ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10009-1977 |
Decreased Placental Perfusion Assessed by Three-dimensional Power Doppler Ultrasound in Pregnancies with Gestational Diabetes Mellitus
1,3Department of Obstetrics and Gynecology, Miyake Clinic, Minami-ku, Okayama, Japan; Department of Perinatology and Gynecology, Kagawa University Graduate School of Medicine, Miki, Kagawa, Japan
2Department of Obstetrics and Gynecology, Miyake Clinic, Minami-ku, Okayama, Japan
4Department of Obstetrics and Gynecology, Faculty of Medicine, Sohag University, Sohag, Egypt
Corresponding Author: Toshiyuki Hata, Department of Obstetrics and Gynecology, Miyake Clinic, Minami-ku, Okayama, Japan; Department of Perinatology and Gynecology, Kagawa University Graduate School of Medicine, Miki, Kagawa, Japan, Phone: +810878912174, e-mail: hata.toshiyuki@kagawa-u.ac.jp
Received on: 06 March 2023; Accepted on: 10 April 2023; Published on: 30 June 2023
ABSTRACT
Objective: To assess placental perfusion in pregnancies with gestational diabetes mellitus (GDM) using placental vascular sonobiopsy (PVS).
Methods: Three-dimensional power Doppler ultrasound (3D PD US) assessment of placental perfusion with virtual organ computer-aided analysis (VOCAL) histogram analysis was performed in 49 normal pregnancies (control) at 18–21 + 6 and 28–31 + 6 weeks of gestation, and 10 diet-controlled GDM pregnancies at 28–31 + 6 weeks gestation. 3D PD indices such as the vascularization index (VI), flow index (FI), and vascularization FI (VFI) were generated for each placenta.
Results: Flow index (FI) values [35.5 (mean) ± 3.5 standard deviations (SD)] at 28–31 + 6 weeks gestation were significantly higher than those [32.3 (mean) ± 4.1 (SD)] at 18–21 + 6 weeks (p < 0.0001), whereas there were no significant differences in VI or VFI values between 18–21 + 6 and 28–31 + 6 weeks of gestation in the control group. FI values [31.9 (mean) ± 3.9 (SD)] in the GDM group were significantly lower than those [35.5 (mean) ± 3.5 (SD)] in the control group at 28–31 + 6 weeks gestation (p = 0.0056), whereas between control and GDM groups no significant differences were found in VI and VFI values.
Discussion: Our findings suggest that placental perfusion is reduced in diet-controlled GDM pregnancies. The lower FI in GDM pregnancies may be interpreted as placental vascular vasoconstriction, indicating placental hypoperfusion.
How to cite this article: Hata T, Koyanagi A, Miyake T, et al. Decreased Placental Perfusion Assessed by Three-dimensional Power Doppler Ultrasound in Pregnancies with Gestational Diabetes Mellitus. Donald School J Ultrasound Obstet Gynecol 2023;17(2):112–116.
Source of support: Nil
Conflict of interest: Dr. Toshiyuki Hata and Dr. Mohamed AM AboEllail are associated as the Editorial Board Members of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of these Editorial Board Members and their research group.
Keywords: Gestational diabetes mellitus, Normal pregnancy, Placental perfusion, Placental vascular sonobiopsy, Three-dimensional power Doppler ultrasound
INTRODUCTION
The incidence of gestational diabetes mellitus (GDM) was 5–8% of all pregnancies worldwide.1 Subclinical inflammation with vascular dysfunction caused by insulin resistance characterizes GDM.2 An abnormal endothelial function was noted in nonobese pregnancies complicated by GDM, in relation to the inflammatory status.2 Maternal hyperglycemia and vascular endothelial growth factors (VEGFs) have a direct influence on the growth, maintenance, and function of fetoplacental vessels, and the expressions of VEGF-A and VEGFR-2 messenger RNAs and protein reduces in placentas affected by GDM.3 The main placental changes on the maternal side of the placenta in GDM pregnancies were increased syncytial knots, calcification, villous agglutination, decidual vasculopathy, and retroplacental hemorrhage.4 On the fetal side, vasculopathy such as significant villous fibrinoid necrosis, chorangiosis, fibromuscular sclerosis, and villous edema were evident.4 The question raised here is whether placental perfusion is altered in GDM pregnancies.
