Animal studies [4] have shown that exposure to intrauterine hyperglycemia may cause abnormal glucose metabolism in the fetus, which may also alter lipid metabolism and cause excessive production of reactive oxygen species, leading to subsequent oxidative stress [11]. Further, it has been reported [12, 13] that reactive oxygen species can directly damage the systolic function of the heart. Excessive glucose may cause fetal hyperinsulinemia, which may lead to a decrease in fetal blood oxygen levels [14]. Fetal hypoxia is accompanied by a surge in the levels of adrenaline and catecholamines, which cause heart remodeling and hypertrophy, resulting in abnormal fetal cardiac function [4]. In addition, a study involving a rat model showed that maternal hyperglycemia can alter fetal cardiac function by down-regulating the expression of KCNIP2, the key regulatory factor mediating fetal cardiac electrophysiology and contractile function [15].
Although the mechanism by which GDM affects fetal cardiac function is not fully clear, physicians can use prenatal ultrasonography to assess the changes in fetal cardiac function. This prospective cohort study is the first to evaluate the cardiac morphology and function of fetuses of mothers with GDM using the fetal HQ online software. The results showed that GDM had negative effects on fetal cardiac morphology and function starting from the second trimester. We also found that fetal HQ showed good feasibility and repeatability for analyzing fetal cardiac function. Overall, these results support our hypotheses.
GLS of the LV and RV in the fetuses of mothers with GDM
Strain is a sensitive indicator of cardiac function. According to the stratification and direction of the myocardium, strain can be divided into longitudinal strain, radial strain, and circumferential strain, corresponding to the movement of the myocardium in different directions. Thus, longitudinal strain is mainly used to reflect the movement of the endocardium because of the longitudinal running direction. When ischemia or hypoxia occurs, the endocardium is the first to be damaged, coupled with a reduction in GLS. Thus, an evaluation of the changes in GLS is useful for early diagnosis of impaired cardiac function [16]. Additionally, previous studies [10], which reported results similar to those of our research study, showed stable values of GLS of the LV and RV in normal fetuses and showed no significant relationship of GLS with factors such as maternal age, EFW, and BMI of the mother. In the present study, fetal HQ was used to obtain the GLS values of the LV and RV, which shortened the operative time, improved patient compliance, facilitated operation by the sonographer, and increased feasibility, which highlight the benefits of our research.
Previous studies comparing the GLS of the fetal ventricles between mothers with GDM and a healthy group did not show results consistent with those of our study. Some authors reported that systolic function of the RV was more susceptible to damage than that of the LV. Joana et al. [17] studied 69 pregnant women with GDM and suggested that systolic function was impaired only in the RV in the second trimester. Yovera et al. [18] examined 112 fetuses of women with GDM, including 43 fetuses at a gestational age of 24–32 weeks and 69 fetuses at a gestational age of 32–40 weeks, and reported reduced RV function but normal LV function. The predominance of the RV in the fetal circulation was used to explain the difference between the ventricles. In addition, some authors reported that the GLS values of both ventricles were reduced in the GDM group. Wang et al. [19] analyzed 35 fetuses of mothers with GDM (gestational age: 28–38 weeks) and found that the GLS values of the apical segment of the left ventricular side wall and interventricular septum were reduced. Rolf et al. [6], who examined 53 fetuses of mothers with GDM and 127 fetuses of healthy mothers at a gestational age of 19–39 weeks, found reduced GLS for both the ventricles. The results of Kulkarni et al.’s study [20] also showed that maternal hyperglycemia may cause a reduction in the GLS of the LV in fetuses. Furthermore, the global circumferential strain (GCS) and global radial strain (GRS) were also reduced, indicating an extensive effect on the myocardium, which was similar to the change observed in cardiomyopathy: the nature of the changes in the LV was considered to be the same as that of the changes in the RV. This seems to better explain the unvaried effect of hyperglycemia on the LV and RV in animal models [3]. Another study showed that the reduction in GLS in fetuses of mothers with GDM was retained in the postnatal period [21]. These differences between studies may be related to differences in the diagnostic criteria for GDM and variation between studies in maternal characteristics, diabetes control status, protocol for optimal image acquisition. Besides, van Oostrum [22] reviewed research published in recent years and found a variation in the GLS of both ventricles of normal fetuses, which may be explained by differences in speckle tracking algorithms and ultrasound devices. However, the mechanism underlying the reduction in GLS caused by GDM is still unclear, and further research is needed.
FAC in the LV and RV in the fetuses of mothers with GDM
FAC is another indicator that reflects the systolic function of the ventricle. Ejection fraction (EF) can only reflect the systolic function of the ventricle, and the systolic function of the LV can be estimated using the two-dimensional Simpson biplane method (four-chamber view or two-chamber view) [23]. This is because the shape of the left ventricular cavity is relatively regular and its cross-section is circular, whereas the cross-section of the RV is crescent-shaped. Therefore, we cannot use the Simpson method to evaluate systolic function of the RV, but instead, FAC can be used to evaluate EF [24].
