【摘要】：背景早產(chǎn)是圍產(chǎn)醫(yī)學(xué)中的一個(gè)重要、復(fù)雜而又常見的妊娠并發(fā)癥。自上世紀(jì)80年代以來,盡管圍產(chǎn)醫(yī)療技術(shù)不斷發(fā)展,早產(chǎn)的發(fā)病率仍呈逐年上升趨勢(shì)。由于早產(chǎn)兒的殘障率和死亡率遠(yuǎn)高于足月兒,其導(dǎo)致近期和遠(yuǎn)期高昂醫(yī)療費(fèi)用以及沉重社會(huì)負(fù)擔(dān),已經(jīng)成為全球的一個(gè)重要公共衛(wèi)生問題。2001年5月至2004年6月,由加拿大皇后大學(xué)Graeme Simth開展的隨機(jī)、雙盲、多中心、安慰劑對(duì)照硝酸甘油貼膜治療早產(chǎn)的臨床試驗(yàn)研究證實(shí),硝酸甘油貼膜是一種能有效延長(zhǎng)妊娠,母嬰不良反應(yīng)少的抗早產(chǎn)藥物,可顯著降低早產(chǎn)兒發(fā)病率和(或)死亡率。然而試驗(yàn)中將近50%參與研究的先兆早產(chǎn)孕婦入組時(shí)發(fā)生誤診,實(shí)際只有一半的孕婦發(fā)生早產(chǎn),而且Smith在進(jìn)行資料分析沒有剔除足月分娩的孕婦。本研究在Smith的支持和加拿大衛(wèi)生研究院及加拿大醫(yī)師協(xié)會(huì)資助下(課題編號(hào)：MCT41550),對(duì)該臨床試驗(yàn)資料進(jìn)行再分析。 目的本研究在加拿大隨機(jī)、雙盲、多中心、安慰劑對(duì)照經(jīng)皮硝酸甘油貼膜治療早產(chǎn)的臨床試驗(yàn)研究的基礎(chǔ)上對(duì)資料進(jìn)行再分析,首先為重新評(píng)價(jià)硝酸甘油貼膜降低孕24至32周的早產(chǎn)兒發(fā)病率和(或)死亡率的臨床療效,其次探討其降低早產(chǎn)兒發(fā)病率和(或)死亡率的可能原因；再運(yùn)用年齡與發(fā)育進(jìn)程量表對(duì)早產(chǎn)兒進(jìn)行隨訪研究,以評(píng)估硝酸甘油貼膜對(duì)早產(chǎn)兒早期發(fā)育的影響；最后進(jìn)行成本—效果分析,評(píng)估硝酸甘油貼膜臨床應(yīng)用的經(jīng)濟(jì)學(xué)效果,為臨床醫(yī)生選擇較優(yōu)治療方案提供依據(jù)。 方法采用分層隨機(jī)對(duì)照設(shè)計(jì)的臨床試驗(yàn)方法,按研究中心和孕周(240周至28。周,.281周至32。周)將參與研究的孕24至32周的先兆早產(chǎn)孕婦隨機(jī)分配至硝酸甘油貼膜組和安慰劑組。貼膜貼于先兆早產(chǎn)孕婦腹部1小時(shí)后,如宮縮不緩解,再加用一片相同貼膜,24小時(shí)后更換一片新貼膜再治療24小時(shí)。整個(gè)試驗(yàn)48小時(shí)后,去除所有貼膜,觀察延遲分娩的時(shí)間及新生兒預(yù)后。隨后對(duì)早產(chǎn)孕婦及早產(chǎn)兒進(jìn)行隨訪,當(dāng)早產(chǎn)兒在年齡12個(gè)月和24個(gè)月時(shí),采用年齡和發(fā)育進(jìn)程量表(ASQ)對(duì)其生長(zhǎng)發(fā)育進(jìn)行測(cè)評(píng)。 對(duì)資料進(jìn)行再分析時(shí),排除所有足月分娩的孕婦,比較組間早產(chǎn)兒發(fā)病率和(或)死亡率、出生孕周、妊娠延長(zhǎng)時(shí)間和糖皮質(zhì)激素使用率的差別。對(duì)隨訪數(shù)據(jù)進(jìn)行分析時(shí),首先對(duì)隨訪和失訪的孕婦及早產(chǎn)兒基線特征情況進(jìn)行比較,探索組間比較的均衡性。再對(duì)組間ASQ總分和五個(gè)維度(語言溝通能力、大動(dòng)作能力、精細(xì)動(dòng)作能力、應(yīng)物能力、應(yīng)人能力)的評(píng)分進(jìn)行比較。最后采用成本一效果分析,只計(jì)算直接住院醫(yī)療費(fèi)用,對(duì)硝酸甘油貼膜的臨床應(yīng)用進(jìn)行經(jīng)濟(jì)學(xué)評(píng)價(jià)。統(tǒng)計(jì)分析分析方法包括Pearson x2檢驗(yàn)(包括確切概率法),t檢驗(yàn),非參數(shù)Wilcoxon秩和檢驗(yàn),Cochran-Armitage趨勢(shì)檢驗(yàn),logistic回歸分析和Kaplan-Meier生存分析等。