Three-dimensional power Doppler ultrasound (3D PD US) with the virtual organ computer-aided analysis (VOCAL) program has been reported to investigate placental vascularization and blood flow, namely perfusion.5,6 3D PD indices such as the vascularization index (VI), flow index (FI), and vascularization FI (VFI) reflects both utero and fetoplacental perfusions.7 We proposed placental vascular sonobiopsy (PVS) using 3D PD US with VOCAL imaging histogram analysis to evaluate placental perfusion in normal and abnormal pregnancies.8,11 In this investigation, we evaluated placental perfusion between normal and GDM pregnancies using PVS with 3D PD US.
SUBJECTS AND METHODS
Three-dimensional power Doppler ultrasound (3D PD US) evaluation of placental perfusion with VOCAL histogram analysis was performed in 63 normal pregnancies (control) at 18–21 + 6 and 28–31 + 6 weeks of gestation, respectively. Ten GDM pregnancies were also studied at 28–31 + 6 weeks of gestation. The definition of GDM set by the International Association of Diabetes and Pregnancy Study Groups recommendations of glucose intolerance of any degree with onset or first recognition during pregnancy was followed.12 Pregnant women with GDM were well-managed solely by nutrition therapy without insulin treatment. The crown-rump length measurement at 8–10 + 6 weeks of gestation was conducted to confirm the fetal age.13 We excluded the following—(1) those with twin pregnancies, (2) preterm labor, (3) antepartum hemorrhage, (4) thyroid disease, (5) maternal systemic disease, and (6) hypertensive disorders of pregnancy. Table 1 presents maternal age, para, gestational age at birth, birth weight, and neonatal sex, Apgar score at 1/5 minutes, umbilical arterial blood pH (UApH), delivery method, neonatal intensive care unit (NICU) admission, neonatal abnormality, maternal complications, and placental weight in control and GDM groups. The study was done after obtaining approval from the Ethics Committee of Miyake Clinic, Okayama, Japan. After a full explanation of the aim of the study to participants, they all provided written informed consent.
| Subject | n | Maternal age | Para | Birth age | Birth weight | Sex | Apgar score | |
|---|---|---|---|---|---|---|---|---|
| (y. o.) | (weeks) | (gm) | (male/female) | 1 minute | 5 minutes | |||
| Mean (SD) | Median (range) | Mean (SD) | Mean (SD) | Median (range) | Median (range) | |||
| Control | 49 | 29.5 (4.1) | 0 (0–5) | 39.3 (1.2) | 3063.2 (357.3) | (25/24) | 9 (1–10) | 9 (8–9) |
| GDM | 10 | 35.8 (4.0) | 1(0–3) | 39.7 (1.2) | 3243.0 (475.0) | (7/3) | 10 (8–10) | 10 (9–10) |
| Significance | p < 0.0001 | NS | NS | NS | NS | NS | NS | |
CS, cesarean section; GA, gestational age; GDM, gestational diabetes mellitus; NICU, neonatal intensive care unit; NS, not significant; SD, standard deviation; UApH, umbilical artery blood pH; VD, vaginal delivery; y.o., years old
All 3D PD scans were performed by one well-trained examiner (A.K.) with a Voluson E10 BT21 (GE Healthcare, Zipf, Austria) and a curved array transabdominal transducer (GE eM6C G2, 2–7 MHz). Only the anteriorly implanted placenta was selected for each examination. The 3D PD US procedure was described in detail in our previous studies.8,11 The 3D volume box was placed over the placenta at a fixed 85˚ angle. Volume acquisition was carried out at 19 seconds. The thermal index was set at 0.2, and the mechanical index ranged from 0.8 to 1.0.
