Study of the Development of Placental Microvascularity by Doppler SMI (Superb Microvascular Imaging): A Reality Today

Elsevier Editorial System(tm) for Placenta Manuscript Draft Manuscript Number: PLAC-S-20-00170 Title: STUDY OF THE DEVELOPMENT OF HUMAN PLACENTAL MICROVASCULARITY IN NORMAL GESTATION BY DOPPLER SMI (Superb Microvascular Imaging) Article Type: Original article Keywords: placental vascularization; Doppler SMI (superb microvascular imaging), ultrasound; IUGR (intrauterine growth restriction) Corresponding Author: Dr. Jose Antonio Sainz, Corresponding Author's Institution: First Author: Eva Arroyo Order of Authors: Eva Arroyo; Jara Carrera; Carlota Borrero; Jose Antonio Garcia-Mejido; Ana Fernandez-Palacin; Antonio Robles; Francisco Sosa; Jose Antonio Sainz Abstract: Introduction. To evaluate the development of placental vascularization in normal gestation without pathology by using Doppler superb microvascular imaging (SMI). Methods. The fetal and maternal parameters of 23 pregnant women without pathology were evaluated at weeks 12, 16, 20-22, 24-26, 28-30, 32-32, 36- 38, and 40-42 by 2D ultrasound and color and pulsed Doppler analysis. Doppler SMI was used to evaluate the placental vascularization, pulsatile index (PI) and peak systolic velocity (PV) of the primary (1st), secondary (2nd) and tertiary (3rd) villi, and qualitative placental descriptions and anatomopathological studies of these placentas were performed. Results. We observed that the number of cotyledons identified by Doppler SMI increased from 2 at 16-18 weeks to an average of 24 between 28 and 38 weeks. We identified the 2nd and 3rd villi starting at 20 weeks of gestation. The PI of the primary villi was constant at approximately 0.8- 0.9 in all pregnancies; in contrast, the PI of the secondary and tertiary villi increased from 1.1 to 1.56 and from 1.4 to 1.51, respectively. The PV underwent a significant increase throughout gestation in the secondary and tertiary villi (increasing from 8.9 cm/s to 28.4 cm/s and from 7.5 cm/s to 42.4 cm/s, respectively). Discussion. We evaluated the development of placental microvascularization using Doppler SMI in pregnancies without pathology and described the normal placental Doppler patterns throughout pregnancy. Suggested Reviewers: jose luis Bartha [email protected] referente author Junichi Hasegawa [email protected] *Conflict of Interest Statement STUDY OF THE DEVELOPMENT OF HUMAN PLACENTAL MICROVASCULARITY IN NORMAL GESTATION BY DOPPLER SMI (Superb Microvascular Imaging) Autorship. Each author must qualify by having participated actively and sufficiently in the study that is being performed and reported. Conflict of interest. It doesn't exist any trade association of any author of the text neither any economic benefit with the realization of this work and their publication Previous publication The declarations and opinions expressed in the articles and communications belong to the authors and not of the editor or publisher. IRB approval. Yes Permissions Charts don't exist neither you figure of other authors Patient consent I have obtained written patient consent. The study (0545‐N‐18) was approved by the local Ethics and Research Committees on 29-05-2018. The RCT was registered at ClinicalTrials.gov (NCT03686956). Fdo Dr Sainz Bueno Conflict of Interest Statement Click here to download Conflict of Interest Statement: Conflict of Interest Statement.doc STUDY OF THE DEVELOPMENT OF HUMAN PLACENTAL MICROVASCULARITY IN NORMAL GESTATION BY DOPPLER SMI (Superb Microvascular Imaging) Authors: Eva Arroyo (1), Jara Carrera (1), Carlota Borrero (1,2), José Antonio García- Mejido (1,2), Ana Fernández-Palacín (3), Antonio Robles (4), Francisco Sosa (4), José Antonio Sainz (2,3) Affiliation: (1). Department of Obstetrics and