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研究生:李欣蔚
研究生(外文):Hsing-Wei Lee
論文名稱:一、母親懷孕期間二手菸暴露與幼童語言發展二、臍帶血的代謝質體分析與胎兒生長發育之關聯探討
論文名稱(外文):1. Prenatal Exposure to Environmental Tobacco Smoke and Language Development in Toddlers2. The Association between Cord Blood Metabolite Profiles and Fetal Growth
指導教授:陳保中陳保中引用關係
指導教授(外文):Pau-Chung Chen
口試委員:謝武勳曹峰銘林靖愉
口試委員(外文):Wu-Shiun HsiehFeng-Ming TsaoChing-Yu Lin
口試日期:2014-07-09
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:63
中文關鍵詞:語言發展二手菸嬰幼兒代謝質體胎兒生長發育臍帶血
外文關鍵詞:language developmentenvironmental tobacco smoking (ETS)cotininetoddlersyoung childrenmetabolitefetal growthcord blood serum
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第一部分

背景與目的:目前已知母親懷孕期間的菸害暴露與孩童的神經行為發展有所相關。亦有研究指出,母親在懷孕期間的抽菸行為,會影響新生兒的語音處理能力。語言為認知發展的一種主要層面,然而目前並沒有針對母親孕程中的二手菸暴露與孩童語言溝通發展之影響的相關研究。本研究目的即是希望透過問卷評量,了解懷孕期間的抽菸行為對孩童語言發展的影響。

方法:本研究自2004年至2005年間建立的Taiwan Birth Panel Study(TBPS)世代中選取103位於北台灣生產的孩童。在其母親生產後進行結構式問卷訪談,並於生產時收集胎兒臍帶血樣本。臍帶血中的cotinine,也就是懷孕期間二手菸暴露的血液指標,再以極致效能液相層析/串聯式質譜儀(UPLC-MS/MS)進行測量。這些孩童在2-3歲期間的語言溝通發展狀況,則以華語嬰幼兒溝通發展量表作為評估工具。根據臍帶血中cotinine濃度,我們將孩童分為暴露組與對照組,以多變項線性及羅吉斯回歸模型對可能的干擾因子進行控制與分析。

結果:母親懷孕期間的二手菸暴露與孩童語言溝通發展有負相關。在多變項線性回歸模型中,暴露組的孩童在華語嬰幼兒溝通發展量表的總分(β = -84.33; p = 0.0155),詞彙表達的子分數(β = -78.25; p = 0.0175)及語法複雜度的子分數(β = -5.39; p = 0.008)都顯著低於對照組的孩童。

討論:本研究結果指出,母親孕程中的二手菸暴露和孩童早期語言發展的負面影響有關。然而臍帶血中的cotinine與孩童語言發展之間的因果關係,則有待進一步的研究釐清。

第二部分

背景與目的:低出生體重(LBW)、早產(preterm)和小於妊娠週數(SGA),都可能代表著胎兒生長率下降和發育不全。儘管產前照護持續進步,SGA的發生率仍維持在5-10%。這些嬰兒後續可能有新生兒死亡率提高的問題,以及造成童年生長遲緩或認知功能的損害,也和成年後的代謝症候群相關。代謝體學為生物代謝所產生之小分子中間產物與最終產物組成之分析,而核磁共振(NMR)是其中一種代謝物分析技術。影響胎兒生長發育的原因十分多元與複雜,包括內在條件、孕婦本身和環境因素。代謝圖譜可以提供生化反應的代謝狀態,或許能對產前環境暴露如何影響胎兒的生長提供更貼近的答案。本研究目的,即是運用核磁共振技術分析臍帶血血清之代謝體,進而找出與胎兒生長發育相關之生物指標。

方法:本研究自2009年至2012年間建立的Taiwan Birth Panel Study II(TBPS II)世代中選取658位於台北市生產的孩童。在其母親生產後進行結構式問卷訪談以及病歷摘錄,並於生產時收集胎兒臍帶血樣本。臍帶血血清樣本以500MHz核磁共振光譜儀(NMR)進行代謝體分析,原始光譜數據資料經多變量分析(PCA)和最小平方區別分析(PLS-DA)方法解析後,再根據胎兒是否為低出生體重、早產以及小於妊娠週數作為分組標準,以單變量分析找出有差異的代謝物。

結果:以早產和小於妊娠週數進行分組,可以看到其最小平方區別分析下的分數圖(score plot)有些許分群情形。其組間的主要差異來自於大部分的脂蛋白和胺基酸,且早產和小於妊娠週數的臍帶血中代謝物差異量有著相反的趨勢。

討論:早產和小於妊娠週數間的相反趨勢可能代表兩者不同的成因機制,而代謝物量的差異可能是在懷孕期間的逐漸改變所造成。其中可能與胎兒發育相關的環境與代謝物交互作用機制,仍須要進一步的研究釐清。

PART 1

Background: Maternal exposure to environmental tobacco smoke (ETS) associated with children’s neurobehavioral development has been reported. There is also a study indicating that maternal smoking during pregnancy can affect newborns’ speech processing ability. Language is a result of cognitive development; however, there is no study focus on the effects of maternal ETS exposure during pregnancy to toddlers’ language and communication development.

Objectives: The aim of this study is to examine the effect of prenatal exposure to ETS on the language development in toddlers.

