Congenital heart disease (CHD) occurs in one to two newborns per 100 live births and is an important cause of perinatal morbidity and mortality(1–4). Prenatal screening and diagnosis of anatomical and functional heart malformations are possible by ultrasonography and fetal echocardiography, allowing for planning of delivery and, in some cases, prenatal therapy, favoring the postnatal prognosis of CHD(5–7).
Cardiac function is routinely evaluated in fetuses with anatomical malformations. In recent years, functional echocardiography has been used to study fetuses with a structurally normal heart but who are susceptible to hemodynamic changes due to the presence of extra-cardiac conditions, including, among others, fetal growth restriction, tumors/masses, twin-to-twin transfusion syndrome, fetal anemia (Rh alloimmunization), congenital infections, or maternal diseases such as diabetes mellitus, systemic arterial hypertension, and Graves’ disease(8–11).
The assessment of cardiac function provides critical information on hemodynamic status and the cardiovascular adaptation of the fetus and can help optimize the best time for delivery and reduce perinatal morbidity and mortality. Various myocardial parameters can be analyzed in combination considering specific applications for different diseases.
The systolic function of the fetal heart can be evaluated by measuring the ejection fraction (EF), shortening fraction (SF), cardiac output (CO), cardiac volume (CV), maximal displacement of the valve ring (tricuspid or mitral), myocardial performance index (MPI), and myocardial strain parameters(8 –13). Cardiac function, including SF, CO, and CV, can be analyzed by one-dimensional (M-mode), 2D, and 3D/4D ultrasound. The measurement of ventricular volumes during diastole and systole by 3D/4D ultrasound combined with virtual organ computer-aided analysis (VOCAL) allows calculating the EF and CO of each ventricle (left ventricle and right ventricle) and both (combined CO)(14,15).
The objective of this study is to review the published studies that assessed systolic function using 3D ultrasound combined with spatio-temporal image correlation (4D-STIC) and VOCAL.
Many techniques are available to evaluate cardiac function in fetuses, including Doppler blood flow, measurement of the heart chambers (cardiac biometrics) and of each interval of the cardiac cycle, CV by 3D/4D ultrasound, or the combination of several parameters. Therefore, MPI, stroke volume (SV), CO, SF, and EF may be used to assess systolic function.
MPI is a quantitative, non-invasive method used for the assessment of systolic and diastolic cardiac function. It is calculated for each ventricle using spectral Doppler and the following formula: isovolumetric contraction time (ICT) + isovolumetric relaxation time (IRT)/ejection time (ET) (Fig. 1). Myocardial dysfunction may lead to prolonged isovolumetric intervals and decreased ET, resulting in increased MPI. MPI values higher than 0.52 were highly sensitive and specific to predict adverse events during pregnancy and the neonatal period(16–19).
The atrioventricular annular movement determined using the M-mode ultrasound/echocardiogram (mitral annular plane systolic excursion [MAPSE] and tricuspid annular plane systolic excursion [TAPSE]) is easy to obtain and has a good correlation with tissue Doppler measurements for evaluating the longitudinal systolic function of the fetal myocardium(20) (Fig. 2 A, B, and C). Moreover, TAPSE can be determined in the 4D-STIC M-mode with good reproducibility, and reference curves for TAPSE by gestational age (GA) have been validated(20–21).
In recent years, the advancements of tissue Doppler with speckle tracking enable the accuracy of the measurements of myocardial strain indexes (strain and strain rate), which are important for assessing left ventricle (LV) function (Fig. 3). Despite the high potential of 2D speckle tracking, its applicability in fetal cardiac analysis needs to be validated(10–13).
SV can be calculated for each ventricle in the 2D mode, multiplying the valve area of the outflow tract by the mean velocity-time integral (VTI) of the ventricular outflow: SV = ϖr2 × VTI (Fig. 4). SV can be determined by 3D/4D ultrasonography using the following formula: end-diastolic volume (EDV) – end-systolic volume (ESV) (Fig. 5). The combined CO can be calculated by multiplying the sum of the SV of the two ventricles by the heart rate (bpm) (CO = RV SV + LV SV × HR). Similarly to the SV, the CO can be calculated for each ventricle and also increases with GA. The SVs of the LV and right ventricle (RV) are positively correlated with GA, and after 24 weeks of gestation, the RV CO predominates over the LV CO. Several z-scores and percentile curves were developed for CO as a function of GA using 2D ultrasound(22–26). CO values below the 5th percentile or below –2.0 are considered low, and CO values above the 95th percentile or above +2.0 are considered high in reference curves by GA. The CO of the fetus may increase in cases of arteriovenous malformations of the central nervous system (Galen’s aneurysm), teratomas, and twin-to-twin transfusion syndrome, or decrease in cases of low cardiac contractility, including myocarditis and fetal cardiomyopathy(8,9,26).
The EF reflects the percentage of blood ejected from the ventricles and can be calculated in each ventricle by 3D ultrasound with 4D-STIC using the following formula: EDV–ESV/EDV. EDV and ESV can be measured by 3D ultrasound using 4D-STIC with VOCAL (Fig. 5). SF is an index that evaluates reduction of ventricular diameter from end-diastole to end-systole. Using the M-mode with 2D and 3D ultrasound (4D-STIC M-mode), the maximum and minimum diameters of each ventricle can be measured in the four-chamber plane. SF can be calculated separately for each ventricle using the following formula: maximal or end-diastolic diameter (EDD) – minimum or end-systolic diameter (ESD)/EDD. SF below 28% on M-mode and EF below 63% on 3D/4D mode without changes by GA are considered altered(27–29).
