本文選題：早產(chǎn) + 孕前BMI�。� 參考：《浙江大學(xué)》2015年博士論文

【摘要】：研究背景及目的 早產(chǎn)(Preterm Birth,PTB)是導(dǎo)致新生兒死亡最主要的原因,也是導(dǎo)致五歲以下兒童死亡的第二大原因。在全球范圍內(nèi),早產(chǎn)的發(fā)病率波動幅度較大(5%-18%),并呈現(xiàn)逐年上升的趨勢。早產(chǎn)的高危因素及早產(chǎn)發(fā)生的具體生物學(xué)機制仍不完全清楚。目前認(rèn)為與早產(chǎn)發(fā)生相關(guān)的因素主要包括孕婦的年齡、種族、職業(yè)、受教育程度、婚姻狀況、孕前體重、孕期增重、體育鍛煉、不良生活行為方式、營養(yǎng)狀況、多胞胎、孕期并發(fā)癥、孕期的心理壓力以及早產(chǎn)史等。 妊娠期對女性而言是一個關(guān)鍵時期,為了保證營養(yǎng)需求,孕婦往往會攝入過多的食物,但孕前肥胖及孕期增重過多與多種不良妊娠結(jié)局相關(guān),譬如妊娠期糖尿病、先兆子病、子癇及早產(chǎn)等。維生素D(VitD)可通過調(diào)節(jié)免疫功能影響早產(chǎn)的發(fā)生。此外,肥胖和維生素D缺乏均可改變體內(nèi)炎癥因子的水平,而促炎因子水平升高可刺激前列腺素等宮縮蛋白水平增高,進(jìn)而誘發(fā)早產(chǎn)。目前,關(guān)于孕前肥胖、孕期增重和維生素D對早產(chǎn)影響的研究結(jié)果并不一致,有研究認(rèn)為孕前肥胖、孕期增重過多及維生素D缺乏會增加早產(chǎn)的發(fā)病風(fēng)險；但也有研究并未發(fā)現(xiàn)這些因素與早產(chǎn)之間存在關(guān)聯(lián)。因此,本研究以舟山市婦幼保健院為研究現(xiàn)場,采用前瞻性隊列研究設(shè)計探討孕前BMI和孕期增重與早產(chǎn)發(fā)病風(fēng)險的關(guān)聯(lián)；并采用巢式病例對照研究設(shè)計探討維生素D、IL-1β和IL-10與早產(chǎn)發(fā)病風(fēng)險的關(guān)聯(lián),為早產(chǎn)的防治提供科學(xué)依據(jù)。 材料和方法 本研究以舟山市婦幼保健院為研究現(xiàn)場,采用前瞻性隊列研究設(shè)計,通過面對面訪談獲得流行病學(xué)調(diào)查問卷資料(包括研究對象一般社會人口學(xué)特征、生活行為方式、身高及體重等基本信息),同時采集孕早、中、晚期血液樣本。從2011年8月開始到2014年4月為止,共收集孕早期有效問卷1580份,孕中期有效問卷1091份。采用對數(shù)二項分布(Log-binomial)回歸模型分析孕前BMI和孕期增重對早產(chǎn)發(fā)病風(fēng)險的影響。 在隊列研究的基礎(chǔ)上,按照1：2巢式病例對照研究設(shè)計,挑選孕早期有血液樣本的62例早產(chǎn)孕婦(妊娠孕周小于37周),并根據(jù)年齡(±2歲)、相同產(chǎn)次和血樣采集月份在對照組中選擇與之匹配的124例足月產(chǎn)孕婦(妊娠孕周大于37周且小于42周)。采用高效液相串聯(lián)質(zhì)譜法檢測血漿中25(OH)D、25(OH)D3和25(OH)D2水平；通過Human Inflammation Array-3芯片篩選在早產(chǎn)組和足月產(chǎn)組有顯著差異的炎癥因子,然后采用Elisa法對篩選出的IL-1β和IL-10進(jìn)行檢測。利用條件Logistic回歸模型探討25(OH)D、25(OH)D3、25(OH)D2、IL-1β、IL-10和IL-10/IL-1β與早產(chǎn)發(fā)病風(fēng)險的關(guān)聯(lián)。結(jié)果 在前瞻性隊列研究納入的1580例孕婦中,早產(chǎn)孕婦的年齡略高于足月產(chǎn)孕婦(28.5vs.27.7歲,p=0.047)；而其他人口學(xué)特征和生活行為方式在兩組間均衡可比。經(jīng)年齡、孕期增重、受教育程度、職業(yè)、被動吸煙、飲茶和胎膜早破調(diào)整后,孕前BMI≥24kg/m2的孕婦早產(chǎn)的發(fā)病風(fēng)險為2.55(95%CI：1.39-4.68),孕前BMI18.5kg/m2的孕婦早產(chǎn)的發(fā)病風(fēng)險為0.73(95%CI：0.37-1.44)。根據(jù)不同分娩方式分層分析的結(jié)果顯示,孕前BMI≥24kg/m2的自然分娩孕婦早產(chǎn)的發(fā)病風(fēng)險并未顯著增加(RR=1.52,95%CI:0.38-6.14),但剖宮產(chǎn)孕婦早產(chǎn)的發(fā)病風(fēng)險顯著增加(RR=2.53,95%CI：1.19-5.38)。孕前BMI24kg/m2的初產(chǎn)婦和單胎孕婦早產(chǎn)的發(fā)病風(fēng)險均明顯增加,RR值分別為2.58和3.08。被動吸煙和孕前BMI的聯(lián)合作用顯著增加了早產(chǎn)的發(fā)病風(fēng)險(RR=4.38,95%CI:1.97-9.72)。雖然未發(fā)現(xiàn)孕早期增重和孕中期增重與早產(chǎn)的發(fā)病風(fēng)險存在關(guān)聯(lián)；但與孕早中期增重在10-15kg的孕婦相比,增重大于15kg的孕婦早產(chǎn)的發(fā)病風(fēng)險為1.99(95%CI：1.01-3.92),增重小于10kg的孕婦早產(chǎn)的發(fā)病風(fēng)險為1.01(95%CI:0.59-1.73)。