The placental perfusion was evaluated by a single experienced observer (A.K.) with PVS. The spherical 3D volume was obtained between the basal and chorionic plates of the placenta. 3D color Doppler indices (VI, FI, and VFI) from each acquired sphere were automatically calculated with the VOCAL program. A sequence of six placental sections separated by successive rotations of 30° was obtained, and two to three spherical sampling sites were chosen in each plane. Each index was an average value of seven spheres in each placenta. The number of 3D PD US examinations for each placenta ranged from two to three, and the total examination time was within 2 minutes. Good intra and interclass correlation coefficients and intra and interobserver agreements were obtained in our previous investigations.8,10,11
Maternal age, birth age, birth weight, UApH, and placental weight between control and GDM groups were analyzed by unpaired t-tests. Those in para and Apgar score values between groups were examined by Mann–Whitney U tests. The sex ratio, delivery method, incidence of NICU admission, the incidence of neonatal abnormality, and incidence of maternal complication were compared between the two groups using the Chi-squared (χ2) test. Systolic, diastolic, and mean blood pressures, and VI, FI, and VFI values between 18–21 + 6 and 28–31 + 6 weeks of gestation in the control group were examined by paired t-tests. Gestational age on examination, systolic, diastolic, and mean blood pressures, and VI, FI, and VFI values at 28–31 + 6 weeks of gestation between control and GDM groups were examined by unpaired t-tests. Statistical software Statistical Package for the Social Sciences (SPSS), version 28 for Windows (SPSS Inc., Chicago, Illinois, United States of America) was used for statistical analysis, with significance set at a p-value < 0.05.
RESULTS
The present study enrolled 63 normal (control) and 10 GDM pregnancies. A total of 14 control pregnancies were excluded with insufficient data on maternal and perinatal outcomes, perinatal management and delivery in other hospitals, or 3D PD acquisition due to excessive fetal movements. Therefore, 49 control and 10 GDM pregnancies were analyzed finally. The control group was examined twice at 18–21 + 6 and 28–31 + 6 weeks of gestation. The clinical characteristics of the subjects are shown in Table 1. Maternal age in [35.8 (mean) ± 4.0 (SD) years old (y.o.)] the GDM group was significantly higher than that [29.5 (mean) ± 4.1 (SD) y.o.] in the control group (p < 0.0001), whereas no significant differences in para, birth age, birth weight, sex ratio, Apgar scores at 1 and 5 minutes, UApH, delivery method, NICU admission, neonatal abnormality, maternal complication, or placental weight between the groups were noted (Table 1). One neonatal abnormality in the control group was a cleft lip.
No significant differences in systolic, diastolic, or mean blood pressures between 18–21 + 6 and 28–31 + 6 weeks of gestation were found in the control group (Table 2). FI values [35.5 (mean) ± 3.5 (SD)] at 28–31 + 6 weeks of gestation were significantly higher than those [32.3 (mean) ± 4.1 (SD)] at 18–21 + 6 weeks (p < 0.0001) (Fig. 1 and Table 2), whereas no significant differences in VI and VFI values between 18–21 + 6 and 28–31 + 6 weeks of gestation were found in the control group (Table 2).
| Subject | n | Systolic BP | Diastolic BP | Mean BP | VI | FI | VFI |
|---|---|---|---|---|---|---|---|
| (mm Hg) | (mm Hg) | (mm Hg) | (%) | ||||
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||
| 18–21 | 49 | 107.5 (13) | 61.9 (9.4) | 77.1 (10) | 47.2 (12.4) | 32.3 (4.1) | 15.7 (5.1) |
| 28–31 weeks | 49 | 108.2 (11.2) | 61.7 (8.2) | 77.2 (7.8) | 46.8 (11.6) | 35.5 (3.5) | 17.3 (5.4) |
| Significance | NS | NS | NS | NS | p < 0.0001 | NS |
BP, blood pressure; FI, flow index; NS, not significant; SD, standard deviation; VI, vascularization index; VFI, vascularization flow index
Fig. 1: Box plot of placental FI at 18–21 + 6 and 28–31 + 6 weeks of gestation in the normal (control) group. The blue and brown horizontal bars indicate the mean. Blue and brown boxes are SDs
No significant differences in gestational age on examination or systolic, diastolic, and mean blood pressures at 28–31 + 6 weeks of gestation between the control and GDM groups were noted (Table 3). FI values [31.9 (mean) ± 3.9 (SD)] in the GDM group were significantly lower than those [35.5 (mean) ± 3.5 (SD)] in the control group at 28–31 + 6 weeks of gestation (p = 0.0056) (Fig. 2 and Table 3), whereas there were no significant differences in VI and VFI values between control and GDM groups (Table 3).
