Maternal diabetes mellitus significantly affects the fetal heart in both structure and function 1. Hypertrophic cardiomyopathy, which is characterized by thickening of the interventricular septum and to a lesser extent the ventricular free walls, is observed in infants of diabetic mothers irrespective of the degree of metabolic control 2. It has been suggested that fluctuations in serum glucose values rather than the basal glycemic state may be more important determinants of fetal cardiac growth 3. Gardiner et al. 4 found that Doppler and fetal myocardial velocities were negatively related and fetal myocardial thickness was positively related to hemoglobin A1c (HbA1c) in fetuses of diabetic mothers.
Tei et al.5 first used the myocardial performance index (MPI) for the evaluation of cardiac function in adults with amyloidosis. The MPI is the ratio between the duration of the isovolumetric periods (contraction and relaxation) and the duration of the ejection period in the left and the right ventricle. Prolongation of the isovolumetric periods and shortening of the ejection period correlate with impaired cardiac function 2. Freidman et al.6 were among the first to propose the use of the MPI in the evaluation of fetal cardiac function and their results showed no change in MPI with advancing gestation in normal pregnancies. Hernandez-Andrade et al.7 proposed the modified myocardial performance index (Mod-MPI) to improve the interobserver and intraobserver reproducibility of the MPI by including the Doppler echoes from the mitral valve (MV) and the aortic valve (AV) movements (clicks) as reference points to measure the different time periods for the MPI.
The aim of this study was to determine whether the fetal cardiac function is impaired in fetuses of diabetic mothers in the third trimester using the Doppler-based Mod-MPI compared with gestational age-matched controls.
Patients and methods
This was a cross-sectional observational study performed in the Cairo Fetal Medicine Unit, Faculty of Medicine, Cairo University, on fetuses of diabetic mothers in the third trimester as well as normal gestational age-matched controls in the period from March 2010 to November 2011. A relevant assessment of history was performed in all patients, followed by basic obstetric ultrasound as well as Doppler studies to determine fetal biometry and to exclude fetal congenital anomalies and evidence of fetal intrauterine growth restriction (defined as an estimated fetal weight below the fifth centile for gestation with abnormal fetal Doppler values). Patients with multifetal pregnancy, fetal congenital anomalies, presence of maternal hypertension or renal disease, maternal use of medication that may affect fetal cardiac function, or evidence of growth restriction were excluded from the study. Our departmental ethics and scientific committees approved the study. All the patients recruited provided informed consent to participate in the study.
The diabetic group included patients with pregestational diabetes as well as patients with gestational diabetes mellitus (GDM). The diagnosis of GDM was made if a 2-hour 75 g oral glucose tolerance test value was at least 160 mg/dl in capillary whole blood or if fasting blood glucose was more than 105 mg/dl according to the published criteria 8. Measurement of glycosylated hemoglobin level was performed before fetal echocardiography in order to allow validation of the quality of metabolic control in the preceding 8–12 weeks. The reference values were 4.0–5.5% for pregnant nondiabetic women 9, less than 7% for well-controlled pregnant diabetics, and more than 7% for poorly controlled diabetics 10 according to previously published studies.
The fetal cardiac studies were performed using a Voluson 730 Pro-v (GE Medical Systems, Milwaukee, Wisconsin, USA), Voluson E-6 (GE Medical Systems), and an Accuvix V-20 Prestige (Medison, Seoul, Korea). The Mod-MPI was measured according to the criteria proposed by Hernandez-Andrade et al.7. Briefly, a four-chamber view of the fetal heart was obtained in the apical position. The Doppler sample gate was set at 3 mm and placed on the lateral wall of the ascending aorta, below the AV and just above the MV (Fig. 1a). Special attention was paid to the velocity of the Doppler sweep representation on the ultrasound screen using the highest velocity available (15 cm/s) for the clear identification of the components of the Doppler tracing. The MV E/A waveform was always displayed as a positive flow and the aortic flow as a negative flow. The angle of insonation was always maintained below 30° and the mechanical and thermal indices never exceeded 1. The Doppler trace showed a clear echo corresponding to the opening and closing of the two valves at the beginning and at the end of the E/A (MV and AV) waveforms (Fig. 1b). The time periods were then estimated as follows: the isovolumetric contraction time (ICT) was estimated from the closure of the MV to the opening of the AV, the ejection time (ET) from the opening to the closure of the AV, and the isovolumetric relaxation time (IRT) from the closure of the AV to the opening of the MV (Fig. 2). The final value for the Mod-MPI was calculated as (ICT+IRT)/ET. All estimations were performed in the absence of fetal corporal and respiratory movements and with the mother in voluntary suspended respiration.
Normality of data was tested for all continuous variables using the Shapiro–Wilk test. Normally distributed parameters are presented as mean±SD and non-normally distributed values are presented as median (range). Analysis of variance test was used for multiple variable analyses. Categorical variables were compared using the χ2 or Fisher’s exact test according to cell size. Nonparametric (continuous) variables were compared using the Mann–Whitney U-test. A P value less than 0.05 was considered as statistically significant. Statistical analysis was carried out using Microsoft Excel 2010 (Microsoft Corporation, Redmond, Washington, USA) and Arcus Quickstat Biomedical version 1.0 (Research Solutions, Cambridge, United Kingdom).