Since 2003, with the advent of the 4D-STIC software, it is possible to evaluate the fetal heart in multiplanar, and rendering modes. This technology, initially described by De Vore
The quantification of ventricular volumes during diastole and systole by 4D-STIC and VOCAL enables calculating the ESV, CO, and EF, combined or not with other modalities, including the inversion mode, Color Doppler, and power Doppler(14,15). The 4D-STIC M-mode also allows measuring the EF and SF of the ventricles by determining their end-diastolic and end-systolic diameters, and its effectiveness in fetuses with hydrops has also been demonstrated(22).
For this review, a search strategy was carried out at the PubMed database to identify articles published in English between 2004 and 2019. The objective of this approach was to identify relevant studies on the functional assessment of a human fetal heart by 3D ultrasonography and 4D-STIC and VOCAL. The following MESH terms were used: “fetal heart,” “cardiac volumes,” and “virtual organ computer-aided analysis.” A total of 18 articles were found. Only studies that performed functional analyses of the normal fetal heart by 3D ultrasound using 4D-STIC and VOCAL were included in the review. The titles and abstracts of these articles were obtained. Four of the 18 studies were excluded for the following reasons: use of VOCAL in hypoplastic left heart syndrome (one study), use of VOCAL for measuring thymus volume (one study), and use of 4D-STIC without VOCAL (two studies). Three other articles were added after analyzing the selected articles and their references. Consequently, 17 articles were analyzed (Tab. 1).
Author | Total number of cases | Gestational age (weeks) | Conclusion |
---|---|---|---|
Bhat |
90 (in vitro) | 15–37 | There was a positive correlation between ventricular mass and gestational age. |
Rizzo |
56 (16 with intrauterine growth restrictions and 40 controls) | 20–34 | There was good agreement between the measurements of the ventricular cardiac volumes using 4D-STIC with VOCAL and 2D- ultrasound with Doppler. |
Messing B |
100 | 20–40 | It was demonstrated that 4D-STIC was simple, highly reproducible, and could be used for assessing fetal cardiac function. Nomograms for ventricular volume, stroke volume, and ejection fraction were established by gestational age. The ratio between RV and LV volumes was 1.4. The stroke volume ranged from 0.78 to 5.50 cm3, and the ejection fraction ranged from 42.5% to 86.0%. |
Molina |
140 | 12–34 | There was a positive correlation of stroke volume and CO of both ventricles with gestational age. |
Hamill |
44 | 19–40 | VOCAL had good reproducibility for measuring cardiac volumes. |
Uittenbogaard |
76 ( |
4D-STIC was shown to be a viable and accurate method for calculating volumes from 0.30 mL. In vitro, 4D-STIC combined with the 3D slice method was more accurate, less time-consuming, and more reliable than VOCAL. | |
Rizzo |
45 (15 with congenital heart disease and 30 healthy controls) | 19–32 | The authors compared ventricular volumes obtained by 4D-STIC with VOCAL and with sonography-based automated volume count (SonoAVC). The time necessary to measure volumes using SonoAVC was significantly shorter than that of the two other methods. However, SonoAVC and VOCAL results were similar. One limitation of the study was the small sample size. |
Simioni |
265 | 20–34 | Reference curves were constructed for stroke volume, CO, and ejection faction according to GA. Stroke volume and CO were positively correlated with GA. |
Hamill |
184 | 19–42 | RV diastolic and systolic volumes were larger than LV volumes. LV ejection fraction was larger than RV ejection fraction. Stroke volume and CO increased with GA, without significant differences between the LV and RV. |
Schoonderwald |
30 (84 acquired volumes – 54 excluded volumes) | 20–34 | Cardiac volume, stroke volume, and ejection fraction were compared using Simpson’s and VOCAL methods, and both methods were highly reproducible. The small sample size was considered a limitation to use 4D-STIC in clinical practice. *Strict criteria were adopted to include high-quality images of cardiac volumes. |
Simioni |
216 (108 fetuses of each sex) | 20–24 | There were no significant sex differences in CO and ejection fraction. |
DeKoninck |
15 | 16, 24, and 24 | There was good reproducibility of 3D ultrasonography with 4D-STIC for measuring CO when compared to 2D- Doppler ultrasonography. 4D-STIC combined with SonoAVC and the inversion mode showed higher intra- and interobserver reproducibility than 4D-STIC combined with VOCAL. |
Hamill |
34 | 20–36 | There was an inverse correlation between ventricular CO and vascular resistance of the umbilical artery using 4D-STIC and VOCAL. |
Rolo |
200 | 18–33 | 4D-STIC with VOCAL was highly reproducible and was used to calculate the volumes of the IVS by GA. |
Barros |
371 | 20–33 | 4D-STIC and VOCAL was highly reproducible and was used to construct reference curves for the volumes of the ventricular walls of the fetal heart by GA. |
Araujo Júnior |
170 | 20–33 | 4D-STIC and VOCAL was used to construct reference curves for atrial wall volumes of the fetal heart. |
CHD – congenital heart disease; EF – ejection fraction; SV – stroke volume; RV – right ventricle; LV – left ventricle; CO – cardiac output; IVS – interventricular septum; GA – gestational age.
Although 4D-STIC was initially used
Rizzo
Hamill
Uittenbogaard
Rizzo
Messing
Schoonderwaldt
Simioni
DeKoninck
Hamill
Rolo
Araujo Júnior
Since 2004, several studies demonstrated a positive correlation of ventricular and atrial volumes with GA using 4D-STIC and VOCAL. Similarly, the CO calculated using these methods showed a positive correlation with GA, and RV volumes were larger than LV volumes. The retrieved studies demonstrated that 4D-STIC and VOCAL had good reproducibility to measure cardiac volumes and developed reference curves for this parameter by GA. Therefore, 4D-STIC and VOCAL are crucial for evaluating cardiac function parameters, including end-systolic volume, CO, and EF.