Methods: A total of 103 children from the Taiwan Birth Panel Study (TBPS) were followed up in northern Taiwan. We enrolled their mothers before delivery, interviewed them using a structured questionnaire, and collected umbilical cord blood. Umbilical cord cotinine, a blood indicator of prenatal ETS exposure, was analyzed by using HPLC-MS/MS. The Mandarin-Chinese Communicative Developmental Inventory (MCDI) for toddlers was used to assess these children’s language and communication development at 2 years of age. We examined the children’s language development between exposed and control groups by multiple linear and logistic regression models to control for potential confounders.

Results: Maternal ETS exposure during pregnancy was negatively associated with language and communication development. The adverse effects to the exposed group was significantly showed on the total MCDI score (β = -84.33; p = 0.0155), words produced (β = -78.25; p = 0.0175) and syntax complexity (β = -5.39; p = 0.008) in multiple linear regression models.

Conclusions: Our results indicate that maternal ETS exposure was related to the adverse effects on early children’s language development. Further studies are needed to clarify the causal relationship between cord blood cotinine and children’s language development.

PART 2

Background: Infants with low birth weight, preterm birth and small for gestational age (SGA) reveal the decrease in fetal growth. The prevalence of SGA remains 5-10% despite the advances in prenatal care. There are studies show the subsequent problems on SGA child, including perinatal and neonatal mortality, childhood growth retardation, impaired cognition function, insulin resistance and metabolic syndrome such as type 2 diabetes, hypertension and coronary heart disease in adulthood. Metabolomics is the analysis of collections of small molecule intermediates and products of diverse biologic processes. Metabolite profiles can provide metabolic statuses of biochemical reaction. It may able to give a closer answer of how the prenatal environmental exposures affect fetal growth.

Objectives: To find the most important metabolite as an adequate biomarkers from the cord blood metabolite profiles for health effects of fetal growth.

Methods: A total of 658 children from the Taiwan Birth Panel Study II (TBPS II) were followed up in Taipei City, Taiwan. We enrolled their mothers before delivery, interviewed them using a structured questionnaire, and collected umbilical cord blood. 500MHz Nuclear magnetic resonance (NMR) spectrometers was used to analyze the cord blood serum metabolite profiles. After the overview of the NMR data using PCA analysis and partial least square-discriminant analysis (PLS-DA), univariate analysis was applied to identify metabolic differences by LBW, preterm and SGA grouping.

Results: The score plot of initial data showed little separation between preterm and full term groups and among LGA, AGA and SGA groups after applying PLS-DA. The major differences were in most lipoproteins and amino acids. Furthermore, the level of most metabolites revealed a divergent direction between preterm and SGA groups.

Conclusions: The different trends of metabolite levels between preterm and SGA groups might indicate that the mechanisms are not the same. Moreover, the differences and changes of cord blood metabolite profiles might occur gradually during the pregnancy. Further studies are needed to provide more information about the possible mechanism of environment-metabolites interactions associated with fetal growth.

i 口試委員會審定書
iii 誌謝

Part I

2 摘要
3 ABSTRACT
5 INTRODUCTION
6 MATERIAL AND METHODS
6 Study Population
7 Prenatal ETS Exposure
8 Language Development
8 Potential Confounding
9 Statistical Analyses
10 RERULTS
14 DISCUSSION
17 REFERENCES

Part II

21 摘要
22 ABSTRACT
24 INTRODUCTION
26 MATERIAL AND METHODS
26 Study Population: Taiwan Birth Panel Study II (TBPS II)
26 Sample Preparation and Instrumental Analysis
27 Spectral Processing
28 Infant’s Birth Outcomes
28 Potential Confounding
29 Statistical Analyses
31 RERULTS
46 DISCUSSION
49 REFERENCES

APPENDIX

53 Mandarin-Chinese Communicative Developmental Inventory (MCDI, Toddler Form)

PART 1

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Fried, Peter A. (2002). Tobacco consumption during pregnancy and its impact on child development. Tremblay RE, Barr RG, Peters RDeV, eds. Encyclopedia on Early Childhood Development, 1-5.
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PART 2

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Tea, I., G. Le Gall, A. Kuster, N. Guignard, M. C. Alexandre-Gouabau, D. Darmaun and R. J. Robins (2012). "1H-NMR-based metabolic profiling of maternal and umbilical cord blood indicates altered materno-foetal nutrient exchange in preterm infants." PLoS One 7(1): e29947.
van den Berg, R. A., H. C. Hoefsloot, J. A. Westerhuis, A. K. Smilde and M. J. van der Werf (2006). "Centering, scaling, and transformations: improving the biological information content of metabolomics data." BMC Genomics 7: 142.
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Wu-Shiun Hsieh, H.-C. W., Suh-Fang Jeng, Hua-Fang Liao, Yi-Ning Su, Shio-Jean Lin, Chia-Jung Hsieh, Pau-Chung Chen (2006). "Nationwide Singleton BirthWeight Percentiles by Gestational Age in Taiwan, 1998-2002." Acta Paediatr Tw 47(1): 25-33.
Yuan-Shun Lee, Y.-H. C. (2005). "Antioxidant Profiles in Full Term and Preterm Neonates." Chang Gung Med J 28: 846-851.

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