Gynecology, Valme University Hospital, Seville, Spain. (2). Department of Obstetrics and Gynecology, University of Seville, Spain. (3). Biostatistics Unit, Department of Preventive Medicine and Public Health, University of Seville, Spain. (4). Department of Pathology. Valme University Hospital, Seville, Spain. Declaration of competing interest The authors declare no conflicts of interest. Corresponding author:, Phone: 0034 955015385 José Antonio Sainz., Department of Obstetrics and Gynecology Valme University Hospital, Seville, Spain. E-mail: [email protected] Ana Fernández-Palacín. Biostatistics Unit, Department of Preventive Medicine and Public Health, University of Seville, Spain. E-mail: [email protected] Word Count of Abstract: 250 Word Count of Main Text: 1856 *Title Page and Abstract ABSTRACT. Introduction. To evaluate the development of placental vascularization in normal gestation without pathology by using Doppler superb microvascular imaging (SMI). Methods. The fetal and maternal parameters of 23 pregnant women without pathology were evaluated at weeks 12, 16, 20-22, 24-26, 28-30, 32-32, 36-38, and 40-42 by 2D ultrasound and color and pulsed Doppler analysis. Doppler SMI was used to evaluate the placental vascularization, pulsatile index (PI) and peak systolic velocity (PV) of the primary (1st), secondary (2nd) and tertiary (3rd) villi, and qualitative placental descriptions and anatomopathological studies of these placentas were performed. Results. We observed that the number of cotyledons identified by Doppler SMI increased from 2 at 16-18 weeks to an average of 24 between 28 and 38 weeks. We identified the 2nd and 3rd villi starting at 20 weeks of gestation. The PI of the primary villi was constant at approximately 0.8-0.9 in all pregnancies; in contrast, the PI of the secondary and tertiary villi increased from 1.1 to 1.56 and from 1.4 to 1.51, respectively. The PV underwent a significant increase throughout gestation in the secondary and tertiary villi (increasing from 8.9 cm/s to 28.4 cm/s and from 7.5 cm/s to 42.4 cm/s, respectively). Discussion. We evaluated the development of placental microvascularization using Doppler SMI in pregnancies without pathology and described the normal placental Doppler patterns throughout pregnancy. KEYWORDS: placental vascularization, Doppler SMI (superb microvascular imaging), ultrasound, IUGR (intrauterine growth restriction) ABBREVIATIONS: SMI (superb microvascular imaging), PI ( pulsatile index), PV ( peak systolic velocity), IUGR (intrauterine growth restriction), 3D PDA (3D power Doppler angiography), 3D CDI (Color Doppler imaging). HIGHLIGHTS.  Through Doppler SMI we were able to identify placental microvascularization.  From 20-weeks of gestation, we observed increase in villous trees using Doppler SMI  In primary villi, IP remains constant during pregnancy and the PV increases very little.  In secondary and tertiary villi, increase in IP and PV is progressive and important *Highlights STUDY OF THE DEVELOPMENT OF HUMAN PLACENTAL MICROVASCULARITY IN NORMAL GESTATION BY DOPPLER SMI (Superb Microvascular Imaging) INTRODUCTION The placenta is the least understood organ and inescapably one of the most important, not only for sustaining maternal-fetal health during pregnancy but also for the lifelong health of both mother and child. At present, our knowledge about the placenta is quite limited [1]. Placental function and structure affect important aspects of maternal health, such as the development of insulin resistance [2] as well as hypertension during the different stages of pregnancy [3-6]. Placental dysfunction affects the fetus, causing prematurity [7], growth restriction, and neurodevelopmental abnormalities [8]. Alterations in placental implantation and development at the onset