High performance of the diffusion magnetic resonance imaging biomarker diffusion-derived ‘vessel density’ (DDVD) for separating placentas associated with pre-eclampsia from placentas in normal pregnancy

Introduction

Pre-eclampsia (PE) typically affects 2–8% of pregnancies and is a leading cause of maternal and perinatal morbidity and mortality (1). The consequences of PE can be serious both for the mother and the fetus, especially when the disease is severe. Severe manifestations include delivery before 37 weeks gestation (preterm PE) and fetal growth restriction (FGR). An earlier diagnosis of PE is important, as an early intervention and treatment can be effective (2,3). PE is thought to be predominantly due to defective implantation of the placenta within the uterine endometrium (4,5). Doppler ultrasound measured index ‘uterine artery pulsatility index (PI)’ is used for assessing the blood flow to the placenta (6-8). Poor placental perfusion, demonstrated by increased uterine artery PI, is associated with the development of PE. Histological studies of the maternal spiral arteries within the wall of the uterus also corroborate the hypothesis that PE is a consequence of impaired placentation. Uterine artery PI combined with maternal factors improves the detection rate from 50% to 59% and 58% to 70%, at a false-positive rate of 10%, for PE requiring delivery before 37- and 34-week gestation, respectively (9). Still, measurement of uterine artery PI is highly operator dependent and associated with various subjectivities. There have been also numerous biochemical markers studied and evaluated for the prediction of PE. PE has been shown to be associated with a low level of circulating pregnancy-associated plasma protein A (PAPP-A). In both the first and second trimesters of pregnancy a reduced concentration of serum placental growth factor (PlGF) have been shown to precede the clinical onset of PE. Screening by a combination of maternal risk factors, uterine artery Doppler, mean arterial pressure, maternal serum PAPP-A and PlGF can identify about 75% of cases of preterm PE for a false-positive rate of 10% (9). Due to the complexity of this disorder, even a combination of risk factors and available tests cannot accurately diagnose or predict PE. The quest to identify pregnant women who are at high risk of developing preterm PE remains a major goal.

Diffusion-derived ‘vessel density’ (DDVD), initially proposed as a straightforward imaging biomarker to evaluate liver perfusion (10), can be calculated from a simple diffusion magnetic resonance imaging (MRI) protocol as:

DDVD=(b0b2)Sb0ROIarea0−Sb2ROIarea2[unit:arbitrary unit (au)/pixel][1]

where Sb0 refers to the measured liver sum signal intensity when b=0 s/mm², and Sb2 refers to the measured liver sum signal intensity when b=2 s/mm². ROI_area0 and ROI_area2 refer to the number of pixels in the selected region of interest (ROI) on b=0 s/mm² and b=2 s/mm² images, respectively. Sb2 and ROI_area2 can also be approximated by other low b-value diffusion image’s data. The blood vessels show high signal when there is no motion probing diffusion gradient (b=0 s/mm²) and low signal when even very low b-values are applied (10-12). The signal difference between the two sets of images can be calculated as DDVD which can be interpreted as a physiological surrogate of the area of functional micro-vessels per unit tissue area. DDVD can be conceptually converted to a surrogate of the volume of functional micro-vessels per tissue unit volume if multiple slices are integrated. The clinical usefulness of DDVD as a diffusion imaging biomarker has been recently demonstrated. Huang et al. (13) showed that DDVD analysis demonstrates liver parenchyma has an age-dependent decrease of micro-perfusion. This agrees with the known physiological age-dependent reduction in liver blood flow which has been well documented using a variety of technical methods including histology, dye dilution, indicator clearance. DDVD is a useful parameter for the distinguishing of livers with and without fibrosis, and livers with more severe fibrosis tend to have even lower DDVD measurements than those with milder liver fibrosis (10,12,14). Chen et al. (11) described a proof-of-concept study that a combination of DDVD map and high b-value diffusion-weighted (DW) image identify the exitance and the size of a penumbra. Hu et al. (15) described that liver hemangiomas can be mostly differentiated from liver mass-forming lesions [hepatocellular carcinomas (HCC) and focal nodular hyperplasia] solely based on DDVD map. Recently, DDVD has been tested for the assessment of placenta perfusion. Lu et al. (16) reported that regional placenta DDVD was significantly higher in placenta accreta spectrum (PAS) disorders than in normal placenta, placenta DDVD measure was positively correlated with blood loss volume during the delivery. He et al. (17) studied 17 early preeclampsia pregnancies and a total of 29 normal pregnancies with GA <34 weeks, and reported that the area under the receiver operating characteristic curve (AUROC) for placenta DDVD to discriminate between normal pregnancies and early PE regardless of FGR was 0.954, and AUROC was 1.000 when early PE without FGR were excluded.

