本研究由兩個假說探討孕婦菸害暴露的情形與新生兒出生結果的相關。考慮母子 CYP2A6 基因多型性的修飾作用後，發現母親懷孕期間暴露於二手菸與新生兒出生頭 圍較窄有關。過去文獻指出CYP1A1、GSTT1、GSTM1 及 NAT2 四種多型性代謝基 因與新生兒DNA 損傷及出生結果有關，但在本研究中並未發現這樣相關。資料顯示 暴露二手菸組的新生兒DNA 損傷基因明顯的高於非吸菸組，表示彗星試驗結果可以 反映受菸害暴露的新生兒 DNA 損傷程度。另一方面，當 DNA 為高度損傷時，二手 菸暴露組之新生兒有較差的出生體重、身長及頭圍。
由本研究結果建議：除了宣導婦女在懷孕過程中應全程戒菸外，也需要加強孕婦 二手菸防治的工作。未來的研究，亦可進一步探討新生兒DNA 損傷程度、新生兒修 補基因與成長過程中疾病發生率(例如，氣喘、心血管疾病、癌症等)等的相關性。
參考文獻
1. WHO. Gender , Health and Tobacco. Gender and Health 2003.
2. 行政院衛生署：18 歲以上人口吸菸率。台灣地區 2010 年衛生指標白皮書, 2005:39.
3. Wen CP, Cheng TY, Lin CL, et al. The health benefits of smoking cessation for adult smokers and for pregnant women in Taiwan. Tob Control 2005;14 Suppl 1:i56-61.
4. 吳芳鴦:吸菸或二手菸影響懷孕期、生產期女性之健康研究。行政院衛生署國 民健康局報告，2004。(補助計畫:BHP-92-Anti-Tobacco-F204).
5. Wen CP, Cheng TY, Eriksen MP, Tsai SP, Hsu CC. The impact of the cigarette market opening in Taiwan. Tob Control 2005;14 Suppl 1:i4-9.
6. Vogler GP, Kozlowski LT. Differential influence of maternal smoking on infant birth weight: gene-environment interaction and targeted intervention. JAMA 2002;287:241-2.
7. Kallen K. The impact of maternal smoking during pregnancy on delivery outcome. Eur J Public Health 2001;11:329-33.
8. Pringle PJ, Geary MP, Rodeck CH, Kingdom JC, Kayamba-Kay's S, Hindmarsh PC. The influence of cigarette smoking on antenatal growth, birth size, and the insulin-like growth factor axis. J Clin Endocrinol Metab 2005;90:2556-62.
9. Kharrazi M, DeLorenze GN, Kaufman FL, et al. Environmental tobacco smoke and pregnancy outcome. Epidemiology 2004;15:660-70.
10. Luck W, Nau H, Hansen R, Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers.
Dev Pharmacol Ther 1985;8:384-95.
11. Li CQ, Windsor RA, Perkins L, Goldenberg RL, Lowe JB. The impact on infant birth weight and gestational age of cotinine-validated smoking reduction during pregnancy. JAMA 1993;269:1519-24.
12. Wang X, Zuckerman B, Pearson C, et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA 2002;
287:195-202.
13. Nakajima M, Kwon JT, Tanaka N, et al. Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clin Pharmacol Ther 2001;69:72-8.
14. Hoffmann H, Hogel J, Speit G. The effect of smoking on DNA effects in the comet assay: a meta-analysis. Mutagenesis 2005;20:455-66.
15. de la Chica RA, Ribas I, Giraldo J, Egozcue J, Fuster C. Chromosomal instability in amniocytes from fetuses of mothers who smoke. JAMA 2005;293:1212-22.
16. Rowland RE, Harding KM. Increased sister chromatid exchange in the peripheral blood lymphocytes of young women who smoke cigarettes.
Hereditas 1999;131:143-6.
17. Littlefield LG, Joiner EE. Analysis of chromosome aberrations in lymphocytes of long-term heavy smokers. Mutat Res 1986;170:145-50.