The study included 45 diabetic pregnant women in the mid-third trimester and 52 gestational age-matched controls. Of the 45 pregnant diabetics, 12 had pregestational diabetes (26.7%) whereas the remaining 33 patients (73.3%) had gestational diabetes. Twenty-eight patients (62.2%) in the diabetic group were considered well-controlled diabetics according to our predefined criteria of a serum HbA1c (<7%), whereas the remaining 17 patients (37.8%) with a serum HbA1c more than 7% were considered to have poorly controlled diabetes. There was a statistically significant difference in the BMI between the three groups, which was the highest in the poorly controlled diabetic group. Table 1 shows the demographic characteristics of the study and the control group.
The myocardial performance parameters in the control and the study group are shown in Table 2 and Fig. 2. A statistically significant difference was found in the myocardial diastolic function between the control and the diabetic group. The left ventricular IRT was significantly shorter in the control group than both the well-controlled diabetics (P<0.01) and the poorly controlled diabetics (P<0.001). The overall Mod-MPI was statistically significantly lower in the control group than the study group as a whole (P<0.001) as well as in the poorly controlled diabetics (P<0.001), but although it was lower than that in the well-controlled diabetics, the difference did not reach statistical significance (P=0.053). No statistically significant difference was found between the study and the control group in the ICT and the ET.
In the present study, we aimed to evaluate the effect of maternal diabetes on fetal myocardial function using the Mod-MPI. The Mod-MPI allows the simultaneous evaluation of the fetal cardiac systolic function in the form of the aortic ET and diastolic function in the form of both the left ventricular ICT and the IRT. This method, which relies on the mitral and AV clicks to accurately measure the diastolic and systolic time periods of the Mod-MPI has been shown by Hernandez-Andrade et al. 7 to be associated with a lower variation and better interobserver and intraobserver agreement than the MPI previously proposed by Friedman et al. 6.
In our study, the BMI of patients with poorly controlled diabetes mellitus was statistically significantly higher than the control group and the well-controlled diabetic group, highlighting the relationship between BMI and the risk of developing GDM as well as glycemic control suggested in previously published studies 11.
Fetal cardiac evaluation in the present study showed a statistically significantly (P<0.001) higher overall Mod-MPI in the study group as a whole (median 0.40, range 0.32–0.66) compared with the control group (median 0.37, range 0.29–0.46) mainly because of a prolonged myocardial relaxation time (IRT), which had a median value of 32 and 39 ms in the control and the diabetic group, respectively. This difference was especially apparent in the fetuses of poorly controlled diabetics (Mod-MPI median 0.47, range 0.38–0.66), which showed a markedly prolonged IRT (median 49 ms, range 34–71 ms), suggesting that poor glycemic control during pregnancy has an adverse effect on ventricular diastolic function.
Hernandez-Andrade et al.12 defined age-adjusted reference values for the left ventricular Mod-MPI in normal fetuses at 19–39 weeks’ gestation and calculated the 5th, 50th, and 95th percentiles for the Mod-MPI as well as its components (ICT, ET, IRT). They found that in normal fetuses, the Mod-MPI did not exceed 0.43 at any gestation (at a fetal heart rate of 140 bpm: median 0.36, range 0.31–0.42). These values are in agreement with our results for the control group, but are much lower than those in the study group, especially the 17 fetuses with poorly controlled diabetes, indicating reduced left ventricular wall compliance in fetuses of diabetic mothers.
Several studies have reported results that are in agreement with our results showing that poor glycemic control during pregnancy has a negative impact on fetal cardiac function 4,13,14.
Turan et al.13 performed an echocardiographic evaluation of fetuses of mothers with pregestational diabetes at 11–14 weeks and gestational age-matched controls by fetal Doppler studies, which included the left and the right ventricular MPI. They found that fetuses of diabetic mothers especially those with an HbA1c more than 7% showed evidence of diastolic dysfunction with a significantly prolonged IRT, resulting in a significantly higher MPI (mean 0.5±0.08). They concluded that fetuses of diabetic mothers showed evidence of first-trimester diastolic myocardial dysfunction with worsening glycemic control.
Wong et al.14 compared the cardiac function in fetuses of well-controlled and poorly controlled pregestational diabetic mothers in the third trimester. They found that the right atrioventricular E/A ratio was significantly lower among the poorly controlled diabetic mothers, indicating that poor glycemic control is associated with fetal cardiac diastolic dysfunction.
Our study was not blinded and the fetal echocardiographic measurements were all performed by either of the two investigators (S.M.M.N or R.A.K), which may have resulted in sampling bias and may have affected the reproducibility of our results. However, our findings, especially in the control group, are in agreement with the previously reported gestational age-adjusted reference values for the Mod-MPI and its components measured by Hernandez-Andrade et al.12. Also, we did not perform a longitudinal follow-up of selected patients and therefore cannot provide information about the persistence of fetal cardiac diastolic dysfunction in the study group. However, Kozák-Bárány et al.15 performed an echocardiographic evaluation of the left ventricular systolic and diastolic function in newborn infants of mothers with well-controlled pregestational diabetes or GDM in comparison with normal-term neonates and found a prolonged deceleration time of early left ventricular diastolic filling in the diabetic group, which they attributed to impaired left ventricular relaxation.
Our study shows that fetuses of diabetic mothers show evidence of third trimesteric diastolic myocardial dysfunction as shown by a higher Mod-MPI than age-matched controls. This dysfunction appears to be more marked in fetuses of poorly controlled diabetics.
Conflicts of interest
There are no conflicts of interest.
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