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。
Background:Preterm labor is a complicated and frequent complication during pregnancy. Despite advances in perinatal medicine, the incidence of preterm birth has increased since the early1980. These babies are at increased risk of death and significant short and long term morbidity. Given the high burden of caring these babies imposed to the health care system and society, preterm birth and its sequelae are a major globe health problem in developed countries. The Canadian Preterm Labor Nitroglycerin Trial demonstrated that transdermal nitroglycerin (GTN), compared with placebo patches, significantly decreased the risk of severe neonatal morbidity and mortality. However, given this analysis in the oringial tial about50%subjects who were not true preterm labor there was about50%subjects were not true preterm births. We therefore conducted a secondary analysis with the support from Dr Graeme Smith and Canadian Institutes for Health Research (CIHR,(MCT41550).
Objectives:This study is based on the previous randomized double-blind placebo controlled GTN trial. The objectives of the secondary analysis of data were to determine the possible mechanism for the improved neonatal outcomes with the use of GTN for preterm labor by examining only the women in the trial who delivered preterm, to evaluate developmental performance in the children born to women who participated in the GTN trial by using Ages and Stages Questionnaire (ASQ), after one year and two year of follow up, to determine the cost-effectiveness of GTN for preterm labor from a hospital perspective.
Methods:Pregnant women who were clinically in preterm labour between24and32weeks were randomly allocated to either GTN or a placebo patch. Randomization is stratified by centre and gestational age (240wks to280ks,281wks to320wks). After first patches placement in the abdomen for 1hour, if there was ongoing uterine activity, an additional study patch was placed. Twenty-four hours after initiation of treatment, the patches were replaced with the same number of patches for further24hours of treatment. At the completion of treatment (48hours total), all patches were removed. The Ages and Stages Questionnaire (ASQ) were used for the children developmental assessments at one-year and two-year follow up study.
For the secondary analysis, women in the original trial who delivered at term were excluded. A composite of severe neonatal outcomes, gestational age at delivery, and corticosteriod use, in additional to Kaplan-Meier survial analysis to assess time from randomization to delivery were examined. Then, the ASQ were used for the children developmental follow-up study. We compared the baseline characteristics between follow-up participants and those who did not in mothers and children, respectively. Total score and five domain scores of child development (communication, gross motor skills, fine motor skills, problem-solving, and personal social skill) were evaluated. Supplementary analyses were performed after stratifying study subjects by gestational age at birth (
引文
[1]徐志红,徐爱群,曾蔚越.早产的定义和分类.实用妇产科杂志,2005,21(11)：643-644.
[2]Beck S, Wojdyla D, Say L, et al:The worldwide incidence of preterm birth:a systematic review of maternal mortality and morbidity. Bull World Health Organiza-tion 2010,88:31-38.
[3]Murphy DJ, Fowlie PW, McGuireW, et al. Obstetric issues in preterm birth. BMJ,2004,329(7469):783-786
[4]Robertson PA, Sniderman SH, Laros RK, Cowan R, Heilborn D, Goldenberg RL, et al. Neonatal morbidity and according to gestational age and birth weight from five tertiary care centers in the United States,1983 through 1986. Am J Obstet Gynecol 1992; 166:1629-1645.
[5]Russell RB, Green NS, Steiner CA, et al. Cost of hospitalization for preterm and low birth weight infants in the United States.Pediatrics 2007;120:e1-9
[6]Canadian Institute for Health Information. Giving Birth in Canada:The Costs. Ottawa:Canadian Institute for Health Information,2006.
[7]Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labour? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993;68:1247-59.
[8]Moutquin J-M. Classification and heterogeneity of preterm birth. BJOG 2003; 110(Suppl20):30-3.
[9]Moutquin J-M. Socio-economic and psychosocial factors in the management and prevention of preterm labour. BJOG 2003; 110(Suppl 20):56-60.
[10]Petrou S. Economic consequences of preterm birth and low birthweight. BJOG 2003; 110(Suppl 20):17-23.
[11]Smith GN. What are the realistic expectations of tocolytics? BJOG 2003;110 (Suppl 20):103-6.
[12]Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Eng J Med 1992; 327:308-312.