The current study is an extension of the work by He et al. (17). In the work by He et al., 82.3% (14/17) had FGR. With this new study, we aim to evaluate the performance of placenta DDVD for more milder PE patients, the relationship between hypertension measure and placenta DDVD, and the possible placenta DDVD difference of PE with FGR and without FGR. In addition, this study evaluated a number of image post-processing approaches.

Methods

This prospective study was approved by the institutional ethic committee, and conducted in accordance with the Declaration of Helsinki (as revised in 2013). All pregnant women participated were recruited consecutively from May 2023 to April 2024 and informed consent was obtained. According to the local practice, all Chinese pregnant women who had an earlier caesarean delivery were scheduled to have placenta MRI for the second pregnancy, and those later had normal delivery comprised the control cases (n=44). The normal control group of pregnancies consisted of healthy women with normal ultrasound scans and Doppler results who delivered an appropriate-for-gestational age infant at term. Study cases were all confirmed PE patients (n=30) diagnosed according to the guidelines (18,19) (Figure 1, Table 1), with new-onset hypertension confirmed on at least 2 occasions measured 4 hours apart, accompanied by proteinuria, other maternal organ involvement, and/or uteroplacental dysfunction. Hypertension was defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg. A maternal history of chronic hypertension or renal disease was exclusion criteria. Appropriate-for-gestational age was defined as final birthweight greater than the tenth percentile based on local references (20,21).

Figure 1 Study subjects enrolment flow diagram. One control case with PAS was excluded from the analysis. For five PE cases, fetal brain was associated with motion artifacts, thus fetal brain DDVD could not be calculated. Eight PE cases had FGR diagnosed according to the local guideline (20,21). PE, pre-eclampsia; PAS, placenta accreta spectrum; FGR, fetal growth restriction; GA, gestation age; DDVD, diffusion-derived ‘vessel density’.

The scanner was a 3.0-T magnet (Siemens MAGNETOM Spectra, Erlangen, Germany), with a body coil used as the signal transmitter and a phase-array surface coil used as the signal receiver. In addition to standard anatomical imaging, DW imaging with fat suppression was acquired with a single-shot spin-echo-type echo-planar imaging (EPI) sequence, and the parameters are: repetition time (TR) =4,600 ms, echo time (TE) =60 ms; EPI factor =94; slice thickness =5 mm; slice gap =1 mm; field of view =40×40 cm; matrix =132×118, number of excitation =3. Three-motion probing gradient directions were applied for each b-value. DDVD protocol included two b-values, being 0 and 50 s/mm². Free breathing was allowed, and the DDVD protocol was run three times to assess scan-rescan repeatability.

For image analysis, ROIs were drawn by a radiology trainee and a radiologist in consensus. With anatomical images used as references, the border of the placenta was identified on the b=0, 50 s/mm² DW images, and DDVD was calculated using the following equation:

DDVD=(b0b50)Sb0ROIarea0−Sb50ROIarea50[unit:au/pixel][2]

where ROIarea0 and ROIarea50 refer to the number of pixels in the selected ROI on b=0 s/mm² and b=50 s/mm² images, respectively. Sb0 refers to the measured sum placenta signal intensity within the ROI when b=0 s/mm², and Sb50 refers to the measured sum placenta signal intensity within the ROI when b=50 s/mm². As a pixel can be considered an individual ROI, DDVD map was constructed pixel-by-pixel with the same principle (22). DDVD was calculated based on the mean signal difference between b=0 s/mm² and b=50 s/mm² DW images, with ROI measured on b=0 s/mm² and b=50 s/mm² DW images respectively; or a single ROI was measured on DDVD map (Figure 2). The mean of all included slice measurements was regarded as the value of the examination, with the last step weighted by the ROI area of each slice. The intraclass correlation coefficient (ICC) for these two measures approaches had excellent agreement, with an ICC value of 0.997, and further analyses were based on DDVD map.