of gestation may lead to inadequate placental evolution of trophoblastic invasion and remodeling of the spiral arteries; this developmental alterations may be associated with intrauterine complications that are not clinically evident until the third trimester, such as low birth weight fetuses or preeclampsia [3-8]. Most placental data are obtained from voluntary abortions between 5 and 6 weeks of gestation, leaving knowledge gaps corresponding to the other gestational phases [9]. Despite the described importance of the placenta, research is limited due to the ethical conflicts of obtaining samples of the placenta during its various formative stages. Noninvasive evaluation of the placenta has been attempted without reaching conclusive results. The current clinical tools for detecting placental dysfunction are based on fetal studies, and these lack the sensitivity and specificity to prevent fetal deaths in a costeffective way [10]. Thus, fetal biometry measures have a sensitivity of 40-74% and a specificity of 72-81% for the diagnosis of a fetus with low weight [11-13]. Umbilical artery (UA) Doppler has a sensitivity and specificity of 19% and 91%, respectively, for predicting low fetal weight in low-risk populations [14] and 55% and 91%, respectively, for high-risk populations [15]. *Manuscript References Click here to download Manuscript + References: smiplacenta4.0.docx Click here to view linked References Therefore, most research currently focuses on the study of the placenta in vivo, taking advantage of current techniques to understand placental development, structure, shape and vascularization with good real-time predictive values for fetal adverse effects, to develop preventive measures and treatments that improve the future health of both mother and child. Recently, there has been growing interest in placental studies using 3- dimensional power Doppler (3DPD) And Doppler superb microvascular imaging (SMI). SMI (Canon Medical Systems, Tustin, CA) uses clutter suppression to extract flow signals at rapid frame rates, which provides high-resolution vessel-branching details without the need for contrast agents [16] Although numerous articles have been published on the application of Doppler SMI for other organs, its diagnostic potential during pregnancy is poorly studied and used. Hasegawa and Suzuki [17] published a study describing the use of SMI to obtain images of a placental infarction. They demonstrated how in a normal placenta, this technology can be used to visualize the vascularization and vascular trees of the cotyledons, while in the placentas of fetuses with severe intrauterine growth restriction (IUGR), the low-velocity placental blood flow cannot be visualized [18]. Therefore, SMI provides new opportunities for the noninvasive characterization of placental vascularization during pregnancy [19]. We intend to evaluate the placental vascularization of normal gestations by Doppler SMI, thus describing normality parameters that will allow its use in pathological situations, such as preeclampsia or IUGR, in the future. MATERIALS AND METHODS. We conducted a prospective observational longitudinal study with 26 pregnant women between September 2018 and September 2019 at the Valme University Hospital (Seville, Spain). The study protocol was reviewed and approved by the Ethics Committee of Valme University Hospital (1001-N-18), and informed consent was obtained from all patients. The 26 pregnant women were all white, underwent spontaneous labor, had single pregnancies without previous obstetric pathology (high blood pressure, diabetes With respect to the quantitative objective data (Table 1), we showed that the primary and secondary villi maintain a close developmental trend regarding their vascular indices, while the tertiary