 ]. ADC only reveals an overall measurement of the water molecules’ diffusion magnitude, lacking information on diffusion direction. Derived from DWI, diffusion tensor imaging (DTI) detects the direction and magnitude of diffusion, which is reported as fractional anisotropy (FA) and mean diffusivity (MD), respectively[ 27 ]. FA represents the anisotropic properties of water molecules within tissues, quantitatively varying between 0 (isotropic diffusion) and 1 (infinite anisotropic diffusion). While MD is similar to ADC in DWI, it quantifies the combined effects of both diffusion and capillary perfusion 27 . The anisotropic diffusion of water is restricted by microstructure[ 28 ]. Therefore, DTI parameters can be used to infer alterations in tissue microstructure[ 29 , 30 ]. During fetal lung development, the lung undergoes extensive microstructural remodeling, including forming the conducting airways, alveolarization, and vascularization[ 31 ]. These developmental stages consist of the pseudo glandular ( 36-week gestation)[ 32 ]. Thus, our study aimed to evaluate the feasibility of DTI to assess the fetal lung and determine, prospectively, whether DTI measurements could be used as markers of fetal lung development. Materials and Methods Study population This study is a single-centre prospective observational study approved by the local ethics review (No: 2022PS1179K). Written informed consent was obtained by all participants before fetal MR imaging, performed between October 2022 and April 2024. Our study included 84 pregnant women (maternal age 18–44 years; mean 29 years) with 74 singleton fetuses. The gestational age (GA) ranged from 18 to 36 weeks (mean 28 weeks) during the prenatal MRI examination. Indications for fetal MRI included suspected fetal anomalies (n = 45), placenta accreta (n = 23), and maternal abnormalities (n = 16) identified during a routine ultrasonographic examination. Inclusion criteria were pregnant women with normal fetal lung development assessed by a previous obstetric ultrasound (i.e., normal lung size and absence of lung lesions), confirmed by our independent MR examination. Exclusion criteria were contraindications to MRI. MRI acquisition Prenatal MRI studies were performed on pregnant women in the supine position using a 3.0 T MRI (Signa HDX; GE Healthcare, Milwaukee, WI, USA) and a 30-element phased array coil. To assess lung development, single-shot echo-planar diffusion-sensitized sequences (TR 8000, TE 90, TI 185 ms, FOV 420 × 300 mm, matrix 192 × 192, thickness 3 mm) were acquired on axial scans of fetal lungs. The diffusion-sensitizing gradients were applied in three orthogonal planes relative to the fetal body, with a b factor of 0 and 200 and 700 s/mm 2 per axis in each patient. The acquisition time of the fetal lung MRI was approximately two minutes. No sedation or contrast agent was administered. MR image analysis Images were reviewed independently by a fetal-imaging radiologist with 10 years of experience and a chest-imaging radiologist with two years of experience. The images were reviewed for image quality, signal-to-noise ratio, distortions, artifacts, and pathological abnormalities. Discrepancies in image findings were resolved through consensus. To improve data consistency and simplify the data processing workflow, all measurements and reconstructions were based on coronal b = 0 images. Regions of interest (ROI) were drawn on the same slice to measure the signal intensity of the lungs and liver ( 3D Slicer USA). Figures 1 A and 1 E showcase examples of fetal lung and liver signal intensity measurements. The lung volume was measured by outlining the lung and performing the three-dimensional reconstruction using 3D Slicer. Figures 1 B and 1 F show examples of the three-dimensional surface model of the fetal lung volume at 18 and 36 weeks of pregnancy, respectively. DTI calculation and post-processing were performed with DSI Studio ( http://dsi-studio.labsolver.org ). The DTI-related indices, including MD (Figs. 1 C and 1 G) and FA (Figs. 1 D and 1 H), were derived from the segmented whole lung. Statistical analysis Statistical analysis was performed using SPSS® version 22.0 for Windows® (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) and GraphPad Prism version 4.02 for Windows (GraphPad Software, San Diego, CA). The Shapiro-Wilk test was used to assess the normality of the data. For continuous variables that follow a normal distribution, such as FA and MD, data were expressed as mean ± standard deviation, and differences between two groups were compared using an independent samples t-test. For continuous variables that do not follow a normal distribution, such as LLSIR and FLV, data were expressed as the median and interquartile range (IQR), and differences between the two groups were compared using the Mann-Whitney U test. Pearson correlation and linear regression analysis were used to evaluate the effect of gestational age on DTI measurements (FA, MD), LLSIR, and FLV. The consistency of measurements between observers was evaluated using the intraclass correlation coefficient (ICC) and Bland-Altman analysis, with ICC > 0.75 indicating good consistency. P value of < 0.05 was considered statistically significant. Results Of the 84 pregnant women enrolled in the study, 32 patients were excluded due to significant motion or other scan artifacts. The 52 remaining patients, at a gestational age (GA) of 18–36 weeks (mean 28 weeks), were included in the final analyses. FA values for the left, right, and both lungs showed a significant inverse correlation with gestational age (Pearson correlation r = -0.696, R² = 0.486; r = -0.711, R² = 0.505; r = -0.711, R² = 0.506, all P < 0.001, Table 1 , Fig. 2 ). The linear regression of the data exhibited two different trends; therefore, we employed segmented linear regression analysis, which provided a better fit (R² = 0.543; 0.614; 0.591). The FA values for the left, right, and both lungs significantly decreased before 29 weeks of gestation (slopes = -0.020; -0.023; -0.022) and stabilized after 29 weeks (slopes = 0.003; 0.003; 0.002). Table 1 the regression equations, correlation coefficients, and p-values for the FA, MD, LLSIR, and FLV of the left lung, right lung, and both lungs in 51 fetuses with normal lung function. Variable Regression formula Correlation coefficient P-value FA-both 1.015-0.014×GA in week -0.711 <0.001 FA-left 0.992-0.015×GA in week -0.697 <0.001 FA-right 1.017-0.014×GA in week -0.711 <0.001 MD-both (mm²/s) 0.480་0.058×GA in week 0.567 <0.001 MD-left (mm²/s) 0.480་0.058×GA in week 0.582 <0.001 MD-right (mm²/s) 0.296་0.077×GA in week 0.492 <0.001 LLSIR-both 0.023་0.100×GA in week 0.637 <0.001 LLSIR-left 0.072་0.095×GA in week 0.608 <0.001 LLSIR-right -0.019་0.105×GA in week 0.634 <0.001 FLV-both (mL) -75.319་4.317×GA