[13]Keirse MJNC. Betamimetric tocolytics in preterm labor. In:Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, editors. Cochrane Updates on Disk. Oxford: 1993.
[14]Moise K, Huhta J, Sharif D. Indomethacin in the treatment of premature labor: Effects on the fetal ductus arteriosus. N Engl J Med 1988; 318-327.
[15]Moise K. Indomethacin therapy in the treatment of symptomatic polyhydram-nios. Clin Obstet Gynecol 1991; 34:310.
[16]Major CA, Lewis DF, Harding JA, Porto MA, Garite TJ. Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low birth-weight neonate. Am J Obstet Gynecol 1994; 170:102-106.
[17]Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor:A randomized study. Am J Obstet Gynecol 1995; 173:20-25.
[18]Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala O, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor. J Pediatr 1994; 124:782-788.
[19]Panter KR, Hannah ME, Amankwah KS, Ohlsson A, Jefferies AL, Farine D. The effect of indomethacin tocolysis for preterm labour on perinatal outcome:A randomized placebo controlled trial. Br J Obstet Gynaecol 1999; 106:467-473.
[20]Mitchell BF. Moratorium on Indomethacin as a tocolytic. J SOGC 1995; 17: 279-280.
[21]Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990; 163:767-772.
[22]Hannah ME, et.al. The Canadian Consensus on the Use of Tocolytics for Preterm Labour. J SOGC 1995; 17:1089-1115.
[23]Smith GN, Bobier HS, Brien JF. The Role of Nitric Oxide in the Maintenance of Normal Pregnancy and Preeclampsia. In:Lee RV, Garner PR, Barron WM, Coustan DR, editors.Current Obstetric Medicine. Toronto:Mosby-Year Book, Inc.,1996:103-127.
[24]Norman J. Nitric Oxide and the Myometrium. Pharmacol.Ther.1996; 70: 91-100.
[25]Heymann MA, Bootstaylor B, Roman C, Natuzzi ES, Parer JT, Harrison MR, et al. Glyceryl trinitrate stops active labour in sheep. In:Moncada S, Feelisch M, Busse R, editors. The Biology of Nitric Oxide. Physiology and Clinical Aspects. London:Portland Press,1994:201-203.
[26]Jennings RW, MacGillivray TE, Harrison MR. Nitric oxide inhibits preterm labour in Rhesus monkeys. J Maternal Fetal Med 1993; 2:170-175.
[27]Rowlands S, Trudinger B, Visva-Lingam S. Treatment of preterm cervical dilatation with glyceryl trinitrate, a nitric oxide donor. Aust NZ J Obstet Gynaecol 1996; 36:377-381.
[28]Smith GN, Walker MC, McGrath MJ. Randomized, double-blind, placebo controlled trial assessing nitroglycerin as a tocolytic. Br J Obstet Gynaecol 1999; 106:736-739.
[29]Bisits A, Madsen G, McLean M, O'Callaghan S, Smith R, Giles W. CRH-A biochemical predictor of preterm delivery in a pilot randomized trial of the treatment of preterm labour. Am J Obstet Gynecol 1998; 178:862-866.
[30]Lees C, Campbell S, Martin J, Moncada S, Brown R, Jauniaux E, et al. Glyceryl trinitrate in management of preterm labour. Author's reply. Lancet 1994; 44: 553-554.
[31]Lees CC, Lojacono A, Thompson C, Danti L, Black RS, Tanzi P, White IR, Campbell S. Glyceryl trinitrate and ritodrine in tocolysis:An International Multi-center Randomized Study. Obstet Gynecol 1999; 94:403-408.
[32]Lees C, Campbell S, Jauniaux E, et al. Arrest of preterm labour and prolongation of gestation with glyceryl trinitrate, a nitric oxide donor. Lancet 1994;3 43:1325-6.
[33]Smith GN, Brien JF. The use of nitroglycerin for uterine relaxation. Obstet Gynecol Survey 1998; 53:559-65.
[34]Smith GN, Walker MC, Ohlsson A, O'Brien K, Windrim R, Canadian Preterm Labour Nitroglycerin Trial Group. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007; 196:37. e1-8.
