臺灣博碩士論文加值系統

研究背景：產前檢查是一個產婦胎兒和新生兒的健康理念。產前篩檢旨在確認胎兒具有異常的風險。大多數國家在第一孕期時實行「結合試驗」，包含妊娠血漿蛋白A (serum PAPP-A marker) ，游離 β-人類絨毛膜激素 (serum free β-hCG)以及超音波測量胎兒頸部透明帶(NT)； 第二孕期則實行「三合一檢查」。全球的篩檢方法從第二孕期推動到第一孕期，可能會對蒙古孕婦照護體系造成問題。 至今蒙古官方一直沒有正式的產前篩檢方案。
研究目的：本研究涵蓋兩目的，首要目標為建立以第一孕期「結合試驗」篩檢標準中間值為基礎的實驗室，即胎兒頸部透明帶 (NT)，游離 β-人類絨毛膜激素 (free β-hCG)以及妊娠血漿蛋白A (PAPP-A)，在11 到13+6 週單胎妊娠與未受影響的胎兒，與相對健康的蒙古女性。其次為確認他們的產婦特徵與第一孕期「結合試驗」篩檢有顯著相關。
研究方法：本計畫以一群相對健康，單胎妊娠的蒙古女性 (首批樣本數N=330) 的臨床研究和胎兒頸部透明帶 (NT)與量測2011-2013 年間蒙古「Grand Med」醫院中，孕週11 到13+6 週的游離 β-人類絨毛膜激素 (free β-hCG)以及妊娠血漿蛋白A (PAPPA)。以標準中位值為基礎所建立的實驗室分布已被建立，以及懷孕特定週數相對的統計中位值的倍數 (MoM)分別表示在11-13+6 週。要從同意參加且懷孕特徵有被問卷我們記錄的女性獲得書面同意。以三個與妊娠血漿蛋白A、游離 β-人類絨毛膜激素以及胎兒頸部透明帶厚度有關的變數做為獨立變數，即所謂第一孕期「結合試驗」篩檢。依變數則為人口統計，人體和臨床因素。使用第一及第二族群樣本(n=313) 所收集到的資料來檢視各種共變數的影響。統計軟體SPSS 16.0 以及微軟Excel 2007 幫助我們對收集到的數據進行分析。描述性分析以產婦年齡、體重、吸菸狀況、懷孕次數及胎兒性別做為特性分佈的篩檢。分佈參數則為統計平均數、中位數和MoM 值的轉換。迴歸相關分析是為了瞭解統計和變數之間的關係。使用多元線性迴歸分析來選擇標準和逐步的預測方法，以決定哪些因素之間的產婦特徵。
研究結果：所有數值顯示平均數、中位數常態分佈值。以MoM為孕齡相關中位值的建立和表示。多元線性迴歸針對free β-hCG、PAPP-A以及胎兒NT相關共變數使用逐步迴歸法。PAPP-A顯示和孕齡、體重、吸菸狀況和胎兒性別 (R2 = .402 for step 4; (p< .05) 有極大的關連；而free β-hCG則與體重、孕齡和胎兒性別 (R2 = .227 for step 3,(p < .05) 有明顯的關係。胎兒NT則與增加的孕齡呈現強大的正相關(R2 = .215 for step 1; (p < .05)，但與減少的孕齡呈現負相關，相反的，與吸菸狀況呈現正相關 (R2= .245 for step 3, (p < .05)。此兩種free β-hCG、PAPP-A生化標記為顯著的趨勢但與妊娠沒有統計學相關，與產婦年齡也沒有顯著關係。由Roche研究的規範價值與我們的非直接參考做比較，PAPP-A顯示35.5%高於總比例；而free β-hCG則少於總比例9,7%。
此外，比較族群參考團體PAPP-A MoM的值，在非洲成長 23.3％，在亞洲則為6.3。和蒙古相比，在沙烏地則降低2%，而free β-hCG的值和蒙古女性比較，在阿拉伯減少了3.1%，南亞則為2%，非洲則成場23.3%。本研究指出兩項血清指標相較於其他族群，在非洲族群中是較高的。
結論：本研究提供單一實驗室，針對蒙古孕期在11-13+6週的單胎妊娠且未受影響的母體，測定PAPP-A, free β-hCG 以及NT厚度的標準中位值。這是第一個以區域樣本為基礎，來確認特定週期的中位值與他們的MoM轉換的研究。影響因素如孕齡、體重和胎兒性別為主要預測變數；而產婦吸菸狀況、種族則為小部分的預測變數。
篩檢項目對於所有懷孕，特別是研究期間被查覺異常結構性缺陷，以及不良狀況為有效方案。

Background: Prenatal care, it is health concept for maternal with fetal and neonatal. Prenatal screening intends to identify at risk for carrying a fetus with a certain anomaly. Most countries perform that “triple test” which is the second-trimester and “combined test” is the first-trimester which is including serum PAPP-A marker and serum free β-hCG with ultrasound measurement fetal NT. World screening approach moving from 2nd to the 1st trimester, which may even pose some problems for the Mongolian maternity care system. Officially, Mongolia has been no formalized for antenatal screening program.