in week 0.874 <0.001 FLV-left (mL) -30.817་1.813×GA in week 0.838 <0.001 FLV-right (mL) -44.162་2.547×GA in week 0.888 <0.001 FA : Fractional Anisotropy ; MD : Mean Diffusivity (mm²/s) ; LLSIR: Liver-to-Lung Signal Intensity Ratio ; FLV: Fetal Lung Volume (mL) ; GA: Gestational Age (weeks) MD values for the left, right, and both lungs showed a significant positive correlation with gestational age (Pearson correlation r = 0.582, R² = 0.339; r = 0.492, R² = 0.242; r = 0.567, R² = 0.322, all P < 0.001, Table 1 , Fig. 3 ). LLSIR values for the left, right, and both lungs showed a significant positive correlation with gestational age (Pearson correlation r = 0.608, R² = 0.369; r = 0.634, R² = 0.402; r = 0.637, R² = 0.405, all P < 0.001, Table 1 , Fig. 4 ). FLV values for the left, right, and both lungs showed a significant correlation with gestational age (Pearson correlation r = 0.838, R² = 0.703; r = 0.888, R² = 0.788; r = 0.878, R² = 0.764, all P < 0.001, Table 1 , Fig. 5 ). The mean FA (0.64 ± 0.10) and MD (2.33 ± 0.66 mm²/s × 10⁻³) values for the left lung were significantly higher than those of the right lung (0.60 ± 0.11, 2.01 ± 0.59 mm²/s × 10⁻³; P = 0.027, 0.011, Figs. 6 A, 6 B). The median FLV of the left lung was 13.59 mL [interquartile range (IQR) 8.74–22.49], significantly lower than that of the right lung [19.12 mL (IQR 12.50–32.27); P = 0.028, Fig. 6 D]. There was no significant difference in the LLSIR values between the left and right lungs [2.44 (IQR 2.03–3.04) vs. 2.63 (IQR 2.21–3.20); P = 0.280, Fig. 6 C]. The intraclass correlation coefficients for FA, MD, LLSIR, and FLV among observers were 0.879 (95% CI: 0.837, 0.911), 0.904 (95% CI: 0.870, 0.929), 0.874 (95% CI: 0.831, 0.907), and 0.986 (95% CI: 0.981, 0.990), respectively. Bland-Altman's analysis demonstrated a good agreement between the measurements of the two radiologists (Fig. 7 ). Discussion Our results indicate that DTI can noninvasively image and quantify values that correspond to the microstructural changes during fetal lung development, the first report, to our knowledge, to do so. We found that FA and MD values were significantly correlated with gestational age. However, FA decreased dramatically before 29 weeks, around the time of the canalicular stage, and then remained stable around the time of the saccular stage. We speculate that FA and MD changes coincide with two aspects of the microstructural changes during fetal lung development: the reduction of lung interstitium (connective tissue) and the vascularization of the terminal tubules, respectively. The trajectory of FA during gestation may correspond to the different microstructural patterns during the two time periods: the transition from the canalicular to the saccular stage and the transition between the saccular and the alveolar stage. Figure 8 presents a schematic illustrating the relationship between FA values and the tissue microarchitecture. We speculate that the dramatic decrease in FA may be due to the reduction of lung interstitium (anisotropic diffusion, high FA value) volume during the transition between the canalicular and saccular stages. In contrast, the stabilized FA may be due to an insignificant change of interstitium volume between the saccular stage and the alveolar stage. This finding is consistent with an observation in fetal lung development studies in sheep: the interstitium volume did not change appreciably between d 121 and d 135 (term approximately 148 d), despite a 40% reduction in alveolar septal thickness and a 270% increase alveolar airspace volume[ 33 ]. Our data fit well into the classical concept of fetal lung development, in which the interstitium (connective tissue components) is reduced to a minimum at the end of the canalicular phase. In contrast, during the saccular and alveolar phases, the volume of the interstitium tissue does not change significantly[ 34 ]. Interestingly, our results suggest that the time point between the canalicular and saccular periods is 28 weeks of gestation, which is slightly delayed compared to the 24-26-week gestation period reported in the literature[ 31 , 32 ]. We think this is reasonable since each patient has its unique developmental timeline, and the fetal lung development stages are inherently overlapping[ 31 , 32 ]. The observed increase in the MD value with gestational age was concentrated in the peripheral area of the lung (Figs. 1 C, G). This correlation is consistent with Moore et al., who demonstrated that a similar value, ADC, increased with gestational age. Based on the proposed three-compartment diffusion model for fetal lungs (i.e., intra-lung amniotic fluid, intra-tissue water, and vascular blood), researchers concluded that the main factor controlling ADC was vascular blood[ 35 ] from the vascularization of the terminal tubules[ 25 , 35 ]. However, other studies have reported different results regarding the correlation with gestation age. For example, Balassy et al. found no significant correlation between gestational age and ADC[ 36 ], while Cannie et al. reported correlations between gestational age and ADC depending on the magnitude of ADC[ 26 ]. These conflicting results may be due to differences in diffusion acquisition and b value. Furthermore, ADC parameters require more than two b values for a reliable calculation[ 25 ] and fail to define the characteristics of diffusion in anisotropic tissue[ 37 ]. By contrast, the MD values in our study represent a more exact value than ADC because it considers the three main directions of water movement and uses multiple b values. Additionally, we found that the FA and MD values of the left lung were significantly higher than those of the right lung. The higher vascular density near the pleura than the central areas in both lungs may account for the higher FA and MD values in these regions.[ 38 – 41 ] The left lung is elongated than the wider and shorter right lung. This morphological difference results in a higher proportion of high vascular density areas near the pleura in the left lung’s overall volume. This specific morphological feature might explain the overall higher FA and MD values observed in the left lung. Our study found that LLSIR in the fetus shows a rising trend as gestational age increases. This phenomenon may be related to increased fetal lung fluid volume[ 21 ]. From the canalicular to the alveolar stage, bronchial lumens gradually enlarge, terminal sacs and alveoli proliferate, and interstitium thickness decreases, which increases lung fluid capacity[ 42 ]. Concurrently, lung fluid secretion gradually increases with the development of pulmonary microvessels and the increase in epithelial surface area. These factors contribute to increased fetal lung signal intensity ratio with gestational age. Our results confirm the conclusions of previous studies[ 21 , 24 , 43 ]. Regarding FLV, our research shows a linear positive correlation with gestational age, consistent with earlier studies[ 18 , 24 , 44 ]. However, different studies show varying predictions of fetal lung volume at the same gestational age, likely due to differences in volume measurement methods and sample gestational age distributions. For instance, we used 3D reconstruction to calculate FLV, while Meyers et al.