Comparison of fetal and neonatal cardiac morphology between the infants of mothers with well-controlled gestational diabetes mellitus and normal controls

Abstract

Objective

To compare fetal and neonatal cardiac morphology in fetuses of mothers with gestational diabetes mellitus (GDM) with the controls

Patients and methods

Pregnant women at average risk of GDM underwent 100-g, 3-h-OGTT at 24–28 weeks of gestation for diagnosis of GDM. Both GDM group and the control group underwent fetal echocardiography at 32–36 weeks to assess cardiac dimensions. The neonates underwent echocardiography within 48 h after birth to assess cardiac morphology.

Results

A total of 154 pregnant women were recruited, including 60 in the GDM group and 94 in the control group. All of the study group were well controlled for GDM. Most baseline characteristics of both groups were comparable. All obstetric outcomes were not significantly different between the two groups. Morphological cardiac dimensions in the fetuses and newborns of both groups were also not significant different. Subgroup analysis in the study group showed no significantly different in cardiac morphology between the group with diet control and that of insulin control.

Conclusion

Fetal and neonatal cardiac morphologic changes among mothers with well-controlled GDM are not significantly different from those in the controls. It is possible that good control of maternal blood glucose can prevent fetal and neonatal cardiac abnormalities.

Keywords

Cardiac morphology diabetes mellitus fetus gestational diabetes mellitus neonate pregnancy

What is already known?

• GDM is associated with fetal and neonatal cardiac abnormalities.

What does this study add?

• Fetal and neonatal cardiac morphologic changes among mother with well-controlled GDM are not significantly different from those in the controls.

• Good control of maternal blood glucose is likely to prevent fetal and neonatal cardiac abnormalities.

Introduction

Gestational diabetes mellitus (GDM) is a condition of carbohydrate intolerance which is first diagnosed during pregnancy.¹ Approximately 7% of pregnancies are complicated by any type of diabetes and that approximately 86% of these cases represent women with GDM.² However, its prevalence may vary depending on the population characteristics and diagnostic criteria. The prevalence of GDM is relatively high among Hispanic, African American, Native American, and Asian women.³ With a greater prevalence of obesity and sedentary lifestyles, the prevalence of GDM among reproductive-aged women is increasing globally. Perinatal morbidity and mortality are increased fourfold in GDM.⁴ Additionally, pregnant women with GDM and their fetuses are exposed to long-term consequences with transgenerational effects such as children with a higher risk of obesity and its related complications.⁵ Several studies have shown that GDM is significantly associated with both morphological and functional changes in the fetal heart.^6–10 Though the true mechanism is still unclear, it has been demonstrated that fetal cardiac changes are partly caused by fetal hyperglycemia and hyperinsulinemia, which triggers fat and protein synthesis in myocardial cells.^11,12 Fetal myocardial changes may be observed in even cases with well-controlled GDM.¹³ Moreover, neonates of mothers with well-controlled GDM are still at increased risk of cardiac hypertrophy, subclinical diastolic dysfunction, and impaired left ventricular relaxation. Nevertheless, most previous studies included GDM with various levels of DM control and it is not well-established whether good control of GDM could prevent cardiac dysfunction and morphological cardiac changes or not. Furthermore, the number of studies on cardiac effects caused by GDM in the neonates are very limited. Accordingly, we conducted this study aimed to compare fetal as well as neonatal cardiac dimensions between the infants of GDM mothers and those of normal pregnancies.

Patients and methods

This was a prospective, cross-sectional study of singleton pregnant women at gestational age between 32 and 36 weeks, attending Maharaj Nakorn Chiang Mai Hospital, a tertiary center, Chiang Mai, university, Thailand. The participants were recruited from women attending routine antenatal care between August 2020 and December 2022. This study was ethically approved by the Institutional Review Board (Committee-4 Faculty Medicine, Chiang Mai University, Research ID OBG2563-9876). The women were invited to participate in the study and provided written informed consents. Inclusion criteria are as follows: (1) singleton pregnancy; (2) gestational age between 32 and 36 weeks of gestation, based on certain last menstrual periods and fetal sonographic biometry in the first half of pregnancy; (3) no medical complications such as chronic hypertension, thyrotoxicosis and renal diseases etc. The study group and control group met the same inclusion criteria, except that the patients in the study group were diagnosed with GDM, whereas those in the control group were tested to have no GDM. Exclusion criteria are as follows: (1) pre-gestational diabetes mellitus; (2) multifetal pregnancy; (3) fetal chromosomal or structural abnormalities; (4) fetal growth restriction; (5) loss to follow-up or unknown pregnancy outcomes; and (6) poorly controlled GDM defined as being unable to consistently achieve target levels of plasma glucose (more than 90% of times).