18. Hoffmann H, Isner C, Hogel J, Speit G. Genetic polymorphisms and the effect of cigarette smoking in the comet assay. Mutagenesis 2005;20:359-64.
19. Donna L. Hoyert TJM, Fay Menacker, Donna M. Strobino and Bernard Guyer.
Annual Summary of Vital Statistics: 2004. Pediatrics 2006;117:168-183.
20. Nakamura MU, Alexandre SM, Kuhn dos Santos JF, et al. Obstetric and
perinatal effects of active and/or passive smoking during pregnancy. Sao Paulo Med J 2004;122:94-8.
21. http://www.doh.gov.tw/cht/index.aspx: 行政院衛生署.
22. Wen CP, Levy DT, Cheng TY, Hsu CC, Tsai SP. Smoking behaviour in Taiwan, 2001. Tob Control 2005;14 Suppl 1:i51-5.
23. Wen CP, Tsai SP, Chen CJ, Cheng TY. The mortality risks of smokers in Taiwan: Part I: cause-specific mortality. Prev Med 2004;39:528-35.
24. Lannero E, Wickman M, Pershagen G, Nordvall L. Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 2006;7:3.
25. Jaakkola JJ, Gissler M. Maternal smoking in pregnancy, fetal development, and childhood asthma. Am J Public Health 2004;94:136-40.
26. Lieberman E, Gremy I, Lang JM, Cohen AP. Low birthweight at term and the timing of fetal exposure to maternal smoking. Am J Public Health 1994;84:1127-31.
27. Jaakkola JJ, Jaakkola N, Zahlsen K. Fetal growth and length of gestation in relation to prenatal exposure to environmental tobacco smoke assessed by hair nicotine concentration. Environ Health Perspect 2001;109:557-61.
28. Martin TR, Bracken MB. Association of low birth weight with passive smoke exposure in pregnancy. Am J Epidemiol 1986;124:633-42.
29. 陳培君, 李中一, 林瑞雄,宋鴻樟。婦女抽菸及二手菸暴露和低出生體重嬰兒。
台灣衛誌 2002;21:321-328.
30. Keyler D, Pentel PR, Kuehl G, Collins G, Murphy SE. Effects of nicotine infusion on the metabolism of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats. Cancer Lett 2003;202:1-9.
31. Haddow JE, Knight GJ, Palomaki GE, Kloza EM, Wald NJ. Cigarette consumption and serum cotinine in relation to birthweight. Br J Obstet Gynaecol 1987;94:678-81.
32. Eskenazi B, Prehn AW, Christianson RE. Passive and active maternal smoking as measured by serum cotinine: the effect on birthweight. Am J Public Health 1995;85:395-8.
33. England LJ, Kendrick JS, Gargiullo PM, Zahniser SC, Hannon WH.
Measures of maternal tobacco exposure and infant birth weight at term. Am J Epidemiol 2001;153:954-60.
34. Nakajima M, Yamagishi S, Yamamoto H, Yamamoto T, Kuroiwa Y, Yokoi T.
Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans. Clin Pharmacol Ther 2000;67:57-69.
35. Benowitz NL, Jacob P, 3rd, Sachs DP. Deficient C-oxidation of nicotine. Clin Pharmacol Ther 1995;57:590-4.
36. Cholerton S, Arpanahi A, McCracken N, et al. Poor metabolisers of nicotine and CYP2D6 polymorphism. Lancet 1994;343:62-3.
37. Oscarson M, McLellan RA, Gullsten H, et al. Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett 1999;460:321-7.
38. Oscarson M, McLellan RA, Gullsten H, et al. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett 1999;448:105-10.
39. Fowles J, Dybing E. Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob Control 2003;12:424-30.
40. Hong YC, Lee KH, Son BK, Ha EH, Moon HS, Ha M. Effects of the GSTM1 and GSTT1 polymorphisms on the relationship between maternal exposure
to environmental tobacco smoke and neonatal birth weight. J Occup Environ Med 2003;45:492-8.
