Deorari et al. [8] mentioned that the most common cardiac pathology in babies of diabetic mothers is asymmetrical septal hypertrophy which might lead to dysfunction in diastole. However, most babies of diabetic mothers may be asymptomatic despite this dysfunction [9]. That was clear in the work of Vural et al. [10] who found that symptomatic hypertrophic cardiomyopathy occurs in 12.1% of infants of diabetic mothers and the prevalence increases to 40% when routinely searched for with echocardiography.
The results of the study conducted by Arslan et al. [11] match ours. They found statistically significant differences in pulsed wave Doppler with lower mitral E velocity, mitral E/A ratio, and tricuspid E velocity in infants of diabetic compared to those of controls (p < 0.0001, p < 0.0001, and p = 0.049 respectively). In addition, they found statistically significant higher mitral A velocity in cases than in the control group (p = 0.002).
E' velocity (measured by tissue Doppler imaging) is considered to be a variable which indicates ventricular relaxation independent of volume load. One of the early stage findings of diastolic dysfunction is significant reduction in E' velocity and increase in A' velocity in tissue Doppler imaging which leads to reversal of the E'/A' ratio (i.e., to become < 1) [12].
It was previously well established that patients with hypertrophic cardiomyopathy suffer a significant reduction in the left ventricular E', A', and S' velocities [13]. In addition, Lopez et al. [14] declared that impairment of left ventricular and right ventricular relaxation results in the decrease E' wave velocity.
Arslan et al. [11] also stated that during analysis of tissue Doppler imaging parameters from left ventricle, right ventricle, and inter-ventricular septum, they found lower E' wave velocity (p < 0.0001, p < 0.001, and p = 0.031 respectively), higher A' wave velocity (p = 0.004, p = 0.009, and p = 0.042 respectively), and lower E'/A' ratio (p < 0.0001, p < 0.0001, and p = 0.044 respectively) in infants of diabetic mothers compared to controls. This matches our results and is attributed to a reduced ventricular relaxation.
The results of the study of Çimen and Karaaslan [4] also match our results to a great extent. The E' velocities in the right ventricle, left ventricle, and septum were significantly lower in the babies of diabetic mothers compared to the control group (p = 0.001, p = 0.001, and p = 0.001 respectively). In addition, the A' velocities in the right ventricle, left ventricle, and septum were significantly higher in the babies of diabetic mothers compared to the control group (p = 0.001, p = 0.001, and p = 0.001 respectively). E'/A' ratios in the right and left ventricles were significantly lower in the babies of diabetic mothers compared to the control group (p = 0.025 and p = 0.030 respectively).
Moreover, Al-Biltagi et al. [15] found significant deterioration of left ventricular diastolic function measured by both conventional echocardiography (E/A ratio) and tissue Doppler imaging (E'/A' ratio) with p < 0.0001 and p < 0.0001 respectively among cases (infants of diabetic mothers) compared to the control group. They also found a significant deterioration of right ventricular diastolic function measured by tissue Doppler imaging (E'/A' ratio) with p < 0.0001 in cases compared to controls.
The Tei index [7] was initially measured by pulsed Doppler in the past and subsequently using tissue Doppler [16]. It is a useful parameter for indicating systolic and diastolic functions [14]; because it is a simple, reproducible and non-invasive index that has close correlation with systolic and diastolic hemodynamic parameters has the potential in the clinical field for the assessment of global cardiac performance.
Again, in accordance with our results, Tei index in the left ventricle, right ventricle, and the inter-ventricular septum were statistically higher (p < 0.0001, p = 0.044, and p = 0.001 respectively) in cases than in controls in the study of Arslan et al. [11] denoting impairment of global myocardial performance in cases.
Similarly, left ventricular and right ventricular Tei indices were higher in infants of diabetic mothers whose mothers had either gestational or pre-gestational diabetes than in healthy control infants in the study of Çimen and Karaaslan [4] (p = 0.015 and p = 0.005 respectively) as well as the study conducted by Al-Biltagi et al. [15] (p = 0.0004 and p = 0.0002 respectively).
Previously, Tsutsumi et al. [17] also found an increased left ventricular and right ventricular Tei index in fetuses of diabetic mothers after 27 weeks.
