| BackgroundPlacenta is a vital organ that supports fetal development during pregnancy.It plays a critical role in determining pregnancy outcomes,and placental dysfunction is known to be associated with adverse pregnancy outcomes,such as stillbirth,fetal growth restriction,preterm birth,and preeclampsia?Mostly used clinical methods of prenatal placental function evaluation are ultrasonic umbilical and uterine artery blood flow measurement.Systolic/diastolic flow velocity(S/D)ratio,pulsatility index(PI)and resistance index(RI)are important parameters reflecting placental blood flow,which are often used as reference indexes for various placental blood flow evaluation methods.In normal pregnancy,the RI,PI and S/D values of umbilical blood flow change gradually with gestational weeks and the increase of placental perfusion.However,ultrasound may be affected by various factors.At the same time,it might only indirectly reflect the microcirculation perfusion of placenta.In utero MRI has been an important diagnostic tool to noninvasively assess the placental structure and function.Particularly,the IVIM technique reveals unique information about microcirculatory blood flow in the capillary and small vessels without injecting contrast agent,and provides quantitative assessments of the placenta,such as the fraction(f)and diffusivity(D*)of the microcirculation,as well as the tissue diffusivity(D).Studies showed that the placental f value increased with gestational week and was negatively correlated with the ultrasonic umbilical blood flow index,suggesting that IVIM has potential in the quantitative evaluation of placental microcirculation perfusion.Another study on fetal intrauterine growth restriction(FGR)placenta by prenatal ultrasound reported that the IVIM f value in the late-onset FGR group was significantly lower than that in the normal late pregnancy group,suggesting that the f value may have a certain predictive value for late-onset FGR.Placental microcirculation is composed of various types of blood flow in capillaries,small blood vessels,blood pools and tissue spaces,and disorderly diffusion blood flow.The gradient used in the classical IVIM model is non flow compensation(NC),which approximates the microcirculatory blood flow as a faster diffusion motion(Brownian motion),thus is often named pseudo diffusion blood flow.However,real microcirculatory components include not only pseudo diffusion blood flow,but also ballistic flow with a fixed direction in small blood vessels.Therefore,the classic NC IVIM could not separately evaluate the ballistic blood flow components of villous vessels.Flow compensation(FC)IVIM is not sensitive to ballistic blood flow.The combination of FC and NC IVIM may separate the ballistic blood flow components in the microcirculatory blood flow to further explore the mechanism of placental microcirculation.Recently,several researchers applied the combination of FC and NC IVIM in brain and liver to provide additional microcirculation information,but no systematic research on human placenta is reported.Placental microcirculation lacks clinically easy-to-use direct evaluation methods.Placental tissue is difficult to obtain for histopathological research from pregnant women during pregnancy,and most diseases during pregnancy are not suitable for invasive or interventional diagnostic methods.Therefore,researchers use ultrasound uterine artery or umbilical artery blood flow index to indirectly reflect the placental circulation function.Change of ultrasonic blood flow index is associated with pathological changes of placental microcirculation.For example,the RI,PI and S/D values of uterine artery or umbilical artery in eclampsia group are higher than those in normal control group and are positively correlated with the expression of adiponectin mRNA.This suggested that the vascular endothelial function in preeclampsia is damaged,resulting in placental villous arteriole lesions and a significant perfusion decrease in villous capillary area.Several previous studies on the evaluation of placental IVIM microcirculation chose ultrasonic blood flow index as the reference of placenta blood flow.It was reported that in normal and SGA population,the f value of placenta was negatively correlated with ultrasonic blood flow index.In this study,we jointly used the FC and NC IVIM to specifically probe the fraction and velocity of ballistic flow(vb)in the placenta.Here,we investigate the two types of velocity measurements in the placenta to provide further information of placental microcirculation.Section I:Probing the ballistic flow in normal placenta using flow-compensated and non-compensated diffusion MRI:a preliminary studyPurposeIntravoxel incoherent motion(IVIM)has shown to be a useful tool in assessing the microcirculatory flow in the brain and body organs,including the placenta.Conventional IVIM uses monopolar or double-refocused diffusion sensitization gradients,which are non-flow-compensated,and