41. Nukui T, Day RD, Sims CS, Ness RB, Romkes M. Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants.
Pharmacogenetics 2004;14:569-76.
42. Karaoguz MY, Cosar B, Arikan Z, Basaran F, Menevse A, Menevse S.
Increased frequency of sister chromatid exchanges in peripheral lymphocytes of alcoholics and cigarette smokers. Cell Biol Int 2005;
29:165-8.
43. Shulman LP, Elias S, Tharapel AT, Li LR, Phillips OP, Simpson JL. Sister chromatid exchange frequency in directly prepared cytotrophoblasts:
demonstration of in vivo deoxyribonucleic acid damage in pregnant women who smoke cigarettes. Am J Obstet Gynecol 1991;165:1877-80.
44. Salonen K, Lahdetie J. No effect of maternal smoking in early pregnancy observed on chromosome aberrations in chorionic villus samples. Mutat Res 1993;298:285-9.
45. Pluth JM, Ramsey MJ, Tucker JD. Role of maternal exposures and newborn genotypes on newborn chromosome aberration frequencies. Mutat Res 2000;465:101-11.
46. Ariyoshi N, Takahashi Y, Miyamoto M, et al. Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C. Pharmacogenetics 2000;10:687-93.
47. Collins AR, Ma AG, Duthie SJ. The kinetics of repair of oxidative DNA damage (strand breaks and oxidised pyrimidines) in human cells. Mutat Res 1995;336:69-77.
48. 邱顯財。孕婦吸菸與暴露二手菸對其胎兒出生結果的影響。中國醫藥大學環境 醫學研究所碩士論文, 2005.
49. Fujieda M, Yamazaki H, Saito T, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 2004;25:2451-8.
50. Yoshida R, Nakajima M, Watanabe Y, Kwon JT, Yokoi T. Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br J Clin Pharmacol 2002;54:511-7.
51. Oscarson M, Gullsten H, Rautio A, et al. Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett 1998;438:201-5.
52. Bourian M, Gullsten H, Legrum W. Genetic polymorphism of CYP2A6 in the German population. Toxicology 2000;144:129-37.
53. Tricker AR. Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology 2003;183:151-73.
54. Goel P, Radotra A, Singh I, Aggarwal A, Dua D. Effects of passive smoking on outcome in pregnancy. J Postgrad Med 2004;50:12-6.
55. Lazzaroni F, Bonassi S, Manniello E, et al. Effect of passive smoking during pregnancy on selected perinatal parameters. Int J Epidemiol 1990;19:960-6.
56. Perera FP, Tang D, Rauh V, et al. Relationships among polycyclic aromatic hydrocarbon-DNA adducts, proximity to the World Trade Center, and effects on fetal growth. Environ Health Perspect 2005;113:1062-7.
表一、孕婦與新生兒之基本人口學資料 40001~60000 50(29.9) 66(37.7) 7(30.4) 123(33.7) 60001~80000 41(24.6) 40(22.9) 5(21.7) 86(23.6) >80000 48(28.4) 34(19.4) 2(8.7) 84(23.0)
是否為第一胎 0.969
否 82(47.7) 87(47.3) 12(50.0) 181(47.6) 是 90(52.3) 97(52.7) 12(50.0) 199(52.4)
表一、孕婦與新生兒之基本人口學資料(續)
出生體重(克) 3206.1(405.0) 3172.4(392.2) 3184.2(635.0) 3188.6(415.9) 0.746 0.409 出生身長(公分) 51.3(2.0) 50.8(2.2) 51.2 (2.5) 50.9(2.1) 0.417 0.652 出生頭圍(公分) 33.5(1.6) 33.5(1.6) 33.6 (1.8) 33.5(1.6) 0.917 0.962 出生胸圍(公分) 32.8(1.7) 32.9(1.7) 32.9(1.9) 32.8(1.7) 0.938 0.827
表二、CYP2A6 基因多型性與對偶基因之分布
表三、新生兒CYP2A6 基因與臍帶血可丁寧濃度之相關
分層分析
非吸菸組 二手菸組 吸菸組
基因型別‡ β(SE) p-value β(SE) p-value β(SE) p-value
整段缺失 referent -- referent -- referent --
≧*1A 0.47(0.6) 0.413 0.69(0.5) 0.143 -4.89(2.2) 0.076
≧*1B 0.78(0.6) 0.216 0.99(0.6) 0.080 . .