[35]Challis JRG, Lye SJ, Gibb W, Whittle W, Patel F, Alfaidy N. Understanding preterm labour. Ann N Y Acad Sci 2001; 943:225-34.
[36]American Pediatric Society position statement. Available:http://brightfutures. aap.org/web/RelatedLiteratureDetail.asp? ContentID=1280 (accessed 2007 Nov 22).
[37]Parry T. The effectiveness of early intervention:a critical review. J Paediatr Child Health 1992; 28:343-6.
[38]Symington A, Pinelli J. Developmental care for promoting development and preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003; 4: CD001814.
[39]Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev2003;3:CD004110.
[40]Glodjo A, Thompson E, Roberts W. Developmental and behavioural disabilities in children-is pediatric education meeting patient needs? J Investig Med 2003; 51 (Suppl 1):S113.
[41]Bricker D, Squires J. Ages and stages questionnaires:a parent-completed child-monitoring system. Baltimore:Paul H Brookes Publishing Co.; 1999.
[42]Heiser A, Curcin O, Luhr C, Grimmer I, Metze B, Obladen M. Parental and professional agreement in developmental assessment of very-low-birth weight and term infants. Dev Med Child Neurol 2000; 42:21-4.
[43]Glascoe F, Dworkin P. The role of parents in the detection of developmental and behavioral problems. Pediatrics 1995; 95:829-35.
[44]Bortolus R, Parazzini F, Trevisanuto D, Cipriani S, Ferrarese P, Zarnado V, et al.Developmental assessment of preterm and term children at 18 months: reproducibility and validity of a postal questionnaire to parents. Acta Paediatr 2002;91:1101-7.
[45]Skellern C, Rogers Y, O'Callaghan M. A parent-completed developmental questionnaire:follow-up of ex-premature infants. J Paediatr Child Health 2001; 37:125-9.
[46]Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308-12.
[47]Dupont WD, Plummer WD:'Power and Sample Size Calculations:A Review and Computer Program', Controlled Clinical Trials 1990; 11:116-28.
[48]Squires J, Bricker D, Potter L. Revision of a parent-completed developmental screening tool:ages and stages questionnaires. J Pediatr Psychol 1997; 22:313-28.
[49]Klamer A, Lando A, Pinborg A, Greisen G. Ages and stages questionnaire used to measure cognitive deficit in children born extremely preterm. Acta Paediatr 2005;94:1327-9.
[50]Janson H, Squires J. Parent-completed developmental screening in a Norwegian population sample:a comparison with US normative data. Acta Paediatr 2004; 93:1525-9.
[51]Squires J, Bricker D, Potter L. Ages and stages questionnaires user's guide.2nd ed. Baltimore, MD:Paul Brookes Publishing; 1999.
[52]Sheennan AT, Dunn MS, Ohlsson A, LennoxK, Hoskins EM. Abnormal pulmonary outcomes in premature infants; prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82:527-32.
[53]Northway WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. N Engl J Med 1967; 276:357-68.
[54]Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187:1-7.
[55]Hannah ME. Search for best tocolytic for preterm labour. Lancet 2000; 356: 699-700.
[56]Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG 2003; 110(Suppl 20):8-16.
[57]Bisits A, Madsen G, Knox M, et al. The randomized nitric oxide tocolysis trial (RNOTT) for the treatment of preterm labor. Am J Obstet Gynecol 2004; 191:683-90.
[58]Wani MP, Barakzai N, Graham I. Glyceryl trinitrate vs. ritodrine for the treatment of preterm labor. Int J Gynecol Obstet 2004; 85:165-7.
[59]Black RS, Lees C, Thompson C, Pickles A, Campbell S. Maternal and fetal cardiovascular effects of transdermal glyceryl trinitrate and intravenous ritodrine. Obstet Gynecol 1999; 94:572-6.
[60]El-Sayed YY, Riley ET, Holbrook H, Cohen SE, Chitkara U, Druzin ML. Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labour. Obstet Gynecol 1999; 93:79-83.
[61]Schleussner E, Moller A, Grob W, et al. Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or intravenous fenoterol combined with magnesium sulfate. Eur J Obstet Gynecol Reprod Biol 2003; 106:14-9.
