Development Of Multiparametric Echocardiography Model For Prenatal Diagnosis Of Pulmonary Valvular Stenosis And Risk Prediction Of Early Intervention After Birth

Part 1:Quantitative Assessment of Myocardial Deformation in Fetuses with Pulmonary Valvular Stenosis Using Two-dimensional Speckle-Tracking Echocardiography[Objective]Pulmonary valvular stenosis（PVS）is one of the most common congenital heart diseases,and there are few studies on myocardial deformation in fetuses with PVS.The study aimed to evaluate the changes in cardiac morphology and function in PVS fetuses by conventional echocardiography and two-dimensional speckle-tracking echocardiography（2D-STE）.[Methods]Fifty-two fetuses suspected with PVS by echocardiography and confirmed by postnatal echocardiography in our center were enrolled in the case group from January2014 to December 2021 retrospectively.Fifty-two GA-matched normal fetuses were enrolled into the control group.Clinical data of the fetuses and pregnant women were collected,and detailed fetal echocardiography was performed according to the guidelines of ISUOG.Obtained the conventional ultrasound parameters of the fetal heart and standard cardiac four-chamber view images were obtained for off-line analysis.The morphological and hemodynamic changes of the fetal heart were analyzed by conventional echocardiography,including the size of the atriums and the ventricles,inner diameter of the ascending aorta and pulmonary artery,the spherical index of the ventricles,the velocity ratio of the pulmonary valve and aortic valve(V_PV/AV),and the ejection fraction of left ventricle（LV EF）,the fractional area change of right ventricle（RV FAC）.2D-STE was used to obtain the atrial and ventricular myocardial deformation parameters,including the biventricular global longitudinal strain（GLS）and the global longitudinal strain rate in systole（SRs）.The strain and strain rate of three phases in one cardiac cycle of left and right atrium,namely reservoir strain（Sr）,conduit strain（Scd）,contraction strain（Sct）,and contraction strain and reservoir strain ratio（Sct/Sr）were also obtained.The differences of the above parameters between PVS fetuses and normal fetuses were assessed.[Results]（1）Conventional ultrasound parameters:Compared with controls,PV Z-score and RV GSI in the PVS group were decreased（P<0.05）,while V_PV/AVwas increased（P<0.001）.And PVS fetuses had lower RA FAC（35.6±9.2%vs.43.1±3.6%,P<0.001）,and normal LV EF（57.2±9.0%vs.59.5±4.0%,P=0.09）.（2）Myocardial deformation parameters:（1）Ventricular myocardial deformation:Compared with controls,the PVS group had significantly lower LV GLS（-21.68±3.80%vs.-25.88±2.63%,P<0.001）and LV GLSRs（-1.93±0.88s-1 vs.-2.56±0.63s-1,P<0.001）,RVGLS（-20.34±3.65%vs.-27.41±3.01%,P<0.001）,RV GLSRs(-1.96±0.85 s^-1 vs.-2.86±1.00 s^-1,P<0.001).（2）Atrial myocardial deformation:The LA deformation parameters of PVS fetuses include LA Sr（25.25±3.82%vs.33.06±6.19%,P<0.001）,LA Sct（13.79±2.83%vs.17.81±6.84）%,P<0.001),LA Scd（11.51±4.55%vs.17.27±7.00%,P<0.001）,LA SRr(1.96±0.76s^-1 vs.2.62±0.46s^-1,P<0.001),LASRct(-1.92±0.62s^-1 vs.-2.58±0.65s^-1,P<0.001),LA SRcd(-1.97±0.64s^-1 vs.-2.27±0.57s-¹,P=0.02)were significantly decreased when compared with normal fetuses,while the LA Sct/Sr was similar in two groups（0.56±0.13 vs.0.51±0.16,P=0.11）.The RA deformation parameters in PVS fetuses were also significantly decreased:RA Sr（25.20±6.12%vs.33.98±6.82%,P<0.001）,RA Sct（14.42±3.47%vs.19.18±5.86%,P<0.001）0.001),RA Scd（10.88±6.06%vs.18.16±8.34%,P<0.001）,RA SRr(2.19±0.82s^-1 vs.2.54±0.46s^-1,P=0.008),RA SRct(-2.28±0.61s^-1)vs.-2.56±0.49s^-1,P=0.019),RA SRcd(-2.19±0.64s^-1 vs.-2.43±0.45s^-1,P=0.048).The RA Sct/Sr was increased in PVS fetuses than in normal fetuses（0.60±0.22vs.0.48±0.15,P=0.003）.[Conclusions]The PV diameter was decreased while the V_PV/AV was increased in isolated PVS fetuses,and the shape of the right ventricle was slightly spherical.Biventricular myocardial deformation in PVS fetuses was decreased,and atrial function was also affected.The assessment of cardiac morphology and function has laid a foundation for prenatal diagnosis and prognostic prediction for PVS fetuses.Part 2: Development of a Diagnostic Model for Fetal Pulmonary Valvular Stenosis by Myocardial Strain Combined with Multiple Ultrasonic Parameters[Objective] Fetal pulmonary valvular stenosis（PVS）presents different echocardiographic features with the progression of gestational age and the degree of stenosis.Currently,there is no standard for prenatal diagnosis of PVS,some fetuses with mild PVS have no typical feature in the second trimester,so some PVS fetuses will not be detected or will be misdiagnosed.This study aimed to find the sensitive ultrasound indicators for predicting the risk of PVS fetuses after birth and to develop a diagnostic model to improve the accuracy of prenatal diagnosis of PVS combined with cardiac morphological,hemodynamic,and functional parameters.