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Left ventricular mass in offspring of diabetic mothers: at 5–7 years old

  • Rista Lestari
  • Noormanto Noormanto
  • Madarina Julia
Original Article
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Abstract

Newborns of mothers with diabetes have increased risk for cardiac left ventricular (LV) hypertrophy. Diabetic pregnancy is also associated with in increased risk for obesity and hypertension, as well as for later cardiovascular morbidity and mortality. This study aimed to examine the connection between being the offspring from a diabetic pregnancy and having hypertension and obesity to the increased risk to have left ventricular mass (LVM) and altered LV geometry in childhood. We conducted a retrospective cohort study on 23 offspring of diabetic mothers and 23 sex- and age-matched control children at the age of 5–7 years. LVM and LV geometry were assessed using M-mode echocardiography and indexed for height2.7. Data analyses were adjusted for birth weight, current overweight/obesity status and blood pressure. Prevalence of increased LVM/height2.7 was higher in children of diabetic mothers, i.e. 43.5 vs. 8.7% in the control group (RR (95% CI) 5.0 (1.2–20.4), p = 0.007). The association between maternal diabetes and increased LVM persisted after adjustment for age, sex, birth weight, current overweight/obesity status and blood pressure, with regression coefficient of (95% CI) 5.7 (1.4–10.1), p = 0.01. Together, maternal diabetes, overweight/obesity status and blood pressure contributed 50% to the increase. Results showed that children of diabetic mothers were more likely to have altered LV geometry (RR (95% CI) 6.0 (1.5–23.9), p < 0.001). Maternal diabetes is a risk factor for increased LVM and altered LV geometry in childhood.

Keywords

Diabetic pregnancy Maternal diabetes Childhood Left ventricular mass Left ventricular geometry Left ventricular hypertrophy 

Introduction

In the face of increasing global prevalence of obesity and diabetes mellitus (DM) type 2, the risk of a fetus to be exposed to hyperglycemia in pregnancy will increase. The International Diabetic Foundation (IDF) estimated that around 16.9% pregnancies were exposed to hyperglycemia, with more than 90% of the cases in the lower- to middle-income countries. The prevalence was worst in the Southeast Asia region, i.e. around 25% of the pregnancies [1].

Diabetic pregnancy was associated with several short- and long-term implications. Perinatal mortality was higher in diabetic pregnancy. The prevalence of stillbirth and neonatal mortality due to asphyxia, respiratory distress, hypoglycemia, congenital anomalies and other neonatal problems was higher in infants of diabetic mothers [2]. Echocardiography on fetuses and newborns of diabetic mothers had also observed an increase in left ventricular mass (LVM) and altered cardiac geometry [3, 4, 5].

Besides those adverse short-term effects, individuals born from a diabetic pregnancy had been observed to have increased risk for DM and cardiovascular disease (CVD) later in life [2, 6, 7]. An increase in LVM is a strong and independent predictor for later cardiovascular events [8]. However, one previous study on the offspring of mothers with type 1 diabetes observed no residual cardiac pathology in 7–8-year-old children who had hypertrophic cardiomyopathy in infancy [9].

Several studies had revealed that children and adolescents born from mothers with diabetes were more likely to be obese and to suffer from insulin resistance and hypertension [10, 11, 12]. Since obesity and hypertension are also risk factors for increased LVM and alteration of cardiac left ventricular (LV) geometry patterns [13, 14], this study aimed to examine the connection between being the offspring from a diabetic pregnancy and having hypertension and obesity to the increased risk to have LVM and altered left ventricular (LV) geometry in childhood.

Methods

We performed a retrospective cohort study involving 5–7-year-old children born from a diabetic pregnancy in Dr. Sardjito Hospital Yogyakarta between January 2007 and December 2009. Maternal diabetes was defined as persistent hyperglycemia (random blood glucose > 200 mg/dL in more than one sample) detected during pregnancy [15]. We excluded children with congenital cardiac malformations or other severe congenital anomalies. Controls were children born with the same sex at the same day.

