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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.