Nghiên cứu tình trạng phì đại cơ tim và chức năng tim của thai nhi bằng siêu âm ở thai phụ bị đái tháo đường trong thai kỳ tt tiếng anh

MINISTRY OF EDUCATION

MINISTRY OF HEALTH

HANOI MEDICAL UNIVERSITY

NGUYEN THI DUYEN

RESEARCH ON HYPERTROPHIC CARDIOMYOPATHY
AND CARDIAC FUNCTION BY ULTRASOUND
IN FETUSES OF DIABETIC MOTHERS

Specialzation : Cardiologist
Code

: 62720141

SUMMARY OF THESIS

HA NOI - 2020


THE DISSERTATION WAS COMPLETED IN HANOI
MEDICAL UNIVERSITY

Scientific supervisor:

Assoc. Prof. MD. Truong Thanh Huong

Scientific supervisor 1: Associate Professor. PHAM HUU HOA

Scientific supervisor 2: Associate Professor. PHAM BA NHA

Scientific supervisor 3: Associate Professor. DINH THI THU HUONG

The thesis will be defended in front of The Council for Philosophy
Doctor in Medicine at Ha Noi University
At….. hour

day

month 2020

The thesis can be found at:
- The National Library
- Ha Noi Medical Library


1
INTRODUCTION
The urgency of the topic
Hypertrophic cardiomyopathy (HCM) and cardiac dysfunction in fetuses of
diabetic mother accounts for 15% of fetal cardiomyopathy, increasing perinatal
mortality by 3%, accounting for 15% of causes general death. However, this is also
one of the rare fetal cardiomyopathy that can be recovered if detected early and
treated promptly. Pre-pregnancy diabetes and uncontrolled diabetes have been
shown to increase the incidence of this disease in the fetus. But if a diabetic mother
is accompanied by obesity, over-weight gain during pregnancy or having fetal
macrosomia could increase the risk of fetal HCM, and how does the HCM affect to
fetal postpartum outcomes are issues that have not been clarified yet. At the
Department of Endocrinology-Diabetes of Bach Mai Hospital, a large number of

diabetic mothers are examined and treated, even though there is a multidisciplinary
combination with extensive experience in managing diabetes in pregnancy, but still
encounter many difficulties in controlling postpartum events in the fetus. With the
trend of developing fetal echocardiography (FE) applications in evaluating fetal
cardiac function and also stemming from practical needs on the subject, we
performed the topic "Research on hypertrophic myocardiopathy and cardiac
function by ultrasound in fetuses of diabetic mothers" with the desire to learn
more about what is left unanswered. The study was conducted with the following
two objectives:
1. To determine the prevalence, characteristics of hypertrophic
cardiomyopathy and cardiac function in fetuses of diabetic mothers.
2. To survey on some factors of mother and fetus related to fetal hypertrophic
cardiomyopathy.
New conclusions of the thesis
1. This is the first study in Vietnam determine the prevalence, characteristics
of hypertrophic cardiomyopathy and cardiac function in fetuses of diabetic
mothers and survey on some factors of mother and fetus related to fetal
hypertrophic cardiomyopathy. The descriptive longitudinal follow-up study on
511 pregnant women ensures rigorous scientificity and high reliability.
2. Diabetic mothers were accompanied by obesity, overweight gain during
pregnancy, fetus that "older than gestational age" could increase the risk of
developing HCM in the fetus and this HCM condition could increase the risk of
preterm birth, low birth weight, low 1 minute Apgar score less than 7. With
HbA1C value increased more than 6,1% could be predicted the occurrence of
HCM in the fetuses of diabetic mothers.
The composition of the thesis
The thesis consists of 128 pages, including: introduction 2 pages, overview
45 pages, research designs and methods 18 pages, results 24 pages, discussion 35
pages, conclusions 2 pages, recommendation 1 page, limitation of the thesis 1
page. The thesis consists of 23 tables, 19 charts, 36 pictures, 7 schematics, 159

references (16 Vietnamese documents and 143 English documents).


2
Chapter 1: OVERVIEW

1.1. Background of hypertrophic cardiomyopathy and cardiac dysfunction in
fetuses of diabetic mothers.
Diabetes in pregnancy is divided into 2 groups: pre-gestational diabetes and
gestational diabetes. According to the International Diabetes Federation,
Vietnam is one of the countries with the highest rates of diabetes in the world. In
addition, the prevalence of gestational diabetes increased significantly from 2,1
to 39% according to different diagnostic criteria. Diabetes in pregnancy has
many consequences for the mother and fetus. Fetal HCM due to diabtetic mother
is a common complication, accounting for about 33,3% of well-controlled
diabetic mothers and up to 75% in uncontrolled diabetic mothers. Fetal cardiac
dysfunction is also a frequent complication in these fetuses with mainly reduced
diastolic function at the rate of 15 - 40% and 5% systolic heart failure.
Fetal HCM related to diabetic pregnancy is an abnormal thickening of the
ventricular walls or interventricular septal (IVS) due to maternal hyperglycemia
without other cardiomyopathic etiologies in the fetus. Pathogenesis mechanisms
through four main pathways: increased fetal blood insulin, changes in the signaling
pathway to the target heart gene, overproduction of oxidative reagents and
increased fetal growth factors. Histopathological damage of fetal cardiomyopathy
due to diabetic mother is glycogen deposition, increases protein synthesis mainly
myosin, leading to an increase in myocardial cells size especially in IVS.
According to the recommendations of the American College of Cardiology and
the American Heart Association on the diagnosis of HCM, the diagnosis of fetal
HCM when the thickness of any cardiac walls or IVS is measured at the end of
diastole on time mode ultrasound is more than 2 time of standard deviations from

the mean of normal fetuses at the same gestational age. HCM in the fetus due to
diabetic mother has a number of specific characteristics such as: common in the
last 3 months of pregnancy, most hypertrophy of the IVS, the severity of
hypertrophy is usually moderate, less likely to obstruct the output of the ventricle,
may present transiently in the fetus and especially must occur in the fetus whose
mother was diagnosed with diabetes during pregnancy. Fetal cardiac dysfunction
due to diabetes is often discreet diastolic function. However, in order to diagnose
fetal anomaly in diabetic mother still need to eliminate other HCM etiologies in fetus,
so the diagnosis and monitoring after birth in these fetuses are very important.
1.2. Characteristic of structure and function of normal fetal heart and the role
of echocardiography in assessing fetal cardiac thickness and function.
The physiology of the fetal circulation is really different from after birth. The
fetal myocardium has inefficient contraction due to immature myocardial cells,
underdeveloped T-duct system, metabolism dependent on lactate metabolism
with low energy source, myocardium contains many protein components less
differentiated, large intracellular matrix makes fetal myocardium less dilated and
low elasticity, leading to reduced "inherent" physiological diastolic function in
the fetus. During pregnancy, fetal myocardial cells gradually improve in quality
and increase in size, reduce intracellular matrix, arrange and differentiate the
structure into a 3-layer pattern as in adulthood, thereby fetal cardiac function
gradually matures and improves. With the existence of internal and external
cardiac flows, the impact of preload and afterload on fetal cardiac performance is
also different from that of adulthood. Therefore, the assessment of fetal cardiac
function must be consistent with the development stage of the fetus.


3
Fetal echocardiography (FE) was introduced more than 50 years ago with the
first role of identifying heart defects. Nowadays, FE becomes more and more
useful in evaluating fetal heart function from an early stage, in order to minimize

fetal mortality. Most of the evaluation parameters for fetal cardaic function have
been widely used in children and adults such as quantifying the velocity of flow
through the heart valves, estimating the strock volume, cardiac output, velocity and
the teleport, deform into the heart. FE can overcome and supplement the
disadvantages of other techniques in evaluating fetal heart function but there are
also certain difficulties and must be adjusted according to gestational age.
1.3. Overview of studies on fetal HCM and cardiac dysfunction due to
diabetic mother
In the world, the first case of HCM was recorded in an infant of a diabetic
mother by Maron et al in 1937. Since 1992, many studies have presented the
prevalence, characteristics of HCM and cardiac dysfunction of fetuses due to
diabetic mother, and proving the relationship between this complication and type
of diabetic mother, the severity of maternal blood glucose, as well as the role of
glucose control in limiting this pathology in the fetus. However, there have been no
studies evaluating the impact of obesity and the excessive weight gain during
pregnancy on fetal HCM and fetal cardiac dysfunction or its impact on postpartum
outcomes. In Vietnam, studies of FE in evaluation of cardiac function is still new.
Nowadays, the best FE study in our country was belonged to Le Kim Tuyen (2014)
on the role of FE in diagnosing congenital heart disease before birth. In the context,
the incidence of diabetic mother in our country is increasing. Many studies by local
authors have determined the prevalence of perinatal events of fetuses whose
mother has diabetes during pregnancy as well as the relationship with the mother's
severity of hyperglycemia. However, there have not been any studies evaluating
the association between fetal HCM and perinatal outcomes of these fetuses.

