Abstract
Background
Gestational diabetes mellitus (GDM) is a common disease, and the placenta shows various functional and morphological changes in these patients. Superb microvascular imaging (SMI) and shear wave elastography (SWE) are innovative ultrasound (US) methods that provide detailed information about tissue vascularization and elasticity.
Purpose
To evaluate placental changes in patients with GDM with SMI and SWE methods.
Material and Methods
For this case-control study, 20 healthy and 20 women with GDM were included. Women at >21 weeks of pregnancy were evaluated with SMI and SWE by two independent radiologists. Mean SMI values and mean SWE values from three different region of interest-based measurements were compared between the two groups.
Results
We identified that the mean SMI and SWE value of the GDM group was found to be significantly higher than that of the control group (P = 0.002, P = 0.001 respectively). Using a receiver operating characteristic curve, the cutoff value of the SMI ratio, which maximizes the prediction of the presence of GDM, was 0.1234279750 (95% confidence interval [CI] = 0.625–0.920), the SWE cut-off value was 15.5 kPa (95% CI = 0.794–0.989).
Conclusion
We have demonstrated that evaluation with SMI and SWE might allow quantitative assessment of the morphological changes of placentas in women with GDM. We believe that the use of innovative methods such as SMI and SWE in addition to conventional US examinations in daily practice and studies will provide significant clinical benefits to patient management.
Introduction
Gestational diabetes mellitus (GDM) is defined as variable degrees of glucose intolerance diagnosed or first recognized during pregnancy (1). GDM affects 16.5% of pregnancies and is becoming more common worldwide (2,3). In approximately 10% of pregnant women with GDM, complications have been reported, such as pre-eclampsia, premature labor, fetal macrosomia, neonatal hypoglycemia, hyperbilirubinemia, shoulder injury, perinatal death, and the development of maternal type 2 DM (4,5).
The placenta has important hormonal functions in addition to providing the nutrients and oxygen needed by the fetus during pregnancy. Patients with GDM present various morphological and functional abnormalities in the placenta (6). In a woman with diabetes, the placenta is enlarged and plethoric and has an elevated placental/fetal weight ratio (7). Based on microscopic examinations, decidual vasculopathy, placental infarction and chorangiosis, fetal thrombotic vasculopathy, villitis, chorioamnionitis, and especially villous immaturity were common in patients with GDM (8). The vessels were larger and centrally located in the placenta, which had immature chorionic villi (8). In addition, villous edema in the placenta, fibrin deposits in the syncytiotrophoblast, and significant hyperplasia in the cytotrophoblast have been found in these patients (9). As a result, the preceding dysfunction causes microcirculatory impairment and anomalies in placental function, resulting in increased fetal morbidity and stillbirth. (6). Therefore, evaluating placental microcirculation and morphometry in patients with GDM is critical.
Conventional Doppler techniques are limited in imaging low flow in small blood vessels due to artifacts caused by close tissue movements (10). Superb microvascular imaging (SMI) can differentiate tissue motion artifacts from overlapping flow signals, thus demonstrating low-velocity blood flow in small vessels with high resolution and high frame rate (10). This ability of SMI to detect low-velocity blood flow allows the direct analysis of placental microcirculation in an easy and non-invasive manner, providing an advantage over other conventional Doppler technologies (11).
Elastography has the potential to be a novel tool for detecting tissue changes induced by elasticity, trauma, degeneration, healing processes, and malignancies (12). Shear wave elastography (SWE) is an elastography technique that uses the force of sound radiation produced by focused ultrasound (US) to induce mechanical vibrations in tissues without the operator applying additional pressure with a probe (13).
To the best of our knowledge, no study has evaluated placental microcirculation in patients with GDM using the SMI method. The aim of the present study was to evaluate placental microcirculation and stiffness in these patients with advanced measurement methods such as SMI and SWE.
Material and Methods
This was a case-control study conducted between December 2020 and June 2021 at our institute. Informed consent was obtained from the patients participating in the study, and the scientific research ethics committee of our institute approved the experimental protocol.
The study included a control group of 24 patients with normal glucose profiles and 31 patients who had been diagnosed with GDM using the GDM diagnostic criteria defined by the International Association of Diabetes and Pregnancy Study Group and the American Diabetes Association. Out of 55 patients, 12 were excluded from the study due to the presence of a posteriorly positioned placenta, and three were excluded due to the presence of extensive subcutaneous fatty tissue. Patients with type 1 and type 2 DM diagnoses were also excluded because of variations in the placenta's functional and morphological alterations (8). Finally, 40 women at >21 weeks of pregnancy (20 diagnosed with GDM and 20 with a normal glucose profile) were included in the study.