孕早中期增重大于15kg的自然分娩孕婦早產(chǎn)的發(fā)病風(fēng)險為3.56(95%CI：1.42-8.90)；孕早中期增重大于15kg的剖宮產(chǎn)孕婦早產(chǎn)的發(fā)病風(fēng)險為1.53(95%CI：0.56-4.21)。聯(lián)合作用的結(jié)果顯示,年齡≥30歲且孕早中期增重15kg的孕婦早產(chǎn)的發(fā)病風(fēng)險顯著增加(RR=4.78,95%CI：1.89-12.10)；被動吸煙且孕早中期增重15kg的孕婦早產(chǎn)的發(fā)病風(fēng)險也顯著增加(RR=2.88,95%CI：1.22-6.81)。 巢式病例對照研究納入的186例孕婦孕早期VitD平均水平為17.2ng/ml;其中有67.2%的孕婦VitD缺乏,有24.2%的孕婦VitD不足,僅有8.6%的孕婦VitD適宜。VitD和VitD3呈現(xiàn)明顯的季節(jié)差異,以冬季水平最低。與VitD20ng/ml的孕婦相比,VitD20ng/ml的孕婦早產(chǎn)的發(fā)病風(fēng)險未顯著增加(OR=1.19,95%CI:0.45-3.15)。年齡及被動吸煙與VitD缺乏的聯(lián)合作用均未顯著增加早產(chǎn)的發(fā)病風(fēng)險。敏感性分析結(jié)果也未見初產(chǎn)、單胎妊娠或不同分娩方式影響VitD缺乏與早產(chǎn)發(fā)病風(fēng)險的關(guān)聯(lián)。VitD3和VitD2與早產(chǎn)的發(fā)病風(fēng)險均不存在統(tǒng)計學(xué)關(guān)聯(lián)。與IL-1β水平在0.13-0.40pg/ml的孕婦相比,IL-1β0.40pg/ml的孕婦早產(chǎn)的發(fā)病風(fēng)險降低66%(OR=0.34,95%CI:0.13-0.87), IL-1β0.13pg/ml的孕婦早產(chǎn)的發(fā)病風(fēng)險未見顯著降低(OR=0.34,95%CI:0.12-1.00)。但未發(fā)現(xiàn)IL-10水平和IL-10/IL-1β比值與早產(chǎn)的發(fā)病風(fēng)險存在統(tǒng)計學(xué)關(guān)聯(lián)。 結(jié)論 與孕前體重正常的孕婦相比,孕前超重的孕婦早產(chǎn)的發(fā)病風(fēng)險顯著增加。孕早中期增重過多會顯著增加早產(chǎn)的發(fā)病風(fēng)險。年齡和被動吸煙分別與孕前BMI及孕期增重對早產(chǎn)發(fā)病風(fēng)險呈現(xiàn)明顯的聯(lián)合作用。孕婦維生素D水平普遍偏低,并存在明顯的季節(jié)差異,以冬季最低。未發(fā)現(xiàn)VitD、VitD3和VitD2對早產(chǎn)的發(fā)病風(fēng)險有顯著影響。與中等濃度的IL-1β相比,高水平IL-1β可降低早產(chǎn)的發(fā)病風(fēng)險,但I(xiàn)L-10和IL-10/IL-1β與早產(chǎn)的發(fā)病風(fēng)險無統(tǒng)計學(xué)關(guān)聯(lián)。
[Abstract]:Background and purpose of research
Preterm Birth (PTB) is the leading cause of neonatal death and the second major cause of death in children under five years of age. The incidence of premature birth has fluctuated considerably (5%-18%) worldwide. The high risk factors for premature birth and the specific biological mechanism of premature birth are still not completely clear. At present, the factors associated with premature birth include the age, race, occupation, education, marital status, pre pregnancy weight, pregnancy weight gain, physical exercise, unhealthy lifestyle, nutritional status, polyplets, pregnancy complications, psychological stress during pregnancy, and the history of preterm birth.
Pregnancy is a critical period for women. In order to ensure nutritional requirements, pregnant women tend to eat too much food, but prepregnancy obesity and excessive weight gain during pregnancy are associated with a variety of bad pregnancy outcomes, such as gestational diabetes, Xian Zhaozi's disease, eclampsia, and premature delivery. Vitamin D (VitD) can affect the occurrence of preterm birth by regulating immune