Figure 2 ROI segmentation of placenta and fetal brain for DDVD calculation. (A) ROI of placenta (in green) and ROI of fetal brain (in red) were drawn on b=0 s/mm² DWI. (B) ROI of placenta (in green) and ROI of fetal brain (in red) were drawn on b=50 s/mm² DWI. (C) DDVD pixel-by-pixel map, calculated from b=0 and b=50 s/mm² DWIs. (D) ROI of placenta and ROI of fetal brain were drawn on DDVD pixel-by-pixel map. DWI, diffusion-weighted image; ROI, region of interest; DDVD, diffusion-derived ‘vessel density’.

As absolute magnetic resonance (MR) signal intensity is influenced by various factors, including B1 spatial inhomogeneity, coil loading, receiver gain, etc., diffusion-derived vessel density ratio (DDVDr) was used to minimize these scaling factors (23,24). The ratios of placenta to fetal brain were taken as:

DDVDr=Placenta DDVDFetal brain DDVD[3]

Inter-cotyledon septations are fibrous structures in the placenta, and show dark-grey signal on DW images. These inter-cotyledon septations were manually excluded during ROI segmentation, and then the results were compared with all inter-cotyledon septations kept in the ROI. Another approach was to only measure the ‘dominant pixels’ of within 90% distribution of DDVD values, pixels with the highest value 5% distribution and the lowest value 5% distribution tentatively discarded.

Quantitative data were processed using GraphPad Prism Software (GraphPad Software Inc., San Diego, CA, USA). Comparisons between two groups were performed using Mann-Whitney U test. Measure-remeasure agreement was assessed with ICC. AUROC was used to determine the diagnostic performance. Pearson test was used for correlation analysis. A P value <0.05 was considered statistically significant, >0.1 as not significant, and between 0.05 and 0.1 as with a trend of significance (as the current study was an exploratory study rather than a confirmatory study with pre-determined statistical power).

Results

The DDVD values of the control placentas [n=44, median: 67.53, 95% confidence interval (CI): 52.84–79.46] were significantly higher than those of the PE patients (n=25, median: 23.66, 95% CI: 17.22–45.57, P<0.0001), while there was no difference of the fetal brain DDVD values of the control cases (median: 29.5, 95% CI: 25.46–34.62) and those of PE patients (median: 33.6, 95% CI: 27.82–35.39, P=0.41). The further analysis was primarily based on DDVDr.

As shown in Figure 3, there was no difference in including all the pixels in the ROI and only measuring the central 90% pixels while removing the 5% pixels with lowest DDVD value and the 5% pixels with highest DDVD value, thus further analysis was based on including all pixels in the ROI. Furthermore, whether inter-cotyledon septations were kept in the placenta ROI segmentation or not had no effect on the DDVDr results (ICC of the two approaches =0.997). Three scans had inter-scan ICC of 0.78 for scan 1 vs. scan 2, 0.86 for scan 1 vs. scan 3, and 0.90 for scan 2 vs. scan 3, suggesting good scan-rescan repeatably. The final results were based on (I) all pixels in the ROI counted; (II) inter-cotyledon septations kept; (III) the mean value of the three scans were adopted.

Figure 3 Testing of two methods for potential optimization of DDVDr analysis. (A,B) DDVD histogram presentation of placenta pixels and fetal brain pixels of one study participant. X-axis: distribution of DDVD values; Y-axis: number of pixels. The red lines denote the 5% of lowest DDVD values and the 5% of highest DDVD values were not counted. Including all pixels and including only 90% of the central DDVD value pixels yield very similar results with an ICC of 0.995 (tested cases n=69). (C,D) An example of placenta ROI segmentation with inter-cotyledon septations remained (C) or removed (D). These approaches in (C) and in (D) derived very similar results with an ICC of 0.997 (tested cases n=69). Arrows in (C): inter-cotyledon septation. ROI, region of interest; DDVDr, diffusion-derived vessel density ratio; DDVD, diffusion-derived vessel density; ICC, intraclass correlation coefficient.

Gestational age (GA) and DDVDr were negatively correlated in the control group (r=−0.26, P=0.085; Figure 4A); however, such a trend was not observed for PE patients (Figure 4B). A trend was observed with systolic blood pressure and DDVDr negatively correlated (r=−0.328, P=0.117; Figure 4C). For PE patients, those with FGR had a trend of lower DDVDr than those without FGR (Figure 4D).