回歸分析(未分層)
單變項 調整菸害暴露狀態 調整其他因子*
β(SE) p-value β(SE) p-value β(SE) p-value
整段缺失 referent -- referent -- referent --
≧*1A 0.20(0.4) 0.587 0.26(0.4) 0.475 0.27(0.4) 0.496 ≧*1B 0.50(0.4) 0.256 0.67(0.4) 0.122 0.69(0.4) 0.119
*調整孕婦年齡、懷孕週數、職業、教育、飲酒習慣及菸害暴露狀況
‡≧*1A(至少帶有一個野生型對偶基因): 1A/1A 、 1A/4C
≧*1B(至少帶有一個變異型對偶基因): 1B/1B 、1A/1B 、 1B/4C 整段缺失: 4C/4C
表四、孕婦菸害暴露情形與新生兒出生結果之迴歸分析
變項 Model 1 Model 2 Model 3 Model 4
β(SE) p-value β(SE) p-value β(SE) p-value β(SE) p-value 出生體重
非吸菸組 referent -- referent -- referent -- referent -- 二手菸組 -34.24(44.5) 0.442 -26.15(50.3) 0.603 -80.21(73.8) 0.279 -55.07(44.4) 0.215
吸菸組 -28.39(92.9) 0.760 -12.53(108.8) 0.908 -25.88(154.6) 0.867 57.79(91.6) 0.528 出生身長
非吸菸組 referent -- referent -- referent -- referent -- 二手菸組 -0.25(0.2) 0.282 -0.17(0.3) 0.493 -0.32(0.4) 0.408 -0.41(0.2) 0.081
吸菸組 0.19(0.5) 0.701 0.12(0.5) 0.828 0.05(0.8) 0.951 0.31(0.5) 0.522 出生頭圍
非吸菸組 referent -- referent -- referent -- referent -- 二手菸組 -0.03(0.2) 0.871 -0.13(0.3) 0.627 -0.66(0.3) 0.010 -0.71(0.3) 0.010
吸菸組 0.04(0.4) 0.901 0.11(0.6) 0.857 -0.27(0.5) 0.613 0.16(0.6) 0.789
【註】Model 1:單變項分析
Model 2:調整(a)出生體重:孕婦第二期血液及尿液可丁寧濃度 (b)出生身長:孕婦第二期尿液可丁寧濃度 (c)出生頭圍:孕婦第一期血液可丁寧濃度
Model 3:調整孕婦及其新生兒 CYP2A6 之基因多型性(整段缺失、至少帶有一個野生型對偶基因、至少帶有一個變異型對偶基因) Model 4:調整孕婦年齡、懷孕週數、職業、教育程度、飲酒習慣以及 Model 2、3 統計上具顯著意義(p<0.05)之變項
表五、四種代謝基因多型性之分布
非吸菸組 二手菸組 吸菸組 全體 卡方檢定
p-value
CYP1A1 MspI 0.249
野生/野生 44(46.8) 61(58.7) 8(53.3) 113(53.1) 野生/變異或變異/變異 50(53.2) 43 (41.4) 7(46.7) 100(47.0)
GSTM1 0.182
非無效型 52(55.3) 58(55.8) 12(80.0) 122(57.3) 無效型 42(44.7) 46(44.2) 3(20.0) 91(42.7)
GSTT1 0.367
非無效型 50(53.2) 55(52.9) 11(73.3) 116(54.5) 無效型 44(46.8) 49(47.1) 4(26.7) 97(45.5)
NAT2 0.936
快型 74(80.4) 78(78.8) 10(76.9) 162(79.4) 慢型 18(19.6) 21(21.2) 3(23.1) 42(20.6)