[ 18 ] used a planimetric method (summing the cross-sectional areas in each MR slice multiplied by slice thickness). Furthermore, we found that the average volume of the right lung is greater than that of the left lung, possibly due to the heart’s position in the left thoracic cavity. This study had several limitations. First, motion artifacts affected fetal lung imaging. In our study, 61.9% of the fetal chest DTI images were obtained without significant movement and were used in our analyses. Similarly, a study by Onur et al. achieved a success rate of 60% with DWI imaging, citing that a significant amount of motion reduced the reliability of the ADC value to produce meaningful results[ 25 ]. Second, the Reproducibility of DTI is also challenging; Andras et al. identified data artifacts in 16–30% of DTI cases of the fetal brain in vivo[ 45 ]. To mitigate the low success rate for DTI imaging of fetuses, a motion-tracked slice‐to‐volume registration (MT‐SVR) method, introduced by Marami et al.[ 46 ], offers a promising post-processing approach. This method has been recently applied to create a spatiotemporal DTI atlas[ 47 ] and perform deterministic tractography of the fetal brain[ 48 ]. Advanced image post-processing methods, such as MT-SVR, may be used to improve fetal diffuse imaging. Conclusions In conclusion, our work presents the first DTI imaging of the fetal lungs in vivo. We identified significant correlations of DTI measurements with gestational age during normal fetal lung development, thus suggesting that DTI is a promising technique for evaluating the microstructural development of fetal lungs. Future longitudinal research is needed to corroborate our findings; however, our results support the use of DTI imaging to examine fetal lung maturity and abnormalities, which may help predict neonate survival. Declarations Competing interests The authors declare no competing interests. Author Contribution Q.L., F.J., and M.W. contributed equally to this work as co-first authors. Q.L., F.J., and M.W. were responsible for the study design, proposal writing, data collection, data analysis, and initial paper drafting. F.J. and M.W. were responsible for recruiting participants and collecting clinical data. Y. C., H.T. C, and W. Z. view MRI images and provide the image data. G.A.Z. and H.B.J. contributed to data analysis. 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Supplementary Files graphicalabstract.pptx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 31 Jan, 2026 Reviews received at journal 05 Jan, 2026 Reviewers agreed at journal 23 Dec, 2025 Reviews received at journal 09 Oct, 2025 Reviewers agreed at journal 04 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviewers invited by journal 03 Oct, 2025 Editor assigned by journal 01 Oct, 2025 Submission checks completed at journal 01 Oct, 2025 First submitted to journal 29 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-7743702","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":526867479,"identity":"52a7cd12-a06f-4bbc-afaa-3c55d90146b7","order_by":0,"name":"Qiang Liu","email":"","orcid":"","institution":"Sheng Jing Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Liu","suffix":""},{"id":526867481,"identity":"e882e2a7-d8ec-4e16-adc6-37d9cefbdb0e","order_by":1,"name":"Feng Jin","email":"","orcid":"","institution":"Sheng Jing 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02:15:10","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":124143,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/e2b3b292f0b3feff02a6797e.html"},{"id":93731118,"identity":"6eb7630f-6cb8-4b41-b79b-7fd77fd3a8c6","added_by":"auto","created_at":"2025-10-17 02:23:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1200638,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative MR images of the fetal lung throughout gestation.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A, E) Coronal view of a fetal lung in the b=0 image at (A) 18 weeks (18W) and (E) 36 weeks (36W). (B, F) Three-dimensional surface model of the fetal lung volume at (B) 18W and (F) 36W. (C, G) Mean diffusivity (MD) of the fetal lung (outlined with white dotted line) at (C) 18W and (G) 36W. The color gradient corresponds to the change in MD, which mainly occurs in the peripheral area of the lung. (D, H), Fractional anisotropy (FA) of the fetal lung (outlined with white dotted line) at (D) 18W and (H) 36W. The color gradient corresponds to the change in FA, which appears throughout the fetal lung but is absent in the bronchial tree (black dotted line).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/b0ffae1a885a5333403bfa64.png"},{"id":93729453,"identity":"1ee7d271-06c7-437f-861e-aa2ab326437f","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":546028,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between gestational age and FA values for the fetal left lung (A), right lung (B), and both lungs (C). A strong linear correlation between these parameters is demonstrated. Solid black lines indicate linear correlation, and the 95% prediction intervals are shown as black dotted lines. A segmental linear regression (solid red line), divided into two segments at the 29 week time point, was performed on FA values.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/10e6e886c54212885cdb42ee.png"},{"id":93729463,"identity":"407a1980-f9ce-4f24-9564-7e87e7376f3b","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":479427,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between gestational age and MD values for the fetal left lung (A), right lung (B), and both lungs (C). A strong linear correlation between these parameters is demonstrated. Solid black lines indicate linear correlation, and the 95% prediction intervals are shown as black dotted lines.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/69016a99cee89f4cb5f5e31b.png"},{"id":93729454,"identity":"6f0c69f1-e3a2-4e68-bbe1-a1c88e85fc7f","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":471791,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between gestational age and LLSIR for the fetal left lung (A), right lung (B), and both lungs (C). A strong linear correlation between these parameters is demonstrated. Solid black lines indicate linear correlation, and the 95% prediction intervals are shown as black dotted lines.