Figure 4 Correlation between DDVDr and GA (A: controls; B: PE patients) or systolic blood pressure (C), and the DDVDr difference between PE patients with and without FGR (D). The PE patients with relatively lower blood pressure had relatively higher DDVDr (particularly the cases marked with 1, 2, 3, 4 in C). (D) shows that patients with FGR had a lower DDVDr than those without FGR (0.664 vs. 0.925, bar: median) without statistical significance (P=0.23). DDVD, diffusion-derived vessel density; DDVDr, diffusion-derived vessel density ratio; GA, gestational age; PE, pre-eclampsia; FGR, fetal growth restriction; MRI, magnetic resonance imaging.

DDVDr results of control cases (n=44, median: 2.00, 95% CI: 1.57–2.50) were significantly higher than those of patients (n=25, median: 0.81, 95% CI: 0.53–1.18, P<0.0001), and AUROC was 0.84 to separate control cases and PE patients (Figure 5A,5B). If only those with GA age ≤35 weeks were considered, AUROC was 0.92 to separate control cases (n=20) and PE patients (n=9) (Figure 5C). If only PE patients with FGR (n=8) were considered with the controls (n=44), AUROC was 0.96 to separate control cases and PE patients (Figure 5D, Table 2). The four PE patients who had the highest DDVD also had relatively ‘lower’ systolic blood pressure among the patient group (Figures 4C,5A).

Figure 5 DDVDr results of control cases and PE patients. (A,B) Scatter plot (bar: median) and AUROC of 0.84 for all controls (n=44) and all PE patients (n=25). (C) Scatter plot for subjects of ≤35 weeks GA (controls n=20, PEs n=9) and AUROC is 0.92. (D) Scatter plot for all controls (n=44) and PE patients with FGR (n=8) and AUROC is 0.96. The cases marked with 1, 2, 3, 4 in (A) are the same as those in Figure 4C. DDVD, diffusion-derived vessel density; PE, pre-eclampsia; AUROC, area under the receiver operating characteristic curve; GA, gestational age; FGR, fetal growth restriction; DDVDr, diffusion-derived vessel density ratio.

If the fetal brain DDVD was not used to normalise the placenta DDVD, then direct placenta DDVD comparison of control cases and PE patients had an AUROC of 0.80 for separating the 44 control cases from all 30 PE patients (AUROC of 0.83 for GA ≤35 weeks cases, AUROC of 0.91 for PE with FGR cases, Figure 6).

Figure 6 Separation of placentas in control cases and placentas in PE patients by directly measured DDVD mean value. The DDVD values of the control placentas (n=44, median: 67.53, 95% CI: 52.84–79.46) were significantly higher than those of the PE patients [n=30, median: 25.25, 95% CI: 17.26–45.57, P<0.0001 (A,B)], and AUROC was 0.80 to separate control cases and PE patients (C). If only those with GA age ≤35 weeks were considered, then AUROC was 0.83 to separate control cases (n=20) and PE patients (n=10) (D,E). If only PE patients with FGR (n=8) were considered with the controls (n=44), then AUROC was 0.91 to separate control cases and PE patients (F,G). DDVD, diffusion-derived vessel density; PE, pre-eclampsia; CI, confidence interval; AUROC, area under the receiver operating characteristic curve; GA, gestational age; FGR, fetal growth restriction.

Discussion

It has been noted that the blood vessels show high signal when there is no diffusion gradient (b=0 s/mm²) and low signal when even very low b-values are applied (10). For spin-echo-type EPI sequence, the second motion probing gradient after the 180-degree RF pulse could not fully re-focus the flowing spins in vessel and micro-vessels after being de-phased by the first motion probing gradient before the 180-degree RF pulse [see supplementary Fig. 1 in ref (11)]. DDVD measure based on this simple principle appears to be useful as a straightforward imaging biomarker (10-17,22-24). Recent works have documented the correlation between DDVD measure and dynamic contrast enhanced computed tomography (CT)/MRI measures. For example, Li et al. (23) reported that DDVD ratio of HCC to adjacent liver to be 2.94 (median, 95% CI: 2.42–3.52) when b=0 and 2 s/mm² were used. With a CT perfusion technique, Sahani et al. (25) measured blood volume (mL/100 g) to be 4.9±3.5 for HCC, whereas 2.6±0.9 for background liver. With an MRI perfusion technique, Abdullah et al. (26) reported normalized total perfusion (mL/100 g/min) of HCC to corresponding tumor-free liver to be 4.0 (range, 0.5–16.5). In a study of rectal carcinoma, Lu et al. (24) found the DDVD ratio of cancerous tissue to tumor-free rectal wall to be 1.950 when b=0 and 5 s/mm² were used. Consistent with this, using perfusion CT, Sahani et al. (27) reported blood flow (mL/100 g/min) ratio of cancerous tissue to tumor-free rectal wall to be 1.94 (60.33/31.02). Lu et al. (24) reported earlier clinical grades rectal carcinoma had a higher DDVDr (tumor to tumor-free rectal wall) than those of the advanced clinical grades (2.245 for grade 0 & I, 1.460 for grade II, 1.430 for grade III, 1.130 for grade IV), which is consistent with CT perfusion results.