| Subject | n | GA at examination | Systolic BP | Diastolic BP | Mean BP | VI | FI | VFI |
|---|---|---|---|---|---|---|---|---|
| (weeks) | (mm Hg) | (mm Hg) | (mm Hg) | (%) | ||||
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||
| Control | 49 | 29.3 (0.9) | 108.2 (11.2) | 61.7 (8.2) | 77.2 (7.8) | 46.8 (11.6) | 35.5 (3.5) | 17.3 (5.4) |
| GDM | 10 | 29.7 (1.1) | 111 (14.3) | 64.4 (9.0) | 80.0 (10.2) | 45.4 (8.5) | 31.9 (3.9) | 14.9 (3.7) |
| Significance | NS | NS | NS | NS | NS | p = 0.0056 | NS |
BP, blood pressure; FI, flow index; GA, gestational age; GDM, gestational diabetes mellitus; NS, not significant; SD, standard deviation; VI, vascularization index; VFI, vascularization flow index
Fig. 2: Box plot of placental FI in normal (control) and GDM pregnancies. The blue and brown horizontal bars indicate the mean. Blue and brown boxes are SDs
DISCUSSION
Regarding the change of 3D PD indices with advancing gestation, results among studies are inconsistent (Table 4).5,7,8,14-17 In seven previous investigations and the present study, three were—one “increase,” four “not changed,” and one “decrease” in VI, five “increase” and three “not changed” in FI, and four “increase” and four “not changed” in VFI (Table 4). The reason for these inconsistencies is unknown. One possible explanation is the difference in the type of study. Seven were cross-sectional studies, and only one was a longitudinal study (Table 4). The second possible explanation could be the difference in the number of studied subjects (38–295 women). The third possible explanation is the difference in the range of gestation studied. The fourth possible explanation may be differences in the methodology of 3D PD measurements in the placenta. The last possible explanation may be the difference in devices used in the studies. Further studies which would involve a larger sample size are mandatory to confirm the true changes of 3D PD indices in the placenta with advancing gestational age.
| Study | Year | Type of study | n | Gestation | Change with advancing gestation | ||
|---|---|---|---|---|---|---|---|
| (weeks) | VI | FI | VFI | ||||
| Yu et al.5 | 2003 | CSS | 100 | 20–40 | Increase | Increase | Increase |
| Mercé et al.7 | 2005 | CSS | 99 | 14–40 | Increase | Increase | Increase |
| Noguchi et al.8 | 2009 | CSS | 208 | 12–40 | Increase | Increase | Increase |
| de Paula et al.14 | 2009 | CSS | 295 | 12–40 | NC | NC | NC |
| Guimarães Filho et al.15 | 2010 | CSS | 283 | 26–35 | NC | Increase | NC |
| Mihu et al.16 | 2010 | CSS | 80 | 23–37 | Decrease | NC | Increase |
| Morel et al.17 | 2011 | CSS | 38 | 15–27, 28–39 | NC | NC | NC |
| Present study | 2023 | LS | 49 | 18–21, 28–31 | NC | Increase | NC |
CSS, cross-sectional study; FI, flow index; LS, longitudinal study; NC, not changed; VI, vascularization study; VFI, vascularization flow index
Stanley et al.18 reported that in vivo uteroplacental perfusion is impaired in mice with GDM because the uterine artery resistance index (RI) significantly increased. Maximal endothelium-dependent relaxation in response to methacholine was also significantly impaired in mesenteric arteries, while sensitivity was significantly reduced in uterine arteries in mice with GDM.18 Suranyi et al.19 reported that 3D PD indices (VI, FI, and VFI) are not different between pregnancies with GDM and DM, and all the indices in diabetic patients (GDM and DM) are significantly reduced compared with those in nondiabetic individuals in mid and late gestation. In the present study, however, only FI values in the diet-controlled GDM women were significantly lower than those in the control women early in the third trimester, whereas no significant differences in VI or VFI values were found between the control