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/b5ff570fcd381da4cb1f8044.png"},{"id":93729456,"identity":"4e51cf55-f468-45e6-a434-2bbe5ad802ed","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":482939,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between gestational age and FLV for the fetal left lung (A), right lung (B), and both lungs (C). A strong linear correlation between these parameters is demonstrated. Solid black lines indicate linear correlation, and the 95% prediction intervals are shown as black dotted lines.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/7a3c38f51d5497815aebbe14.png"},{"id":93731120,"identity":"ae73009d-bbfe-4cf8-a3e7-7ec79a8ff08c","added_by":"auto","created_at":"2025-10-17 02:23:09","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":302703,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots of overall values for the left and right lungs for FA (A), MD (B), LLSIR (C), and FLV (D). The boxplots and whiskers represent the median and quartiles, * indicating \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. FA: fractional anisotropy; MD: mean diffusivity; LLSIR: liver-to-lung signal intensity ratio; FLV: fetal lung volume.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/3f2dc5976f651cd794fc76c7.png"},{"id":93729471,"identity":"15ee5ab1-4743-4ebf-8a64-be7dfa1f5c03","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1606929,"visible":true,"origin":"","legend":"\u003cp\u003eBland-Altman plots showing the agreement analysis between two readers’ measurements. (A) Differences in agreement of FA values between the two readers. (B) Differences in agreement of MD values between the two readers. (C) Differences in agreement of LLSIR between the two readers. (D) Differences in agreement of FLV between the two readers. The middle line represents the mean difference between the two readers, while the upper and lower lines represent the 95% limits of agreement.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/88aa55da6b19809faff3cacc.png"},{"id":93731124,"identity":"92ad454e-7005-4959-9614-252758bf31f1","added_by":"auto","created_at":"2025-10-17 02:23:09","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":896429,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic depicting changes in the fractional anisotropy across periods of fetal lung\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/516d713297afacf800e9d583.png"},{"id":93732400,"identity":"0a27876a-f823-4392-b08d-a32bc6681920","added_by":"auto","created_at":"2025-10-17 02:31:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6579189,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/96ec14c2-f7b0-4294-bc6e-cf5c8581858c.pdf"},{"id":93729458,"identity":"183a892b-e33e-4d10-a0f6-28ce66775f60","added_by":"auto","created_at":"2025-10-17 02:15:09","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1491998,"visible":true,"origin":"","legend":"","description":"","filename":"graphicalabstract.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7743702/v1/cc4aef05e955f76b4b4759a2.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Diffusion tensor MR imaging of the normal fetal lung: a preliminary report","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePulmonary disease remains the leading cause of morbidity and mortality among preterm neonates[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] due to their inability to oxygenate adequately[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. When faced with iatrogenic preterm delivery or spontaneous preterm delivery, knowledge of fetal lung maturity status is valuable for delivery decision-making, such as timing or the use of corticosteroids[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Thus, an accurate assessment of fetal lung development before delivery may reduce the risk of adverse neonatal outcomes.\u003c/p\u003e\u003cp\u003eFetal lung maturation traditionally has been measured by lecithin/sphingomyelin (L/S) ratios and surfactant levels in the amniotic fluid; however, the invasiveness of the amniocentesis procedure increases the risks of rupture of membranes, bleeding, injury to the fetus, and isoimmunization [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Non-invasive measures of normal and pathological fetal lung development have relied mainly on biometric measurements of lung size, including two‐dimensional lung-to-head circumference ratios using ultrasound[\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] or three‐dimensional (3D) volume measurements of the fetal lung using ultrasound[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] or magnetic resonance imaging (MRI)[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, neither biometric measure provides information regarding histological or functional changes during fetal lung development. Several studies employ relative signal intensity from T2-weighted MRI (T2WI) of the fetal lung to assess fetal lung development [\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]; however, T2WI only provides information about the fluid content of the fetal organ. By contrast, the apparent diffusion coefficient (ADC) value, calculated from diffusion-weighted MRI (DWI), is highly correlated with gestational age and can reflect the developmental process of vascularization[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. ADC only reveals an overall measurement of the water molecules\u0026rsquo; diffusion magnitude, lacking information on diffusion direction.\u003c/p\u003e\u003cp\u003eDerived from DWI, diffusion tensor imaging (DTI) detects the direction and magnitude of diffusion, which is reported as fractional anisotropy (FA) and mean diffusivity (MD), respectively[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. FA represents the anisotropic properties of water molecules within tissues, quantitatively varying between 0 (isotropic diffusion) and 1 (infinite anisotropic diffusion). While MD is similar to ADC in DWI, it quantifies the combined effects of both diffusion and capillary perfusion\u003csup\u003e27\u003c/sup\u003e. The anisotropic diffusion of water is restricted by microstructure[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, DTI parameters can be used to infer alterations in tissue microstructure[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDuring fetal lung development, the lung undergoes extensive microstructural remodeling, including forming the conducting airways, alveolarization, and vascularization[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. These developmental stages consist of the pseudo glandular (\u0026lt;\u0026thinsp;16-week gestation), canalicular (16- to 26-week gestation), saccular (24- to 36-week gestation), and alveolar stages (\u0026gt;\u0026thinsp;36-week gestation)[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Thus, our study aimed to evaluate the feasibility of DTI to assess the fetal lung and determine, prospectively, whether DTI measurements could be used as markers of fetal lung development.