Normal fetal echocardiography ratios - a multicenter cross-sectional retrospective study

Study population

A retrospective analysis included 23,313 healthy fetuses from three medical institutions: Beijing Anzhen Hospital, Fujian Maternity and Child Health Hospital, and Ningxia Women and Children’s Hospital, from August 2010 to March 2023. Each fetus contributed data once, with gestational ages ranging from 16 to 37 weeks (25.61±2.53 weeks), divided into 10 units of 0.1 weeks. Maternal ages ranged from 17 to 45 years (31.71±4.13 years), with all fetuses of Han Chinese ethnicity. Gestational age was determined by the last menstrual period and fetal biometric measurements.

Inclusion criteria comprised: [1]: singleton pregnancy; [2] mid to late gestation; [3] comprehensive and normal fetal echocardiogram; [4] absence of maternal high-risk factors; [5] absence of intrauterine or extrauterine fetal abnormalities; [6] absence of fetal arrhythmias. Exclusion criteria included: [1] multiple pregnancies; [2] early gestation; [3] maternal conditions such as hypertension, hyperthyroidism, diabetes, liver disease, or other potentially fetal-affecting illnesses; [4] fetal intrauterine or extrauterine abnormalities; [5] arrhythmias; [6] intrauterine growth restriction.

The study adhered to the principles of the Helsinki Declaration and was approved by the Ethics Committees of Beijing Anzhen Hospital and the participating institutions. Written informed consent from prospective parents was waived by the ethics committees.

Data acquisition

Fetal echocardiographic assessments were performed using the Voluson E8 and E10 systems, Aloka 10 system, and Philips iU22 system, following guidelines from the American Society of Echocardiography and the International Society of Ultrasound in Obstetrics and Gynecology [3], [6], [7], [8], [9], [10]. The images were acquired on the machines and exported on hard drives and sent to Beijing Anzhen Hospital for subsequent analysis. All imagery, measurements, and clinical data were archived. Each fetus underwent a systematic fetal echocardiographic examination, with measurements conducted solely on zoomed-in images.

Study variables

Eleven cardiac and hemodynamic ratios were established from literature and institutional expertise (Table 1). Measurements were performed by operators with at least 5 years of experience, recorded as the mean of three measurements, and images were sent to Beijing Anzhen Hospital for analysis.

Statistical analysis

Test of intra-observer and inter-observer variability

Fifty randomly selected studies were utilized to evaluate intra-observer and inter-observer variability. Inter-observer variability was evaluated by three observers performing fetal echocardiographic measurements without knowledge of other observers’ results. Three observers measured all parameters and repeated the measurements after 3–4 weeks. Intraclass correlation coefficients (ICC) were employed to determine consistency within and between observers.

Statistical analysis was conducted using Python and R software, version 4.3.2 (R Foundation for Statistical Computing). All statistical tests were two-tailed, with significance set at p<0.05. The flow chart of the overall research is shown in Figure 1.

Figure 1:

Flow chart.

Left and right heart system development

Our study further confirms that during 16–37 weeks of gestation, the fetal heart exhibits right heart dominance. The right ventricle accounts for approximately 2/3 of the total ventricular output [19], the average pressure in the right atrium is 1–2 mmHg higher than in the left atrium, and the right heart experiences a greater workload, with an increase in both the number and volume of myocardial cells. Morphologically, the right heart’s internal diameter has always been larger than that of the left heart. We found that the ratios RA/LA and RV/LV began to increase more rapidly from 21.7 weeks, continuing to accelerate until 25.5 and 27.3 weeks, respectively, after which the growth rate remained constant. This indicates that during this period, the fetal heart and overall development enter a phase of rapid growth [20], 21]. The pronounced right heart dominance observed is due to this rapid growth phase. In late gestation, the constant growth rate is attributed to the decreased pressure load, with reductions in placental, pulmonary, and cerebral vascular resistance. Among these, placental vascular resistance is the primary factor affecting right heart afterload. Therefore, in late gestation, the reduction in right heart afterload is more pronounced, leading to increased right heart output and maintaining right heart dominance, with the ratio of right to left heart gradually increasing at a constant rate as gestational age progresses [22], 23].