and diet-controlled GDM groups. The reason for different results regarding placental perfusion assessed by 3D PD US in GDM pregnancies between Suranyi’s and our studies is unknown. The main possible explanation is the difference in subjects between both studies. In Suranyi’s study,19 diabetic patients consisted of those with GDM and DM pregnancies, whereas cases in the present study were only diet-controlled GDM pregnancies. Reiter et al.20 reported that the umbilical artery RI indices in patients with insulin-treated GDM pregnancy were not different from those of a healthy control group after 34 weeks of gestation, while a significant decrease was noted in patients with diet-controlled GDM pregnancy. FI denotes the average flow signal intensity within the placenta.5,21 Therefore, the lower FI in diet-controlled GDM pregnancies may be interpreted as placental vascular vasoconstriction, indicating placental hypoperfusion in this study.
A possible limitation of the present study was that only an anteriorly implanted placenta was chosen to keep the maximum depth of the placenta constant. Raine-Fenning et al.22 stated that a significant reduction in each 3D PD index was observed as the distance between the transducer and vessel increased. Zalud and Shaha23 focused on only anterior implanted placentas in their 3D PD study to prevent the bias of Doppler signal attenuation. We also selected the anterior implanted placenta for obtaining placental 3D Doppler indices in our previous investigations.8,10,11 Another possible limitation is excessive fetal movements, which affect 3D PD volume acquisition. In the present study, volume acquisition was carried out at 19 seconds to obtain whole placental 3D PD volume data. Rapid 3D volume data acquisition will prevent the effect of excessive fetal movements. These limitations of 3D PD US will be resolved as further technical advances in 3D volume measurement become available.
In conclusion, placental perfusion was reduced in diet-controlled GDM pregnancies. The lower FI in GDM pregnancies might be interpreted as placental vascular vasoconstriction, indicating placental hypoperfusion. Further studies which would involve a larger sample size are mandatory to evaluate placental perfusion with 3D PD US in diet-controlled and insulin-treated GDM pregnancies which may develop hypertensive disorders during pregnancy.
REFERENCES
1. Rodrigues S, Robinson EJ, Ghezzo H, et al. Interaction of body weight and ethnicity on risk of gestational diabetes. Am J Clin Nutr 1999;70:1083–1089. DOI: 10.1093/ajcn/70.6.1083
2. Mrizak I, Arfa A, Fekih M, et al. Inflammation and impaired endothelium- dependant vasodilatation in non obese women with gestational diabetes mellitus: preliminary results. Lipids Health Dis 2013;12:93. DOI: 10.1186/1476-511X-12-93
3. Meng Q, Shao L, Luo X, et al. Expression of VEGF-A and VEGFR-2 in placentae from GDM pregnancies. Reprod Biol Endocrinol 2016;14(1):61. DOI: 10.1186/s12958-016-0191-8
4. Aldahmash WM, Alwasel SH, Aljerian K. Gestational diabetes mellitus induces placental vasculopathies. Environ Sci Pollut Res Int 2022;29(13):19860–19868. DOI: 10.1007/s11356-021-17267-y
5. Yu CH, Chang CH, Ko HC, et al. Assessment of placental fractional moving blood volume using quantitative three-dimensional power Doppler ultrasound. Ultrasound Med Biol 2003;29(1):19–23. DOI: 10.1016/s0301-5629(02)00695-6
6. Merce LT, Barco MJ, Bau S. Reproducibility of the study of placental vascularization by three-dimensional power Doppler. J Perinat Med 2004;32(3):228–233. DOI: 10.1515/JPM.2004.043
7. Merce LT, Barco MJ, Bau S, et al. Assessment of placental vascularization by three-dimensional power Doppler “vascular biopsy” in normal pregnancies. Croatia Med J 2005;46(5):765–771.