應(yīng)用SAS9.2(SAS Institute, Cary, NC)對(duì)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,統(tǒng)計(jì)檢驗(yàn)的顯著性水準(zhǔn)定為0.05。 結(jié)果.從2001年5月至2004年6月,共158名符合納入排除標(biāo)準(zhǔn)的先兆早產(chǎn)孕婦隨機(jī)分配至硝酸甘油貼膜組和安慰劑組(硝酸甘油組77人安慰劑組81人,平均年齡28.5歲)。剔除5例病例后,153例病例納入分析。 1.排除所有足月分娩孕婦后,該試驗(yàn)最終有77例(50.3%)孕婦發(fā)生早產(chǎn)。其中,硝酸甘油組39人,平均年齡29.5歲,安慰劑組38人,平均年齡28.7歲。兩組在社會(huì)人口學(xué),產(chǎn)次,胎次,早產(chǎn)史等基線資料差異無統(tǒng)計(jì)學(xué)意義。 (1)硝酸甘油組早產(chǎn)兒發(fā)病率和(或)死亡率為7.7%(3/39),安慰劑組為28.9%(11/38)。硝酸甘油治療組顯著降低早產(chǎn)發(fā)病率和(或)死亡率(RR=0.20,[95%CI0.05,0.81][P=0.02])；率差為-0.21,[95%CI-0.38,-0.05][P=0.03]；需治療人數(shù)為5[95%CI3,22]。 (2)隨機(jī)入組時(shí),組間平均孕齡無差異(P=0.75),分娩時(shí)組間孕齡差異有統(tǒng)計(jì)學(xué)意義(按天計(jì)算,P=0.04；按孕周計(jì)算,P=0.03)。早產(chǎn)孕婦中使用硝酸甘油貼膜的孕婦比安慰劑組的平均妊娠時(shí)間長(zhǎng)10天(P=0.02)。 (3) Kaplan-Meier生存分析結(jié)果顯示,硝酸甘油比安慰劑延長(zhǎng)妊娠時(shí)間長(zhǎng)(20.9vs.10.1, log rank test:P=0.02)。按隨機(jī)入組時(shí)孕周進(jìn)行分層(≤280周和≥281周),入組時(shí)孕周小于28周時(shí),硝酸甘油組比安慰劑組妊娠時(shí)間長(zhǎng)23天(27.4vs.4.0, log rank test:P=0.02);入組時(shí)孕周在28至32周間,硝酸甘油組與安慰劑組妊娠延長(zhǎng)時(shí)間差異無統(tǒng)計(jì)學(xué)意義(16.4vs.15.0, log rank test:P=0.58)。 (4)入組時(shí)孕齡小于28周的孕婦,硝酸甘油貼膜組比安慰劑組有更多完成全療程糖皮質(zhì)激素治療的趨勢(shì)(Cochran-Armitage趨勢(shì)檢驗(yàn)P=0.04),而孕齡滿28周的孕婦在入組后,接受糖皮質(zhì)激素的治療率組間差異無統(tǒng)計(jì)學(xué)意義。 2.共153名先兆早產(chǎn)孕婦及新生兒參與隨訪研究。其中,111例(72.5%)新生兒(硝酸甘油組55例,安慰劑組56例)在12月時(shí)完成隨訪。83例(54.2%)新生兒(硝酸甘油組42例,安慰劑組41例)在24個(gè)月時(shí)完成隨訪。參與隨訪和失訪的孕婦在種族、教育水平、婚姻狀況、吸毒等構(gòu)成組間無顯著性差異。除性別外,參與隨訪和失訪的新生兒在是否早產(chǎn)、出生孕周、1分鐘Apgar評(píng)分、5分鐘Apgar評(píng)分、出生體重的組間差異無統(tǒng)計(jì)學(xué)意義。無論是在12個(gè)月還是24個(gè)月,硝酸甘油組ASQ各維度分和總分均高于安慰劑組,由于樣本較小,組間差別在a=0.05水平上無統(tǒng)計(jì)學(xué)意義。在24個(gè)月ASQ評(píng)分時(shí),盡管a=0.05顯著水平上,統(tǒng)計(jì)分析顯示無差別,安慰劑組比硝酸甘油組各維度異常評(píng)分的頻數(shù)似乎有升高趨勢(shì)。 3.成本效果分析中,硝酸甘油組中有24例早產(chǎn)兒被送入新生兒重癥監(jiān)護(hù)室(NICU), NICU入院率為32.4%(24/74),安慰劑對(duì)照組有31例早產(chǎn)兒進(jìn)入NICU, NICU入院率為39.2%(31/79)。