SMI and SWE measurements were performed by a senior radiologist with six and eight years of experience in SMI and SWE, respectively, as well as an independent second radiologist with four years of experience in SMI and SWE, without informing the operators of the patients’ GDM status before the procedure. An US evaluation was performed using a high-resolution US device (Aplio 500; Canon Medical Systems, Otawara, Japan) and a convex probe (PVT-375BT; Canon Medical Systems, Otawara, Japan) available in our department. The gain setting, dynamic range, pulse repetition frequency (PRF) value, and wall filter setting were kept constant before each evaluation.
After visualizing that the placenta was located anteriorly, vascularity assessment was performed in the central part of the placenta with monochrome SMI (mSMI), and elasticity measurements were performed using three regions of interest (ROIs) with SWE in the same plane. The obtained images were saved to the Picture Archiving and Communication System (PACS; Sectra Workstation IDS7 v.21.2, Linköping, Sweden). In the SMI evaluation, the ratio of white pixels representing vascular structures to all pixels in the obtained color box was calculated using the Java SE 15 software (Oracle Corp., Austin, TX, USA) (Fig. 1). The background scattering artifact was avoided by establishing certain threshold values for hue, saturation, and brightness in the measurements. Later, the arithmetic mean of three independent measurements taken on SWE images was calculated (Fig. 2). Finally, all measurements of the patients, as well as age, height, weight, body mass index (BMI) values, parity, gestational age at delivery, first and fifth-minute APGAR scores, birth weight, and hemoglobin A1c (HbA1c) values were recorded in the statistical program.
Evaluation of placenta with mSMI in two cases with GDM and control group. (a) Example of evaluation of placenta with mSMI mode in the control group. (b) Example of evaluation of placenta with mSMI mode in the GDM group. GDM, gestational diabetes mellitus; mSMI, monochrome superb microvascular imaging.
Evaluation of placenta with SWE in two cases with GDM and control group. (a) Example of evaluation of placenta with SWE mode in the control group. The mean stiffness value obtained by the SWE method was measured as 10.9 kPa. (b) Example of evaluation of placenta with SWE mode in the GDM group. The mean stiffness value obtained by the SWE method was measured as 21.4 kPa. GDM, gestational diabetes mellitus; kPa, kilopascal; SWE, shear wave elastography.
Statistical analysis
SPSS version 24 (IBM Corp., Armonk, NY, USA) was used to analyze the data of the 40 patients who participated in the study. The Shapiro–Wilk test was used to determine whether the variable distribution was normal.
Quantitative data from all patients collected by two separate operators were included in the study. A Pearson correlation analysis was performed to evaluate correlations between variables and GDM status. Where relevant, the data are represented as mean ± standard deviation (SD). Differences between group means were determined using the Student’s t-test. P <0.05 was considered statistically significant.
The intraclass correlation coefficient (ICC) was used to assess operator agreement in both groups. Each ICC was given a 95% confidence interval (CI), with an ICC >0.80 indicating perfect compatibility (14). The cutoff values to predict the presence of GDM in SMI and SWE were established using receiver operating characteristic (ROC) curve analysis. Sensitivity and specificity values were calculated to distinguish the presence of GDM using SMI.
Results
The median age of 40 patients included in our study was 31 (range = 17–46 years). The BMIs of the women were in the range of 20 and 51 kg/m2 (mean BMI = 32.21 ± 6.593 kg/m2). The weeks of pregnancy of the women were in the range of 25–40 (mean = 36 ± 3.53 weeks). The demographic data of the cases are shown in Table 1, separated by GDM status.
Demographic data.
BMI, body mass index; GDM, gestational diabetes mellitus; US, ultrasound.
SMI measurements in the GDM group were calculated by the first and second operators to be the range of 0.07424616–0.24745685 (mean = 0.1511856565 ± 0.04782695385) and 0.08255443–0.27344055 (mean = 0.1532959520 ± 0.04859406315), respectively. SMI measurements in the control group were calculated by the first and second operators to be the range of 0.05910597–0.16199689 (mean = 0.1083218130 ± 0.02969554004) and 0.04495638–0.17599403 (mean = 0.1070550705 ± 0.03312193259), respectively. The mean SMI value of the GDM group was found to be significantly higher than that of the control group (P = 0.002).
SWE measurements of the first operator were in the range of 10.90–42.10 kPa (mean = 24.6250 ± 9.10008 kPa), while those of the second operator were in the range of 10.5–38.3 kPa (mean = 25.495 ± 7.7796 kPa) in the GDM group. Measurements of the first and second operators in the control group were calculated as 7.30–21.40 kPa (mean = 12.0105 ± 3.86722) and 5.6–9.6 kPa (mean = 11.415 ± 3.7841), respectively. The mean elasticity value in the GDM group was significantly higher than that in the control group (P = 0.001) (Table 2).