PA/AO ratio consistently >1 from 16 to 37 weeks of gestation also reflects right heart dominance but does not show a growth pattern consistent with cardiac chambers. After 26 weeks of gestation, the PA/AO ratio growth rate stabilizes, indicating consistent aortic diameter development post-26 weeks. Notably, Sahn et al. [24] suggest minimal influence of perinatal circulation changes on aortic diameter size, as the PA/AO ratio only slightly decreases from 1.18±0.01 in the fetal period to 1.14±0.02 within 36 h after birth.

Arterial duct development

During fetal development, DA plays a vital role by receiving 80 % of its blood supply from PA to maintain circulatory balance. Sutton et al. [25] found that while fetal blood flow velocity in the DA is similar to that in the PA from 18 to 22 weeks of gestation, it notably exceeds pulmonary artery flow velocity after 22 weeks. Our research confirms this, focusing on the velocity ratio between the DA and aortic arch. We observed a surpassing of systolic flow velocity in the DA compared to the aortic arch after 23.3 weeks of gestation, and from 30.9 weeks onward, the DA’s flow velocity exceeds that in the aortic arch. This ductal constriction likely results from increased fetal lung perfusion as pregnancy progresses, leading to enhanced prostaglandin degradation [26].

Ventricular diastolic function

Fetal ventricular myocardial stiffness exceeds that of neonates or adults, with atrial contraction primarily driving ventricular filling [27]. This is reflected in the consistently lower maximum rate of active filling (E wave) compared to passive filling (A wave), resulting in an E/A ratio of less than 1. MV-E/A and TV-E/A can reflect ventricular diastolic function. Previous studies have shown that when the mother has diabetes, the MV-E/A and TV-E/A of the fetus are lower than those of normal fetuses [28]. This suggests a reduction in ventricular diastolic function in these fetuses. The establishment of normal reference values for atrioventricular valve E/A ratios in a large sample of normal fetuses in this study will provide a foundational basis for such research.

Fetal ventricular stiffness decreases with gestational age [29], as shown by increasing MV-E/A and TV-E/A ratios, both peaking at 25.7 weeks. This indicates a progressive improvement in active ventricular filling, with the most rapid enhancement occurring around this time. Moreover, the increase in MV-E/A occurs faster than in TV-E/A, likely due to postnatal hemodynamic changes that demand greater active filling capacity in the left ventricle, setting the stage for left heart dominance after birth [30].

Other categories

CTAR revealed gradual growth from weeks 16–37 with stable velocity changes, indicating balanced fetal heart and overall fetus development. CTAR variations are indicators of fetal cardiac and extracardiac anomalies [31].

The extensive CPR literature is gaining attention for its value in predicting adverse outcomes related to the fetal-placental-cardiac axis [32]. Our findings align with Ebbing et al. [33], indicating a continuous increase in CPR values throughout pregnancy, signaling improved fetal cerebral blood supply. We noted the fastest CPR growth at 25.6 weeks, peaking at 34.7 weeks, and stabilizing thereafter, providing insights into cerebral blood flow in CHD-affected fetal brains. For example, fetuses with hypoplastic left heart syndrome may exhibit lower CPR values due to protective mechanisms in late gestation [34], [35], [36]. The rising evidence points to a higher risk of neurodevelopmental impairment in CHD fetuses, highlighting challenges in predicting neurological outcomes in modern CHD management, with CPR ratio studies offering a foundation. Fetal growth restriction can also impact fetal cardiac development by increasing placental circulatory resistance. Previous studies have shown that fetal cardiac remodeling occurs in a significant proportion of pregnancies complicated by late-onset fetal growth restriction [37], 38]. CPR, as an effective indicator, can help identify these fetuses, thereby improving management strategies.

Limitation

This study utilized a large multicenter sample, but data were mainly collected during mid-pregnancy, as fetal echocardiography is typically performed between weeks 20–26. Late pregnancy imaging is challenging due to increased fetal weight and amniotic fluid, leading to fewer data points after 37 weeks. This limitation may bias findings when extrapolating to the entire gestational period. Additionally, relying on the last menstrual period for gestational age limited the analysis to a single independent variable, neglecting potential relationships with other indicators like biparietal diameter and femur length. This study included many parameters beyond those recommended by guidelines, but it is still not comprehensive, such as the ventricular sphericity index, among others. The study included only East Asian participants, requiring validation across other ethnic groups.