thus,the measured IVIM effect includes both the pseudo-diffusive microcirculatory flow and the bulk blood flow(or ballistic flow).In this study,we propose a joint use of flow-compensated(FC)and nonFC diffusion gradient waveforms to specifically probe the fraction and velocity of the ballistic flow,assuming diffusive flow is negligible at a relatively short diffusion time.Methods1.PatientsForty-three pregnant women(22.57 to 38 weeks of gestation)were recruited in this study.Inclusion criteria:Pregnant women who underwent prenatal examination in our hospital during the study.GA between 16-40 weeks.Single pregnancy.Patients who had indications and willingness to conduct fetal MR examination.No maternal complications or systemic diseases.No obvious placental structural abnormalities in routine prenatal examination.Down's screening,noninvasive DNA or amniocentesis did not suggest fetal chromosome abnormalities.Exclusion criteria:Fetal MR examination could not be completed for any reason.Patients who fail to give birth in our hospital.Abnormal fetal or placental structure found at any time during pregnancy.Fetal abnormalities found at delivery or within 42 days follow-up postpartum.Abnormal placental histopathological findings.2.Ultrasonic umbilical blood flow measurementUltrasound umbilical artery blood flow was measured within 21 days before or after MRI scanning.PI and SD were used as umbilical artery impedance indexes.Obtain the spectrum parameters within 2cm from the umbilical cord insertion point,the sampling volume is 2mm.The angle between the pulse sampling line and the direction of the blood vessel is less than 30°,the smaller the better.The pulse spectrum diagram of sampling points must have more than 5 continuous complete,clear,and consistent standard spectra.3.Pulse sequence and joint modelingThe FC and NC diffusion encodings were achieved using bipolar diffusion gradients with identical(FC)or mirrored(NC)polarity before and after the 180°refocusing pulse such that the first-order moment of the FC gradient becomes zero.We used a gradient duration of 15 ms(effective diffusion time=15 ms).The diffusion signals that take into account the ballistic flow and the tissue water can be represented as:S/S0=(1-f)e-bDt+fe-bDbe-?2vb2,where Dt and Db are the diffusive coefficients of the water molecules in the tissue and the blood with Db set to be 1.5 ?m2/ms,and a is the first-order moment of the gradient for flow-sensitization.In the FC sequence,?=0,and therefore,by the joint analysis of FC and NC signals,both f and vb can be resolved.4.IVIM experimentPatients were scanned on a 1.5T Siemens Aera system.IVIM scans with FC and NC gradients were performed at 9 b-values from 10 to 600 s/mm2,6 directions,FOV of 350×350mm,2.73×2.73mm in-plane resolution,10 slices with 6mm slice thickness,and scan time of 2.5 min.5.Data postprocessIVIM data are motion corrected by iterative registration,and then the FC and NC signals are jointly analyzed using MATLAB(MathWorks,Inc.,Natick,MA)to obtain the joint models f and vb.Conventional IVIM parameters(f,D,and D*)were also fitted,separately with the FC and NC data.We manually delineated the regions of interests(ROIs)for the whole placenta covering all imaging slices,as well as separate maternal and fetal side ROIs.6.Statistical AnalysisQuantitative data are expressed as meanąstandard deviation.IVIM metrics including vb from the joint model were correlated with the PI,SD,and gestational age(GA)from the umbilical Doppler ultrasound using Spearman correlation.Metrics in the maternal and fetal sides of the placenta were compared using paired t-test.p<0.05 was set to be significant.Results1.The use of FC and NC sequences led to different IVIM signal decay patterns in the placenta.The discrepancy between the FC and NC based signal curves,which resulted from the ballistic flow,varied across the placentas.The placenta with high umbilical flow showed high flow effect according to the signal curves and high vb from the joint model,while the one with low umbilical flow showed the low flow effect and low vb.2.The indexes of FC IVIM sequence were significantly lower than those of NC sequence(p<0.001).3.An age dependency was observed in vb,fD*and D*values from FC data.Negative correlations were found between GA with the vb.While FC D*and fD*values showed significant positive correlations with GA(p<0.001).4.Positive correlations were found between the ultrasound-based flow measurements with the vb.While D*and fD*values from both FC/NC showed significant negative correlations with PI and SD.5.Ballistic velocity vb from both maternal and fetal side of placenta was found significantly correlated with gestational age,as well as the D*and fD*values of both sides from FC sequences.There was a significant positive correlation between vb and SD/PI in both maternal and fetal sides.The FC D*,JD*and NC D*values of both sides of placenta were negatively correlated with gestational age.The