function. In addition, obesity and vitamin D deficiency can change the level of inflammatory factors in the body, and the increase of proinflammatory factors can stimulate the increased levels of prostaglandin and other uterine contraction proteins and induce preterm labor. Excessive weight and vitamin D deficiency may increase the risk of preterm birth; but there are also studies that have not been found to be associated with preterm labor. Therefore, a prospective cohort study was used to explore the association between pre pregnancy BMI and pregnancy weight gain and preterm birth risk in Zhoushan maternal and child health care hospital. Case control study designed to explore the association between vitamin D, IL-1 beta and IL-10 and the risk of premature delivery, so as to provide a scientific basis for prevention and treatment of premature delivery.
Materials and methods
In this study, a prospective cohort study was designed in Zhoushan maternal and child health care hospital. Through face-to-face interviews, the epidemiological survey data (including the basic information on the general demographic characteristics, lifestyle, height and weight) of the subjects were collected, and the early, middle, and late blood samples were collected from August 2011. From the beginning of April 2014, 1580 effective questionnaires were collected and 1091 effective mid-term questionnaires were collected. The effects of pre pregnancy BMI and pregnancy weight gain on the risk of preterm birth were analyzed by the logarithmic two distribution (Log-binomial) regression model.
On the basis of the cohort study, according to the 1:2 nested case control study, 62 preterm pregnant women with blood samples (gestational gestational weeks less than 37 weeks) were selected in the early pregnancy, and 124 full term pregnant women (gestational pregnancy weeks greater than 37 weeks and less than 42 weeks) were selected according to the age (+ 2 years), the same birth and blood sample months in the control group. High performance liquid phase tandem mass spectrometry was used to detect 25 (OH) D, 25 (OH) D3 and 25 (OH) D2 levels in plasma, and a Human Inflammation Array-3 chip was used to screen the inflammatory factors which were significantly different in the preterm and full term groups. Then Elisa method was used to detect IL-1 beta and IL-10. 25 (25) H) D3,25 (OH) D2, IL-1 beta, IL-10 and IL-10/IL-1 beta were associated with risk of preterm birth.