The diagnosis of GDM was made at gestational age between 24 and 28 weeks, using two-step screening test; first, the 50-g glucose challenge test was performed, and, if this was positive (using cut-off point of 140 mg/dL), the 100-g, 3-h oral glucose tolerance test was carried out and this was considered to be positive if two or more plasma glucose levels were greater than the thresholds (fasting glucose level > 105 mg/dl, 1-h level > 190 mg/dL, 2-h level > 165 mg/dL and 3-h level > 145 mg/dL).

The participants diagnosed with GDM were counseled by the nutritionists for diet control and were followed-up to keep blood glucose levels less than the upper target levels; 95 mg/dL for fasting levels, 140 mg/dL for 1-h levels, and 120 mg/dL for 2-h levels. Traditionally, insulin was added to nutrition therapy if blood glucose levels greater than the target levels. The participants diagnosed with non-GDM were given a standard of antenatal care. All were prospectively recorded for demographic data such as maternal age, ethnicity, parity, height, pre-pregnancy weight and height, obstetric history, method of conception, cigarette smoking.

All participants underwent once fetal echocardiography at gestational age between 32 and 36 weeks by MFM (maternal-fetal medicine) specialist, using ultrasound machine Voluson E8 and Voluson E10 models (GE Healthcare Ultrasound; Milwaukee, WI, USA), equipped with transabdominal curvilinear transducer (2–4 MHz), using both two-dimensional B-scan images and M-mode ultrasound. On echocardiographic measurements, firstly a systematic two-dimensional fetal echocardiography scan was performed to record fetal parameters, including head circumference, biparietal diameter, abdominal circumference and femur length. The thickness of fetal interventricular septum (IVS) and of ventricular walls were measured on a transverse four-chamber view with the cursor perpendicular to the IVS, performed under maternal voluntary suspended breathing, during no fetal movement and breathing. The measurements were taken at the middle of IVS and ventricular wall at end-diastole, using cine loop to precisely identify the correct phase. The average of three best measurements was used for analysis. Neonatal echocardiography was performed on the second days after birth by a neonatal cardiologist. Steps of measurements were as follows: IVS thickness and posterior wall thickness (PWT) were measured during end-diastole using two-dimensional imaging on parasternal long axis view (PSLAX) view. In cases of difficulty in presenting proper plane by two-dimensional images, then M-mode cursor is positioned to cross the left ventricle (LV) at the end of mitral valves, with fine adjustment to keep M-cursor line perpendicular to the long-axis of the LV. Also the interventricular septum thickness at end-diatole (IVSd), the left ventricular internal dimension at end- diastole (LVIDd) and the posterior wall thickness at diastole (PWTd) could be measured on the M-mode image. LV mass could be calculated using the following equation: LV mass (g) = 0.08×[1.04×(IVSd+PWTd+LVIDd)³-(LVIDd)³]+0.6 (specific gravity of muscle is 1.04 g/cm³, used for calculation of relative wall thickness to determine the type of hypertrophy (concentric or eccentric hypertrophy) (RWT = 2xPWTd/LVIDd (RWT >0.42 indicated concentric hypertrophy; RWT ≤ 0.42 indicating eccentric hypertrophy)

Statistical analysis was performed using the statistical package for the social sciences (SPSS) program version 26.0 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0). The continuous data are expressed as mean ± SD or median (IQR) based on normality of distribution, whereas the categorical data are presented as number and percentage. In comparison of the demographic data and ultrasound parameters, categorical variables were compared using Chi-square test, and the continuous variables were compared using a student’s t-test or Mann–Whitney U test as appropriate. A p-value of less than 0.05 was considered statistically significant. Given that the prevalence of abnormally thickened interventricular septum (> +2SD) is approximately 38% among fetuses of GDM mothers before treatment, based on lower limit of 95%CI in the study of Palmieri et al,¹⁴ and that is 5% among non-GDM mothers. This study needs a sample size of 68 cases (34 for each group) to gain power of 90% at 99% confidence interval.

Results

During the study period, 154 pregnant women with average risk of GDM underwent 3-h OGTT. All were of Thai ethnicity. Of them, 60 were diagnosed with GDM, included in the study group, and the remaining 94 were non-GDM mothers which were included in the control group. The prevalence of GDM among the women with average risk was 39.0%. All of the study group were well controlled for GDM, including 52 (86.7%) with diet control and 8 (13.3%) requiring insulin treatment. Most baseline characteristics of the two groups were comparable, as presented in Table 1. However, maternal age was significantly higher in the study group. Note that birth weight and gestational age at delivery was also not significantly different between the two groups. Cesarean section rate was also comparable and no case of shoulder dystocia was noted.

Table 1.

Baseline characteristics of the patients.