Chapter 2: RESEARCH DESIGNS AND METHODS
2.1. Subjects
2.1.1. Inclusion criteria and exclusion criteria
a. Inclusion criteria:
 Pregnant women greater than or equal to 18 years of age at the time of the study,

 Single pregnancy,
 Natural pregnancy,
 Pregnancy from 28 weeks or more,
 Pregnant women agreed to participate in the study.
b. Exclusion criteria:
 On the mother' side:
 Having diseases that affect to glucose metabolism, acute and chronic diseases,
 Using drugs that affect to glucose metabolism or fetal cardiac function,
 Have pregnancy by intervention methods
 On the fetus’ side:
 Having basic prenatal mid-high risk screening tests,
 Having abnormal structural heart: congenital heart disease, tumor,..
 Having arrhythmias,
 Fetal HCM due to other uterio etiologies,
 Was still-borned at the time of study.


4
2.1.2. Criteria for categorizing disease groups and control groups
 Disease group criterias: women diagnosed with diabetes during pregnancy
according to American Diabetes Association(ADA) in 2017.
 Control group criterias: healthy pregnant women who had the same
maternal age and gestational week matching with disease group, had normal
BMI before pregnancy, had standard weight gain during pregnancy and were
excluded from gestational diabetes by negative oral glucose tolerance test at 28
weeks gestation at the Endocrinology Department of Bach Mai Hospital. As
well as, their fetuses satisfied the criteria afterbirth such as full term birth,
normal birth weight and normal postpartum screening.
2.2. Research methods
2.2.1. Study design: a descriptive longitudinal follow-up study.

2.2.2. Sample size and sample selection:
 The sample size was calculated by using the formula to find the incidence,
with p = 0,33 (was the incidence of the fetal HCM of diabetic mothers in previous
studies)  at least 120 diabetic mothers.
 Sample selection: by the convenient method, we took in the study of pregnant
women from the Department of Endocrinology and Obstetrics - Bach Mai
Hospital from 1/2017 to 1/2019, which satisfy research standards. Based on
classification criteria, we selected a minimum of 120 diabetic subjects and a
minimum of 120 normal subjects (at a minimum ratio of 1: 1)
2.2.3. Time, location, researcher and machines
 Period: from 1/2017 to 1/2019.
 Location:Endocrinology-Diabetes,Obstetrics Department-Bach Mai Hospital.
 Researchers: 01 Endocrinologist and 2 Cardiologists
 Facilities: 01 Alphiniti 50G ultrasound machine, Philips brand, the probe
has a frequency of 4-8MHz, the results were stored on a CD
2.2.4. Study variables: including fetal and fetal characteristics
2.2.4.1. Variables of pregnancy characteristics
 General variable: maternal age, risk factors for gestational diabetes, prepregnancy BMI, weight gain during pregnancy up to the time of study, oral
glucose tolerance test, HbA1C, hemoglobin, cholesterol, triglycerides.
 Additional variables in diabetic group: adjust diet or inject insulin
2.2.4.2. Variables on the characteristics of the fetus
 Prenatal variables: gestational week, fetal weight.
 FE variables: fetal heart rate, ventricular cardiac thickness, systolic function
(FS, Ao-VTI, PA-VTI, LV-IVCT, RV-IVCT; MV-S’, TV-S’); diastolic function
(E/A, E/A, E’/A’, E’/A’, LV-IVRT, RV-IVRT); overall cardiac function (MPI)
 Postpartum variables: delivery week, caesarean section method, 1 minute
Apgar’s score, birth weight, perinatal death.
2.2.5. The ultrasound procedure evaluates the wall thickness and fetal
cardiac function
 Step1: Measure the thickness of the ventricular walls and calculate the FS

 Step 2: Measure VTI through aortic valve and pulmonary valve a, fetal heart rate.
 Step 3: Measure the velocity of the E wave, A wave, E/A ratio through MV, TV.
 Step 4: Measure A', E' wave velocity, ratio E'/A' at MV annulus and TV annulus;
IVCT, IVRT time, MPI calculation on tissue Doppler ultrasound.


5
2.2.6. The standards applied in the study
 Diagnostic criteria for diabetes in pregnancy according to ADA 2017
 Diabetes subgroup based on HbA1C above and below 6% according to ADA 2017
 Classification of maternal weight before pregnancy (BMI) and weight gain in
pregnancy (at the time of the study) according to WHO for Asian Pacific people.
 Classification of dyslipidemia according to Vietnam Endocrinology-Diabetes
Association 2019
 Classify anemia of pregnant women according to WHO 2011
 Grouping the risk of gestational diabetes according to ADA 2017
 Classify Apgar scale according to the Ministry of health protocol 2017
 Classification of fetal weight according to WHO
 Classify pregnancy weeks at birth according to WHO
 Classify birth weight according to WHOSIS 2011
 Diagnosis of fetal HCM in diabetic mother according the American School of
Cardiology and the American Heart Association
2.2.7. Data analysis: data was entered by excel and analyzed on Stata software 13.1
2.2.8. Schematic of the protocol study

2.3. Research ethics: in line with the Helsinki Declaration of the World Health
Association (2000) and approved by Ethics Council of Hanoi Medical University.

Chapter 3: RESULTS
3.1. General characteristics of the research team

3.1.1. General characteristics of control and disease groups
a. General characteristics of pregnant women
Comments on table 3.1: The study had similarities in general characteristics,
only the average HbA1C concentration, miscarriage/stillbirth history of the
diabetic group were much higher than the control group (p <0,05 ).


6
Table 3.1. General characteristics of pregnant women
General characteristics
Maternal age (year)
Maternal age rate ≥25 (n,%)

Control (n=150) Diabetic group (n=361)
28,30 ± 4,56
29,00 ± 4,37
118(78,6)
291(80,6)
History of maternity
28(18,7)
117(32,4)
2(1,3)
12(3,3)
1(0,7)
9(2,5)
3(2,0)
14(3,8)
5(3,3)
16(4,4)
Subclinical

14(9,3)
26(7,2)
51(69,9)
160(78,8)
54(74,0)
153(75,4)
5,10 ± 0,39
5,6 ± 0,85

Miscarriage/Stillbirth (n,%)
Preterm (n,%)
Macrosoma (n,%)
Impaired glucose tolerance
Familial diabetic history
Anemia (n,%)
Hypercholesterolimia (n,%)
Hypertriglycerid (n,%)
Serum HbA1C (%)

P value
0,068
0,168
0,002
0,371
0,294
0,481
0,569
0,414
0,122
0,813

0,000

b, General characteristics of fetuses
 Distribution of gestational age
Percentage

20,5%
19,7%

Nhómgroup
chứng
Control

30,9%

9,7%

11,6%

11,4%

5%
9,5%
28

Nhóm bệnh
Diabetic
group

9%

1,7% 10,7%
29
30

8,9% 3,9%

9%

6,7%
32
33
34
Gestational week

31

5,1%
35

4,4%
3%
12,9%
36

1,9%
2,3%
37

2,2%

≥ 38

Fetal weight (gam)

Chart 3.1. Distribution of number of fetuses by gestational week
Comments: The average gestational age in the study was 32,3 ± 3,28 (week),
minimum was 28 week, maximun was 39 week. There was no difference in mean
gestational age and weekly fetal distribution between control and diabetic groups.
 Fetal weight.
4000

Nhóm chứng
Control
group

Nhóm bệnh
Diabetic
group

*

(*) p<0,05
2000

*

*

0
28

29

30

31

32
33
34
Gestational week

35

36

37

≧ 38

Chart 3.2. Average fetal weight by pregnant week
Comments: The fetal weight increased with gestational age and this parameter of the
disease group was much higher than the controls at gestational weeks 29, 31, 36.
 Fetal heart rate
Comment on chart 3.3: Average fetal heart rate of 146 ± 8,5 (beats/minute), no
difference between control and diabetic group.