Data on birth weight were extracted from medical records. Birth weights were measured immediately after birth. Measurement of weight, height and blood pressure (BP) at the age of 5–7 years was performed by trained nurses. Overweight and obesity were defined as body mass index (BMI) for age above + 1 SDS (standard deviation scores) of the WHO child growth reference 2007 [16].

Blood pressure (BP) was measured using the standard techniques described by the fourth report of the National High Blood Pressure Education Program (NHBPEP) Working Group on Children and Adolescents. The percentiles of every subject’s systolic and diastolic BPs were also computed using the formula given by the NHBPEP. Elevated BP was defined as systolic and diastolic BP at or above the 90th percentile for gender, age and height observed from three independent measurements [17].

A pediatric cardiologist measured LVM using M-mode echocardiography as recommended by the American Society of Echocardiography (ASE). LVM was calculated using the formula introduced by Devereux et al., [18] according to the ASE guidelines (Box 1). LVM were indexed for height (in m2.7) into LVM/height2.7. LVM/height2.7 values were classified as high if they were above the 95th percentile of the reference introduced by Khoury et al. 2009 [19].
Box 1

Formulas for calculating left ventricular mass (LVM) and relative wall thickness (RWT)

LVM (g)

0.81 × {1.04 × (interventricular septal thickness at diastole + left ventricle posterior wall thickness at diastole + left ventricular internal dimension at diastole)3 − (left ventricular internal dimension at diastole)3} + 0.06

RWT

2 × (posterior wall thickness ∕ left ventricle internal dimension at diastole)

Subjects were classified into four groups of left ventricular (LV) geometry based upon LVM/height2.7 and relative wall thickness (RWT). RWT was estimated and classified using methods by Hanevold et al. 2004 (Box 1) [13]. LV geometry was considered to be normal when LVM/height2.7 was < 95th percentile and RWT < 0.41; concentric remodelling when LVM/height2.7 was < 95th percentile and RWT ≥ 0.41; concentric hypertrophy when LVM/height2.7 was ≥ 95th percentile and RWT ≥ 0.41; and eccentric hypertrophy when LVM/height2.7 was ≥ 95th percentile and RWT < 0.41 [14].

This study was approved by the Medical and Health Research Ethics Committee, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia. Written informed consent was obtained from parents before data collection.

Mean difference of continuous data was analysed using independent sample t tests. Univariate regression analyses were used to assess the associations between LVM/height2.7 as the dependent variable and maternal diabetes and other potential predictors for increased LVM/height2.7, i.e. BMI for age SDS and blood pressures as the dependent variables. Multiple regression analyses were then performed to estimate the independent contribution of maternal diabetes to LVM/height2.7 adjusted for sex, age, BMI for age SDS and blood pressures.

Results

Out of 27 diabetic pregnancies recorded in the hospital’s medical records, we identified 24 live offspring (age range 5.2–7.8 years). One child was excluded because she had a congenital cardiac malformation. We included 23 children (48% males) born from mothers with diabetes, and 23 matched for sex and age controls. All of the diabetic mothers were first detected as having diabetes in the last semester of this pregnancy.

Offsprings of diabetic mothers were more likely to be born heavy (RR (95% CI) 8.0 (2.1–30.9), p < 0.001). At age 5–7 years, they were more likely to be overweight/obese (RR (95% CI) 2.0 (1.0–4.0), p = 0.04). Although not statistically significant, they were also more likely to have elevated blood pressure (BP), i.e. RR (95% CI) 3.5 (0.81–15.1), p = 0.13.