[Methods] There were 123 fetuses suspected isolated PVS who underwent prenatal echocardiography in our center enrolled in this study retrospectively from January 2014 to October 2021.According to postnatal echocardiography/postinduction autopsy,the fetuses were classified into two groups: true positive group（n=75）and false-positive group（n=48）.The clinical data of the fetuses and pregnant women were collected.All fetuses underwent systematic echocardiography according to the guidelines of ISUOG.The sonographic features were recorded,including the echocardiographic presence of the pulmonary valve,movement of the valve leaflet,tricuspid,and pulmonary regurgitation,etc.Conventional echocardiography obtained fetal cardiac morphology and hemodynamic parameters,including biventricular spherical index（GSI）,biventricular end-diastolic diameters（LVEDD,RVEDD）ratio,left and right atrial transverse diameter ratio（LA/RA）,pulmonary and aortic annulus（PV,AV）inner diameters ratio,main pulmonary artery（MPA）and ascending aorta（AAo）inner diameter ratio,left and right pulmonary arteries（LPA,RPA）and ductus arteriosus（DA）inner diameter,the velocity of pulmonary valve/aortic valve(V_PV/AV),etc.（the absolute values of the two-dimensional measurements above are calculated by Z-score according to the fetal GA）,and fractional area change of RV（RV FAC）.Standard four-chamber view images are stored for offline analysis,and 2D STE obtained right heart myocardial deformation parameters,including RA reservoir strain（RA Sr）,RV global longitudinal strain（RV GLS）.Univariate Logistic regression analysis was used to find the variables above and potential predictors with significant differences（P < 0.05）were analyzed by multivariate Logistic regression,then developed a diagnostic model and got the nomogram.Receiver operating characteristic（ROC）curve,calibration curve,and Hosmer-Lemeshow goodness-of-fit test were used to analyze the discrimination and calibration of the diagnostic model,respectively.The clinical applicability of the model was assessed by decision curve analysis（DCA）.[Results]（1）Among the 123 fetuses suspected with PVS by prenatal ultrasound,52 fetuses were confirmed by postnatal echocardiography,and 23 were confirmed by autopsy after induction of labor.A total of 75 cases were included in the true positive group（75/123,60.2%）,and the remaining 48 cases were confirmed by postnatal echocardiography and included in the false-positive group（48/123,39.0%）.（2）We found 12 predictors of the risk with postnatal PVS by univariate Logistic regression analysis,including pulmonary valve echo enhancement,restriction of pulmonary valvular movement,tricuspid regurgitation,RV GSI,LA/RA,PV Z-score,PV/AV,MPA/AAo,V_PV/AV,RA Sr,RV GLS and RV FAC.Multivariate logistic regression analysis was performed on the above 12 variables,and the results showed that V_PV/AV,PV Z-score,RV GSI,RA Sr,and RV GLS（OR: 7.25,0.53,0.01,0.78,0.83）.A nomogram was drawn according to the above variables.（3）The area under the ROC curve（AUC）of the diagnostic model was 0.93（95%CI: 0.89-0.97）.The Hosmer-Lemeshow goodness-of-fit test showed the diagnostic rate of the model had a good agreement with the actual diagnostic rate（P=0.49）.Decision curve analysis（DCA）showed that within the risk threshold range of 30%⁷0%,the model could achieve a high net benefit rate,indicating that the diagnostic model has good clinical predictive value.