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eThis study is a single-centre prospective observational study approved by the local ethics review (No: 2022PS1179K). Written informed consent was obtained by all participants before fetal MR imaging, performed between October 2022 and April 2024. Our study included 84 pregnant women (maternal age 18\u0026ndash;44 years; mean 29 years) with 74 singleton fetuses. The gestational age (GA) ranged from 18 to 36 weeks (mean 28 weeks) during the prenatal MRI examination. Indications for fetal MRI included suspected fetal anomalies (n\u0026thinsp;=\u0026thinsp;45), placenta accreta (n\u0026thinsp;=\u0026thinsp;23), and maternal abnormalities (n\u0026thinsp;=\u0026thinsp;16) identified during a routine ultrasonographic examination. Inclusion criteria were pregnant women with normal fetal lung development assessed by a previous obstetric ultrasound (i.e., normal lung size and absence of lung lesions), confirmed by our independent MR examination. Exclusion criteria were contraindications to MRI.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMRI acquisition\u003c/h3\u003e\n\u003cp\u003ePrenatal MRI studies were performed on pregnant women in the supine position using a 3.0 T MRI (Signa HDX; GE Healthcare, Milwaukee, WI, USA) and a 30-element phased array coil. To assess lung development, single-shot echo-planar diffusion-sensitized sequences (TR 8000, TE 90, TI 185 ms, FOV 420 \u0026times; 300 mm, matrix 192 \u0026times; 192, thickness 3 mm) were acquired on axial scans of fetal lungs. The diffusion-sensitizing gradients were applied in three orthogonal planes relative to the fetal body, with a b factor of 0 and 200 and 700 s/mm\u003csup\u003e2\u003c/sup\u003e per axis in each patient. The acquisition time of the fetal lung MRI was approximately two minutes. No sedation or contrast agent was administered.\u003c/p\u003e\n\u003ch3\u003eMR image analysis\u003c/h3\u003e\n\u003cp\u003eImages were reviewed independently by a fetal-imaging radiologist with 10 years of experience and a chest-imaging radiologist with two years of experience. The images were reviewed for image quality, signal-to-noise ratio, distortions, artifacts, and pathological abnormalities. Discrepancies in image findings were resolved through consensus. To improve data consistency and simplify the data processing workflow, all measurements and reconstructions were based on coronal b\u0026thinsp;=\u0026thinsp;0 images. Regions of interest (ROI) were drawn on the same slice to measure the signal intensity of the lungs and liver ( 3D Slicer USA). Figures\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE showcase examples of fetal lung and liver signal intensity measurements. The lung volume was measured by outlining the lung and performing the three-dimensional reconstruction using 3D Slicer. Figures\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF show examples of the three-dimensional surface model of the fetal lung volume at 18 and 36 weeks of pregnancy, respectively. DTI calculation and post-processing were performed with DSI Studio (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dsi-studio.labsolver.org\u003c/span\u003e\u003cspan address=\"http://dsi-studio.labsolver.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The DTI-related indices, including MD (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG) and FA (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH), were derived from the segmented whole lung.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using SPSS\u0026reg; version 22.0 for Windows\u0026reg; (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) and GraphPad Prism version 4.02 for Windows (GraphPad Software, San Diego, CA). The Shapiro-Wilk test was used to assess the normality of the data. For continuous variables that follow a normal distribution, such as FA and MD, data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and differences between two groups were compared using an independent samples t-test. For continuous variables that do not follow a normal distribution, such as LLSIR and FLV, data were expressed as the median and interquartile range (IQR), and differences between the two groups were compared using the Mann-Whitney U test. Pearson correlation and linear regression analysis were used to evaluate the effect of gestational age on DTI measurements (FA, MD), LLSIR, and FLV. The consistency of measurements between observers was evaluated using the intraclass correlation coefficient (ICC) and Bland-Altman analysis, with ICC\u0026thinsp;\u0026gt;\u0026thinsp;0.75 indicating good consistency. \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 84 pregnant women enrolled in the study, 32 patients were excluded due to significant motion or other scan artifacts. The 52 remaining patients, at a gestational age (GA) of 18\u0026ndash;36 weeks (mean 28 weeks), were included in the final analyses.\u003c/p\u003e\u003cp\u003eFA values for the left, right, and both lungs showed a significant inverse correlation with gestational age (Pearson correlation r = -0.696, R\u0026sup2; = 0.486; r = -0.711, R\u0026sup2; = 0.505; r = -0.711, R\u0026sup2; = 0.506, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The linear regression of the data exhibited two different trends; therefore, we employed segmented linear regression analysis, which provided a better fit (R\u0026sup2; = 0.543; 0.614; 0.591). The FA values for the left, right, and both lungs significantly decreased before 29 weeks of gestation (slopes = -0.020; -0.023; -0.022) and stabilized after 29 weeks (slopes\u0026thinsp;=\u0026thinsp;0.003; 0.003; 0.002).\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\u003ethe regression equations, correlation coefficients, and p-values for the FA, MD, LLSIR, and FLV of the left lung, right lung, and both lungs in 51 fetuses with normal lung function.