经皮硝酸甘油贴膜疗法对早产儿预后影响的流行病学研究
发布时间：2018-08-08 21:51
【摘要】：背景早产是围产医学中的一个重要、复杂而又常见的妊娠并发症。自上世纪80年代以来,尽管围产医疗技术不断发展,早产的发病率仍呈逐年上升趋势。由于早产儿的残障率和死亡率远高于足月儿,其导致近期和远期高昂医疗费用以及沉重社会负担,已经成为全球的一个重要公共卫生问题。2001年5月至2004年6月,由加拿大皇后大学Graeme Simth开展的随机、双盲、多中心、安慰剂对照硝酸甘油贴膜治疗早产的临床试验研究证实,硝酸甘油贴膜是一种能有效延长妊娠,母婴不良反应少的抗早产药物,可显著降低早产儿发病率和(或)死亡率。然而试验中将近50%参与研究的先兆早产孕妇入组时发生误诊,实际只有一半的孕妇发生早产,而且Smith在进行资料分析没有剔除足月分娩的孕妇。本研究在Smith的支持和加拿大卫生研究院及加拿大医师协会资助下(课题编号：MCT41550),对该临床试验资料进行再分析。 目的本研究在加拿大随机、双盲、多中心、安慰剂对照经皮硝酸甘油贴膜治疗早产的临床试验研究的基础上对资料进行再分析,首先为重新评价硝酸甘油贴膜降低孕24至32周的早产儿发病率和(或)死亡率的临床疗效,其次探讨其降低早产儿发病率和(或)死亡率的可能原因；再运用年龄与发育进程量表对早产儿进行随访研究,以评估硝酸甘油贴膜对早产儿早期发育的影响；最后进行成本—效果分析,评估硝酸甘油贴膜临床应用的经济学效果,为临床医生选择较优治疗方案提供依据。 方法采用分层随机对照设计的临床试验方法,按研究中心和孕周(240周至28。周,.281周至32。周)将参与研究的孕24至32周的先兆早产孕妇随机分配至硝酸甘油贴膜组和安慰剂组。贴膜贴于先兆早产孕妇腹部1小时后,如宫缩不缓解,再加用一片相同贴膜,24小时后更换一片新贴膜再治疗24小时。整个试验48小时后,去除所有贴膜,观察延迟分娩的时间及新生儿预后。随后对早产孕妇及早产儿进行随访,当早产儿在年龄12个月和24个月时,采用年龄和发育进程量表(ASQ)对其生长发育进行测评。 对资料进行再分析时,排除所有足月分娩的孕妇,比较组间早产儿发病率和(或)死亡率、出生孕周、妊娠延长时间和糖皮质激素使用率的差别。对随访数据进行分析时,首先对随访和失访的孕妇及早产儿基线特征情况进行比较,探索组间比较的均衡性。再对组间ASQ总分和五个维度(语言沟通能力、大动作能力、精细动作能力、应物能力、应人能力)的评分进行比较。最后采用成本一效果分析,只计算直接住院医疗费用,对硝酸甘油贴膜的临床应用进行经济学评价。统计分析分析方法包括Pearson x2检验(包括确切概率法),t检验,非参数Wilcoxon秩和检验,Cochran-Armitage趋势检验,logistic回归分析和Kaplan-Meier生存分析等。应用SAS9.2(SAS Institute, Cary, NC)对数据进行统计分析,统计检验的显著性水准定为0.05。 结果.从2001年5月至2004年6月,共158名符合纳入排除标准的先兆早产孕妇随机分配至硝酸甘油贴膜组和安慰剂组(硝酸甘油组77人安慰剂组81人,平均年龄28.5岁)。剔除5例病例后,153例病例纳入分析。 1.排除所有足月分娩孕妇后,该试验最终有77例(50.3%)孕妇发生早产。其中,硝酸甘油组39人,平均年龄29.5岁,安慰剂组38人,平均年龄28.7岁。两组在社会人口学,产次,胎次,早产史等基线资料差异无统计学意义。 (1)硝酸甘油组早产儿发病率和(或)死亡率为7.7%(3/39),安慰剂组为28.9%(11/38)。硝酸甘油治疗组显著降低早产发病率和(或)死亡率(RR=0.20,[95%CI0.05,0.81][P=0.02])；率差为-0.21,[95%CI-0.38,-0.05][P=0.03]；需治疗人数为5[95%CI3,22]。 (2)随机入组时,组间平均孕龄无差异(P=0.75),分娩时组间孕龄差异有统计学意义(按天计算,P=0.04；按孕周计算,P=0.03)。早产孕妇中使用硝酸甘油贴膜的孕妇比安慰剂组的平均妊娠时间长10天(P=0.02)。 (3) Kaplan-Meier生存分析结果显示,硝酸甘油比安慰剂延长妊娠时间长(20.9vs.10.1, log rank test:P=0.02)。按随机入组时孕周进行分层(≤280周和≥281周),入组时孕周小于28周时,硝酸甘油组比安慰剂组妊娠时间长23天(27.4vs.4.0, log rank test:P=0.02);入组时孕周在28至32周间,硝酸甘油组与安慰剂组妊娠延长时间差异无统计学意义(16.4vs.15.0, log rank test:P=0.58)。 (4)入组时孕龄小于28周的孕妇,硝酸甘油贴膜组比安慰剂组有更多完成全疗程糖皮质激素治疗的趋势(Cochran-Armitage趋势检验P=0.04),而孕龄满28周的孕妇在入组后,接受糖皮质激素的治疗率组间差异无统计学意义。 2.共153名先兆早产孕妇及新生儿参与随访研究。其中,111例(72.5%)新生儿(硝酸甘油组55例,安慰剂组56例)在12月时完成随访。83例(54.2%)新生儿(硝酸甘油组42例,安慰剂组41例)在24个月时完成随访。参与随访和失访的孕妇在种族、教育水平、婚姻状况、吸毒等构成组间无显著性差异。除性别外,参与随访和失访的新生儿在是否早产、出生孕周、1分钟Apgar评分、5分钟Apgar评分、出生体重的组间差异无统计学意义。无论是在12个月还是24个月,硝酸甘油组ASQ各维度分和总分均高于安慰剂组,由于样本较小,组间差别在a=0.05水平上无统计学意义。在24个月ASQ评分时,尽管a=0.05显著水平上,统计分析显示无差别,安慰剂组比硝酸甘油组各维度异常评分的频数似乎有升高趋势。 3.成本效果分析中,硝酸甘油组中有24例早产儿被送入新生儿重症监护室(NICU), NICU入院率为32.4%(24/74),安慰剂对照组有31例早产儿进入NICU, NICU入院率为39.2%(31/79)。硝酸甘油组早产儿的平均住院费用为CAN$34,357,安慰剂对照组为CAN$44,326。对于所有随机入组的病例住院费用(无论有无NICU费用),硝酸甘油组平均为CAN$13,397,安慰剂组是CAN$18,427。总的来说,硝酸甘油组每个病例平均住院费用比安慰剂组节省CAN$5,030,而其NICU入院避免率比安慰剂组高6.8%,是较优的治疗治疗方案。同时对住院费用和硝酸甘油临床效果进行单因素灵敏度分析,结果均显示硝酸甘油为较优治疗方案。 结论1)硝酸甘油降低早产儿发病率和(或)死亡率和延长孕周的疗效主要作用于孕周24至28周的妊娠,硝酸甘油贴膜抗早产作用具有孕周特异性。2)通过延长妊娠,为使用糖皮质激素促进胎儿肺成熟争取时间可能是硝酸甘油贴膜显著降低早产儿发病率和(或)死亡率的原因之一3)硝酸甘油治疗早产孕妇不影响早产儿早期发育,但仍需更大规模的研究来进一步证实。4)硝酸甘油治疗早产孕妇减少了早产儿NICU入院时间,其住院费用比安慰剂组低而且改善了早产儿预后结局,是较优的治疗方案。5)硝酸甘油贴膜治疗早产,由于其安全、有效、费用低廉,操作方便,进一步研究后,可考虑至临床推广试用。
[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.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R722.6
本文编号：2173144
[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.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R722.6
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