FC f value and NC fD*value were only correlated with umbilical blood flow index on the maternal side.ConclusionWith a joint use of the FC and NC diffusion sequences,we were able to probe the velocity of the ballistic IVIM component in the placenta,which demonstrated a strong correlation with umbilical flow and moderate correlation with gestational age.The joint approach provides a potential way to noninvasively examine flow velocity in the placental villi for assessment of pregnancy complications.Section ?:Detecting placental microvascular abnormality in FGR and GDM based on flow-compensated and non-compensated intravoxel incoherent motion imagingPurposeThe data obtained from traditional IVIM based on non-flow-compensation sequence could not separate pseudo diffusion blood flow and ballistic blood.In the first part of the study,the new FC/NC IVIM joint model is used to separate the two blood flows mentioned above,and the correlation between the separated ballistic blood flow velocity and umbilical blood flow and gestational weeks is demonstrated.Here we tried to further estimate the fraction and velocity of ballistic microcirculatory flow using a joint analysis of FC/NC IVIM in FGR and GDM placenta,to evaluate the diagnostic value of the new markers detect maternal and fetal disorders associated with the placenta.Methods1.PatientsInclusion criteria:Pregnant women who underwent prenatal examination in our hospital during the study.GA between 16-40 weeks.Single pregnancy.Patients who had indications and willingness to conduct fetal MR examination.Exclusion criteria:Fetal MR examination could not be completed for any reason.Patients who fail to give birth in our hospital.FGR and GDM were diagnosed according to the current clinical guidelines and standards.Fetal malformations found during prenatal examination and postpartum(excluding simple SGA)were excluded to reduce heterogeneity of study population.2.Data AcquisitionAll MRI data were acquired on a 1.5T Siemens Aera scanner with an 18-channel body coil.We used the house-made diffusion sequence with the FC and NC gradients with the parameters mentioned in Section I.T2*mapping parameters were as follows:TR=900 ms,TE=4.76/9.53/14.29/19.06/23.82/37.87/51.92 ms,FA=30°,FOV=350 ×350mm2,slice thickness=5 mm,15 slices.The acquisition time was 2.5 mins.3.Data analysisThe same as Section I.4.Statistical analysisIVIM parameters and T2*value was compared between GDM and control,as well as FGR and control using independent sample t-test.A linear correlation was used to analyze the relationship between the parameters of GDM,FGR and controls,and the FGR classification accuracy of each IVIM marker and T2*value were evaluated.The significance levels were set to be*p<0.05.Results1.There was no significant difference in maternal age or gestational age between the two abnormal groups and the normal control group.The birth weight of FGR group was significantly lower than that of normal group(2804.82gą525.30g vs.3301.94gą576.43g,p<0.05).2.The statistical results of IVIM parameters in the normal group were similar to those in the first part of this study.In FGR group,there was a positive correlation between vb and gestational age,which was opposite to that in control group(p<0.05).A negative correlation was found between T2*value and gestational age in all three groups.3.The vb value of GDM and FGR patients was significantly lower than that of the control group(p<0.05).In addition,the T2*value of FGR group was significantly lower than that of normal group(p=0.0013).No significant difference between GDM group and normal group(p=0.125).4.Divide placenta to maternal and fetal side.In both GDM and FGR group,the vb of fetal and maternal placentas was significantly lower than that of control group(p<0.05).The result was similar to that of whole placenta.However,the FGR T2*value was significantly lower than that of the control group only in the fetal side of placenta(p<0.05).5.The AUC of T2*and vb were 0.665 and 0.660,respectively.The sensitivity of vb(91.67%)was slightly higher than that of T2*(87.50%),but the specificity of both parameters was not ideal(41.94%).6.In the normal control group,the vb value of combined model was positively correlated with BW(p<0.05),and negatively correlated with D*value of NC sequence(p<0.01).In FGR group,only the D*value of NC sequence was negatively correlated with birth weight(p<0.01).There was no significant correlation between fetal birth weight and MRI parameters in GDM group.ConclusionBallistic velocity vb from the new joint FC/NC IVIM model showed superior performance in the diagnosis of GDM and FGR as well as T2*mapping,indicating the potential of the joint FC/NC IVIM method to evaluate placenta function.Besides,the unique changing patterns of MRI indexes in different pathology groups may provide clues to explore the placental microcirculation of pregnancy complications in vivo. |
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