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegression formula\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCorrelation coefficient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFA-both\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.015-0.014\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.711\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFA-left\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.992-0.015\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.697\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFA-right\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.017-0.014\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e-0.711\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMD-both (mm\u0026sup2;/s)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.480་0.058\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMD-left (mm\u0026sup2;/s)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.480་0.058\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.582\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMD-right (mm\u0026sup2;/s)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.296་0.077\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.492\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLLSIR-both\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.023་0.100\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.637\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLLSIR-left\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.072་0.095\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLLSIR-right\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.019་0.105\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.634\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFLV-both (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-75.319་4.317\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.874\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFLV-left (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-30.817་1.813\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.838\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFLV-right (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-44.162་2.547\u0026times;GA in week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.888\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eFA : Fractional Anisotropy ; MD : Mean Diffusivity (mm\u0026sup2;/s) ; LLSIR: Liver-to-Lung Signal Intensity Ratio ; FLV: Fetal Lung Volume (mL) ; GA: Gestational Age (weeks)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eMD values for the left, right, and both lungs showed a significant positive correlation with gestational age (Pearson correlation r\u0026thinsp;=\u0026thinsp;0.582, R\u0026sup2; = 0.339; r\u0026thinsp;=\u0026thinsp;0.492, R\u0026sup2; = 0.242; r\u0026thinsp;=\u0026thinsp;0.567, R\u0026sup2; = 0.322, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eLLSIR values for the left, right, and both lungs showed a significant positive correlation with gestational age (Pearson correlation r\u0026thinsp;=\u0026thinsp;0.608, R\u0026sup2; = 0.369; r\u0026thinsp;=\u0026thinsp;0.634, R\u0026sup2; = 0.402; r\u0026thinsp;=\u0026thinsp;0.637, R\u0026sup2; = 0.405, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFLV values for the left, right, and both lungs showed a significant correlation with gestational age (Pearson correlation r\u0026thinsp;=\u0026thinsp;0.838, R\u0026sup2; = 0.703; r\u0026thinsp;=\u0026thinsp;0.888, R\u0026sup2; = 0.788; r\u0026thinsp;=\u0026thinsp;0.878, R\u0026sup2; = 0.764, all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe mean FA (0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10) and MD (2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66 mm\u0026sup2;/s \u0026times; 10⁻\u0026sup3;) values for the left lung were significantly higher than those of the right lung (0.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11, 2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59 mm\u0026sup2;/s \u0026times; 10⁻\u0026sup3;; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027, 0.011, Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). The median FLV of the left lung was 13.59 mL [interquartile range (IQR) 8.74\u0026ndash;22.49], significantly lower than that of the right lung [19.12 mL (IQR 12.50\u0026ndash;32.27); P\u0026thinsp;=\u0026thinsp;0.028, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD]. There was no significant difference in the LLSIR values between the left and right lungs [2.44 (IQR 2.03\u0026ndash;3.04) vs. 2.63 (IQR 2.21\u0026ndash;3.20); P\u0026thinsp;=\u0026thinsp;0.280, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe intraclass correlation coefficients for FA, MD, LLSIR, and FLV among observers were 0.879 (95% CI: 0.837, 0.911), 0.904 (95% CI: 0.870, 0.929), 0.874 (95% CI: 0.831, 0.907), and 0.986 (95% CI: 0.981, 0.990), respectively. Bland-Altman's analysis demonstrated a good agreement between the measurements of the two radiologists (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results indicate that DTI can noninvasively image and quantify values that correspond to the microstructural changes during fetal lung development, the first report, to our knowledge, to do so. We found that FA and MD values were significantly correlated with gestational age. However, FA decreased dramatically before 29 weeks, around the time of the canalicular stage, and then remained stable around the time of the saccular stage. We speculate that FA and MD changes coincide with two aspects of the microstructural changes during fetal lung development: the reduction of lung interstitium (connective tissue) and the vascularization of the terminal tubules, respectively.\u003c/p\u003e\u003cp\u003eThe trajectory of FA during gestation may correspond to the different microstructural patterns during the two time periods: the transition from the canalicular to the saccular stage and the transition between the saccular and the alveolar stage. Figure\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e presents a schematic illustrating the relationship between FA values and the tissue microarchitecture. We speculate that the dramatic decrease in FA may be due to the reduction of lung interstitium (anisotropic diffusion, high FA value) volume during the transition between the canalicular and saccular stages. In contrast, the stabilized FA may be due to an insignificant change of interstitium volume between the saccular stage and the alveolar stage. This finding is consistent with an observation in fetal lung development studies in sheep: the interstitium volume did not change appreciably between d 121 and d 135 (term approximately 148 d), despite a 40% reduction in alveolar septal thickness and a 270% increase alveolar airspace volume[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Our data fit well into the classical concept of fetal lung development, in which the interstitium (connective tissue components) is reduced to a minimum at the end of the canalicular phase. In contrast, during the saccular and alveolar phases, the volume of the interstitium tissue does not change significantly[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Interestingly, our results suggest that the time point between the canalicular and saccular periods is 28 weeks of gestation, which is slightly delayed compared to the 24-26-week gestation period reported in the literature[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. We think this is reasonable since each patient has its unique