Fetal Cardiac Volume Derived from Cardiac Spatiotemporal Image Correlation (Cardio-STIC) in predicting Fetal Hemoglobin (Hb) Bart’s Disease among pregnancies at risk

Abstract

Background and Rationale: Based on literature review regarding fetal response to anemia using fetal hemoglobin (Hb) Bart's disease as a study model, several cardio- vascular changes in early phase of fetal anemia can be detected, probably leading to early detection of the disease. In response to fetal anemia, the fetus initially develops hypervolemia as well as an increase in cardiac output, resulting in increased cardiac size, together with an increase in blood velocity of fetal blood circulation because of low blood viscosity caused by anemia. Several cardiovascular changes caused by fetal anemia are clinically useful in early detection of the disease. Of them, an increase in fetal cardiac size is the earliest change in response to fetal anemia and evaluation of cardiac size represented by cardio-thoracic diameter ratio (CTR) gives the highest sensitivity and specificity in predicting the affected fetuses, followed by assessment of middle cerebral artery- peak systolic velocity (MCA- PSV) . Nevertheless, cardiac size may be, theoretically, best evaluated by cardiac volume (CV) measurement rather than CTR since it is derived from all dimensions of the heart, not only a single one. Therefore, we hypothesize that fetal CV measurement is most effective ultrasound markers in predicting the affected fetuses. To date, there has been no study on the effectiveness of CV measurement on such a purpose before. Probably, this gap of knowledge is due to the fact that, technically, reliable measurement of CV with 2D-ultrasound is much more difficult than measurement of CTR. Nevertheless, with advance in 4D-ultrasound technology with cardio-STIC (spatiotemporal imaging correlation), we are able to acquire volume datasets (VDS), containing fetal virtual heart, within short time and the VDS are readily off-line analyzed and measured for the CV, using the VOCAL (virtual organ computer-aided analysis) technique with the software 4D-View. Thus, we conducted this study to assess the effectiveness of CV measurement in predicting fetal Hb Bart's disease, using 4D- ultrasound with VOCAL technique. Nevertheless, since there has been no reference ranges of fetal CV derived from VOCAL technique available for use in evaluation of its effectiveness. Therefore, in the first part of this project we constructed the normal reference ranges of CV for each gestational week, derived from normal fetuses of the low-risk pregnancies, to base the analysis in the second part, in which effectiveness of CV was evaluated. Objectives: 1) To develop the normal reference ranges of fetal cardiac volume based on cardio- STIC using VOCAL technique for each gestational week; 2) To assess the performance of fetal cardiac volume derived from cardio-STIC in predicting the affected fetuses among pregnancies at risk of fetal Hb Bart' disease and 3) To compare the performance of fetal cardiac volume in differentiating the affected and unaffected fetuses among fetuses at risk of Hb Bart's disease with other conventional methods including cardio-thoracic diameter ratio (CTR) and middle cerebral artery - peak systolic velocity (MCA-PSV). Methods: Part 1 (construction of reference intervals of fetal cardiac volume between 14 and 40 weeks of gestation): Low risk singleton pregnancies with normal fetuses were prospectively recruited to acquire 4D-cardio-STIC volume datasets (VDS). Subsequent off-line analyses of VDS were anonymously performed to calculate CV using the VOCAL (Virtual Organ Computer-aided Analysis) technique. The reference intervals were established as a function of gestational age (GA), biparietal diameter (BPD) and head circumference (HC), based on the best-fitted models for both mean and standard deviation (SD). Part 2 (performance of fetal CV in predicting Hb Bart's disease): Fetuses at risk of Hb Bart's disease between 18 and 22 weeks of gestation prospectively underwent echocardiography with acquisition of the volume datasets (VDS) of fetal heart, using 4D-cardiac STIC. Subsequently, off-line analysis was blindly performed to measure cardiac volume using VOCAL technique. Results: Part 1: A total of 668 VDS were successfully calculated for CV. The best-fitted models for the means and SDs are as follow: 1) GA in week = 6.422 + e(-100.653 xGA) (SD=0.641-(0.170xGA)+(0.009xGA2)). 2) BPD=0.016x(BPD)3.589 (SD= 2.663- (1.410xBPD)+(0.224x BPD2)).3) HC = 0.00017x(HC)3.537 ( SD= 2.341(0.341xHC)+(0.015xHC2) ) . The CV progressively increased with advancing fetal age (GA) and size (BPD, HC). Part 2: A total of 502 fetuses at risk meeting the inclusion criteria were included in the analysis, consisting of 117 (23.3%) fetuses with Hb Bart's disease and 385 (76.7%) unaffected fetuses. The mean (± SD) gestational age at the time of ultrasound examination was 19.70+ 1.3 weeks. In predicting fetal Hb Bart's disease, CV, using a cut-off Z-score of 1.7, had a sensitivity of 94.9% and specificity of 94.0%. The performance of CV was slightly better than that of CTR but very superior to that of MCA-PSV (areas under curve: 0.988, 0.974 and 0.862, respectively). Conclusion: Based on the findings of this study, the reference intervals of CV, theoretically best representing cardiac size, in relation to GA, BPD and HC were first established and Z-score was readily calculated. The fetal cardiac volume has a very high performance in predicting fetal Hb Bart's disease in mid-pregnancy comparable with and CTR and much better than MCA-PSV