臺灣博碩士論文加值系統

根據世界衛生組織2014年估計，全世界大概有90%的人其居住地未達世界衛生組織空氣品質標準，且已有許多研究發現環境中空氣汙染會造成孩童肺功能惡化、產生過敏性疾病、和影響氣喘病情控制。關於空氣汙染對孕婦的影響，一般認為胎兒對某些環境毒物的感受性甚至比孩童來得顯著，人類絕大部分器官在胚胎發育階段(embryonic period)就會成形，緊接著才在胎兒發育階段(fetal period)逐漸成熟；對吸呼系統而言，肺泡的發育更是要一直延續到孩童時期才會完全。因此，目前已越來越清楚了解到，對胎兒不同器官的發育而言，在關鍵的時間點暴露到特定環境毒物，會比其所暴露到的總劑量來得重要。
近幾十年來文獻指出，懷孕時期如果暴露到較高濃度的空氣汙染物，會造成胎兒的不良健康效應，諸如低出生體重(low birth weight)、子宮內生長遲滯(intrauterine growth retardation)、早產(preterm delivery)、早夭(fetal mortality)、甚至是先天性缺陷(congenital anomalies)。然而究竟懷孕時期的空氣汙染物暴露，對胎兒各別器官間的發育影響程度為何?目前仍尚未被完全釐清；加以和過往許多歐美研究相比，台灣的細懸浮微粒(PM2.5)濃度明顯高於世界衛生組織訂定標準，究竟暴露在這樣高濃度汙染物的環境之下，其健康效應是否仍然一樣?亦是我們有興趣討的。
因此本研究之整體目標為：
1.評估胚胎發育階段所暴露到的細懸浮微粒濃度高低，對新生兒罹患先天性心臟病(congenital heart diseases)之影響。
2.探討懷孕期間和剛出生後時期所暴露到空氣汙染物，對六個月大嬰兒被診斷有異位性皮膚炎(atopic dermatitis)之風險。
3.比較懷孕期間與出生後一年內所暴露到的空氣汙染物，對十八個月大孩童發生肺炎(pneumonia)所扮演之角色差異。

首先，我們利用環保署全台空氣品質監測站的每日監測平均濃度，結合地理資訊系統與克利金方法(kriging)來推估全台各鄉鎮的每日平均PM10, PM2.5, PM2.5–10, SO2, NO2, CO和O3濃度。再進一步將各指標空氣汙染物的暴露資料連結到2007–14年間的台灣出生通報資料庫(Taiwan Birth Registration Database)，來評估在胚胎發育階段所暴露到空氣汙染物濃度高低，特別是細懸浮微粒，對新生兒被診斷有先天性心臟病之影響程度。第二部分，我們將空汙資料連結到台灣出生世代(Taiwan Birth Cohort Study)六個月大的調查結果，評估懷孕不同時期及出生後三個月內的空氣污染暴露狀況，對六個月大嬰兒罹患有異位性皮膚炎的風險。而第三部分，我們將更進一步延伸台灣出生世代研究的追蹤到十八個月大孩童，比較和探討其在懷孕時期與出生後一歲以前的空氣汙染暴露情形，對孩童發生肺炎所扮演的角色差異。
第一部分的研究結果發現，在2007–14年間總共有782位新生兒被診斷有先天性心臟病，其中最常見的類型依序為複雜性先天性心臟病(30.3%)、心室中膈缺損(27.9%)、和心房中膈缺損(18.8%)；分析懷孕第3–8週所暴露到的指標空氣汙染物，發現細懸浮微粒暴露會顯著增加先天性心臟病發生的風險(aOR = 1.18, 95% CI: 1.01–1.38)，特別是心內膜墊缺損(aOR = 2.30, 95% CI: 1.04–5.06)和肺動脈瓣狹窄(aOR = 1.66, 95% CI: 1.01–2.76)這兩項異常。在第二部分研究結果，總共有16,686位新生兒符合條件被納入，其中有1,206位(7.6%)在六個月大前曾被醫師診斷有異位性皮膚炎；統計分析發現在整個懷孕期間如果暴露到較高濃度的一氧化碳，會顯著增加其罹患異位性皮膚炎的風險(aOR = 1.37, 95% CI: 1.06–1.78)，其中又以第一個孕期的暴露最為重要(aOR = 1.51, 95% CI: 1.16–1.97)。而第三部分的研究結果顯示，共有448位(2.8%)孩童曾經在18個月大前發生過肺炎；分析發現懷孕第二個孕期暴露到較高濃度的二氧化硫，會與其日後肺炎的發生呈現顯著負相關(aOR = 0.58, 95% CI: 0.41–0.82)，但在出生後一年內的空氣汙染物暴露則沒有看到任何顯著的影響。
綜上，我們發現懷孕時期若暴露到較高濃度的特定空氣汙染物，確實會影響胎兒、甚至是出生後嬰兒的健康，且針對不同器官健康效應的關鍵暴露時期，也會因各個器官發育時程不同而有所差異。雖然確切致病機轉仍有待進一步研究釐清，然而站在健康危害提早預防的角度，一方面除需宣導教育孕婦避免接觸特定環境危害因子、並做適當個人防護外，政府在推動空汙防治的腳步上亦應大步跨前，以維護整體國人健康。