表六、孕婦菸害暴露與新生兒DNA 損傷積分之比較 DNA 損傷積分
個數 平均值 標準差 中位數
t 統計量或 F 統計量§
p-value z 統計量或 χ2統計量‡
p-value 比較方式*
目視判定方法
非吸菸組 94 54.0 33.8 48.8 -2.91U 0.004 -2.61 0.009 N-E
二手菸組 104 69.7 42.3 59.8 0.98 0.329 -0.94 0.349 E-S
吸菸組 15 58.5 34.3 52.9 -0.49 0.628 0.63 0.529 S-N
4.27 0.015 7.05 0.030 多樣本 影像分析方法
非吸菸組 91 53.8 40.5 41.3 -1.65 0.101 -1.64 0.101 N-E
二手菸組 103 64.4 47.9 48.4 0.17 0.863 -0.09 0.929 E-S
吸菸組 15 62.0 53.8 49.2 -0.70 0.489 0.67 0.502 S-N
1.34 0.265 2.74 0.255 多樣本
*N: 非吸菸組(non-smoker) E:二手菸暴露組(ETS) S:吸菸組(smoker)
§有母數檢定統計量：雙樣本比較為獨立t 檢定之 t 統計量(U：兩組變異數不相等) 多樣本比較為 ANOVA 之 F 統計量
‡無母數統計檢定量：雙樣本比較為Wilcoxon rank sum test 之 z 統計量 多樣本比較為 Kruskal wallis test 之χ2統計量
表七、孕婦菸害暴露與新生兒彗星試驗頭部與尾巴拖曳長度比值之比較 尾巴拖曳長度/頭部直徑
個數 平均值 標準差 中位數
t 統計量或 F 統計量§
p-value z 統計量或 χ2統計量‡
p-value 比較方式*
非吸菸組 91 2.1 3.0 1.6 0.44U 0.662 -1.75 0.080 N-E 二手菸組 103 2.0 0.6 1.7 -0.93U 0.369 -0.13 0.897 E-S 吸菸組 15 3.0 4. 5 1.7 -0.78U 0.447 0.74 0.457 S-N
1.36 0.258 3.14 0.208 多樣本
*N: 非吸菸組(non-smoker) E:二手菸暴露組(ETS) S:吸菸組(smoker)
§有母數檢定統計量：雙樣本比較為獨立t 檢定之 t 統計量(U：兩組變異數不相等) 多樣本比較為 ANOVA 之 F 統計量
‡無母數統計檢定量：雙樣本比較為Wilcoxon rank sum test 之 z 統計量 多樣本比較為 Kruskal Wallis test 之χ2統計量
表八、孕婦菸害暴露情形與新生兒DNA 損傷積分之迴歸分析
線性迴歸 調整基因型a
β(SE) p-value β(SE) p-value
非吸菸組 referent -- referent --
二手菸組 15.8(5.4) 0.004 16.9(6.9) 0.015
吸菸組 4.6(10.6) 0.667 2.9(13.4) 0.826
a調整CYP1A1、GSTT1、GSTM1、NAT2 之基因多型性
表九、孕婦菸害暴露狀態與出生結果之迴歸分析(以新生兒 DNA 損傷積分做分層)
5 30 55 80 105 130 155 180 D.BSCORE
2000 3000 4000 5000
BABY.WT
圖一、新生兒DNA 損傷積分與出生體重之相關
5 30 55 80 105 130 155 180 D.BSCORE
46 51 56 61
BABY.H
圖二、新生兒DNA 損傷積分與出生身長之相關
5 30 55 80 105 130 155 180 D.BSCORE
30 32 34 36 38
BE.HEAD
圖三、新生兒DNA 損傷積分與出生頭圍之相關
5 30 55 80 105 130 155 180 D.BSCORE
28 30 32 34 36 38
BE.CH
圖四、新生兒DNA 損傷積分與出生胸圍之相關