硝酸甘油組早產(chǎn)兒的平均住院費(fèi)用為CAN$34,357,安慰劑對(duì)照組為CAN$44,326。對(duì)于所有隨機(jī)入組的病例住院費(fèi)用(無論有無NICU費(fèi)用),硝酸甘油組平均為CAN$13,397,安慰劑組是CAN$18,427�？偟膩碚f,硝酸甘油組每個(gè)病例平均住院費(fèi)用比安慰劑組節(jié)省CAN$5,030,而其NICU入院避免率比安慰劑組高6.8%,是較優(yōu)的治療治療方案。同時(shí)對(duì)住院費(fèi)用和硝酸甘油臨床效果進(jìn)行單因素靈敏度分析,結(jié)果均顯示硝酸甘油為較優(yōu)治療方案。 結(jié)論1)硝酸甘油降低早產(chǎn)兒發(fā)病率和(或)死亡率和延長(zhǎng)孕周的療效主要作用于孕周24至28周的妊娠,硝酸甘油貼膜抗早產(chǎn)作用具有孕周特異性。2)通過延長(zhǎng)妊娠,為使用糖皮質(zhì)激素促進(jìn)胎兒肺成熟爭(zhēng)取時(shí)間可能是硝酸甘油貼膜顯著降低早產(chǎn)兒發(fā)病率和(或)死亡率的原因之一3)硝酸甘油治療早產(chǎn)孕婦不影響早產(chǎn)兒早期發(fā)育,但仍需更大規(guī)模的研究來進(jìn)一步證實(shí)。4)硝酸甘油治療早產(chǎn)孕婦減少了早產(chǎn)兒NICU入院時(shí)間,其住院費(fèi)用比安慰劑組低而且改善了早產(chǎn)兒預(yù)后結(jié)局,是較優(yōu)的治療方案。5)硝酸甘油貼膜治療早產(chǎn),由于其安全、有效、費(fèi)用低廉,操作方便,進(jìn)一步研究后,可考慮至臨床推廣試用。
[Abstract]:Background preterm birth is an important, complicated and common complication of pregnancy. Since the 80s last century, the incidence of preterm birth has been increasing year by year despite the continuous development of perinatal medical technology. The heavy social burden has become an important public health problem worldwide from May to June 2004.2001. A randomized, double blind, multicenter, placebo-controlled nitroglycerin sticker for preterm labor, conducted by Graeme Simth, Queen's University, Canada, confirmed that the nitroglycerin patch is an effective extension of pregnancy and poor mother to child. A less reactive preterm drug can significantly reduce the incidence of preterm infants and (or) mortality. However, in the trial, nearly 50% of the preterm preterm pregnant women who participated in the study were misdiagnosed, only half of the pregnant women had preterm birth, and the Smith was not excluded from the pregnant women. This study was supported and added in Smith. The data of the clinical trial were reanalyzed under the assistance of the grand Institutes of health and the Canadian Medical Association (MCT41550).