[62]De Spirlet M, Treluyer JM, Chevret S, et al. Tocolytic effects of intravenous nitroglycerin. Fundam Clin Pharmacol 2004; 18:207-13.
[63]Leszczynska-Gorzelak B, Laskowska M, Marciniak B, Oleszczuk J. Nitric oxide for treatment of threatend preterm labor. Int J Gynecol Obstet 2001;73:201-6.
[64]贺茜,沙金燕,顾清等.硝酸甘油贴膜治疗早产的临床效果及机理研究.中华妇产科杂志,2002,37(3)：134-5.
[65]Bustard MA, Farley A, Bennett BM, Smith GN. Steady-state maternal and fetal plasma concentrations of glyceryl trinitrate (GTN) in the preterm sheep. Can J Phsiol Pharmacol 2003; 81:884-9.
[66]Maytt L, Brockman DE, Eis ALW, et al. Immuno-histochemical localization of nirtic oxide synthase in the human placenta. Placenta,1993,14:487-495.
[67]Roe CM, Leitch IM, Borua AL, et al. Nitric oxide regulation of corticotropin- releasing hormone release from the human perfused placenta in vitro. J Clin Endocrinol Metab,1996,81 (2):763-769.
[68]Smith GN and Brien JF. Use of nitroglycerin for uterine relaxaiton. Obstet Gynecol Surv,1998,53 (9):559-565.
[69]Vinatier D, Dufour P and Berard J. Utilization of intravenous nitroglycerin for obstetrical emergencies. Int J Gynecol Obstet,1996,55 (2):129-134.
[70]Sajimomaa O, Laatikainen T, Washlstrom T. Corticotropin-releasing factor in human placenta:localization, concentration and release in vitro. Placenta,1998, 9:373-385.
[71]Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308-12.
[72]Goldenberg RL, Iams JD, Mercer BM, et al. What we have learned about the predictors of preterm birth. Sem Perinatol 2003;27:185-93.
[73]Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005; 192:350-9.
[74]Smith GN. What are the realistic expectations of tocolytics? Br J Obstet Gynaecol 2003; 110 (Suppl 20):103-6.
[75]The Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agent Ritodrine. N Engl J Med 1992;327:308-12.
[76]Gill A, Madsen G, Knox M, Bisits A, Giles W, Tudehope D, et al. Neonatal neurodevelopmental outcomes following tocolysis with glycerol trinitrate patches. Am J Obstet Gynecol 2006; 195:484-7.
[77]Lindsay N, Healy G, Colditz P, Lingwood B. Use of the Ages and Stages Questionnaire to predict outcome after hypoxic-ischaemic encephalopathy in the neonate. J Paediatr Child Health 2008;44:590-5.
[78]Johnson S, Marlow N, Wolke D, Davidson L, Marston L, O'Hare A, et al. Validation of a parent report measure of cognitive development in very preterm infants. Dev Med Child Neurol 2004;46:389-97.
[79]Hollie HX, Marks K, Squires J, Nickel R. Impact of implementing developmental screening at 12 and 24 months in a pediatric practice. Pediatrics 2007;120;381-9.
[80]Tucker M. MgSO4 does not raise disability risk in children:follow-up study of Magpie Trial participants also shows no increased risk of death. OB/GYN News 2004. Available t:http://findarticles.com/p/articles/mi_m0CYD/is_24_39/ai_n8697291. Accessed August 23,2010.
[81]Williams D, Gelijns A, Moskowitz AJ,Weinberg AD, Ng JH, Crawford E, et al.Hypoplastic left heart syndrome:valuing the survival. J Thorac Cardiovasc Surg 2000; 119(4 Pt 1):720-31.
[82]Jakovljevic M, Varjacic M, Jankovic SM. Cost-effectiveness of ritodrine and fenoterol for treatment of preterm labour in a low-middle-income country:a case study. Value Health 2008; 11:149-53.
[83]Kam KY, Lamont RF. Developments in the pharmacotherapeutic management of spontaneous preterm labour. Expert Opin Pharmacother 2008; 9:1153-68.
[84]Rushing S, Ment LR. Preterm birth:a cost benefit analysis. Semin Perinato 2004; 28:444-50.