7

Percentage

Chart 3.3. Average fetal heart rate by pregnant week
3.1.2. Unique characteristics of the diabetic group
a. Unique characteristics of diabetic mother
85,9%
82%
75,3%

89,2%

24,7%

18%

14,1%

10,8%

Pre-GD
GD
≥ 6%
< 6%
Yes
No
Yes
No
Type of DM
HbA1C
Obesity

Over-weight gain
DM(Diabetic Mother), GD(Gestational Diabetes), Pre-GD(Pre- Gestational Diabetes)

Chart 3.4. Characteristics of pregnant women in diabetic group
Comments:
 According to the classification of diabetes in pregnant women of ADA 2017,
the rate of diabetes actually only accounts for 18% (65 women).
 According to the average HbA1C, the proportion of diabetic women with
HbA1C ≥ 6% accounts for 24,7% (89 pregnant women).
 According to combined clinical factors, 51 (14,1%) of women were obese
before pregnancy and 39 (10,8%) of over-weight gain in pregnancy.
b. Unique characteristics of fetuses of diabetic group
4,2%
15%
Comments:
Of the 361 fetuses in the
disease group, 54 (15%)
had large pregnancies, the
rest were underweight and
80,8%
normal weight
Fetal macrosomia

Normal weight

Low weight

Chart 3.5. Unique fetal characteristics in diabetic group

8
3.2. Characteristics of fetal ventricular wall thickness and cardiac function
in control group
3.2.1. Characteristics of ventricular wall thicknes of fetuses in control group
Table 3.2. The normal fetal cardiac wall thickness by fetal week
Gestational age(n)
28 (n=88)
29 (n=21)
30 (n=54)
31 (n=58)
32 (n=129)
33 (n=57)
34 (n=44)
35 (n=23)
36 (n=39)
37 (n=15)
≥ 38 (n=11)
28 (n=88)
29 (n=21)
30 (n=54)
31 (n=58)
32 (n=129)
33 (n=57)
34 (n=44)
35 (n=23)
36 (n=39)
37 (n=15)
≥38 (n=11)

Ventricular wall thickness(mm) (Mean ± SD)

IVS
RVW
LVW
Diastole
3,08 ± 0,54
2,84 ± 0,48
2,67 ± 0,46
3,10 ± 0,39
2,81 ± 0,37
2,64 ± 0,33
3,11 ± 0,37
2,87 ± 0,36
2,70 ± 0,34
3,15 ± 0,43
2,90 ± 0,44
2,78 ± 0,40
3,39 ± 0,41
3,20 ± 0,35
3,03 ± 0,34
3,41 ± 0,58
3,16 ± 0,30
3,05 ± 0,28
3,49 ± 0,36
3,31 ± 0,33
3,10 ± 0,30
3,50 ± 0,47
3,21 ± 0,28
3,01 ± 0,24
3,81 ± 0,25
3,47 ± 0,24

3,28 ± 0,29
4,02 ± 0,29
3,50 ± 0,28
3,38 ± 0,28
4,04 ± 0,30
3,59 ± 0,29
3,40 ± 0,36
Systole
4,05 ± 0,52
3,82 ± 0,49
3,62 ± 0,46
4,06 ± 0,38
3,84 ± 0,38
3,64 ± 0,30
4,08 ± 0,37
3,89 ± 0,88
3,67 ± 0,42
4,11 ± 0,42
3,90 ± 0,44
3,75 ± 0,42
4,33 ± 0,34
4,13 ± 0,35
3,92 ± 0,35
4,34 ± 0,35
4,16± 0,30
3,98 ± 0,31
4,47 ± 0,35
4,28 ± 0,34
4,02 ± 0,32
4,51 ± 0,40

4,32 ± 0,28
4,06 ± 0,27
4,72 ± 0,29
4,36 ± 0,26
4,17 ± 0,30
4,94 ± 0,30
4,44 ± 0,29
4,30 ± 0,24
4,96 ± 0,32
4,48 ± 0,33
4,32 ± 0,43

Table 3.3. Correlation coefficient between cardiac thickness
and gestational week – gestational weight in a normal fetus.
Ventricular wall thickness
Diastolic IVS (mm)
Diastolic RVW (mm)
Diastolic LVW (mm)
Systolic IVS (mm)
Systolic RVW (mm)
Systolic LVW (mm)

Correlation coefficient (r)
Fetal age (week)
Fetall weight
0,813*
0,752*
*
0,791
0,733*

*
0,769
0,732*
*
0,777
0,745*
*
0,729
0,678*
*
0,658
0,628*

IVS (interventricular septum), RVW (right ventricular wall), LVW (left ventricle
wall) (*)The correlation coefficient is statistically significant at p < 0,05.
Comments in table 3.2, table 3.3: The cardiac walls thickness in both diastole
and systole increased gradually, tightly correlated with linear gestation and fetal
weight. The largest thickness was IVS, the smallest thickness was LVW.


9
3.2.2. Characteristics of cardiac function of fetuses in control group
Table 3.4. Characteristics of fetal cardiac function in control group
Variables
Ao - VTI (cm)
PA - VTI (cm)
MV - S’(cm/s)
TV - S’(cm/s)
LV - IVCT(ms)
RV - IVCT(ms)

LV - FS (%)
MV - E/A
TV - E/A
MV - E’/A’@
TV - E’/A’
LV - IVRT (ms)
RV - IVRT (ms)
LV - MPI
RV - MPI

Gestational age
28-31+6 week (n=55) 32-35 +6 week (n=92) 36-39+6 week (n=31)
Systolic cardiac function
8,0 ± 0,42
9,6 ± 1,35
11,2 ± 1,15
7,1 ± 0,38
7,8 ± 0,54
9,5 ± 0,84
3,8 ± 0,51
4,0 ± 0,52
4,2 ± 0,64
5,2 ± 0,81
5,4 ± 0,89
5,9 ± 1,13
35,0 ± 3,61
37,5 ± 5,99
37,0 ± 3,16
39,0 ± 5,01
39,0 ± 5,86

38,0 ± 6,68
34,0 ± 4,67
35,5 ± 5,44
35,0 ± 4,66
Diastolic cardiac function
0,67 ± 0,04
0,74 ± 0,05
0,77 ± 0,05
0,74 ± 0,04
0,76 ± 0,05
0,79 ± 0,72
0,74 ± 0,07
0,81 ± 0,07
0,82 ± 0,06
0,72 ± 0,06
0,76 ± 0,09
0,78 ± 0,09
39,0 ± 4,81
41,0 ± 5,94
42,0 ± 5,94
40,0 ± 6,28
42,0 ± 6,47
42,0 ± 5,12
Overall cardiac function
0,38 ± 0,04
0,37 ± 0,04
0,38 ± 0,04
0,39 ± 0,03
0,38 ± 0,03
0,41 ± 0,04

P value
0,000
0,000
0,000
0,005
0,432
0,894
0,206
0,000
0,000
0,000
0,003
0,137
0,228
0,116
0,117

Table 3.5. Correlation coefficient between fetal cardiac function and
gestational age in control group.
Correlation coefficient (r)
Variables

By week
By month Variables
By week
By month
Systolic cardiac function
Diastolic cardiac function
Ao - VTI

0,807*
0,728*
MV - E/A
0,476*
0,546*
PA - VTI
0,830*
0,749*
TV - E/A
0,450*
0,485*
*
*
@
*
MV - S’
0,321
0,269
MV - E’/A’
0,397
0,384*
*
*
*
TV - S’
0,244
0,230
TV - E’/A’
0,213
0,206*

LV – IVCT
0,083
0,097
LV - IVRT
0,124
0,149
RV - IVCT
-0,025
-0,002
RV - IVRT
0,005
0,124
LV - FS
0,055
0,045
Overall cardiac function
LV - MPI
0,037
0,057
@: standard variables,
(*): correlation coefficient is statistically significant RV - MPI
-0,048
-0,011
Ao(aortic valve) VTI (velocity time integral), PA( pulmonary valve), MV(mitral valve),
TV(tricuspid valve), S’(systolic tissue velocity), LV(left ventricle), RV(right ventricle),
IVCT(isovolumetric contraction time), FS(fraction shortening),
IVRT(isovolumetric relaxation time), MPI(myocardial performance index)

Comments on table 3.4 and table 3.5:
 Systolic cardiac function:

 Increased Ao-VTI, PV-VTI reflect an increase in the volume of the squeeze
in the absence of blood flow obstruction. These two indicators increased
significantly by gestation week, closely correlated with gestational age.
 MV-S’, TV-S’ reflect the systolic function due to intrinsic contraction ability of
myocardium, also increased gradually, averagely correlating with gestational age.