Group	GDM	Control	p-value
Age	32.3 ± 4.5	29.9 ± 5.3	0.003
Prepregnancy weight (Kg)	57.7 ± 13.7	57.2 ± 11.6	0.825
Maternal weight at delivery	66.3 ± 11.8	67.6 ± 11.1	0.504
Maternal height (cm)	156.9 ± 5.5	157.5 ± 6.6	0.500
Prepregnancy BMI	23.0 ± 6.1	23.1 ± 4.4	0.894
Maternal BMI at delivery	27.0 ± 4.6	26.7 ± 5.7	0.763
Gestational age at fetal echo (week)	34.2 ± 1.6	34.3 ± 1.3	0.610
Gestational age at delivery (week)	38.4 ± 2.2	38.6 ± 1.1	0.616
Birth weight (gm)	2972 ± 601	3131 ± 309	0.085
Random blood glucose	95.7 ± 14.4		—
Fasting blood glucose	83.4 ± 7.2		—
Postprandial blood glucose	107.4 ± 16.9		—
Neonatal blood glucose	71.2 ± 14.3		—
Parity (nulliparity/total)	26/60	49/94	0.287
Cesarean section rate	14/60	22/94	0.992
Smoking (yes/total)	0/59	2/91	0.252
Low Apgar score (yes/total)	1/60	1/94	0.747

Concerning the main outcomes, all of the fetal cardiac dimensions were not significantly different between the two groups, as presented in Table 2. Also, neonatal echocardiographic parameters were comparable. No any case of ventricular hypertrophy was observed in both groups. Most had normal appearance of ventricular wall. However, concentric remodeling was noted in two cases of the study group and two cases in the control group (p-value: 0.548). On subgroup analysis of GDM group, comparisons of fetal and neonatal echocardiographic parameters between the subgroup of no insulin requirement and that of insulin requirement showed no significant differences in all parameters, as presented in Table 3.

Table 2.

Fetal and neonatal echocardiographic data.

Group	DM Mean + SD	Control Mean + SD	p-value
Fetal echocardiography
Left ventricular wall thickness (mm)	4.86 ± 0.91	4.73 ± 0.98	0.437
Interventricular septal thickness (mm)	4.42 ± 0.83	4.44 ± 0.75	0.875
Right ventricular wall thickness (mm)	4.71 ± 0.97	4.64 ± 0.84	0.641
Cardiac width (mm)	37.10 ± 3.90	36.31 ± 3.21	0.176
Cardiac length (mm)	45.27 ± 4.61	45.03 ± 4.67	0.752
Global sphericity index (GSI)	1.23 ± 0.13	1.24 ± 0.11	0.464
Neonatal echocardiography
Right ventricular free wall thickness (mm)	2.45 ± 0.54	2.55 ± 0.50	0.403
Interventricular septal thickness (IVS: mm)	2.71 ± 0.51	2.75 ± 0.58	0.766
left ventricular internal dimension in diastole (LVIDd: mm)	17.97 ± 1.85	18.19 ± 2.31	0.643
Posterior wall thickness (PWT: mm)	2.56 ± 0.52	2.49 ± 0.45	0.557
Left ventricular mass	30.94 ± 7.29	32.30 ± 6.36	0.364
Relative wall thickness (RWT: mm)	0.30 ± 0.14	0.28 ± 0.07	0.209

Table 3.

Comparisons of fetal and neonatal echocardiographic data between the group of GDM with no insulin requirement and that with insulin requirement.

Group	GDM No insulin treatment Mean ± SD	GDM Insulin treatment Mean ± SD	p-value
Fetal echocardiography
Left ventricular wall thickness (mm)	4.87 ± 0.96	4.81 ± 0.55	0.863
Interventricular septal thickness (mm)	4.50 ± 0.84	3.91 ± 0.65	0.064
Right ventricular wall thickness (mm)	4.66 ± 1.00	5.15 ± 0.67	0.185
Cardiac width (mm)	37.20 ± 4.04	36.79 ± 3.24	0.785
Cardiac length (mm)	45.53 ± 4.66	44.39 ± 4.10	0.517
Global sphericity index (GSI)	1.23 ± 0.14	1.21 ± 0.05	0.618
Neonatal echocardiography
Right ventricular free wall thickness (mm)	2.48 ± 0.56	2.23 ± 0.33	0.384
Interventricular septal thickness (IVS: mm)	2.71 ± 0.54	2.71 ± 0.25	0.995
Left ventricular internal dimension in diastole (LVIDd: mm)	18.00 ± 1.91	17.73 ± 1.39	0.780
Posterior wall thickness (PWT: mm)	2.60 ± 0.54	2.20 ± 0.22	0.157
Left ventricular mass	30.81 ± 7.60	32.00 ± 4.24	0.762
Relative wall thickness (RWT: mm)	0.31 ± 0.14	0.25 ± 0.01	0.383

Two pregnancies had fetal macrosomia (birth weight of 4005 and 4440 g), accounting for 1.3% of all cases. Both were in the study group with well-controlled GDM without insulin requirement and had no other obstetric complications. Additionally, both babies had normal echocardiographic data, no ventricular hypertrophy and normal appearance of myocardium.