developmental timeline, and the fetal lung development stages are inherently overlapping[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe observed increase in the MD value with gestational age was concentrated in the peripheral area of the lung (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC, G). This correlation is consistent with Moore et al., who demonstrated that a similar value, ADC, increased with gestational age. Based on the proposed three-compartment diffusion model for fetal lungs (i.e., intra-lung amniotic fluid, intra-tissue water, and vascular blood), researchers concluded that the main factor controlling ADC was vascular blood[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] from the vascularization of the terminal tubules[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, other studies have reported different results regarding the correlation with gestation age. For example, Balassy et al. found no significant correlation between gestational age and ADC[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], while Cannie et al. reported correlations between gestational age and ADC depending on the magnitude of ADC[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These conflicting results may be due to differences in diffusion acquisition and b value. Furthermore, ADC parameters require more than two b values for a reliable calculation[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and fail to define the characteristics of diffusion in anisotropic tissue[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. By contrast, the MD values in our study represent a more exact value than ADC because it considers the three main directions of water movement and uses multiple b values.\u003c/p\u003e\u003cp\u003eAdditionally, we found that the FA and MD values of the left lung were significantly higher than those of the right lung. The higher vascular density near the pleura than the central areas in both lungs may account for the higher FA and MD values in these regions.[\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] The left lung is elongated than the wider and shorter right lung. This morphological difference results in a higher proportion of high vascular density areas near the pleura in the left lung\u0026rsquo;s overall volume. This specific morphological feature might explain the overall higher FA and MD values observed in the left lung.\u003c/p\u003e\u003cp\u003eOur study found that LLSIR in the fetus shows a rising trend as gestational age increases. This phenomenon may be related to increased fetal lung fluid volume[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. From the canalicular to the alveolar stage, bronchial lumens gradually enlarge, terminal sacs and alveoli proliferate, and interstitium thickness decreases, which increases lung fluid capacity[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Concurrently, lung fluid secretion gradually increases with the development of pulmonary microvessels and the increase in epithelial surface area. These factors contribute to increased fetal lung signal intensity ratio with gestational age. Our results confirm the conclusions of previous studies[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRegarding FLV, our research shows a linear positive correlation with gestational age, consistent with earlier studies[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, different studies show varying predictions of fetal lung volume at the same gestational age, likely due to differences in volume measurement methods and sample gestational age distributions. For instance, we used 3D reconstruction to calculate FLV, while Meyers et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] used a planimetric method (summing the cross-sectional areas in each MR slice multiplied by slice thickness). Furthermore, we found that the average volume of the right lung is greater than that of the left lung, possibly due to the heart\u0026rsquo;s position in the left thoracic cavity.\u003c/p\u003e\u003cp\u003eThis study had several limitations. First, motion artifacts affected fetal lung imaging. In our study, 61.9% of the fetal chest DTI images were obtained without significant movement and were used in our analyses. Similarly, a study by Onur et al. achieved a success rate of 60% with DWI imaging, citing that a significant amount of motion reduced the reliability of the ADC value to produce meaningful results[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Second, the Reproducibility of DTI is also challenging; Andras et al. identified data artifacts in 16\u0026ndash;30% of DTI cases of the fetal brain in vivo[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. To mitigate the low success rate for DTI imaging of fetuses, a motion-tracked slice‐to‐volume registration (MT‐SVR) method, introduced by Marami et al.[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], offers a promising post-processing approach. This method has been recently applied to create a spatiotemporal DTI atlas[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] and perform deterministic tractography of the fetal brain[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Advanced image post-processing methods, such as MT-SVR, may be used to improve fetal diffuse imaging.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our work presents the first DTI imaging of the fetal lungs in vivo. We identified significant correlations of DTI measurements with gestational age during normal fetal lung development, thus suggesting that DTI is a promising technique for evaluating the microstructural development of fetal lungs. Future longitudinal research is needed to corroborate our findings; however, our results support the use of DTI imaging to examine fetal lung maturity and abnormalities, which may help predict neonate survival.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eQ.L., F.J., and M.W. contributed equally to this work as co-first authors. Q.L., F.J., and M.W. were responsible for the study design, proposal writing, data collection, data analysis, and initial paper drafting. F.J. and M.W. were responsible for recruiting participants and collecting clinical data. Y. C., H.T. C, and W. Z. view MRI images and provide the image data. G.A.Z. and H.B.J. contributed to data analysis. W.X.Q. provided technical and material support, revised subsequent drafts of the paper, and provided a critical review of the article's intellectual content. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTochie JN, Sibetcheu AT, Arrey-Ebot PE, Choukem SP. Global, Regional and National Trends in the Burden of Neonatal Respiratory Failure and essentials of its diagnosis and management from 1992 to 2022: a scoping review. Eur J Pediatr. 2024;183(1):9-50. https://doi.org/10.1007/s00431-023-05238-z.