10
 LV-IVCT, RV-IVCT are the acceleration of myocardium, reflecting the
systolic function due to the intrinsic ability of myocardium. These two indices
did not change and did not correlate with gestational age in the last trimester.
 LV- FS reflects total systolic function, whether due to changes in preload or
internal myocardium. This index was also not changed by pregnancy week, not
correlated with gestational age in the last trimester.
 Diastolic cardiac function
 The ratio of E/A and E'/A' of left and right ventricle increased gradually
with gestational week, reflecting the maturation of diastolic function. The
linear average correlation but weak with gestational age in the last trimester.
 LV-IVRT, RV-IVRT are relaxation times of the ventricles, reflecting the
diastolic function of the ventricles without relying on loading. These indices
did not change and correlate with gestational age in last trimester.
 Overall cardiac function:
 LV-MPI, RV-MPI are indicators reflecting systolic and diastolic function,
unchanged and did not correlat with gestational age in the last trimester.
3.3. The prevalence, characteristics of fetal HCM and cardiac function of
diabetic mother.
3.3.1. The prevalence and characteristics of HMC in fetuses of diabetic mothers
3.3.1.1. The prevalence of fetal hypertrophic myocardiopathy
 According to type of diabetic mother and the severity of HbA1C
Non - HCM

43,2%

38,2%

56,8%

61,8%

HCM

34,6%
66,1%

69,7%
65,4%

33,9%

30,3%

Diabetic group
Gestational
Pregestational
(n=361)
diabetes (n=296) diabetes (n=65)

HbA1C < 6%
(n=272)

HbA1C ≧ 6%
(n=89)

Chart 3.6. The prevalence of fetal HCM according to type of DM & HbA1C
Comments: The prevalence of fetal HCM in general diabetic group was 43,2%,
increased in pregestational diabetes (66,1%), and in group with HbA1C ≥ 6% (69,7%).
 According to the combined clinical factors of the mother
Fetal Non - HCM

41%
59%

56,9%
43,1%

No (n=310)
Yes (n=51)
Diabetic mother combined obesity

Fetal HCM

41,3%
58,7%

59%

41%

No (n=322)
Yes (n=39)

Diabetic mother combined over
weight gained

Chart 3.7. Prevalence of fetal HCM according to the maternal clinical factors


11
Comments: The prevalence of fetal HCM was significantly increased in obese
mothers was 56,9% and in over-weight gain during pregnancy was 59% compared to
the rest (p <0,05)
 According to fetal weight
40%

40,1%

60%

59,9%

Low weight (n=15)

Normal
weight(n=292)

55,6%

44,4%

Fetal HCM
Fetal non-HCM

Macrosomia
(n=54)

Chart 3.8.The prevalence of fetal HCM according to fetal weight
Comments: The prevalence of fetal HCM in the macrosomia group was 55,6%,
significantly higher than the other groups (p <0,05).
3.3.1.2. Characteristics of HMC in fetuses of diabetic mother
 The severity of fetal cardiac wall thickness
Normal

5,4mm

≤ 1SD
4,9mm

1SD - 2SD
> 2SD
5,6mm

33%

30,7%

34,6%

16,3%

21,3%

16,1%

23,8%

19,4%

23,8%

26,9%

28,5%

25,5%

19,7%
15,5%

RVW

LVW

IVS

Common

43,2%
21,6%

Percentage

Chart 3.9. The severity of fetal cardiac wall thickness in diabetic group
Comments: The absolute absolute cardiac thicknesses were not too thick, there
was no case of obstruction of the outflow of ventricles. Beside that, 19,7% and
21,6% of fetuses increased cardiac wall thickness at ≤ 1SD and 1-2SD.
 Hypertrophic region
80%
76,2%
70,5%
51%
24%

LVW
RVW
IVS
Hypertrophic region

25%

1 region 2 regions 3regions
Number of hypertrophic region

Chart 3.10. The prevalence of HCM by region of hypertrophy


12
Comments: the percentage of hypertrophy in IVS was highest (80%) and the
hypertrophy of all 3 cardiac walls was the most (51%).
3.3.2. Manifestations of cardiac function in fetuses of diabetic mother
3.3.2.1. Manifestations of systolic function
Table 3.6. Systolic function of the fetuses in diabetic group

Categorize fetuses of diabetic group
according to the fetal HCM
Non-HCM (n=205)
HCM (n=156)
28-31+6 week
n
55
80
86
Ao - VTI (cm)
8,0 ± 0,42
8,4 ± 0,95*
9,25 ± 1,66*#
PA - VTI (cm)
7,1 ± 0,38
7,4 ± 0,44*
8,4 ± 1,47*#
MV - S’(cm/s)
3,8 ± 0,51
3,8 ± 0,33
4,0 ± 0,40*#
TV - S’(cm/s)
5,2 ± 0,81
5,3 ± 0,29
5,4 ± 0,38*#
LV - IVCT(ms)
35,0 ± 3,61
36,0 ± 2,25
37,0 ± 1,54*#
RV - IVCT(ms)

39,0 ± 5,01
39,0 ± 3,52
39,0 ± 4,52
LV - FS (%)
34,0 ± 4,67
35,0 ± 3,28
35,0 ± 3,22
32-35+6 week
n
92
102
59
Ao - VTI (cm)
9,3 ± 1,35
9,5 ± 1,07
11,1 ± 1,33*#
PA - VTI (cm)
7,8 ± 0,54
8,15 ± 0,93*
9,6 ± 1,27*#
MV - S’(cm/s)
4,0 ± 0,52
4,1 ± 0,49
4,3 ± 0,48*
TV - S’(cm/s)
5,4 ± 0,89
5,4 ± 0,36
5,5 ± 0,37#
LV - IVCT(ms)
37,5 ± 5,99

37,0 ± 1,77
38,0 ± 1,23#
RV - IVCT(ms)
39,0 ± 5,86
39,0 ± 0,89
40,0 ± 1,30*#
LV - FS (%)
35,5 ± 5,44
35,0 ± 3,14
35,0 ± 3,08
36-39+6 week
n
31
23
11
Ao - VTI (cm)
11,2 ± 1,15
11,4 ± 0,84
12,5 ± 1,78*
PA - VTI (cm)
9,5 ± 0,84
9,8 ± 0,77
10,3 ± 1,67*
MV - S’(cm/s)
4,2 ± 0,64
4,3 ± 0,22
4,5 ± 0,69#
TV - S’(cm/s)
5,9 ± 1,13
6,1 ± 0,28

6,2 ± 0,34
LV - IVCT(ms)
37,0 ± 3,16
37,0 ± 1,44
39,0 ± 1,62#
RV - IVCT(ms)
38,0 ± 6,68
39,0 ± 0,87
40,0 ± 0,75*#
LV - FS (%)
35,0 ± 4,66
34,0 ± 3,38
34,0 ± 2,46
Ao(aortic valve) VTI (velocity time integral), PA( pulmonary valve), MV(mitral valve),
TV(tricuspid valve), S’(systolic tissue velocity), LV(left ventricle), RV(right ventricle),
IVCT(isovolumetric contraction time), FS(fraction shortening), (*): Significantly
different from control group , (#):Significantly different from non –HCM group
Variables