[85]Lyndrup J, Lamont RF. The choice of a tocolytic for the treatment of preterm labour:a critical evaluation of nifedipine versus atosiban. Expert Opin Investig Drugs 2007; 16:843-53.
[86]Canadian Institute for Health Information. Too Early, Too Small:A Profile of Small Babies Across Canada. Ottawa:Canadian Institute for Health Information, 2009.
[87]Tommiska V, Tuominen R, Fellman V. Economic costs of care in extremely low birthweight infants during the first 2 years of life. Pediatr Crit Care Med 2003;4: 157-63.
[88]Petrou S. Economic consequences of preterm birth and low birth weight. BJOG 2003;110:17-23.
[89]Gennaro S. Leave and employment in families of preterm low birth weight infants. Image J Nurs Sch 1996;28:193-8.
[90]McCormick MC, Bernbaum JC, Eisenberg JM, et al. Costs incurred by parents of very low birth weight infants after the initial neonatal hospitalization. Pediatrics 1991; 88:533-41.
[91]Papiernik K, Keith LG. The cost effectiveness of preventing preterm delivery in twin pregnancies. Acta Genet Med Gemellol (Roma) 1990;39:361-9.
[92]Odibo AO, Stamilio DM, Macones GA, Polsky D.17_-hydroxyprogesterone caproate for the prevention of preterm delivery:a cost-effectiveness analysis. Obstet Gynecol 2006:108:492-9.
[1]Jawn JE, Cousens S, Zupan J:Four million neonatal deaths:when? Where? Why? Lancet 2005,365:891-900.
[2]Rajaratnam JK, Marcus JR., Flaxman AD, et al:Neonatal, postneonatal, childhood, and under-5 mortality for 187 countries,1970-2010:a systematic analysis of progress towards millennium development goal 4. Lancet 2010,375:1988-2008.
[3]Behrman RE:Institute of Medicine, Committee on Understanding Premature Birth and Assuring Healthy Outcomes:Preterm Birth:Causes, Consequences, and Prevention. Washington, DC,2007 National Academies Press.
[4]Beck S, Wojdyla D, Say L, et al:The worldwide incidence of preterm birth:a systematic review of maternal mortality and morbidity. Bull World Health organization 2010,88:31-38.
[5]Darmstadt GL, Lee AC, Cousens S, et al:Sixty million non-facility births:who can deliver in community settings to reduce intrapartumrelated deaths? Int J Gynecol Obstet 2009 (suppl),107:S89-112.
[6]Rosenberg RE, Ahmed AS, Ahmed S, et al:Determining gestational age in a low-resource setting:validity of last menstrual period. J Health Popul Nutr 2009,27: 332-338.
[7]Steer P:The epidemiology of preterm labour. Br J Obstet Gynaecol 2005 (suppl), 112:1-3.
[8]Goldenberg RL, Culhane JF, lams JD, et al:Epidemiology and causes of preterm birth. Lancet 2008,371:75-84.
[9]Ananth CV, Joseph KS, Oyelese Y, et al:Trends in preterm birth and perinatal mortality among singletons:United States,1989 through 2000. Obstet Gynecol 2005,105:1084-1091.
[10]Barros FC, Velez Mdel P:Temporal trends of preterm birth subtypes and neonatal outcomes. Obstet Gynecol 2006,107:1035-1041.
[11]Saigal S, Doyle LW:An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008,371:261-269.
[12]Velaphi SC, Mokhachane M, Mphahlele RM, et al:Survival of very-lowbirth-weight infants according to birthweight and gestational age in a public hospital. S AfrMed J 2005,95:504-509.
[13]Barros FC, Huttly SR, Victora CG, et al:Comparison of the causes and consequen -ces of prematurity and intrauterine growth retardation:a longitudinal study in southern Brazil. Pediatrics 1992,90:238-244.
[14]Moster D, Lie RT, Markestad T:Long-term medical and social consequences of preterm birth. N Engl J Med 2008,359:262-273.
[15]Swamy GK, Ostbye T, Skjaerven R:Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth. JAMA 2008,299:1429-1436.