Children of diabetic mothers had larger measurements in all aspects of cardiac dimensions (Table 1). They were more likely to have high LVM/height2.7, i.e. 43.5% in children of diabetic pregnancy vs. 8.7% in control children (RR (95% CI) 5.0 (1.2–20.4), p < 0.007).
Table 1

Results of M-mode echocardiography measurements

Parameter

Offspring of diabetic mothers (n = 23)

Control (n = 23)

Mean difference

95% CI

p

Mean (SD) LVIDd (cm)

3.65 (0.23)

3.39 (0.17)

0.25

0.13–0.37

< 0.001

Mean (SD) IVSd (cm)

0.65 (0.05)

0.58 (0.07)

0.07

0.03–0.10

0.001

Mean (SD) LVPWd (cm)

0.67 (0.07)

0.58 (0.06)

0.09

0.05–0.13

< 0.001

Mean (SD) LVM (g)

62.95 (12.76)

47.58 (8.56)

15.37

8.91–21.83

< 0.001

Mean (SD) LVM/height2.7 (g/m2.7)

40.96 (7.24)

31.79 (5.06)

9.17

5.45–12.88

< 0.001

Mean (SD) RWT (cm)

0.37 (0.04)

0.34 (0.04)

0.02

0.00–0.04

0.05

95% CI 95% confidence interval, LVIDd left ventricular internal dimension at diastole, IVSd interventricular septal thickness at diastole, LVPWd left ventricle posterior wall thickness at diastole, LVM left ventricular mass, LVMi left ventricular mass index, RWT relative wall thickness

Table 2 displays univariate and multivariate linear regression analyses of variables associated with LVM/height2.7. The table shows that maternal diabetes, overweight/ obesity status and elevated BP were independent predictors for high LVM/height2.7.
Table 2

Adjusted and unadjusted linear regression coefficient for LVM/height2.7 as the dependent variable and maternal diabetes and BMI-for-age SDS and blood pressures as the independent variables

Variable

Unadjusted β

Adjusted β

β

95% CI

p

β

95% CI

p

Maternal diabetes (1 = yes, 0 = no)

9.16

5.43–12.88

< 0.001

5.77

1.42–10.11

0.01

Overweight/obesity (1 = yes, 0 = no)

7.86

3.85–11.88

< 0.001

4.37

0.58–8.16

0.03

Elevated blood pressure (1 = yes, 0 = no)

9.35

4.22–14.49

0.001

5.71

1.17–10.24

0.02

Birth weight (g)

0.01

0.00–0.01

0.002

0.001

− 0.002–0.004

0.56

Age (months)

0.04

− 0.22–0.29

0.77

− 0.04

− 0.23–0.14

0.64

Sex (1 = male, 0 = female)

− 1.29

− 5.93–3.35

0.58

− 2.21

− 5.62–1.21

0.20

Adjusted R-squared

 

0.50

LVM left ventricular mass, BMI-for-age SDS body mass index-for-age standard deviation scores, 95% CI 95% confidence interval

Results showed that offspring of maternal diabetes were more likely to have altered left ventricular (LV) geometry, i.e. 12 (52.2%) out of 23 in the offspring of maternal diabetes compared to 2 out of 23 (0.1%) in the control group (RR (95% CI) 6.0 (1.5–23.9), p < 0.001). Distribution of LV geometry of the study subjects, stratified by maternal diabetes, overweight/ obesity and elevated BP status is displayed in Fig. 1. The figure also shows the association between the combinations of the presence and the absence of the three risk factors, i.e. maternal diabetes, obesity and elevated BP, with the types of the alteration of the LV geometry.
Fig. 1

Distribution of LV geometry of the study subjects stratified by maternal diabetes, overweight/obesity and elevated BP status. Solid black columns: offspring of diabetic mothers; striped columns: control group

Discussion

Our study observed that maternal diabetes, along with overweight/obesity status and elevated blood pressure, were independent risk factors for high left ventricular mass (LVM) in childhood. Together, they contributed around 50% to the increase. To the best of our knowledge, this is the first research to report the persistence of increased LVM and altered LV geometry in offsprings of mothers with diabetes. Most previous studies did not observe any residual cardiac hypertrophy after the first months of life [9, 20].