In normal pregnancy, the spiral arteries, latter becoming the uteroplacental arteries in the placental bed, undergo a complex series of morphological changes. The vessels are invaded by trophoblast, which becomes incorporated into the vessel wall and replaces the endothelium, muscular layer and neural tissue. The result of these physiological changes is the conversion of the small spiral arteries into vessels of greater diameter with low resistance and high compliance, that are unresponsive to maternal vasomotor activity. This vascular transformation in the uterus is necessary to ensure a dramatic increase in blood supply to the intervillous space. In PE and FGR, there is failure of the perivascular and endovascular trophoblastic invasion of spiral arteries. Cross-sectional studies in pregnancies with PE or FGR have shown that impedance to flow in the uterine arteries is increased. This is compatible with the findings from histopathological studies that, in such pregnancies, there is failure of the normal development of maternal placental arteries into low resistance vessels. Doppler ultrasound PI is commonly used for PE screening. Uterine artery PI is influenced by GA at screening, maternal age, and history of PE in the previous pregnancy, and is therefore expressed as multiple of the median (MoM) after these factors are taken into consideration. There is a significant linear correlation between the uterine artery PI and severity of PE (28,29). MRI has the potential to offer a more objective, more reproducible, and hopefully more sensitive assessment of PE risk than ultrasound method. To a large extent, the current study confirms the pilot study of He et al. (17). AUROC to separate control cases and PE patients achieved 0.92 for subjects with GA age ≤35 weeks, and 0.96 for comparing control cases with PE patients with FGR. Of note, this study had a higher proportion of milder cases than the study of He et al., with FGR in 32% cases in this study and 82.3% cases in the study of He et al. In agreement with the reports of He et al. (17) and Lu et al. (16), for the control group, we also noted DDVDr decreased following increasing GA, and the limited data in this study suggest such a trend did not exist among PE patients; therefore, DDVDr may be even more sensitive in predicting PE for earlier pregnancy. Another interesting point is that a trend was observed with higher systolic blood pressure associated with lower DDVDr (r=−0.375, P=0.06). The four PE patients had the highest placenta DDVDr also had relatively ‘lower’ blood pressure among the PE group (Figures 4C,5A). Thus, it is likely that a lower DDVDr is associated with a higher risk for subsequent development of more severe PE. This study suggests that FGR is associated with even lower DDVDr, though statistical significance was not reached likely due to insufficient sample size.

This study also analysed a number of image post-processing approaches. A surprise was that the exclusion of inter-cotyledon septations did not affect the results. Initially, we assumed that inter-cotyledon septations would be less vascularized, and removal of inter-cotyledon septations from placenta would improve the DDVDr analysis. Our results suggest that such a step would be unnecessary in future studies. This study showed excluding very high and very low DDVD value pixels did not affect the results. In our study, fetal brain DDVD was not measurable in five cases due to motion artefacts. If the fetal brain DDVD was not used to normalise the placenta DDVD, then direct placenta DDVD comparison of control cases and PE patients had an AUROC of 0.80 for separating the 44 control cases from all 30 PE patients (Figure 6), highlighting the benefits of using DDVDr instead of direct DDVD measure.