Controls
(n=178)

Comments:
 Compared to control group, in non-HCM fetuses of diabetic group, changes
in systolic function was associated with a significant increased in simple VTI,
especially PA- VTI, without differences in the rest of systolic index.
 In HCM fetuses of diabetic group, both of apparent increased in VTI,
myocardial velocity (MV-S', TV-S') and isovolumetric time (LV-IVCT, RVIVCT) also increased, and were significantly higher than that of non-HCM and
control group.
 FS was within normal limits and no difference between study groups

13
3.3.2.2. Manifestations of diastolic function and overall cardiac function
Table 3.7. Diastolic function and overall cardiac function of the fetuses in
diabetic group
Diastolic and
overall cardiac
function variables
n
MV - E/A@
TV - E/A
MV - E’/A’ @
TV - E’/A’
LV - IVRT (ms)
RV - IVRT (ms)
LV - MPI
RV - MPI
n
MV - E/A@
TV - E/A
MV - E’/A’ @
TV - E’/A’
LV - IVRT (ms)
RV - IVRT (ms)
LV - MPI
RV - MPI
n
MV - E/A@
TV - E/A

MV - E’/A’ @
TV - E’/A’
LV - IVRT (ms)
RV - IVRT (ms)
LV - MPI
RV - MPI

Categorize fetuses of diabetic group
according to the fetal HCM
Non - HCM (n=205)
HCM (n=156)
28-31+6 week
55
80
86
0,67 ± 0,04
0,69 ± 0,04
0,66 ± 0,04#
0,74 ± 0,04
0,76 ± 0,04*
0,74 ± 0,04#
*
0,74 ± 0,07
0,71 ± 0,05
0,70 ± 0,05*
0,72 ± 0,06
0,71 ± 0,05*
0,70 ± 0,04*
39,0 ± 4,81
39,0 ± 0,94

41,5 ± 3,92*#
40,0 ± 6,31
40,0 ± 1,26
43,0 ± 4,22*#
0,37 ± 0,04
0,38 ± 0,02
0,42± 0,04*#
0,39 ± 0,03
0,39 ± 0,01
0,43 ± 0,04*#
32-35+6 week
92
102
59
0,74 ± 0,05
0,74 ± 0,03
0,71 ± 0,04*#
0,76 ± 0,05
0,77 ± 0,03
0,76± 0,06*
*
0,79 ± 0,07
0,76 ± 0,06
0,73 ± 0,05*#
*
0,76 ± 0,07
0,74 ± 0,03
0,73 ± 0,04*
41,0 ± 5,94
40,0 ± 1,16

43,0 ± 3,72*#
42,0 ± 6,47
42,0 ± 1,25
45,0 ± 3,71*#
0,36 ± 0,04
0,38 ± 0,02
0,44 ± 0,04*#
0,38 ± 0,01
0,40 ± 0,01
0,46 ± 0,04*#
+6
36-39 week
31
23
11
0,77 ± 0,05
0,77 ± 0,03
0,73 ± 0,06*#
0,79 ± 0,07
0,80 ± 0,04
0,79 ± 0,06
0,82 ± 0,06
0,80 ± 0,05
0,76 ± 0,06#
0,76 ± 0,09
0,74 ± 0,06
0,75 ± 0,03
42,0 ± 5,94
42,0 ± 1,72
47,0 ± 3,76*#

42,0 ± 5,12
42,0 ± 2,19
42,0 ± 4,50*#
0,38 ± 0,04
0,40 ± 0,03
0,49 ± 0,04*#
0,41 ± 0,04
0,41 ± 0,03
0,51 ± 0,04*#
Controls
(n=178)

(@):expressed as mean ± standard deviation (*): Significantly different from
control group (#):Significantly different from non – HCM group
Comments:
 In the non HCM fetus of diabetic group, there was a significant decrease in
diastolic function, manifested by a simple decrease of E/A and E'/A' in both
ventricles compared to control group, while MPI only increased significantly at 3235+6 weeks of gestation.
 In the HCM fetuses of diabetics group, the right ventricular and left ventricular
diastolic function were significantly reduced, not only decreased the ratio of E/A
and E'/A' but also significantly increased IVRT of both ventricles. The MPI of
right ventricle and left ventricle decreased significantly compared to other group.


14
 The prevalence of decreased overall cardiac function in fetuses of diabetic mothers
Normal overall cardiac function

Reduced overall cardiac function

16,9%
40,8%
79,8%

83,1%
59,2%
20,2%
Diabetic group (n=361) non - HCM - diabetic HCM - diabetic group
group (n=205)
(n=156)

Chart 3.11. Prevalence of overall cardiac dysfunction in fetuses of diabetic mothers
Comments: The prevalencw of the decreased overall cardiac function of the fetuses
of diabetic mothers was 40,8%, higher in the HCM fetus group (79.8%)
3.4. Relationship between some factors of mother and fetuses to fetal HCM

3.4.1. Relationship between some maternal factors and fetal HCM
Factors included maternal weight, HbA1C and treatment of maternal
hyperglycemia.
3.4.1.1. Relationship between maternal weight, HbA1C and fetal HCM

Table 3.8. Relationship between maternal weight, HbA1C and fetal HCM
The fetal HCM
Some factors of mother

Univariate analysis

Multivariate

OR

95%CI

OR

95%CI

Obesity before pregnancy

1,89

1,04 - 3,45

1,41

0,74 - 2,69

Over-weight gain during pregnancy

2,04

1,03 - 4,01

1,47

0,71 - 3,03

HbA1C ≥ 6,0%

4,34

2,59 - 7,28 3,99

2,36 - 6,76

Comments:
 The univariate analysis showed that the risk of developing HCM in the
fetuses of diabetic mother with obesity, over-weight gain in pregnancy and had
HbA1C ≥ 6% was 1,89 times higher than the cases of mothers with diabetes
without obesity, was 2,04 times higher than pregnant women without overweight
gain and 4,34 times than mothers with HbA1C below 6%.
 Results of multivariate analysis showed that the risk of developing fetal
anomalies in mothers with HbA1C ≥ 6% was 3,99 times higher than that of
mothers with diabetes and HbA1C <6%, when there was an interaction of other
factors such as obesity or over-weight gain during pregnancy.


15

Chart 3.12. Prognostic value of HbA1C with fetal HCM of diabetic mother
(n = 361, AUC = 0,753; Sensitivity = 59%, Specificity = 97,5%, cutoff value = 6,1%, PR2 = 18%)

Comments: With an HbA1C value from over 6,1%, it was likely to predict the
development of HCM in the fetus whose mother has diabetes during pregnancy
with sensitivity = 59%, specificity = 97,5% and the AUC = 0,753.
3.4.1.2. Relationship between diabetes treatment in pregnancy and fetal HCM
361 women with gestational diabetes were managed in the Department of
Endocrinology and Obstetrics Department of Bach Mai Hospital, in which, 240
fetuses received FE at least 2 times with the average follow-up period of 5,02 weeks.

Chart 3.13. Variations in fetal HCM Chart 3.14. Variations in fetal cardiac
frequency in the treatment group
function in the treatment group
Comments: Treatment of hyperglycemia during pregnancy significantly reduced
the prevalence of HCM and overall cardiac function reduction in fetuses of
diabetic mother, this result appeared in both diet-adjusted and insulin group.
3.4.2. Relationship between some fetal clinical factors and fetal HCM
3.4.2.1. Relationship between fetal weight and fetal HCM
Table 3.9. Relationship between fetal weight and fetal HCM
Fetal HCM
Fetal weight
OR
95%CI
Macrosomia
1,02 - 3,21
1,8
Comments: The univariate analysis showed that the risk of developing HCM in the
fetus was 1,8 times than in the case of non-large fetuses and the difference was
statistically significant with 95% confidence level.


