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 perina
Trang 1MINISTRY 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
SUMMARY OF THESIS
HA NOI - 2020
Trang 2MEDICAL 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
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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
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)
Trang 4Chapter 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
Trang 53 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
Trang 62.1.2 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, pregnancy BMI, weight gain during pregnancy up to the time of study, oral glucose tolerance test, HbA1C, hemoglobin, cholesterol, triglycerides
pre- 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
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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 )
Trang 8Table 3.1 General characteristics of pregnant women
General characteristics Control (n=150) Diabetic group (n=361) P value
Maternal age (year) 28,30 ± 4,56 29,00 ± 4,37 0,068 Maternal age rate ≥25 (n,%) 118(78,6) 291(80,6) 0,168
b, General characteristics of fetuses
Distribution of gestational age
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
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
Diabetic group Control group
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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
DM(Diabetic Mother), GD(Gestational Diabetes), Pre-GD(Pre- Gestational Diabetes)
Chart 3.4 Characteristics of pregnant women in diabetic group
Chart 3.5 Unique fetal characteristics in diabetic group
Trang 103.2 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) Ventricular wall thickness(mm) (Mean ± SD)
Ventricular wall thickness Correlation coefficient (r)
Fetal age (week) Fetall weight
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
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3.2.2 Characteristics of cardiac function of fetuses in control group
Table 3.4 Characteristics of fetal cardiac function in control group
28-31 +6 week (n=55) 32-35 +6 week (n=92) 36-39 +6 week (n=31) P value
Systolic cardiac function
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
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
Trang 12 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
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
Chart 3.7 Prevalence of fetal HCM according to the maternal clinical factors
Pregestational diabetes (n=65)
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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
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
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