8. Noguchi J, Hata K, Tanaka H, et al. Placental vascular sonobiopsy using three-dimensional power Doppler ultrasound in normal and growth restricted fetuses. Placenta 2009;30(5):391–397. DOI: 10.1016/j.placenta.2009.02.010
9. Hata T, Tanaka H, Noguchi J, et al. Three-dimensional ultrasound evaluation of the placenta. Placenta 2011;32(2):105–115. DOI: 10.1016/j.placenta.2010.11.001
10. Noguchi J, Tanaka H, Koyanagi A, et al. Three-dimensional power Doppler indices at 18-22 weeks’ gestation for prediction of fetal growth restriction or pregnancy-induced hypertension. Arch Gynecol Obstet 2015;292(1):75–79. DOI: 10.1007/s00404-014-3603-z
11. Sato M, Noguchi J, Mashima M, et al. 3D power Doppler ultrasound assessment of placental perfusion during uterine contraction in labor. Placenta 2016;45:32–36. DOI: 10.1016/j.placenta.2016.06.018
12. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3):676–682. DOI: 10.2337/dc09-1848
13. Okai T. Standard values of ultrasonic measurements in Japanese fetuses. J Med Ultrason 2003;30:J415–J440.
14. de Paula CFS, Ruano R, Campos JA, et al. Quantitative analysis of placental vasculature by three-dimensional power Doppler ultrasonography in normal pregnancies from 12 to 40 weeks of gestation. Placenta 2009;30(2):142–148. DOI: 10.1016/j.placenta.2008.11.010
15. Guimarães Filho HA, Araujo Júnior E, Matter R, et al. Placental blood flow measured by three-dimensional power Doppler ultrasound at 26 to 35 weeks gestation in normal pregnancies. J Matern Fetal Neonatal Med 2010;23(1):69–73. DOI: 10.3109/14767050903121431
16. Mihu CM, Mihu D, Drugan T, et al. Study of intraplacental vascularization 3D power Doppler ultrasound in pregnancies with normal evolution. Gineco 2010;6:210–216.
17. Morel O, Grangé G, Fresson J, et al. Vascularization of the placenta and the sub-placental myometrium: feasibility and reproducibility of a three-dimensional power Doppler ultrasound quantification technique. A pilot study. J Matern Fetal Neonatal Med 2011;24(2):284–290. DOI: 10.3109/14767058.2010.486845
18. Stanley JL, Cheung CC, Rueda-Clausen CF, et al. Effect of gestational diabetes on maternal artery function. Reprod Sci 2011;18(4):342–352. DOI: 10.1177/1933719110393029
19. Suranyi A, Kozinszky Z, Molnar A, et al. Placental three-dimensional power Doppler indices in mid-pregnancy and late pregnancy complicated by gestational diabetes mellitus. Prenat Diagn 2013;33(10):952–958. DOI: 10.1002/pd.4172
20. Reiter A, Hajduk B, Geka F, et al. Doppler studies of gestational diabetes in the third trimester. Ultraschall Med 2011;32(Suppl 2):E162–E168. DOI: 10.1055/s-0031-1273415
21. Pairleitner H, Steiner H, Hasenoehrl G, et al. Three dimensional power Doppler sonography: imaging and quantifying blood flow and vascularization. Ultrasound Obstet Gynecol 1999;14(2):139–143. DOI: 10.1046/j.1469-0705.1999.14020139.x
22. Raine-Fenning NJ, Nordin NM, Ramnarine KV, et al. Determining the relationship between three-dimensional power Doppler data and true blood flow characteristics: an in-vitro flow phantom experiment. Ultrasound Obstet Gynecol 2008;32(4):540–550. DOI: 10.1002/uog.6110
23. Zalud I, Shaha S. Three-dimensional sonography of the placental and uterine spiral vasculature: influence of maternal age and parity. J Clin Ultrasound 2008;36(7):391–396. DOI: 10.1002/jcu.20485
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