16
3.4.2.2. Relationship between fetal HCM and the postnatal outcomes.
All 511 fetuses were clinically monitored postnatal through patient
questions, direct examinations and medical records.
Table 3.10. Relationship between fetal HCM and the postnatal outcomes.
Categorize fetuses of diabetic group
Postpartum outcome
according to the fetal HCM (n=361)
variables

Non- HCM
HCM
P value OR (95%CI)
(n=205)
(n=156)
No
195(95,1)
139(89,1)
Preterm birth
2,38
0,031 (1,06-5,36)
(n,%)
Yes
10(4,9)
17(10,9)
No
198(96,6)
142(91)
Low birth weight
2,78
0,025 (1,09-7,08)
(n,%)
Yes
7(3,4)
14(9)
Cesarean section
No
202(98,5)
149(95,5)
3,16

due to fetal failure
0,083
(0,80-12,4)
Yes
3(1,5)
7(4,5)
(n,%)
199(97,1)
143(91,7)
1st minute Apgar No
3,01
0,023 (1,11-8,12)
score ≤ 7 (n,%)
Yes
6(2,9)
13(8,3)
Perinatal deaths
0
0
(n,%)
Comments:
 The percentage of preterm birth was significantly higher among the diabetic
group. The risk of preterm birth in a HMC fetuses was 2,38 times higher than
in the cases of non-HCM group.
 The percentage of low birth weight of the HCM group was much higher than
the non-HCM group (p = 0,025). The risk of low birth weight in HCM group
increased by 2,78 times compared with non-HCM group.
 The method of cesarean section due to fetal failure was not significantly
different between the diabetic group with HCM and without HCM.
 The percentage of fetuses with low 1st minute Apgar score ≤ 7 in HCM

group was significantly higher than non-HCM group (p = 0,023). The risk of
low 1st minute Apgar score ≤ 7 in the HCM fetuses were increased by 3,01
times compared with non-HCM fetuses.
 There was no perinatal death during the study period.
Chapter 4: DISCUSSION
4.1. General characteristics of the study groups
4.1.1. General characteristics of controls and disease groups
Our study had a similarity in gestational age, which helped to partially
eliminate the effect of this factor on fetal development in the uterine. In addition,
for the risk factors for diabetes during pregnancy, only the history of miscarriage
or stillbirth of diabetic group was significantly higher than the controls.
Meanwhile, the rate of anemia, increased cholesterol and triglycerides of
pregnant women at the time of the study were 7,8%, 76,5% and 75% similar to
the study of Hiramatsu Y et al (2012), Barrett HL et al (2014) in healthy
pregnant women, and there was no difference between the control and diabetic
group. This may help limit the effects of physiological anemia as well as lipid


17
metabolism disorders on fetal myocardium, which has been reported in several
previous studies. The average HbA1C of the disease group was not too high (5,6
± 0,85,%) and was the only subclinical index that was different from controls
(table 3.1).
The fetuses in the study had an average gestational week at the start of the
study which was 32,3 ± 3,28 (weeks), dispersed from week 28 to week 39, but
focused mainly on fetal weeks 28 and 32 (chart 3.1), because this was the time
for the women usually checking for blood glucose tolerance test and birth
registration. The average gestational weight of the groups in the study increased
linearly with the gestational week and was only actually larger in the gestational
group at gestational weeks 29, 31 and 36 (chart 3.2). The uniformity and

fluctuation within the normal range of fetal heart rate in chart 3.3 would help to
limit errors in measurement of cardiac function in the fetus.
4.1.2. Unique characteristics of diabetic group
Compared with gestational diabetes, pre-gestational diabetes poses a higher
risk for fetal heart disease Of the 361 women with diabetes during pregnancy,
only 65 (18%) of diabetic mothers actually were gestational diabetes. Because
the average HbA1C level of the disease group was not too high (5,6±0,85,%),
based on the goal of controlling blood glucose for diabetic mother if there is no
sign of hypoglycemia of ADA 2017 is HbA1C <6%, and based on the
recommendation of the American Heart Association fetal echocardiography for
diabetic mother with HbA1C ≥ 6% in the last trimester, we chose upper and
lower HbA1C threshold 6% to clarified risk group for diabetic mother. The
results presented in chart 3.4 showed that the blood glucose level of disease
group in our study was not too high with the proportion of diabetic mother
having HbA1C blood ≥ 6%, accounting for only 24,7%. This was probably
because 39,5% of pregnant women in the moderate risk group, while cases of
stillbirth due to complications of maternal hyperglycemia without previous FE
were excluded from the study. Along with the development of obesity was the
explosion of gestational diabetes, the obesity rate of diabetic group was 14,1%
higher than previous studies. In addition, according to Scifres, CM et al (2014),
excessive weight gain during pregnancy was also a risk factor for causing a
macrosomia. And in our study, the over-weight gain rate during pregnancy was
10,8%. Hyperglycemia in the third trimester of pregnancy had been shown to be
one of the major risk of fetal macrosomia, and in our study, the rate of
macrosomua in diabetic group was 15%.
Thus, the blood glucose level of the disease group in our study was not too
high, however, the proportion of pregnant women with a combination factor such
as obesity, over-weight gain in pregnancy also accounted for to 14,1% and
10,8%. Especially, up to 15% of fetuses in the disease group were "larger than
the gestational age".

4.2. Characteristics of fetal cardiac thickness and cardiac function in controls
In this study, we chose a cross-sectional study to establish normal values of
fetal cardiac thickness and function by the last trimester of pregnancy for the
following reasons: firstly, only ultrasound survey in line with the
recommendations of the World Association of Obstetrics and Gynecology,
secondly, the data collection is easier with the best statistical strength because


18
the data is more representative for the surveyed population. And to overcome the
disadvantage that is difficult to control in the fetus with abnormal development
later, we only included studies of fetuses who met the postpartum selection
criteria. However, there were 28 cases having the second FE control group after
an average of 5,02 weeks to ensure adequate normal data as a basis for comparison
for the disease group in late pregnancy (after 36 weeks). Therefore, although there
were 178 FE records of the control group, it represented only 150 normal fetuses
and this is one of the limitations of this study. However, 150 normal fetuses still be
enough to match the sample size requirements of the control.
4.2.1. Characteristics of fetal cardiac wall thickness in control group
During the last trimester of pregnancy, fetal myocardial cells continue to
grow in quality, so the cardiac wall thickness of the heart increases in response to
changes in preload and afterload. In the fetal circulation, the right ventricle is
predominantly working than the left ventricle so the thickness of RVW is thicker
than LVW, while IVS is the myocardial region under the interaction of the two
ventricles in pressure and volume, so it is usually thicker than other ventricular
walls. Our research results showed that, the average cardiac wall thickness in
both systole and diastole of the control groups increased gradually by gestational
week, in which the IVS thickness was the most dominant, followed by RVW,
and LVW was smallest (table 3.2). In addition, both cardiac and diastolic cardac
wall thickness were strongly and linearly correlated with gestational week and

fetal weight (table 3.3), consistent with the regression model of the size of the
cardiac wall according to gestational age by Le Kim Tuyen et al (2014). The
results of IVS thickness in our study was similar to those of Veille et al (1996),
Lawan Patchakapat MD et al (2006) when evaluating the same gestational age
and technique using.
4.2.2. Characteristics of fetal cardiac function in control group.
As with the thickness of the cardiac wall, parameters that reflect systolic
function also increase with fetal heart maturation, in order to accommodate the
increase in preload and post-shift changes. Increasing the velocity of blood flow
over time (VTI) through the aortic valve and aortic valve indicates an increase in
preload in the absence of obstruction of the ventricular ejection pathway.
Besides, increasing the maximum myocardial velocity in the systolic (S wave)
due to the maturation of myocardial intrinsic also reflects the improvement in
systolic function in the third trimester of pregnancy. Results of our study that
presented in tables 3.4 and 3.5 showed that the PA-VTI, Ao-VTI increased
significantly and correlated linearly with gestational week, MV-S', TV-S' also
increased by week, but with the moderate correlation, while the time of
isovolumetric contraction of the right ventricle and left ventricle (RV-IVCT, LVIVCT) and left ventricular fraction shortening (FS) fractions reflects total
systolic function even due to changes in loading and myocardial intrinsic, almost
not change and not correlation with gestational week. The above results were
quite similar with some previous studies such as Maria Ame’lia et al (2008),
CHU chen et al (2012), Sevket Balli vs cs (2013).
In the last trimester, immaturity of myocardial cells and fetal heart
architecture has created a pattern of physiologically impaired relaxation,
expressed as an E/A ratio of always less than 1. As normal pregnancy progresses,
the preload increases while afterload decreases and the ability to expand