Objective this study reanalyzed the data on the basis of a randomized, double blind, multicenter, placebo-controlled clinical trial of transdermal nitroglycerin patch in the treatment of preterm labor. First, the clinical efficacy of nitroglycerin patch was re evaluated to reduce the incidence and (or) mortality of preterm infants 24 to 32 weeks pregnant, and then to explore the reduction of preterm delivery. In order to evaluate the effect of nitroglycerin patch on the early development of premature infants, the effect of nitroglycerin on the early growth of preterm infants was evaluated by using the age and development process scale to evaluate the effect of the cost-effectiveness analysis on the clinical application of the nitroglycerin patch for the clinicians. The scheme provides the basis.
Methods a randomized controlled clinical trial was used to randomly assign preterm preterm pregnant women who participated in the study for 24 to 32 weeks of pregnancy (240 weeks to 28. weeks,.281 weeks, 32. weeks) to the nitroglycerin patch group and placebo group. The patch attached to the abdomen of preterm preterm pregnant women after 1 hours, such as contraction of uterine contraction, and then added one The same patch was replaced by a new patch after 24 hours and then treated for 24 hours. After 48 hours the whole experiment, all the sticker was removed, the time of delayed delivery and the prognosis of the newborn were observed. Then the preterm pregnant and preterm infants were followed up, and the age and development process scale (ASQ) were used when the preterm infants were aged 12 months and 24 months. Education is evaluated.
During the reanalysis of the data, the difference between the incidence of preterm and (or) mortality, the birth week, the prolongation of pregnancy and the use of glucocorticoid were compared between all the pregnant women in full term delivery. The score of ASQ total score and five dimensions (language communication ability, great action ability, fine action ability, physical ability, human ability) were compared. Finally, the cost analysis was used to calculate the direct hospitalization cost only, and the clinical application of nitric acid glycerin sticker was evaluated. The analysis methods include Pearson x2 test (including the exact probability method), t test, non parametric Wilcoxon rank sum test, Cochran-Armitage trend test, logistic regression analysis and Kaplan-Meier survival analysis. The statistical analysis of the data is carried out with SAS9.2 (SAS Institute, Cary, NC).
Results from May 2001 to June 2004, 158 preterm preterm pregnant women who met the exclusion criteria were randomly assigned to the nitroglycerin patch group and the placebo group (81 in the nitroglycerin group, 77 in the placebo group, with an average age of 28.5 years old). After 5 cases were eliminated, 153 cases were analyzed.
1. after all full term deliveries were excluded, 77 cases (50.3%) of the pregnant women had premature birth. Among them, the nitroglycerin group was 39, the average age was 29.5, the placebo group was 38, and the average age was 28.7 years. There was no statistical difference in the baseline data of social demography, birth, birth, and preterm birth in the two groups.
(1) the incidence and mortality of preterm infants in the nitroglycerin group were 7.7% (3/39) and 28.9% (11/38) in the placebo group. The rate of premature delivery and (or) mortality (RR=0.20, [95%CI0.05,0.81][P=0.02]) was significantly reduced in the nitroglycerin group (RR=0.20, [95%CI0.05,0.81][P=0.02]), and the rate was -0.21, [95%CI-0.38, -0.05][P=0.03]; the number of patients needed was 5[95%CI3,22].