[16]谷祖善.早产的危险因素及预防.中国实用妇科与产科杂志,1991,12(1)：14-15.
[17]罗姣红,尹春艳.早产病因学研究进展.2008,12(8)：3-6.
[18]Keelan JA, Yang J, Romero RJ. et al. EpithelialCell-De2rived Neutrophil Activating Peptide-78 Is Present in Fetal Membranes and Amniotic Fluid at Increased Concentrations with Intra-amniotic Infection and Preterm Delivery. Biol Rep rod 2004,70 (70):253-259.
[19]Errol R, Norwitz, Julian N, et al. Challis-The control of labor. N Engl J Med 1999,341 (27):2098-2099.
[20]Goldenberg RL, Hauth JC, Andrewsw W. Intrauterine infection and preterm delivery. N Engl J Med 2000,342 (20):1500-1507.
[21]Ertelendy F, Zakar T. Regulation of myometrial smooth muscle functions. Curr Pharm Des 2004,10 (20):2499-2517.
[22]Goldenberg RL, Mwatha A, Read JS, et al. The efficacy of antibiotics to prevent chorioamnionitis and preterm birth. Am J Obstet Gyn ecol 2006,194 (3): 650-661.
[23]韩茜,周魏军,段丽等TORCH感染与孕妇早产的关系研究.中国优生与遗传杂志,2008,16(8)：84.
[24]吴立涛,肖虹.早产病因及预测研究进展.昆明医学院学报,2009,(3B)：226-230.
[25]Heep A, S chu eller AC, Kattner E, et a 1. Associat ion of tw o tumour necros is factor gen e polym orph ism sw ith the inciden ce of severe intraventricular haemorrh -age in preterm in fants. J Med Genet 2005,42 (7):604-608.
[26]Guerra B, Ghi T, Quarta S, et al. Pregnancy outcome after early detection of bacterial vaginosis. Eu r J Obstet Gynecol Reprod Biol 2006,128 (1-2):40-45.
[27]余艳萍.下生殖道感染与早产相关性的探讨.实用医技杂志,2008,15(12)：1524-1525.
[28]Czeizela E, Rochenbarer M. A lower rate of preterm birth after clotrimazole therapy during pregnancy. Paeditric and Perinatal Epidemiology 1999,13:58-64.
[29]梁欧.支原体生殖道感染与早产关系.中外健康文摘.临床报道,2008,5(6)：125.
[30]董明驹.早产儿感染病原体情况分析.实用医技杂志,2008,15(7)：907-909.
[31]Berger A, Witt A, Haiden N, et al. Microbial inva sion of the amni otic cavity at birth is associated with adverse short- term outcome of preterm infants. J Perinat Med 2003,31(2):115-121.
[32]Perin SC, vardh ana S, korneeva I, et al. Mycoplasmahominis and Ureaplasma urealyticum in mid-trimester amniotic fluid:association with amniotic fluid cytokine levels and pregnancy outcome. Am J Obstet Gynecol 2004,191 (4): 1382-1385.
[33]Lopez NJ, Da Silva I, Ipinza J, et al. Periodontal therapy reduces the rate of preterm low birth weight in women with pregnancy associated ging ivitis. J Per iodontal 2005,76 (11 Supp 1):2144-2153.
[34]Shub A, Sw in JR, Newnham JP. Periodontal disease and adverse p regnancy outcomes. J Matern Fetal Neonatal Med 2006,19 (9):521-528.
[35]Tar I, Martos R. Periodontal disease and general health Literature review (in Hungarian). Fogorv Sz 2002,95:73-77.
[36]Jeffcoat MK, Geurs RC, Reddy MS, et al. Periodontal infection and preterm birth: results of a prospective study. J Am Dent Assoc 2001,132:875-888.
[37]梁秋羽,梁艳楠,张静等.牙周病与自然流产、早产的相关性研究.齐齐哈尔医学院学报,2007,28(10)：1197-1198.
[38]Rajapakse PS, Nagarathe M, Chandrasekra KB, et al. Periodontal Disease and Prematurity among Non-smoking Sri Lankan Women. Dent Res 2005,84 (3): 274-277.