Yovera et al.’s study [18] found that the FAC in the RV of fetuses of mothers with GDM was significantly reduced at the gestational ages of 24–32 weeks and 32–40 weeks, similar to our results. The systolic function of the RV is mainly attributable to the contraction of longitudinal muscle fibers [25]. Therefore, to a certain extent, the change in FAC may be correlated with the GLS of the RV, which needs to be confirmed by further studies. However, Yovera et al. mentioned that the FAC in the LV in the GDM group only decreased at 24–32 weeks. Besides, there were no differences in the FAC on comparing the two gestational groups, both in the GDM and control groups. These findings are inconsistent with our results. Pearson correlation performed for FAC and other factors indicated that the FAC in the LV had a linear negative correlation with EFW (Table 4), while the FAC in the RV had no obvious correlation with EFW. Such differences may be caused by differences in grouping and the distribution of gestational age or differences in the rate of growth of the ventricles. DeVore et al. [26] found that at the gestational age of 20–30 weeks, the FAC in both ventricles decreased slowly with increasing gestational age and then remained stable. Further large-sample multicenter studies on the alterations in FAC in healthy fetuses and the influence of GDM on FAC are required.
GSI and 24-segment SI in the fetuses of mothers with GDM
Previous studies have found that the shape and size of the heart were closely related to the structure and function of the heart [27, 28]. As an emerging technology, fetal HQ integrates STE and 24-segment myocardial analysis, assessing cardiac function in a more detailed manner. In addition to the GSI, the 24-segment SI can be analyzed, which is another highlight of our research. The GSI of the heart, the ratio of the overall longitudinal length to the transverse length of the 4CV at end-diastole, can be used to assess the overall shape of the heart. Moreover, the 24-segment SI of the ventricles, the ratio of the longitudinal length to the transverse length in each segment of the ventricle, can be used to evaluate the shape of each ventricle. Previous studies have found that there was no significant correlation between the 24-segment SI and fetal size or gestational age [27], which has been confirmed by our research, and this finding laid the foundation for evaluating the changes in the shape of the heart.
The structure of the heart is complex, including the four chambers macroscopically. The whole heart can look more coordinated only if it maintains a relatively fixed ratio between all of its parts. A change in the shape or size of a certain part does not necessarily affect the overall shape or size of the heart. Thus, even if the overall shape and size seem to be normal, it is still necessary to measure the shape and size of each chamber when the proportion of one part seems to be abnormal [27].
According to our study, the GSI was relatively stable and did not change with increasing gestational age in the control group. Additionally, the GSI of fetuses of mothers with GDM was slightly lower than that of healthy fetuses starting from the second trimester, which indicated that the fetal heart had a rounder shape in the GDM group than in the control group. This difference may be related to fetal hypoxia [29]. There was no significant difference between the GDM and control groups in the analysis of the 24-segment end-diastolic diameters of each ventricle. However, there was a significant difference in the SI of the basal segments of the LV in the analysis of the 24-segment SI. We speculated that this difference may be related to the shape of the LV itself and the effect of hyperglycemia on the myocardium. According to the data of the control group, the SI of the RV was significantly lower than that of the LV for segments 1–19, suggesting that the RV has a more globular shape at the basal, mid, and proximal apical segments. This finding is roughly consistent with those of a previous study [27]. The difference in the SI indicated that the normal anatomical structure of the LV had a bullet shape, whereas that of the RV had a pyramidal shape. Therefore, small changes in the shape of the LV were more likely to cause changes in the SI than those in the shape of the RV. This does not mean that the decrease in the GSI was only caused by the abnormal SI of the segments of the LV, but it should be understood that a “quantitative change caused a qualitative change”.
Strength and limitations
Fetal HQ is a new technology and can be considered as a fusion of TomTec’s Cardiac Performance Analysis and GE Voluson E10 Ultrasound System. In addition to the aforementioned advantages, this technology seems to be more suitable for the evaluation of the fetal heart compared to previously used methods (applying the adult mode that divided the LV into 16 or 17 segments according to the coronary blood flow distribution). Besides, Fetal HQ has a lower operating threshold compared with other speckle tracking software. 4CV, which is a necessary section of fetal cardiac ultrasound examination, is also the easiest view to obtain. However, the speckle tracking software of other manufacturers needs to obtain the “three-chamber heart” view and “two-chamber heart” view except 4CV. Due to the changeable position, bones, and depth of fetus, it sometimes becomes impossible to obtain these three views at the same time, which greatly increases the threshold of the analysis. What’s more, the evaluation of fetal cardiac function using Fetal HQ is faster, which can be reflected in two aspects. One is that the preparation time before analysis, that is, the image acquisition time is short—the time to obtain a 4CV image is much shorter than the three views combined. The other is the short time of analysis. Fetal HQ does not require offline analysis or layered analysis, which shortens part of time. Finally, in addition to providing cardiac functional parameters like GLS, Fetal HQ also can evaluate changes in cardiac morphology, such as SIs.
However, this study has several limitations. First, this was a single-center study, and the gestational ages of the study subjects were not evenly distributed, with few pregnant women at a gestational age ≥ 36 weeks. Secondly, the design was not longitudinal. Many of the pregnant women would not go back to the following-up echo as they may live in the suburbs or other cities. Moreover, most of the pregnant women with GDM in our study showed good blood sugar control; thus, we could not obtain results for fetuses of mothers with poor blood sugar control. Future studies still need to supplement the effects of glycemia, anti-diabetic therapy and its duration on GLS, FAC, GSI, 24-segment SI, and other factors. Additionally, the long-term follow-up after birth should also be improved to observe the influence of the changes in the indicators on the prognosis.