(2) there was no difference in average gestational age between groups at random (P=0.75). The difference in gestational age between groups during childbirth was statistically significant (P=0.04, P=0.03). The average pregnancy time of pregnant women using nitroglycerin sticker in preterm pregnant women was 10 days longer than that of placebo group (P=0.02).
(3) Kaplan-Meier survival analysis showed that nitroglycerin prolonged the pregnancy time (20.9vs.10.1, log rank test:P=0.02). The pregnancy weeks were stratified at random (< < 280 weeks and 281 weeks), and the pregnancy time of the group was 23 days longer than that of the placebo group (27.4vs.4.0, log rank test:P=0.02). There was no significant difference in prolonged gestation between nitroglycerin and placebo groups between 28 and 32 weeks of gestation (16.4 vs. 15.0, log rank test: P = 0.58).
(4) the gestational age of pregnant women was less than 28 weeks, and the nitroglycerin sticker group had more complete course of glucocorticoid treatment than the placebo group (Cochran-Armitage trend test P=0.04), but there was no significant difference in the treatment rate of glucocorticoid after 28 weeks of pregnant women.
2. of 153 preterm preterm pregnant women and newborns were followed up in the follow-up study. Among them, 111 (72.5%) neonates (55 cases of nitroglycerin and 56 placebo groups) completed the follow-up of.83 (54.2%) neonates (42 cases of nitroglycerin and 41 in the placebo group) in December. They were followed up at 24 months. The pregnant women who were followed up and lost their visits were in race, education, marriage. There was no significant difference between the groups of marriage and drug abuse. In addition to sex, there was no significant difference in the difference between the groups of newborn babies who participated in the follow-up and lost children in the preterm birth, birth week, 1 minute Apgar score, 5 minute Apgar score, and the difference in the ASQ dimension and total score of the nitroglycerin group was higher than that of the placebo group at 12 months or 24 months. In the dose group, there was no statistical difference between the groups at the a=0.05 level because of the smaller samples. At the 24 month ASQ score, the statistical analysis showed no difference in the significant level of a=0.05, and the frequency of the abnormal scores in the placebo group seemed to be higher than that of the nitroglycerin group.
3. in the cost-effectiveness analysis, 24 cases of preterm infants were sent to the neonatal intensive care unit (NICU) in the nitroglycerin group. The admission rate of NICU was 32.4% (24/74). The placebo control group had 31 premature infants entering NICU, NICU admission rate was 39.2% (31/79). The average hospitalization cost of the preterm infants in the nitroglycerin group was CAN$34357, and the placebo control group was CAN$44326. pairs. The average hospitalization cost (regardless of NICU cost), nitroglycerin group was CAN$13397, the placebo group was CAN$18427., and the average hospitalization cost of each case in the nitroglycerin group saved CAN$5030 than the placebo group, and the NICU admission avoidance rate was 6.8% higher than that of the placebo group, and the same treatment regimen was better. Univariate sensitivity analysis of hospitalization costs and clinical effects of nitroglycerin showed that nitroglycerin was the best treatment.
Conclusion 1) the effect of nitroglycerin on the incidence of premature infants and (or) mortality and prolongation of pregnancy is mainly based on the pregnancy of 24 to 28 weeks of pregnancy. The anti preterm effect of nitroglycerin has a gestational specific.2) by prolonging pregnancy, and the time for promoting fetal lung maturation by using glucocorticoid may be significantly reduced by nitroglycerin sticker. The incidence of preterm infants and (or) one of the causes of mortality is 3) nitroglycerin (nitroglycerin) does not affect early birth in preterm infants, but a more large-scale study is needed to further confirm that.4) nitroglycerin is used to reduce the NICU admission time of preterm infants, and its hospitalization fee is lower than that of the placebo group and improves the prognosis of premature infants. It is a better treatment program.5) nitroglycerin sticker for the treatment of premature delivery, because of its safety, effectiveness, low cost, convenient operation, further study, can be considered in clinical trial.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R722.6

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