Objective: Our study has carrying two major of objectives which are firstly, to establish the laboratory based a normative median values of first-trimester “combined test” screening namely, fetal nuchal translucency (NT), concentrations of maternal serum free beta-human chorionic gonadotrophin (free β-hCG) and pregnancy associated plasma protein-A (PAPP-A), at 11 to 13+6 weeks of singleton pregnancy with unaffected fetuses, and relatively healthy women of Mongolian. Secondly, to identify their maternal characteristics that are significantly associated with “combined test” screening in firsttrimester of pregnancy.
Methods: A cohort of Mongolian women (first cohort N=330) with relatively healthy and singleton pregnancies prospectively participated in the present research of clinical study and fetal NT together with maternal serum free beta -hCG and PAPP-A were measured at 11 weeks to 13+6 weeks of gestation during the 2011-2013 at “Grand Med” hospital in Mongolia. The distribution of laboratory based a normative median values are established, and gestation weeks-specific multiples of the median (MoM) values were expressed at 11-13 weeks respectively. To written informed consent was obtained from the women agreeing to participate and maternal characteristics were recorded by our questionnaires. The three variables related to maternal serum PAPP-A, free β-hCG and fetal NT thickness served as dependent variables, as mean called “combined screening” in first-trimester of pregnancy. Independent variables were demographical, anthropometric and clinical factors. The influence of various co-variables were examined using the data collected from the first and the second cohorts (n=313). The statistical software package SPSS 16.0, Microsoft Excel 2007 is employed to help us analyze the collected data. Descriptive analysis made for maternal age, body weight, smoking status, number of pregnancy, fetal gender in the screening distribution of characteristics. The distribution of parameters made up by statistical mean, median and MoM values transformation. The regression correlation analysis is to know statistical relationship between variables. Multivariate linear regression analysis was used for standard and stepwise methods selection of predictors to determine which of the factors amongst maternal characteristics.
Results: All markers exhibited mean, median-normally distributed values. Gestational age-dependent normative median values were established and expressed by multiple of median (MoM). Multivariate linear regression using stepwise methods for maternal free β-hCG, PAPP-A and fetal NT in relation to co-variables. Serum PAPP-A exhibited a significant relationship with gestational age, maternal body weight, maternal smoking status and fetal gender (R2 = .402 for step 4; (p < .05), while serum free β-hCG exhibited a significant relationship with maternal body weight, gestational age and fetal gender. (R2= .227 for step 3, (p < .05). Fetal NT showed a strong positive relationship with increasing gestational age (R2 = .215 for step 1; (p < .05), but a negative relationship with decreasing maternal age and inversely, showed a positive relationship with maternal smoking status. (R2 = .245 for step 3, (p < .05). Both biochemical markers free β-hCG and PAPP-A shown significant trend but no statistical relevance with maternal gravidity, and also no significant relationship with maternal age. Study performance of normative values compared with our non-direct reference by Roche, serum PAPP-A showed 35.5% higher of total percentage ratio while serum free β-hCG showed 9.7% lower of a total percentage ratio. Moreover, by comparison ethnicity reference groups for serum PAPP-A MoM values were increased in Africans (by 23.3%), Sought Asians (by 6.3%), as compared to Mongolian women, but value was decreased in Saudis (by 2%), as also compared to Mongolian, while maternal serum free β-hCG values were decreased in Arabs (by 3.1%), South Asians (by2%), as compared to Mongolian women, but value was increased in African (by 23.3%), as compared to Mongolian. The present study addressed that both serum markers were higher in ethnic African, as compared to others.
Conclusion: The present study offers the single laboratory based a normative median values of maternal serum PAPP-A, free β-hCG and fetal NT thickness were determined in Mongolian singleton, unaffected pregnancies at 11-13+6 weeks of gestation. This is the first effort of study to determined that gestational weeks-specific a normative median values were converted by their MoMs based on study sampling performance of our regional.
Factors influencing that gestational age, body weight, and fetal ganders were most predictor variables, while maternal smoking status, maternal ethnicity and gravidity were less predictor variables.
Screening project has been effective program for all underwent pregnancy, a particularly, which been detected for abnormal structural defects, and adverse outcome during the study period.