Among 1580 pregnant women who were enrolled in prospective cohort study, the age of preterm pregnant women was slightly higher than that of full term pregnant women (28.5vs.27.7 years old, p=0.047), while other demographic and lifestyle behaviors were proportional to the balance between the two groups. The age, weight gain during pregnancy, education, occupation, passive smoking, tea and premature rupture of membranes, BMI more than 24kg/ before pregnancy The risk of preterm birth of pregnant women in M2 was 2.55 (95%CI:1.39-4.68), and the risk of preterm birth of pregnant women with BMI18.5kg/m2 before pregnancy was 0.73 (95%CI:0.37-1.44). The results of stratified analysis according to different modes of childbirth showed that the risk of premature birth of pregnant women with BMI more than 24kg/m2 before pregnancy did not increase significantly (RR=1.52,95%CI:0.38-6.14), but the incidence of premature delivery was not significantly increased (RR=1.52,95%CI:0.38-6.14). The risk of preterm birth was significantly increased (RR=2.53,95%CI:1.19-5.38). The risk of preterm birth of pre pregnant BMI24kg/m2 primiparas and single pregnant women increased significantly. The combination of RR values of 2.58 and 3.08. for passive smoking and pre pregnancy BMI significantly increased the risk of premature delivery (RR=4.38,95%CI:1.97-9.72). Although no pregnancy was found, the risk of pregnancy was significantly increased. Early weight gain and midtrimester weight gain were associated with the risk of preterm birth, but the risk of preterm birth of pregnant women with weight gain more than 15kg in 10-15kg was 1.99 (95%CI:1.01-3.92), and the risk of premature birth of pregnant women with weight gain less than 10kg was 1.01 (95%CI:0.59-1.73). The weight gain of early pregnancy was greater than 15kg. The risk of preterm birth was 3.56 (95%CI:1.42-8.90), and the risk of premature birth in the cesarean section was 1.53 (95%CI:0.56-4.21). The combined effect showed that the risk of premature birth of pregnant women aged over 30 years and 15kg in the middle and middle pregnancy was significantly increased (RR=4.78,95%CI:1.89-12.10). The risk of premature delivery in women who had passive smoking and increased 15kg in the early and middle pregnancy also increased significantly (RR=2.88,95%CI:1.22-6.81).
The average VitD level of 186 pregnant women in the nested case control study was 17.2ng/ml, including 67.2% of pregnant women with VitD deficiency, 24.2% of pregnant women with VitD deficiency, and only 8.6% of pregnant women with VitD suitable for.VitD and VitD3 to present a distinct seasonal difference, with the lowest level in winter. The risk of disease was not significantly increased (OR=1.19,95%CI:0.45-3.15). The combination of age and passive smoking and VitD deficiency did not significantly increase the risk of preterm birth. No primipara, single pregnancy or different delivery methods affected the association of VitD deficiency with the risk of preterm birth, and the risk of.VitD3 and VitD2 and preterm birth were no longer associated with the risk of premature birth. There was a statistical correlation. The risk of premature birth in pregnant women with IL-1 beta 0.40pg/ml decreased by 66% (OR=0.34,95%CI:0.13-0.87) compared with IL-1 beta levels in 0.13-0.40pg/ml pregnant women, and the risk of premature delivery in pregnant women with IL-1 beta 0.13pg/ml was not significantly decreased (OR=0.34,95%CI:0.12-1.00). There was a statistically significant association between the risk of disease.
conclusion
The risk of preterm birth was significantly increased in pregnant women who were overweight before pregnancy compared with those with normal pre pregnancy weight. Excessive weight gain in the middle of early pregnancy could significantly increase the risk of preterm birth. Age and passive smoking were combined with prepregnancy BMI and weight gain during prepregnancy, respectively. The levels of vitamin D in pregnant women were generally low and coexisted. The obvious seasonal differences were lowest in winter. No VitD, VitD3 and VitD2 were found to have a significant impact on the risk of preterm birth. Compared with the medium concentration of IL-1 beta, the high level of IL-1 beta could reduce the risk of preterm birth, but there was no statistical correlation between the risk of premature birth and IL-10 and IL-10/IL-1 beta.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R714.21

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