[Conclusions] This study developed a diagnostic model for fetuses with suspected PVS including 5 predictor variables(V_PV/AV,PV Z-score,RV GSI,RA Sr,RV GLS).The model has a good degree of discrimination and calibration,which can improve the accuracy of prenatal diagnosis of PVS and has potential clinical application value and prospects.Part 3 Assessment of Early Postnatal Intervention Risk for Fetuses with Pulmonary Valvular Stenosis[Objective] The route of perinatal management and postnatal intervention decisions for fetuses with pulmonary valvular stenosis（PVS）mainly depends on the degree of stenosis.It is also related to various factors such as fetal heart function and general conditions.How to use prenatal ultrasound parameters to predict the risk of early intervention after birth,can provide clinical recommendations for prenatal counseling and postnatal management,to improve fetal outcome and reduce mortality.Our study aimed to investigate the value of PVS fetal ultrasound parameters and myocardial deformation parameters in predicting the risk for early intervention after birth.[Methods] Fifty-two fetuses underwent prenatal echocardiography in our center,and confirmed PVS after birth by echocardiography,were enrolled in this study from January 2014 to December 2021.According to whether early intervention was performed after birth（within one year）,the fetuses were divided into early intervention group（n=20）and without early intervention group（n=32）.Collected the fetal and maternal clinical data,postnatal echocardiography results,fetal outcomes,operation time,operation methods and postoperative outcomes（all fetuses were followed up for more than one year after birth）.All fetuses enrolled in our study underwent systematic echocardiography according to the guidelines of ISUOG.Conventional echocardiographic parameters including: left and right ventricular spherical index（LV GSI,RV GSI）,left and right ventricular end-diastolic diameter（LVEDD,RVEDD）and ratio,left and right atrial diameter ratio（LA/RA）,pulmonary and aortic annulus（PV,AV）diameter and ratio,main pulmonary artery（MPA）and ascending aorta（AAo）diameter and ratio,diameter of left and right pulmonary artery（LPA,RPA）and ductus arteriosus（DA）,pulmonary valve velocity / aortic valve velocity(V_PV/AV),LV ejection fraction（LV EF）,and fractional area change of RV（RV FAC）（the absolute values of the two-dimensional measurements above are calculated by Z-score according to fetal GA）,pulmonary regurgitation,tricuspid regurgitation;2D-STE was used to obtain fetal myocardial deformation parameters,including left and right ventricular global longitudinal strain（LV GLS,RV GLS）,left and right atrial reservoir strain（LA Sr,RA Sr）.Univariate Logistic regression analysis was used to analyze the variables of the two groups above,and the predictors with significantly differences（P<0.05）were obtained.ROC curves of the independent predictors of early postnatal intervention risk were drawn and their predictive value were assessed by the area under the curve（AUC）.[Results]（1）Postnatal echocardiography confirmed 25（48.1%）,22（42.3%）and 5（9.6%）cases of mild,moderate and severe PVS in 52 fetuses,respectively.There were 27 cases（51.9%）had underwent surgical correction or percutaneous balloon pulmonary valvuloplasty,and the remaining 25 cases（48.1%）had not accepted surgery until the end of follow-up.Among the 27 cases who accepted operation,74.1%（20/27）accepted operation within one year after birth,and the other 7 cases（25.9%）received intervention at 1.5 to 2.5 years after birth.Only 3 cases died after the intervention,the others all survived,and no residual stenosis was found in cases who underwent surgery.（2）Univariate Logistic regression analysis showed that V_PV/AV（AUC=0.79,95%CI: 0.65-0.93,P<0.001）,RV GSI（AUC=0.74,95%CI: 0.59-0.88,P=0.005）,RV FAC（AUC=0.68,95%CI: 0.53-0.84,P=0.029）,RV GLS（AUC=0.70,95%CI: 0.55-0.86,P=0.014）can predict the risk of early postnatal intervention PVS fetuses.（3）Multivariate Logistic regression analysis showed that V_PV/AV（OR=13.79,95%CI: 3.06-62.15,P=0.001）,RV GLS（OR=0.72,95%CI: 0.56-0.93,P=0.012）were independent predictors for early postnatal intervention in PVS fetuses.The combined use of V_PV/AV and RV GLS has a higher predictive power for the risk of early intervention after birth than the above indicators.（AUC=0.86,95%CI: 0.75-0.97,P<0.001）.[Conclusions] V_PV/AV,RV GLS,RV FAC,and RV GSI can be used to predict the need for postnatal early intervention in PVS fetuses.The combined application of hemodynamics(V_PV/AV)and myocardial deformation parameters（RV GLS）can predict early intervention after birth more accurately,and provide clinical information for prenatal counseling,postnatal clinical pathway and treatment strategy.