19
myocardium increases, so the E/A ratio increases during pregnancy, however,

this indicator is prone to affected by loading. Similar to the E/A ratio, the E’/A’
ratio also increased due to the increase in rapid filling that explained by the
improvement in active cardiac relaxation. At any gestational week, the ratio of
E/A, E'/A' of the right ventricle are always higher than the left ventricle because
the vertical distribution of myocardial fibers in RVW differs from the
distribution of periodic muscle fibers in IVS, or evenly distributed vertical and
circumference in the LVW. According to author Noirin E. Russell (2008), in
normal pregnancies, the duration of volume expansion is also improved due to
the improvement of the ventricular dilatation, but almost unchanged in the last 3
months. In our study, we found a gradual increase in gestational weeks of E/A,
E'/A' ratio through mitral valve and tricuspid valve, TV-E'/A' always lower than
MV-E'/A', while the isovolumetric relaxation time were almost unchanged (table
3.4), and these two indicators were also weakly correlated with gestational week
(table 3.5), similar to the results of some authors done in same gestational week
and the same measurement method as CHU chen et al (2012), Sevket Balli et al
(2013), Anupama Nair et al (2018).
MPI is an index of myocardial performance, which reflects the systolic and
diastolic function due to the formation of the isovolumetric relaxation time
(IVRT), which reflects the diastolic function and the isovolume contraction time
(IVCT), ejection time (ET) reflects systolic function. Tsutsumi et al used the
MPI index to assess the overall cardiac function of the normal fetus, showing
that the LV-MPI was 0,62 ± 0,07 at 18-26 weeks, then decreased and constant at
normal value with 0,43 ± 0,03 after 34 weeks gestation due to maturation of
myocardium. MPI inversely correlated with gestational age was also noted in
Chen et al. (2006). Our research results in table 3.4 showed that the LV-MPI,
RV-MPI in the control group were almost unchanged in the last 3 months and
RV-MPI was always higher than LV-MPI, and was not relevant with gestational
weeks, similar studies of some authors Eidem et al (2001), Acharya et al (2004),
Sevket Balli et al (2013).
4.3. The prevalence, characteristics of HCM and cardiac manifestation in

fetuses of diabetic mothers
4.3.1. The prevalence and characteristics of fetal HCM in diabetic mothers
4.3.1.1. The prevalence of fetal HCM
The overall prevalence of developing a fetus with a mother with diabetes in our
study is 43,2% (chart 3.6), which was similar to other studies such as 40% of
Hatem MA(Brazil, 2008), 40,3% of EL. Ganzoury (Greece, 2012), 40% of Tabib
(Iran,2013). The prevalence of fetal HCM of pre-gestational group was actually
higher than that of gestational diabetes (66,1% vs 38,2%) (chart 3.6) and increased
in diabetic group with HbA1C ≥ 6% (69,7%), similar to Corolina, Zielinsky P et al
(2004). However, even in diabetic group with HbA1C <6%, there were 34,6% of
the HCM fetuses (chart 3.6), that was also recorded in the study of Usama M.
Fouda et al (2013) with 9% fetus of IVS hypertrophy with normal HbA1C.
Therefore, periodic FE is really necessary screening test for all diabetic mothers,
and contributes to coordinate the evaluation of well controlled diabetes.
In addition to hyperglycemia, the prevalence of HCM significantly increased in
diabetic mother with obesity or overweight gain during pregnancy (56,9%, 59%)
(table 3.7). Beside that, 85% of obese pregnant women and 78,4% of over weight


20
gain women had hyper-cholesterol and/or hyper-triglyceridemia. Thus, it seemed that
the problem of weight and hyperlipidemia during pregnancy may be the combined
risk factors in diabetic mother, affecting the HCM in the fetuses.
Fetal macrosomia is one of the most common manifestations in diabetic
mother. Fetal HCM in diabetic mother appears in fetus with 38 - 59%. In our
study, although the fetal incidence was only 15% (chart 3.5), the prevalence of
fetal HCM in the fetal macrosomia group was 55,6%, much higher than the
remaining group (chart 3.8).
4.3.1.2. Characteristics of HCM in fetuses of diabetic mothers
The results of our study once again showed the classic features of HCM in

fetuses due to diabetes in pregnancy. With the severity of hypertrophy not so
much, there was no case of outflow tract obstruction of ventricles. However, in
order to distinguish them from some other HCM in the fetus, these women were
consulted and advised to periodically monitor FE until the fetus's heart was
completely normal. In addition, our study also reported that IVS region
hypertrophy accounting for the most (80%) similar to that of Veille JC et al
(1992), which was explained by the highest distribution of insulin receptors in
this region. This condition can cause the type of eccentric hypertrophy and
obstruction of the left ventricular outflow as previously noted by Gutgesell H et
al (1980). However, in our study, the severity of hypertrophy was not too much,
along with the rate of hypertrophy of all 3 ventricular walls was the most (51%)
(chart 3.10), perhaps so that we did not see any case of the outflow obstruction.
4.3.2. Manifestations of fetal cardiac function in diabetic mothers.
In our study, there was almost no difference in the systolic function of fetus
between the non-HCM diabetic group and the controls, except of increasing flow
velocity (VTI) through aortic valve and pulmonary valve before the 36 gestational
week (table 3.6), similar to Ren et al (2011), Chu C et al (2012). This phenomenon
reflected an increase in fetal circulation under the influence of hyperglycemia and
this change was evident in the poor controlled control group or in fetal HCM
group. In addition, the intrinsic changes of myocardium are more pronounced in
the HCM diabetic group with a marked increase in the velocity of myocardial
tissue (TV-S', MV-S') and prolong the isovolumetric contraction interval (IVCT)
(table 3.6). Hatem MA et al (2008) demonstrated a reduction in relaxation and
expansion of the ventricles in the fetus of diabetic mother that promoted an
increase in myocardial velocity as an adaptation to hypertrophy rather than
distortion of the ventricles in other HCM pathology. Thus, the increase in systolic
function manifested very discreetly in the fetus of diabetic mother, the systolic
function only becomes serious reducing when there was manifestation of the
outflow tract obstruction or hypertrophic myocardial tissue was severe, so the left
ventricular fraction shortening in our study was still in the normal range (table 3.6).

About the diastolic function, the results in our study as well as Pinar
Dervisoglu et al (2018), the ratio of TV-E/A decreased prematurely in fetuses of
non-HCM diabetic group, suggesting the impact on right ventricular diastolic
function was earlier than the left ventricle, as the right ventricle operated
predominantly during pregnancy and maternal hyperglycemia increased the
placental vascular resistance affecting the posterior right ventricular afterload. In
addition, the E'/A' ratio in both right and left ventricles also decreased
significantly compared to the control group, which was mainly due to the


21
decrease in E' wave velocity (table 3.7). Therefore, a decrease in the ratio of E/A,
E'/A' were a discreet manifestation of decreased diastolic function in fetuses of
diabetic mother and this early disorder may not be related to HCM. For the HCM
fetus, the diastolic dysfunction appeared to be more complicated by the intrinsic
cardiac changes rather than the changes in the preload and afterload. Our study
showed that in the HCM fetus group, besides reducing the ratio of E/A and E'/A',
IVRT in both right and left ventricle were also significantly reduced (table 3.7),
similar to Rizzo et al (1992). However, the severity of fetal diastolic dysfunction
of diabetic mothers even with HCM was usually not too severe, no case had
pathological diastolic E/A rate (1 phase wave) or severe atrioventricular valve
regurgitation.
For a fetuses of diabetic mothers, the overall reduction in cardiac function was
manifested by an increase in myocardial performance index (MPI), primarily due
to prolongation of the period of isovolumetric time. In our study, the MPI index
increased prematurely at 32-35+6 weeks of non-HCM fetuses and significantly
increased in the HCM group with a corresponding prolonged isovolumetric time
(table 3.7). According to a study by Meigham, V et al (2009) on 117 healthy
fetuses in the second and third trimesters of pregnancy, LV-MPI≥ 0,43 was the cutoff value to determine the reduction of overall cardiac function of fetus in the last
trimester. The result of our study in chart 3.11 showed that the frequency of overall