In this study, we were not able to classify the types of maternal diabetes, whether they were gestational diabetes or pre-existing diabetes mellitus (DM), i.e. either type 1 or type 2, because diabetes was first diagnosed in the last part of the third semester of this pregnancy only by several random blood glucose measurements of above 200 mg/dL without any further workups [15]. Moreover, as measurement of glycosylated hemoglobin (HbA1c) was not performed, we were also unable to assess the glucose control of DM. A study in Egypt observed influence of diabetic control on fetal cardiac pathology. Thicker interventricular septum (IVS) and right and left myocardial wall were observed in newborns of uncontrolled diabetic pregnancy (HbA1c > 6.5) compared to newborns from well-controlled diabetic pregnancy (HbA1c < 6.5) [21]. However, a study in Spain observed a tendency towards mild IVS hypertrophy even in well-controlled diabetic pregnancies [4].

The pathogenesis of increased LVM in infants of diabetic mothers is still unclear. Although fetal hyperinsulinism has long been suggested as the cause, the association between hypertrophic cardiomyopathy and high insulin levels in amniotic fluid has only recently been demonstrated [20]. The normalisation of post-natal insulin level might be the explanation of the post-natal regression of the cardiomyopathy observed in most studies [20]. As this study observed persistent cardiac hypertrophy at later age, it is interesting to know the insulin level of those children.

Despite the fact that offspring of mothers with diabetes were at increased risk for obesity and hypertension, the mechanism of how fetal exposure to diabetes increased the risk for later cardiovascular disease (CVD) remains unclear [7, 22]. Some argue that this was associated with higher risk for macrosomia, i.e. macrosomic infants were at higher risk for obesity. Others concluded that this was purely coincidence, i.e. diabetic women had genetic risks and life styles that were associated with higher risk for diabetes mellitus and cardiovascular risk. The risks, including the lifestyle, were inherited by her offspring [6]. This study, however, observed that the risk for increased LVM was independent from both birth weight and overweight/obesity status.

Most alterations in cardiac geometry reported prenatally or immediately after birth affected preferentially the interventricular septum (IVS), due to its abundance in insulin cardiac receptors [21]. However, at a lesser degree, left and right posterior free walls might also thicken [20, 21]. Our study observed increased dimension of both the IVS and the left ventricular posterior wall that lead to increased left ventricular mass (LVM) which was a strong and independent predictor for later cardiovascular events [8, 23]. It was not known, however, whether the thickening of the posterior wall was already present at birth or had developed thereafter because cardiac LVM and left ventricular (LV) geometry were not assessed in fetal life or at birth. This study could indicate, however, that the presence of post-natal factors, such as obesity and elevated BP, was associated with more severe alteration of LV geometry.

Conclusions

We concluded that diabetic pregnancy, along with overweight/obesity status and elevated BP, were independent risk factors for high left ventricular mass (LVM) in childhood. Together, they contributed 50% to the increase in LVM. As diabetic pregnancy was also associated with the offspring’s increased risk for obesity and elevated BP, the presence of the three risk factors seemed to result in a more severe alteration of LV geometry.

Notes

Author contributions

All the three authors’ (RL, N, MJ) contributed to the conception and the design of the study. RL and N contributed to the acquisition of the data, and RL and MJ analysed the data. All authors (RL, N, MJ) contributed to the interpretation of the data. RL drafted the article. N and MJ critically revised the draft. All (RL, N, MJ) approved the version to be published and agreed to be accountable for all aspects of the work, including ensuring integrity and accuracy.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Medical and Health Research Ethics Committee, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and national regulations and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from parents before data collection.

Prior publication in the abstract form

The abstract of this paper has been presented in The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society (APPES) in Tokyo, Japan, in November 19, 2016.

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Copyright information

© Research Society for Study of Diabetes in India 2018

Authors and Affiliations

  1. 1.Department of Child Health, Faculty of MedicineUniversitas Gadjah Mada/Dr. Sardjito HospitalYogyakartaIndonesia
  2. 2.Division of Paediatric Cardiology, Department of Child Health, Faculty of MedicineUniversitas Gadjah Mada/Dr. Sardjito HospitalYogyakartaIndonesia
  3. 3.Division of Paediatric Endocrinology, Department of Child Health, Faculty of MedicineUniversitas Gadjah Mada/Dr. Sardjito HospitalYogyakartaIndonesia

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