villi follow a different pattern. The PI decreases in the primary and secondary villi throughout most of pregnancy and then slightly increases at the end of pregnancy, while the tertiary villi follows a different pattern, maintaining higher values than the primary and secondary villi throughout the entire pregnancy (Figures 2 and 3). PV increases progressively throughout pregnancy in the three parts of the placenta and in the three vascular trunks of placental branching, with lower velocities observed in larger-diameter vessels and primary villi and higher velocities observed in the tertiary villi (Figures 2 and 3). Like our group, LeGallo described the cotyledon as a functional and anatomical unit of fetal circulation. Each cotyledon consists of a main villous trunk and its branches. Two types of angiogenesis are described. Angiogenesis with branching occurs until approximately week 24 and is responsible for the development of the placental flow system. In the third trimester, angiogenesis without branching predominates and is correlated with the formation of mature intermediate villi that increase in length [36]. In our study, we observed this growth pattern because, as we have previously noted, we observed an increase in the number of cotyledons in weeks 20-28 that peaked at week 32, and we observed the appearance branching of the villous trunks. In the ultrasound performed in the third trimester, we observed a pause in the increase in the number of cotyledons, although villous density increased and reached its maximum during weeks 28 to 36. Our next objective is to extrapolate these normality parameters to pathological pregnancies in order to compare them and determine whether we are truly capable of identifying early differences in placental indices and performing a qualitative assessment of the placenta. As we have previously mentioned, the introduction of new technologies such as ultrafast Doppler [33,37] and Doppler SMI, which is what we used in the present study, allows the evaluation of placental vasculature without image artifacts, thus providing a new noninvasive tool for assessing placental functioning. We found limitations in our study, such as the difficulty of obtaining measurements during the last weeks of gestation due to fetal size, which hinders access to the placenta. Likewise, we found greater difficulty in the measurement of the posterior placenta, which was less accessible to us. Ethics statement Written patient consent was obtained for publication of this research. The research was granted approval by the Ethics Committee of Valme University Hospital (1001-N-18) Funding. Not funded Author contribution Eva Arroyo. A. B Jara Carrera. A Carlota Borrero A José Antonio García-Mejido. A Ana Fernández-Palacín. B, C Antonio Robles. A Francisco Sosa. A José Antonio Sainz . 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Figure 1 Fig 1a (left): Placental capture of 20 week pregnancy where we can identify the placental arborization. Fig 1b (right): The arrangement of the placenta (red) in the relation to the maternal cranio-caudal axis is shown in the outline. The next image shows placental división, and the last one shows a functional unit. Figure 2. Pulsatility index (PI) evolution throughout pregnancy in the different parts. A) chorionic and basal plate, B) primary villus, C) secondary villus and D) tertiary villus Figure 3. Peak velocity (PV) evolution throughout pregnancy in the different parts. A) chorionic and basal plate, B) primary villus, C) secondary villus and D) tertiary villus Figure 4. Image captures of placental arborization evaluated by Doppler SMI throughout pregnancy. Figure Legend Table 1. 