[39]Katherine H, John M, Thorp JR, et al. Cervical Dimensions and Risk of Preterm Birth:A Prospective Cohort Stud y. Obstet Gynecol 1999,93 (93):504-509.
[40]Lindsay H. Anemia and iron deficiency:effects on p regnancy outcome. Am J Clinical Nutrition 2000,71 (5):1280-1284.
[41]Christian P. Micronutrients and Reproductive Health Issues:An International Perspective. J Nutr 2003,133 (133):1969-1973.
[42]Johns J, Jauniau E. Threatened Miscarriage as a Predictor of Obstetric Outcome. Obstet Gynecol 2006,107(107):845-850.
[43]Juang CM, Chou P, Yen MS, e t al. Adenomyosis and risk of preterm delivery. BJOG 2007,114(2):165-169.
[44]Monique M. Hedderson M, Assiamira F, et al. Gestational Diabetes Mellitus and Lesser Degrees of Pregnancy Hyperglycemia:Association with Increased Risk of Spontaneous Preterm Birth. Obstetrics & Gynecology 2003,102 (102):850-856.
[45]Georgioup E, Politie N, Katsimbri P, et al. Outcome of lupus p regnancy:a controlled study. Rheumatology,2000,39 (9):1014-1019.
[46]Drenthen W, Petronella G, Pieper MP, et al. Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. Eur. Heart J2005,26 (23):2588-2595.
[47]Webster RP, Brockmand D, Myatt L. Nitration of p38 MAPK in the placenta: association of nitration with reduced catalytic activity of p38MAPK in p reeclampsia. Mol Hum Reprod 2006,12 (11):677-685.
[48]Laughon S, Honorm W, Anthony G, et al. Prior Cesarean and the Risk for Placenta Previa on Second Tri mester Ultrasonography. Obstetrics &Gynecology 2005, 105 (105):962-965.
[49]Lorente S. Montoro MA. Cholestasis of pregnancy. Gastroenterol Hepatol 2007, 30 (9):541-547.
[50]Urielkayam P, Tummala KR. Maternal and Fetal Outcomes of Subsequent Pregnancies in Women with Peripartum Cardiomyopathy. Engl J Med 2001,344 (21):1567-1571.
[51]Defranco E, Teramo K, Muglia L. Genetic influences on preterm birth. Semin Reprod Med 2007,25(1):40-51.
[52]Gibson CS, Maclennan AH, Dekker GA, et al. Genetic polymorphisms and spontaneous preterm birth. Obstet Gynecol 2007,109 (2 Pt 1):384-391.
[53]Huynh M, Parker J, Harper S, et al. Contextual effect of income inequality on birth outcomes. Int J Epidemiol 2005,34 (4):888-895.
[54]Gandhi SG, Gilbert W, Meclvy SS, et al. Maternal and neonatal outcomes after attempted Suicide. Obstet Gynecol 2006,107 (107):984-990.
[55]Flint C, Larsen H, Nielen GL, et al. Pregnancy outcome after suicide attempt by drug use:a Danish population-based study. Acta Obstet Gynecol Scand 2002,81 (6):516-522.
[56]Coussons-read ME, Okun ML, Schmitt MP, et al. Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy. Psychosom Med 2005, 67(67):625-631.
[57]Ng SP, Steinetz BG, Lasno SG, et al. Hormonal changes accompanying cigarette smoke-induced p reterm births in amouse model. Exp Biol Med 2006,231 (8): 1403-1409.
[58]Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the betaadrenergic agonist ritodrine. N Eng J Med 1992; 327:308-312.
[59]Keirse MJNC. Betamimetic tocolytics in preterm labour. In:Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, editors. Cochrane Updates on Disk. Oxford: 1993
[60]Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993,168:1247-1259.
[61]Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med 1998, 339:313-320.
[62]Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990,163:767-772.
[63]Keirse MJNC. Magnesium sulfate in preterm labour. In:Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, editors.1992
[64]Gruslin A, Bonin B. Complications associated with the administration of tocolytic agents. SOGC 1998,20:953-969.
[65]Mittendorf R, Covert R, Boman J, Khoshnood B, Lee K-S, Siegler M. Is tocoly-ticmagnesium sulphate associated with increased total paediatric mortality? Lancet 1997,350:1517-1519.