According to a World Health Organization (WHO) estimate in 2014, about 90% of the world population inhabited in areas where the WHO Air Quality Guidelines were not met. Evidence has shown that ambient air pollution can affect children health such as deterioration of lung function, development of allergy, and manifestation of asthma. For the context of prenatal exposure, fetuses are generally considered to be highly susceptible to a variety of environmental toxicants. Almost all the organs acquire its basic structure by the end of embryogenesis and get its maturation subsequently throughout the fetal period. For respiratory system, the development and maturation of alveolus will continue up till childhood. Therefore, it is increasingly obvious that there are critical windows of development for different organ systems when the timing of exposure can be more important than the overall exposure dose.
Recent literature has suggested that exposure to ambient air pollution during pregnancy can cause adverse birth outcomes in fetus like low birth weight, intrauterine growth retardation, preterm delivery, fetal mortality, and birth defects. Whether other organ specific influences also related to air pollution exposure during critical periods of pregnancy remains not totally elucidated. Moreover, the concentration of fine particulate matter (PM2.5) in Taiwan was higher than those of the WHO guideline and previously published studies. The health effects of exposure to air pollution at such an exposure level remained unexplored and were investigated in the present work.
The aims of this study were to:
1.Evaluate the risk of exposure to PM2.5 during the embryogenic period on congenital heart diseases (CHDs) in Taiwan.
2.Investigate the effect of prenatal and early postnatal exposure to air pollution on infantile atopic dermatitis (AD) development.
3.Explore and compare the roles of prenatal and postnatal exposure to air pollution in the occurrence of infantile pneumonia.

In this study, we first utilized the 2007–14 Taiwan Birth Registration Database to evaluate the risk of exposure to ambient air pollution during weeks 3–8 of pregnancy on CHDs. Daily average concentrations of criteria air pollutants, including PM10, PM2.5, PM2.5–10, SO2, NO2, CO, and O3, were retrieved from the Air Quality Monitoring Networks in Taiwan and interpolated to each township using the kriging method. Second, we enrolled infant-mother pairs from the Taiwan Birth Cohort Study (TBCS) to explore the association between exposure to air pollution during pregnancy and early postnatal period on AD occurrence before 6 months old. Third, the risk of developing infantile pneumonia before age of 18 months was investigated using participants from the TBCS 18-month survey. We compared the influences of exposure to air pollution during pregnancy and one year postnatally.
Firstly, there were 782 fetuses reported to have CHDs during 2007–14 and the most common subgroup was complex congenital heart diseases (30.3%), followed by ventricular septal defect (27.9%) and atrial septal defect (18.8%). The results revealed a positive correlation between exposure to PM2.5 during weeks 3–8 of pregnancy and the occurrence of CHDs (aOR = 1.18, 95% CI: 1.01–1.38). In subgroup analysis, we found that endocardial cushion defect (aOR = 2.30, 95% CI: 1.04–5.06) and pulmonary artery and valve stenosis (aOR = 1.66, 95% CI: 1.01–2.76) were significantly correlated to PM2.5 exposure during the embryonic period. Secondly, among the 16,686 enrolled infants from TBCS, 1,206 (7.2%) had been diagnosed as having AD before age of six months. The occurrence of AD was significantly associated with CO exposure during the whole gestational period (aOR = 1.37, 95% CI: 1.06–1.78) and the first trimester (aOR = 1.51, 95% CI: 1.16–1.97). Lastly, 448 out of 16,686 infants (2.8%) had ever developed pneumonia by 18 months old. Furthermore, infantile pneumonia occurrence was significantly associated with SO2 exposure (aOR = 0.58, 95% CI: 0.41–0.82) during the second trimester. No similar association was observed for the other air pollutants or during the first year postnatally.
In conclusion, we found that exposure to high levels of specific air pollutants during pregnancy was related to certain infantile health outcomes. Furthermore, the critical exposure windows for various organ systems were also different depending on the fetal developmental timeline. Although the underlying mechanisms remained to be elucidated, it is of crucial importance to prevent the adverse health impacts of air pollution on the fetus in advance. We can educate pregnant women to avoid contact with certain detrimental environmental modifiers, as well as adequately protect themselves during more polluted days. The authorities should also make more efforts to reduce the burden of air pollution.