\u003c/li\u003e\n\u003cli\u003eTeune MJ, Bakhuizen S, Gyamfi Bannerman C, Opmeer BC, van Kaam AH, van Wassenaer AG, et al. A systematic review of severe morbidity in infants born late preterm. 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The fetal lung-to-liver signal intensity ratio on magnetic resonance imaging as a predictor of outcomes from isolated congenital diaphragmatic hernia. Pediatr Surg Int. 2018;34(2):161-8. https://doi.org/10.1007/s00383-017-4184-2.\u003c/li\u003e\n\u003cli\u003eDeshmukh S, Rubesova E, Barth R. MR assessment of normal fetal lung volumes: a literature review. AJR Am J Roentgenol. 2010;194(2):W212-7. https://doi.org/10.2214/ajr.09.2469.\u003c/li\u003e\n\u003cli\u003eJakab A, Tuura R, Kellenberger C, Scheer I. In utero diffusion tensor imaging of the fetal brain: A reproducibility study. Neuroimage Clin. 2017;15:601-12. https://doi.org/10.1016/j.nicl.2017.06.013.\u003c/li\u003e\n\u003cli\u003eMarami B, Mohseni Salehi SS, Afacan O, Scherrer B, Rollins CK, Yang E, et al. Temporal slice registration and robust diffusion-tensor reconstruction for improved fetal brain structural connectivity analysis. Neuroimage. 2017;156:475-88. https://doi.org/10.1016/j.neuroimage.2017.04.033.\u003c/li\u003e\n\u003cli\u003eKhan S, Vasung L, Marami B, Rollins CK, Afacan O, Ortinau CM, et al. Fetal brain growth portrayed by a spatiotemporal diffusion tensor MRI atlas computed from in utero images. Neuroimage. 2019;185:593-608. https://doi.org/10.1016/j.neuroimage.2018.08.030.\u003c/li\u003e\n\u003cli\u003eJaimes C, Machado-Rivas F, Afacan O, Khan S, Marami B, Ortinau CM, et al. In vivo characterization of emerging white matter microstructure in the fetal brain in the third trimester. Hum Brain Mapp. 2020;41(12):3177-85. https://doi.org/10.1002/hbm.25006.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"pediatric-radiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prad","sideBox":"Learn more about [Pediatric Radiology](http://link.springer.com/journal/247)","snPcode":"247","submissionUrl":"https://submission.nature.com/new-submission/247/3","title":"Pediatric Radiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Magnetic resonance imaging, diffusion tensor imaging, fetus, lung","lastPublishedDoi":"10.21203/rs.3.rs-7743702/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7743702/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eFetal lung development is a complex and continuous process involving the progressive maturation of multiple structural and functional aspects. From early embryonic stages to birth, the fetal lung transforms primitive alveoli into mature lung tissue, encompassing four main stages: the canalicular, saccular, canalicular, and alveolar stages. Accurate assessment of fetal lung development stages is essential for the health management of the fetus.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003ethis study aims to evaluate the feasibility of magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) to assess the normal fetal lung and prospectively determine whether DTI measurements can be used as markers of fetal lung development.\u003c/p\u003e\u003ch2\u003eMaterials and methods\u003c/h2\u003e\u003cp\u003eDiffusion tensor imaging of normal fetal lungs was performed on 84 pregnant women at a gestational age (GA) of 18\u0026ndash;36 weeks. Regions of interest (ROI) for both liver and lung were drawn on the b\u0026thinsp;=\u0026thinsp;0 images to obtain the lung-to-liver signal intensity ratio (LLSIR), and the 3D segmentation measured the fetal lung volume (FLV). At the same time, DTI-related indices, fractional anisotropy (FA), and mean diffusivity (MD) were derived. Using regression analysis,DTI measurements, LLSIR, and FLV were correlated with gestational age.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThirty-two patients were excluded due to fetal motion artifacts during DTI imaging. The remaining 52 patients (61.9%) were analyzed for DTI indices. FA (r = -0.697; r = -0.711; r = -0.711; all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), MD (r\u0026thinsp;=\u0026thinsp;0.582; r\u0026thinsp;=\u0026thinsp;0.492; r\u0026thinsp;=\u0026thinsp;0.567, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), LLSIR (r\u0026thinsp;=\u0026thinsp;0.608; r\u0026thinsp;=\u0026thinsp;0.634; r\u0026thinsp;=\u0026thinsp;0.637, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and FLV (r\u0026thinsp;=\u0026thinsp;0.838, r\u0026thinsp;=\u0026thinsp;0.888, r\u0026thinsp;=\u0026thinsp;0.874, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were significantly correlated with gestational age. FA decreased dramatically before 29 weeks (slope = -0.020; -0.023; -0.022) but remained stable after 29 weeks (slope\u0026thinsp;=\u0026thinsp;0.003; 0.003; 0.002).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eDTI measurements coincided with the microstructural changes of the developing fetal lung. In particular, a dramatic decrease in the FA value may correspond to development from the canalicular to the saccular stage.\u003c/p\u003e","manuscriptTitle":"Diffusion tensor MR imaging of the normal fetal lung: a preliminary report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 02:15:04","doi":"10.21203/rs.3.rs-7743702/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-31T14:44:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-05T17:32:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165148532753465489838000345863709793128","date":"2025-12-23T18:16:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-09T05:30:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58417394403338053905786687874308501078","date":"2025-10-04T17:52:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78742061332932060401614981635597709142","date":"2025-10-03T15:58:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-03T15:45:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-02T01:27:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-02T01:26:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Radiology","date":"2025-09-29T15:34:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-radiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prad","sideBox":"Learn more about [Pediatric Radiology](http://link.springer.com/journal/247)","snPcode":"247","submissionUrl":"https://submission.nature.com/new-submission/247/3","title":"Pediatric Radiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"eff4b8b3-99f5-47e0-aaf1-684d0f3ce7bf","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-26T15:38:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 02:15:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7743702","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7743702","identity":"rs-7743702","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}