Discussion

New insights gained from this study are as follows: (1) morphological cardiac changes in the fetuses of GDM mothers are not different from the controls, indirectly indicating that such abnormalities could be prevented by GDM control. (2) Either taking control of GDM with diet or with insulin can result in similar effect on fetal and neonatal cardiac changes, though this conclusion is based on limited data of this study. (3) The prevalence of GDM is relatively high (39%) because of screening among the cases with average risk, not universal screening. Also, the baseline prevalence of GDM among Asian women is higher than that in the western women.¹⁵

Good control of GDM was also supported by several biomarkers. For examples, no significant difference between both groups was observed in normal birthweight, no polyhydramnios case, no shoulder dystocia, and comparable cesarean section rates. Also, no neonatal hypoglycemia was noted in this series, suggesting good control of blood glucose in the mothers. Nevertheless, macrosomia was identified in two out of 60 cases and both were in the GDM group, possibly indicating not perfectly controlled in some cases.

Several previous studies have demonstrated a significant association between GDM and fetal ventricular hypertrophy and cardiac dysfunction. For examples, Wang et al.¹⁶ recently showed significant increases in several fetal right heart indicators in the GDM group, suggesting that GDM affects fetal right heart structural and functional growth during late-term pregnancy. In recent meta-analysis performed by Papazoglou et al.¹⁷ indicates that GDM is strongly associated with an increased risk of fetal heart malformations, especially cardiac septal hypertrophy, ventricular wall thickening, and ventricular outflow tract obstruction. Likewise, Yovera et al.¹⁸ demonstrated that GDM was associated with a reduction mainly in fetal right ventricular function, and global sphericity index was also reduced in GDM pregnancies, when compared with controls. Nevertheless, most authors did not describe in details about the levels of glucose control. Unlike in the findings in most previous studies, the contradictory findings in our study may partly be explained by good GDM control as mentioned earlier. It is possible that failure of prevention cardiac abnormalities in cases of good control in previous studies might not be tightly controlled. However, some unknown factors other than fetal hyperglycemia might play a role, since some studies showed cardiac abnormalities in spite of good control. For examples, Garcia et al.¹³ reported that IVS hypertrophy was observed even in well-controlled diabetic pregnancies and D’Ambrosi et al.⁸ showed that fetal right cardiac function is altered in GDM pregnancies, even in cases that GDM is well controlled.

Limitations of this study are as follows: (1) no comparison between the group of well-controlled GDM and poorly-controlled group; (2) too small sample size of insulin requirement subgroup; (3) no assessment of cardiac function. Therefore, we cannot conclude that taking good control of GDM can prevent fetal and neonatal cardiac dysfunction.

The strengths of this study are as follows: (1) including neonatal echocardiographic assessment, not only in fetal echocardiography as performed in most previous studies; (2) high homogeneity of study population; all were of Thai ethnicity; (3) the same baseline data with no underlying maternal disease together with exclusion of fetal structural abnormalities. Additionally, the consistent findings of no difference in cardiac morphology between the two groups could be demonstrated in both fetuses and newborns, reinforcing the reliability of the conclusion. Note that, though maternal age in the GDM group was significantly higher, as expected, the difference was unlikely to interfere with the interpretation of the results.

In conclusion, this study demonstrates a negative association between well-controlled GDM and fetal or neonatal cardiac morphological changes. It is possible that good control of maternal blood glucose might have favorable impact on fetal heart health, theoretically protecting cardiovascular diseases in adult life in the light of fetal programming hypothesis.

Footnotes

Acknowledgements

We would like to express our gratitude to MFM team who helped us in patient recruitment and collecting data.

Author contributions

PS: conceptualization, proposal development, acquisition of data, data validation, manuscript writing; SL: conceptualization, proposal development, data validation, acquisition of data, manuscript editing, final approval; RS: data validation, acquisition of data, manuscript editing, final approval; N.K.: data validation, acquisition of data, manuscript editing, final approval; TT.: data validation, formal analysis and manuscript editing, final approval; All authors have read and agreed to the published version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Chiang Mai University Research Fund (CMU-2566).

Institutional review board statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Research Ethics Committee, Faculty of Medicine, Chiang Mai University (Research ID: OBG-2563-9876)

Informed consent

Written informed consent was obtained from all subjects involved in the study.

ORCID iD

Theera Tongsong

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