誌謝 II
摘要 III
Abstract V
Glossary XIII
Chapter 1. Introduction 1
Characteristics of Air pollution 2
Primary pollutants 3
Secondary pollutants 5
Critical window of prenatal development 6
Air pollution and cardiac defect 8
Air pollution and allergic skin disease 10
Air pollution and respiratory morbidity 12
Chapter 2. Objectives 14
Chapter 3: Material and Methods 15
3.1 Prenatal exposure to air pollution and congenital heart diseases in Taiwan 15
3.1.1 Taiwan Birth Registration Database 15
3.1.2 Definitions of cases and controls 15
3.1.3 Exposure assessment 16
3.1.4 Spatial interpolation and cross-validation 17
3.1.5 Estimating exposure levels during critical periods 18
3.1.6 Statistical analysis 18
3.2 Prenatal air pollution exposure and risk of atopic dermatitis 19
3.2.1 Taiwan Birth Cohort Study 6-month survey 19
3.2.2 Definition of the outcome 20
3.2.3 Interpolation of air pollutants 20
3.2.4 Estimating exposure levels in different periods 20
3.2.5 Statistical analysis 21
3.3 Prenatal and postnatal exposure to air pollution and infantile pneumonia 22
3.3.1 Taiwan Birth Cohort Study 18-month survey 22
3.3.2 Definition of the outcome 22
3.3.3 Interpolation of air pollutants 22
3.3.4 Estimating exposure levels in different periods 23
3.3.5 Statistical analysis 23
Chapter 4: Results 25
4.1 Prenatal exposure to air pollution and congenital heart diseases in Taiwan 25
4.1.1 Incidence of congenital heart diseases 25
4.1.2 Distribution of air pollutants 25
4.1.3 Risk of congenital heart diseases 26
4.2 Prenatal air pollution exposure and occurrence of atopic dermatitis 26
4.2.1 Characteristics of the enrolled cohort 26
4.2.2 Distribution of air pollutants 27
4.2.3 Risk of developing atopic dermatitis 27
4.3 Prenatal and postnatal exposure to air pollution and infantile pneumonia 28
4.3.1 Characteristics of the enrolled cohort 28
4.3.2 Distribution of air pollutants 28
4.3.3 Risk of pneumonia occurrence 28
Chapter 5: Discussion 30
5.1 Risks of prenatal exposure to PM2.5 on congenital heart diseases 30
5.1.1 Major findings 30
5.1.2 Consistency with previous knowledge 30
5.1.3 Possible mechanism 32
5.2 Risks of prenatal air pollution exposure on developing infantile AD 33
5.2.1 Major findings 33
5.2.2 Consistency with previous knowledge 33
5.2.3 Possible mechanism 34
5.3 Risks of prenatal exposure to air pollution on infantile pneumonia occurrence 35
5.3.1 Major findings 35
5.3.2 Possible mechanism 35
5.3.3 Consistency with previous knowledge 36
5.3.4 Role of postnatal exposure to air pollutants 36
5.4 Spatial interpolation 37
5.5 Strengths 38
5.6 Limitations 39
Chapter 6: Conclusion and Recommendation 41
Conclusion 41
Recommendation 42
References 44
Publication List 89
Appendix 90

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