In addition to DDVD, intravoxel incoherent motion (IVIM) has also been attempted for assessing placenta perfusion. However, not only IVIM data acquisition is time-consuming, IVIM commonly suffers from data-fitting instability (30,31). The study of Kristi et al. (32) found placenta IVIM perfusion fraction (PF) decreased linearly with GA in normal pregnancies, while Capuani et al. suggested a positive linear correlation between placenta IVIM-PF and GA (33). A few previous studies reported placenta PF did not correlate with GA (34,35). The studies of Lu et al. (16), He et al. (17), and the current study showed consistently that placenta DDVD is negatively correlated with GA. It has been known that, with the continuing growth of the placenta, the placental parenchyma became more fibrotic, calcium deposits and infarction occurred, influencing the physiological microperfusion of the placenta (36). In addition, recent evidence suggests that IVIM-PF estimation is affected by tissue T2, with longer T2 leading to lower PF estimation (37). Li et al. applied DDVD to assess the perfusion of HCC and demonstrated higher HCC perfusion relative to background liver tissue, while IVIM studies showed HCC’s PF was paradoxically lower relative to native liver tissue (23,37). IVIM-slow diffusion (D_slow) and IVIM-PF have been noted to be mutually constrained, for example, a reduction in IVIM-D_slow may be associated with an artificial elevation of IVIM-PF (13,38,39).

There are some limitations to this study. The DDVD protocol of this study scanned two b-values, namely b=0 and 50 s/mm². Due to the limitation of our MR scanner, very low b-values could not be acquired. Our earlier experience showed that using b=0 s/mm² image and a very low b-value image (such as b=2 s/mm²) increases the sensitivity in evaluating tissue perfusion, compared with a second b-value of ≥10 s/mm² (Figure 7) (23,24). Thus, the second b-value of 50 s/mm² in this study was high for DDVD analysis. Another limitation is that a surface coil was used for the MR signal receiving, which led to regional signal inhomogeneity; though we checked the images and noted the signal inhomogeneity was evenly distributed in both control cases and PE patients, thus this would not have led to a selection bias. It should be noted that PE is a spectrum disorder, and the diagnosis and the severity of PE is pathophysiologically a continuous rather than a categorical variable. Therefore, a perfect AUROC (i.e., =1) would be an unreasonable expectation. Another important limitation is that we did not include sufficient earlier GA PE patients. It is noted that DDVDr may be even more sensitive in earlier GA patients, as tentative results showed DDVDr in controls was higher at the earlier GA, while DDVDr in PE patients did not change following the increase of GA. This is a point certainly deserving more studies as an early detection of PE is more clinically relevant.

Figure 7 Using b=0 s/mm² image and a very low b-value image increases the sensitivity in separating tissues by DDVD. (A) Ratios of HCC DDVD value to tumor-free liver DDVD value (DDVDr). A better separation of HCC from liver tissue is seen with DDVDr (b0b2, calculated from b=0 and 2 s/mm² images) than with DDVDr (b0b10, calculated from b=0 and 10 s/mm² images), as HCC DDVDr (b0b2) is more different from tumor-free liver than DDVDr (b0b10). (B,C) AUROC in separating rectal Ca from tumor-free rectal wall. (B) DDVD (b0b5) calculated from b=0 and 5 s/mm² images; (C) DDVD (b0b10) calculated from b=0 and 10 s/mm² images. DDVD (b0b5) has slightly higher AUROC than DDVD (b0b10). Note DDVD is not meant to separate rectal Ca from tumor-free rectal wall; instead, DDVD is meant to evaluate tissue perfusion. HCC, hepatocellular carcinoma; Ca, carcinoma; DDVD, diffusion-derived vessel density; AUROC, area under the receiver operating characteristic curve.

Conclusions

In conclusion, this study further confirms that placenta perfusion is diffusion MRI-detectably decreased in PE patients, and placenta DDVD appears to be negatively correlated with the severity of PE. Upon further technical optimization for placenta DDVD data acquisition and image post-processing, with the integration of DDVD into other prediction models, DDVD may play an important role in patient PE prediction and follow-up management.

Acknowledgments

Funding: This work was supported by Hong Kong GRF Project (No. 14112521).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2412/coif). Y.X.J.W. serves as the Editor-in-Chief of Quantitative Imaging in Medicine and Surgery. Y.X.J.W. is the founder of Yingran Medicals Ltd., which develops medical image-based diagnostics software. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the institutional ethic committee, and conducted in accordance with the Declaration of Helsinki (as revised in 2013). All pregnant women participated were recruited consecutively from May 2023 to April 2024 and informed consent was obtained.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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