1a: Results of the subjective quantitative evaluation of placental parameters evaluated by Doppler SMI. 1b: Results of the objective quantitative evaluation of placental parameters evaluated by Doppler SMI. Table1a WEEK 12-14 N:24 WEEK 16-18 N:24 WEEK 20-22 N:24 WEEK 24-26 N:22 WEEK 28-30 N:23 WEEK 32-34 N:22 WEEK 36-38 N:22 WEEK 40-42 N:22 Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage No of cotyledons/ No of primary villi Part 1 ( upper part) - - 4.96±1.50 6.36±1.60 7.57±2.08 7.82±2.42 7.68±2.60 6.50±2.17 Part 2 ( middle part) 1.00±1.10 2.71±0.75 6.27±2.08 6.77±2.22 7.30±1.74 7.95±2.51 8.40±2.81 6.33±2.06 Part 3 ( lower part) - - 4.77±1.39 6.23±2.24 6.70±2.32 6.82±2.85 6.95±1.98 6.11±2.02 No of villi * Secondary Part 1 ( upper part) - - 20(80.8%) 20(76.9%) 21(80.8%) 20(76.9%) 19(73.1%) 8(30.8%) Part 2 ( middle part) - - 20(80.8%) 21(80.8%) 21(80.8%) 20(76.9%) 18(69.2%) 7(26.9%) Part 3 ( lower part) - - 19(76.9%) 20(76.9%) 21(80.8%) 19(73.1%) 18(69.2%) 6(23.1%) Tertiary Part 1 ( upper part) - - 1(3.8%) 3(11.5%) 5(19.2%) 6(23.1%) 7(26.9%) 1(3.8%) Part 2 ( middle part) - - 1(3.8%) 2(7.7%) 5(19.2%) 6(23.1%) 7(26.9%) 1(3.8%) Part 3 ( lower part) - - 1(3.8%) 3(11.5%) 5(19.2%) 6(23.1%) 7(26.9%) 1(3.8%) Table 1b. WEEK 12-14 N:24 WEEK 16-18 N:24 WEEK 20-22 N:24 WEEK 24-26 N:22 WEEK 28-30 N:23 WEEK 32-34 N:22 WEEK 36-38 N:22 WEEK 40-42 N:22 Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Mean / Percentage Pulsatile index Basal plate ( maternal) 0.63±0.12 0.50±0.20 0.50±0.33 0.52±0.43 0.54±0.52 0.58±0.61 0.67±0.76 1.11±2.28 Chorionic plate ( fetal) 0.75±0.20 1.29±0.60 1.23±0.84 1.10±0.42 0.83±0.76 1.06±0.76 0.96±0.89 0.92±0.46 Primary villi Part 1 ( upper part) - - 1.07±1.05 0.73±0.36 1.31±2.49 0.80±0.55 1.01±0.75 0.66±0.34 Part 2 ( middle part) 0.89±0.70 1.33±0.77 1.09±1.37 0.86±0.85 0.88±0.44 0.77±0.56 0.80±0.55 1.03±0.82 Part 3 ( lower part) - - 1.20±1.46 1.07±1.00 1.14±0.74 1.04±0.67 1.21±1.52 1.65±1.77 Secondary villi Part 1 ( upper part) - - 0.99±0.57 0.90±0.82 1.43±1.73 1.56±2.45 0.92±0.74 1.52±1.61 Part 2 ( middle part) - - 1.12±1.99 1.44±1.66 1.10±0.82 1.23±2.39 1.35±1.70 1.56±1.19 Part 3 ( lower part) - - 1.19±1.94 0.96±0.96 1.04±1.03 1.47±1.14 1.11±1.17 1.46±1.52 Tertiary villi Part 1 ( upper part) - - 1.43±1.08 1.25±1.27 1.79±1.54 2.41±4.40 1.34±1.92 3.79±3.32 Part 2 ( middle part) - - 1.41±1.48 1.59±2.01 1.81±2.16 1.34±1.56 1.51±1.53 7.32±7.32 Part 3 ( lower part) - - 1.42±1.10 1.68±1.38 1.27±1.22 1.42±1.61 3.14±4.73 1.71±1.59 Peak systolic velocity + Basal plate ( maternal) 31.17±18.84 37.01±10.21 23.95±12.57 20.43±9.14 30.27±23.91 21.07±12.57 20.62±12.35 22.41±16.15 Chorionic plate ( fetal) 11.76±3.48 9.70±2.05 11.87±3.69 13.67±2.69 15.80±5.05 20.23±27.68 14.73±5.60 14.59±8.18 Primary villi Part 1 ( upper part) - - 10.07±2.83 14.31±8.15 15.73±6.45 14.39±5.18 13.78±5.01 14.81±2.55 Part 2 ( middle part) 11.23±3.50 10.84±2.31 10.17±4.45 12.59±4.07 15.21±7.64 13.46±3.60 14.48±4.71 11.40±2.66 Part 3 ( lower part) - - 9.33±2.95 13.06±3.04 14.24±8.84 14.06±4.88 14.52±5.07 22.67±21.41 Secondary villi Part 1 ( upper part) - - 9.23±3.34 9.14±2.57 13.19±6.50 9.88±3.20 11.79±4.49 13.55±7.14 Part 2 ( middle part) - - 8.95±3.68 10.48±5.11 10.35±2.93 9.46±3.89 11.77±4.25 28.48±31.86 Part 3 ( lower part) - - 8.60±3.28 9.71±3.40 11.48±4.53 11.08±3.09 11.37±3.13 11.03±1.90 Tertiary villi Table Click here to download Table: Table1.2.docx Note: * Expressed as a percentage of placentas with abundant development of secondary and tertiary villi. + Expressed in cm/seg peak systolic velocity value Part 1 ( upper part) - - 8.03±2.78 8.46±4.06 8.00±2.35 8.31±2.93 12.66±11.00 22.92±30.51 Part 2 ( middle part) - - 7.52±2.75 8.43±3.93 9.03±5.50 9.18±4.10 13.51±15.17 42.48±64.76 Part 3 ( lower part) - - 7.66±2.47 7.77±2.85 9.16±4.00 8.72±3.13 8.64±2.91 9.92±5.15 SEMANA 36-38 SEMANA 40-42 Video Still Click here to download Video Still: smiplacenta.mp4