The increased left ventricular, right ventricular, and septal Tei indices in the newborns of diabetic mothers indicated impairment of the global ventricular function. These significantly high values of the right and left ventricular Tei indices show that left ventricular functions were also affected in addition to right ventricular dysfunction which could be attributed to physiological pulmonary hypertension (elevated pulmonary vascular resistance) in the early neonatal period.
Another important target in our study was to evaluate the effect of maternal diabetes control on echocardiographic parameters in infants of diabetic mothers.
Sub-optimally controlled diabetes (associated with higher levels of glucose during gestation) leads to hyperinsulinemia which increases leptin and free fatty acids transfer leading to macrosomia [18,19,20].
El-Ganzoury et al. [21] found in their study that all infants with hypertrophic cardiomyopathy were born to mothers with sub-optimally controlled diabetes and 86.6% of them were large for gestational age. Moreover, all small for gestational age and large for gestational age neonates in their study were born to mothers with sub-optimally controlled diabetes, while 88% of appropriate for gestational age neonates were born to mothers with optimal metabolic control. These data highlight the impact of good maternal diabetic control.
Similarly, other studies had shown an association between poor maternal glycemic control and asymmetrical septal hypertrophy [22,23,24].
On the contrary, other studies noted that even strict glycemic control does not efficiently prevent the fetuses of diabetic mothers from abnormal cardiac growth [25, 26].
Kozak-Barany et al. [27] showed that infants of mothers with well-controlled pre-gestational or gestational diabetes had impaired left ventricular relaxation. They related this finding to the effects of maternal hyperglycemia during the third trimester and subsequent fetal hyperinsulinemia leading to neonatal cardiac hypertrophy.
Also, Ren et al. [28] found that diastolic filling abnormalities are present in pregnancies with good diabetic control and they were more evident in pregnancies with poor glycemic control. Fetal E values in pulsed wave Doppler and the E/A ratio were significantly lower in pregnancies with uncontrolled gestational diabetes mellitus.
As noted previously, our group of infants of diabetic mothers with poor maternal glycemic control showed statistically significant higher incidence of left ventricular diastolic dysfunction than those with good maternal glycemic control in both pulsed wave Doppler (defined as E/A ratio < 1) and tissue Doppler (defined as E'/A' ratio < 1), while there was no difference as regards the incidence of right ventricular diastolic dysfunction. However, as regards tissue Doppler-based Tei index parameters, we could not demonstrate significant differences between infants of diabetic mothers with poor maternal glycemic control and those with good maternal glycemic control. This highlights two facts: first, global myocardial function is affected in both categories and second, and most important, is that assessment of myocardial function is important in newborns of diabetic mothers regardless the degree of maternal glycemic control.
Roodpeyma et al. [29] showed that the somatic findings of newborns were not related to the occurrence of cardiac complications. The relation between increased somatic growth and cardiac dysfunction could be only that both are attributable to the same mechanism. Insulin resistance-associated hyperinsulinemia (frequently associated with pregnancy-associated diabetes) can induce smooth muscle cell hypertrophy and hyperplasia and increased extracellular proteins which contributes to increase birth weight and at the same time affect the cardiac function [30].
In the present work, left ventricular diastolic dysfunction in individual neonates was detected more with tissue Doppler than with conventional pulsed wave Doppler. This fact highlights the importance of tissue Doppler imaging (if available) in detecting diastolic dysfunction as many cases would be missed by conventional pulsed wave Doppler alone.
We focused in the present study on the occurrence of diastolic dysfunction and not just a hypertrophied inter-ventricular septum because the finding of diastolic function is more important and more related to the clinical status than septal hypertrophy per se.
Limitations of the study
Tissue Doppler imaging has its own limitations which are encountered in any study relying on this modality of echocardiography. Tissue Doppler imaging measures only motion that is parallel to the direction of the ultrasound beam. In addition, active motion of the myocardium cannot be surely differentiated from passive motion of the heart inside the thorax.
Our study has certain limitations such as relatively small number of cases in the studied subgroups and lack of follow-up period. We did not do speckle-tracking as it was not available in the area where the study was done and transfer of such neonates to specialized echocardiography laboratory carries its own hazards.