Comparison of SMI and SWE values using student's t test.
DF, degree of freedom; kPa, kilopascal; SD, standard deviation; SMI, superb microvascular imaging; SWE, shear wave elastography; T, t-test.
The results of the ROC analysis performed to predict the presence of GDM based on the mean values of SMI and SWE are shown in Fig. 3. According to our results, the cutoff value of the SMI ratio, which maximizes the prediction of the presence of GDM, was 0.1234279750 (area under the ROC curve [AUC] = 0.772, 95% CI = 0.625–0.920), and the sensitivity and specificity values were 75% and 70%, respectively. The SWE cutoff value was 15.5 kPa (AUC = 0.891, 95% CI = 0.794–0.989), and the sensitivity and specificity values were 80% and 85%, respectively. The correlation analysis result for the operators is shown in Table 3. SMI and SWE measurements for both the GDM and control groups showed ICC values, which were evaluated as “perfect compatibility” between observers.
Receiver operating characteristic (ROC) curve analysis of SMI and SWE. SMI, superb microvascular imaging; SWE, shear wave elastography.
SMI and SWE values and correlation coefficients by operator.
GDM, gestational diabetes mellitus; ICC, intraclass correlation coefficient; kPa, kilopascal; SD, standard deviation; SMI, superb microvascular imaging; SWE, shear wave elasticity.
Discussion
Complex pathophysiological processes such as GDM can affect tissue blood supply with or without inflammation although vascularity in soft tissues usually increases due to inflammation. SMI is an innovative US technique that has been proven more sensitive in revealing tissue vascularity than other Doppler techniques and is broadly utilized today. Several studies in the literature have reported the evaluation of the placenta using SMI. It has been emphasized in some studies that SMI can make a more significant contribution to the diagnosis of certain pathologies, such as placental abruption and placental infarction, than conventional techniques (15,16). Another study demonstrated that pathologies such as placenta accreta/increta and placental chorangioma could be displayed in more detail with SMI than with the Doppler technique (17). Furuya et al. used mSMI to demonstrate the vascular anatomy of the normal placenta, including the villi structures and minute blood flows originating from the spiral artery. It could also detect pathologies like infarct or avascular villi in the diseased placenta (18). mSMI, which is thought to be a method with more sensitivity than color SMI, was used in our study to evaluate the cases (19). In addition, in order to eliminate the scattering artifact on the background, the vascularity ratios were measured by setting a certain threshold value in the pixels’ hue, saturation, and brightness parameters.
It is known that the placental volume, blood supply, and angiogenesis increase because of high insulin levels and other pathophysiological factors in patients with GDM. We attribute the fact that placental vascularity is higher in GDM cases compared with normal pregnancies, which is the major finding of our study, to these pathophysiological alterations.
SWE is an advanced imaging technique to quantify tissue stiffness, providing an objective assessment by eliminating the user-dependent variability caused by probe compression. In clinical practice, SWE is used in tissues such as the liver, breast, thyroid, lymph node, kidney, and prostate. Since the placenta is an important parenchymal organ in the obstetric examination, it can be evaluated with SWE routinely in the future. Yüksel et al. found that the mean placental elasticity value in cases with GDM was higher than that in the control group (20). In our study, the mean SWE value was also significantly higher in the group with GDM, and a significant and positive correlation was found between the presence of GDM and SWE elasticity values according to the Pearson correlation analysis (P <0.01). In addition, in the study of Anuk et al., the placental elasticity values of the GDM group requiring pharmacological treatment were found to be higher than the GDM group requiring only diet modification or having a low-risk pregnancy. (21). In another study, placental elasticity values were found to be positively correlated with BMI (22); similarly, in our study, a significant and positive correlation was found between BMI and placental SWE values (P <0.01). Pathological changes such as focal fibrinoid necrosis, villous immaturity, thickening of the villous trophoblastic membrane, chorangiosis, ischemia, and cytotrophoblastic hyperplasia in the placenta of diabetic pregnancies have been reported (23,24), and we think that the increased elasticity in the GDM placenta might be due to these pathological changes.
The present study has some limitations. These include the relatively low number of patients, the placenta's heterogeneity, particularly in terms of vascularization, the use of the conventional ROI-based technique during the SWE examination, and the unavailability of histological evaluation of placentas. These factors should be considered carefully during the interpretation of the data presented. Even so, we believe that our study has a guiding significance for future clinical applications as it reports for the first time the successful evaluation of the GDM placenta using SMI.
In conclusion, despite the undeniable place of US in obstetrics with its lack of radiation exposure, reproducibility, and ease of application at the bedside, we believe that the use of innovative methods such as SMI and SWE in addition to conventional US examinations in daily practice and studies will provide significant clinical benefits to patient management.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