Abstract
中文摘要
OUTLINE OF CONTENTS I
LIST OF TABLES IV
LIST OF FIGURES VI
ABBREVIATIONS VII
CHAPTER ONE INTRODUCTION 1
1.1 Research Background Information 1
1.2 Research Motivation 3
1.3 Clinical Project Overview (PS-(PAPP-A)/GM2011-01) 6
1.4 Research Purpose 9
1.5 Research Contributions 9
1.6 Research Questions 10
1.7 Research Procedure 11
1.8 The Content of This Paper 12
CHAPTER TWO LITERATURE REVIEW 13
2.1 Basic Concept of Antenatal Care 13
2.1.1 Antenatal Routine Care 13
2.1.2 Prenatal Screening 14
2.1.2.1 Invasive Diagnostic Methods in Prenatal Care 15
2.1.2.2 Non-invasive Screening Methods in Prenatal Care 17
2.1.2.2.1 Maternal Age and Gestation 17
2.1.2.2.2 Previous Affected Pregnancy 18
2.2.1 Second-trimester Screening 18
2.2.2 First-trimester Screening 19
2.2.2.1 Pregnancy Associated Plasma Protein-A 21
2.2.2.2 Free Beta Human Chorionic Gonadotropin 24
2.2.3 Ultrasound Examination 25
2.2.3.1 Fetal Crown-Rump-Length Measurement (CRL) 25
2.2.3.2 Fetal Nuchal Translucency Thicknes (NT) 26
2.2.3.3 Measurement of Nuchal Translucency Thickness (NT) 27
2.2.4. Training and Quality Assessment in the Measurements of NT 30
2.2.5 Detection Rate for Chromosomal Abnormality 31
2.2.6 Patient-Specific Risk Calculation 33
2.2.7 Normative Median and Multiple of Median Value (MoM) 38
2.2.8 Factors Influencing First-trimester Screening Markers 41
2.2.8.1 Maternal Ethnicity 43
2.2.8.2 Maternal Body Weight 45
2.2.8.3 Maternal Gestational Age (CRL) 46
2.2.8.4 Maternal Gravidity 47
2.2.8.5 Maternal Smoking 48
2.2.8.6 Fetal Gender 51
2.2.8.7 Additional factors 51
CHAPTER THREE RESEARCH DESIGN AND METHODOLOGY 54
3.1 Research Framework 54
3.2 Research Hypotheses 55
3.2.1 Alternative Hypotheses 55
3.2.2 Null Hypotheses 56
3.3 Operational Definition of Research Variables 57
3.3.1 Dependent Variable 57
3.3.2 Independent Variable 58
3.3.3 Additional Question forms Definition 59
3.4 Research Design 60
3.5 Research Method 60
3.5 Research Setting 61
3.6 Research Sample Plan 64
3.7 Clinical Measurements of Procedure 64
3.7.1 Laboratory Materials and Procedures 64
3.7.2 Ultrasound Materials and Procedures 69
3.8 Clinical Ethic Committee 70
3.9 Data Analysis of Statistical Procedures 70
3.9.1 Descriptive Statistic Analysis 70
3.9.2 Relationships among Research Variables 71
CHAPTER FOUR RESEARCH RESULTS 72
4.1 Descriptive Analysis 72
4.1.1 The Characteristics of Participants 72
4.1.2 Mean, Median, (MoM) Values of Distribution Parameters 74
4.1.3 Descriptive Analysis for Additional Question Forms 78
4.2 Correlation Results 81
4.2.1 Interpretation of Correlation Results for 1st Dependent variable PAPP-A 82
4.2.2 Interpretation of Correlation Results for 2nd Dependent variable hCG 83
4.2.3 Interpretation of Correlation Results for 3rd Dependent variable NT 84
4.4 Multivariate Linear Regression Analysis 86
4.4.1 Interpretation of Standard Method 86
4.4.1.1 Interpretation of Standard Method for 1st Dependent variable (PAPP-A) 86
4.4.1.2 Interpretation of Standard Method for 2nd Dependent variable (hCG) 89
4.4.1.3 Interpretation of Standard Method for 3rd Dependent variable (NT) 90
4.4.2 Interpretation of Stepwise Method 92
4.4.2.1 Interpretation of Stepwise Method for 1st Dependent variable (PAPP-A) 92
4.4.2.2 Interpretation of Stepwise Method for 2nd Dependent variable (hCG) 95
4.4.2.3 Interpretation of Stepwise Method for 3rd Dependent variable (NT) 98
CHAPTER FIVE DISCUSSION 103
5.1 Discussion 103
5.1.1 Effects of Maternal Age 104
5.1.2 Effects of Gestational Age 105
5.1.3 Effects of Maternal Body Weight 106
5.1.4 Effects of Gravidity 107
5.1.5 Effects of Maternal Smoking 108
5.1.6 Effects of Fetal Gender 110
5.1.7 Effects of Maternal Ethnicity 110
5.2 Hypotheses Confirmation 114
5.3 Limitation of the Study 115
5.4 Strength of the Study 115
CHAPTER SIX CONCLUSION AND RECOMMENDATION 116
6.1 Conclusion 116
6.2 Recommendation 117
6.2.1 Recommendation for health care administrations 117
6.2.2 Recommendation for health care specialists 117
6.3 Clinical Implications for Further Research 117