fetal heart function reduction in diabetes was 40,8%, higher than study of
Meigham, V (2009) was 27%, the study of Miyake T (2001) was 35%. The
condition of fetal HCM increased the rate of total cardiac function impairment.
4.4. Relationship between some factors of mother and fetuses with fetal HCM.
4.4.1. Relationship between some maternal factors and fetal HCM
4.4.1.1. Relationship between maternal weight, HbA1C and fetal HCM
A study by Johansson S et al (2014) showed that maternal obesity increased
the risk of fetal HCM, along with an increased incidence of fetal macrosomia or
a decrease in the systolic and diastolic function of the fetus in Penfold NC et al
(2015), Siri Ann Nyrnes et al (2017). Our research results showed that diabetic
mothers accompanied by obesity or over-weight gain during pregnancy, the risk
of HCM in fetuses would be 1,89 times higher than that of diabetic mother
without obesity, increased 2,04 times the case of normal weight gain mothers.
The complex interaction between glucose and lipid metabolism not only
increases the risk of fetal HCM (even with well controlled maternal diabetes) but
also impairs myocardial function (even if there was no structural change). In
addition, the study by Egan et al (2014) showed that excessive weight gain also
increased the risk of fetal macrosomia to 3,58 times higher and macrosomia was
associated with fetal HCM. In the context of increasing obesity incidence in our
country, we found that if poor weight control for diabetic pregnancy could also
increase the risk of HCM and reduced fetal cardiac function. In addition, with
HbA1C ≥ 6%, the risk of HCM in the diabetic group was 4,34 times higher than
that in the group with HbA1C <6%. In Ehab et al (2010), there was a correlation
between hypertrophic IVS and maternal HbA1C concentration (r = 0,67). The
results of multivariate analysis in table 3.8 once again showed that the main role
of maternal hyperglycemia increased the risk of developing fetal HCM in
addition to the interaction of other factors such as maternal obesity or over-


22

weight gain during pregnancy. And with an increase in maternal HbA1C
concentration from over 6,1%, it was also possible to predict the occurrence of
HCM in the fetus with 59%, of sensitivity and 97,5% of specificity (chart 3.12).
This was also in accordance with the recommendations of the American Heart
Association to conduct fetal echocardiography screening for complications of
HCM and cardiac dysfunction in fetuses of diabetic mother whose HbA1C ≥ 6%
in the third trimester of pregnancy, although according to ADA 2017, HbA1C ≥
6,5% was the high-risk group. However, because the study subjects were only
diabetic women, excluding women without diabetes, this was also a limitation of
the study participants selection.
4.4.1.2. Relationship with diabetes treatment in pregnancy and fetal HCM
Although, only 240 women participated in the FE follow-up with 60 cases of
insulin injection and 180 cases of diet adjustment. Results of our study showed
that maternal hyperglycemia treatment during pregnancy significantly reduced
the prevalence of fetal HCM and improved fetal cardiac dysfunction, although
the average follow-up time was 5,02 ± 2,17 weeks, this improvement occurred in
both diet-adjusted group or insulin group (chart 3.13 and 3.14). Our study as well
as Aman J et al (2011) showed the role of well controlled diabetes in reducing
the incidence of fetal HCM, because the proportion of HCM still in neonates was
only 20% compared to 46% of fetuses. Although, to confirm that well control of
maternal blood glucose can completely eliminate this pathology, future
intervention studies are needed.
4.4.2. Relationship between some factors of fetuses and fetal HCM
4.4.2.1. Relationship between fetal weight and fetal HCM
Our research results showed that, although the prevalence of fetal macrosomia
accounted for only 15%, the frequency of HCM in the fetal macrosomia group was
higher than that of normal or low birth weight group and macrosomia may increase
the risk of HCM occurrence was 1,8 times higher than that of normal fetal weight
(table 3.9), similar to the study of P. Tsyvian et al (1998). The mechanism of this
phenomenon was due to chronic hyperglycemia in the fetus under the direct effect

of maternal hyperglycemia, increasing the total body weight of the fetus and
selective insulin-sensitive organs, including the heart. Therefore, along with the
phenomenon of "fetus is older than gestational age", the fetal heart was also
hypertrophic. Thus, it is recommended to carefully screen for complications of
HCM in the case of fetal macrosomia due to diabetic mothers.
4.4.2.2. Relationship between fetal HCM fetus and the fetal postpartum outcomes.
To the best of our knowledge, this is the first study to evaluate the association
between the HCM and the postpartum outcomes of fetuses of diabtetic mothers.
Although the postpartum basic data collected from obstetric and neonatal records
was still limited, we only analyzed highly reliable parameters such as: preterm
birth, low birth weight, cesarean delivery due to fetal distress, low Apgar score
and perinatal death.
The frequency of premature and low birth weight in our study was only 7,5%
and 5,8%, lower than the research results of some other authors such as Cyganek
Wahabi H et al (2017) and Holmran et al (2011), but these proportions increased
significantly in the fetal HCM group (10,9% and 9%). HCM could increase the
risk of preterm birth by 2,38 times, the risk of low birth weight by 2,78 compared
with the non - HCM group. However, one of the limitations of our study was that


23
the direct association between preterm birth and fetal HCM status had not been
determined and 60% of low birth weight neonates in the study were among
preterm births. Thus, although the women in the study were managed at
specialized facilities, there was still a lower rate of preterm and low birth weight,
although lower than other studies. And fetal HCM appeard to be related to these
clinical manifestations. However, in order to further clarify the above
relationship, it is necessary to conduct other intervention studies with FE at the
time of labor.
The frequency of cesarean delivery due to fetal distress accounted for 2,8%

and the proportion of neonates with Apgar score at 1 minute under 7 points
accounted for 5,2%. A poorly evaluated Apgar score at birth is an early indicator
of perinatal mortality. In a cross-sectional study conducted in 12 perinatal centers
in France in 2000-2001 in women with type 1 and type 2 diabetes, the perinatal
mortality was 4,1% (accounting for 2,2% of the cause of general mortality) and
the mortality rate of the fetal HCM group of diabetic mother with secondary
congestive heart failure due to outflow obstruction was 5%. In our study,
although there was no case of perinatal death, the rate of fetuses with the 1
minute Apgar score ≤ 7 points, accounted for 5,2%, also increased significantly
in the fetal HCM group (8,3%). In addition, the condition of fetal HCM can
increase the risk of neonates with the first Apgar score under 7 to 3,01 times
compared with the non HCM group. Similar to the study of Cem Yasar Sanhal et
al (2016), diabetic mothers in the study were usually terminated at 38 weeks of
pregnancy, so the survival rate was high (100%), there was no perinatal deaths,
though, the rate of other adverse clinical manifestations, for example neonates
with an Apgar score of 1 minute below 7, labor-induced respiratory failure,
umbilical cord pH test <7,15, or treated in the neonatal emergency unit were also
higher than in fetal HCM diabetic group.
Thus, our study results initially showed that although the severity of
hyperglycemia in pregnant women was not too high, the characteristics of fetal
HCM and fetal cardiac dysfunciton were not too severe but it could increase the
frequency of fetal adverse postpartum manifestations. However, due to the low
rate of perinatal complications and not too severe, this was also a limitation of
our study, so our study results should not be deduced to other research samples
with high maternal blood glucose levels as well as a higher incidence of fetal
complications
CONCLUSION
Through the study of 511 pregnant women and 511 fetuses, the topic
"Research on hypertrophic cardiomyopathy and cardiac function by
ultrasound in fetuses of diabetic mothers " has obtained the following results:

1. The prevalence, characteristics of HCM and cardiac manifestation in
fetuses of diabetic mothers
1.1. The prevalence of fetal HCM
 The prevalence of HCM in fetuses of diabetic mothers was diabetes is 43,2%.
 The prevalence of fetal HCM increased in the pre-gestational diabetes group
(66,1%), the group with HbA1C ≥ 6% (69,7%), the obese mother group (56,9%),
the mother having gaining weight above the standard in pregnancy period (59%)
and in fetal macrosomia (55,6%).