REFERENCES 118
APPENDIX 126

LIST OF TABLES
Table 1: History of Prenatal Screening 15
Table 2: 1st trimester Combined Marker Patterns in various Aneuploides 31
Table 4: Down Syndrome Screening Tests and Detection Rates (5% FPR) 32
Table 3: Operational Definition of Dependent Variables 57
Table 4: Operational Definition of Independent Variables 58
Table 5: Additional Question Forms Definition 59
Table 6: Reference Range for 1st trimester Biochemical Markers by Roche (2010) 68
Table 7: Percentage and mean distribution of pregnant women according to the
demographic and obstetric characteristics, who underwent first-trimester screening project 73
Table 8: Frequency of Maternal Age by gestational weeks 74
Table 9: The 5th, 25th, 50th, 75th, and 95th percentile limits in first-trimester combined screening markers during the 11-13+6 weeks of gestation 75
Table 10: Gestational weeks-specific mean, median values and multiple of median value (MoM) of the fetal NT thickness and biochemical markers of free β-hCG and PAPP-A in the first trimester of Mongolian pregnant women studied in 2011-01 76
Table 11: First-trimester biochemical markers (PAPP-A and Free β-hCG) gestational weeks-dependent values 76
Table 12: Mean values of Biochemical Markers (PAPP-A and free β-hCG) by Gestational age and Maternal Body Weight Group77
Table 13: Mean values of Biochemical Markers (PAPP-A and Free β-hCG), maternal weight-dependent value 78
Table 15: Correlation of Maternal Age (MA), Maternal Body Weight (BW), Maternal number of Pregnancy (GV), Maternal Smoking Status (SS), Fetal Gender (FG), Gestational Age (GA) and dependent variables which are maternal serum PAPP-A, free β-hCG and fetal NT values for Standard Regression method 82
Table 16: Multiple Linear Regressions for Single Set of Predictors with serum PAPP-A, free β-hCG and fetal NT respectively, in Standard Method 87
Table 17: Multiple Linear Regressions for Single Set of Predictors in Standard Method 88
Table 18: Stepwise Multiple Linear Regressions as dependent variables are single entered with a selection of the most significant predictors 94
Table 19: Stepwise Multiple Linear Regressions as dependent variables are single entered with a selection of the most significant predictors 96
Table 20: Stepwise Multiple Linear Regressions as dependent variables are single entered with a selection of the most significant predictors 98
Table 21: Ethnicity differences of median values of serum PAPP-A, and Free β-hCG concentrations on the “Non-direct” reference range by Roche,German. (2010) 111
Table 22: Demographic characteristics, median (MoM) values for first-trimester combined markers in different ethnic populations as compared with Mongolian women studied 112
Table 23: Summary of the Hypotheses Testing 114

LIST OF FIGURES
Figure 1: Steps of Screening Procedures 7
Figure 2: The research project conducted with those provinces in Mongolia 8
Figure 3: UB post, News Paper of Mongolia in March, 2011. Vol-15 8
Figure 4: The Flow Chart of Research 11
Figure 5: Pyramid of Traditional Prenatal Care & Pyramid of New Prenatal Care 13
Figure 6: Amniocentesis and Chorion Villus Sampling 16
Figure 7: Maternal Age related Risk of Down Syndrome in live Births (%) 18
Figure 8: One-Stop Clinic Assessment of Risk (OSCAR) 20
Figure 9: Fetal Crown-Rump-Length (CRL) 26
Figure 10: CRL in correct a Neutral Position and NT in a Sagitall Position 28
Figure 11: Positive Predictive Value Determination 33
Figure 12: Prenatal Screening Software 37
Figure 13: Prenatal Screening Risk Assessment 37
Figure 14: The Research Framework (Descriptive & Conceptual) 54
Figure 15: The Sample Selection Chart 63
Figure 16: Crown-Rump-Length and Nuchal translucency measurement 69
Figure17: Percentage Distribution of Participants by Gestational Age 72
Figure 18: Percentage distribution of Participants by Home Region 78
Figure 19: Distribution of Promotion Type 79
Figure 20: Distribution of Personal Reason that Who Undergoing Screening 80

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