[66]Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birthweight children aged 3 to 5 years. JAMA 1996,276:1805-1810.
[67]Hannah ME, et.al. The Canadian Consensus on the Use of Tocolytics for Preterm Labour. SOGC 1995,17:1089-1115.
[68]Keirse MJNC. Indomethacin tocolysis in preterm labour. In:Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, editors. Pregnancy and Childbirth Module 'Cochrane Database of Systematic Reviews'.1994 ed. Oxford:1992:Review No. 04383,14 Aug.
[69]Moise K. Huhta J, Sharif D. Indomethacin in the treatment of premature labor: Effects onthe fetal ductus arteriosus. N Engl J Med 1988,318:32725.
[70]Moise K. Indomethacin therapy in the treatment of symptomatic polyhydramnios. Clin Obstet Gynecol 1991,34:310.
[71]Major CA, Lewis DF, Harding JA, Porto MA, Garite TJ. Tocolysis with indome- thacin increases the incidence of necrotizing enterocolitis in the low birth-weight neonate. Am J Obstet Gynecol 1994,170:102-106.
[72]Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indome-thacin and sulindac therapy for threatened preterm labor:A randomized study. Am J Obstet Gynecol 1995,173:20-25.
[73]Norton ME, Merrill JD, Cooper BAB, Kuller JA, Clyman RI. Neonatal compli-cations after the administration of indomethacin for preterm labor. N Engl J Med 1993,329:1602-1607.
[74]Merrill JD, Clyman RI, Norton ME. Indomethacin as a tocolytic agent:The contro-versycontinues. J Pediatr 1994,124:734-736.
[75]Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala O, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indome-thacin to prevent preterm labor. J Pediatr 1994,124:782-788.
[76]Panter KR, Hannah ME, Amankwah KS, Ohlsson A, Jefferies AL, Farine D. The effect of indomethacin tocolysis for preterm labour on perinatal outcome:A randomized placebo controlled trial. Br J Obstet Gynaecol 1999,106:467-473.
[77]Mitchell BF. Moratorium on Indomethacin as a tocolytic. J SOGC 1995,17:279-280.
[78]Bracero I, Leikin E, Kirschenbaum N, Tejani N. Comparison of nifedipine and ritodrine forthe treatment of preterm labor. Am J Perinatol 1991,8:365.
[79]Shubert PJ. Atosiban. Clin Obstet Gynecol 1995,38:722-724.
[80]Sibai BM, Romero R, Sanchez-Ramos L, Valenzuela G, Veille JC, Tabor B, et al. Adouble-blind placebo-controlled trial of an oxytocin-receptor antagonist (antocin) in thetreatment of preterm labor. Am J Obstet Gynecol 1997, S2 Abstract.
[81]Goodwin TM, Valenzuela GJ, Silver H, Creasy G, The Atosiban Study Group. Dose ranging study of the oxytocin antagonist Atosiban in the treatment of preterm labor. Obstet Gynecol 1996,88:331-336.
[82]Smith GN, Bobier HS, Brien JF. The Role of Nitric Oxide in the Maintenance of Normal Pregnancy and Preeclampsia. In:Lee RV, Garner PR, Barron WM, Coustan DR, editors.Current Obstetric Medicine. Toronto:Mosby-Year Book, Inc., 1996:103-127.
[83]Norman J. Nitric Oxide and the Myometrium. Pharmacol Ther.1996,70:91-100.
[84]Lees C, Campbell S, Jauniaux E, Brown R, Ramsay B, Gibb D, et al. Arrest of pretermlabour and prolongation of gestation with glyceryl trinitrate, a nitric oxide donor. Lancet 1994,343:1325-1326.
[85]Rowlands S, Trudinger B, Visva-Lingam S. Treatment of preterm cervical dilatation with glyceryl trinitrate, a nitric oxide donor. Aust NZ J Obstet Gynaecol 1996,36:377-381.
[86]Heymann MA, Bootstaylor B, Roman C, Natuzzi ES, Parer JT, Harrison MR, et al.Glyceryl trinitrate stops active labour in sheep. In:Moncada S, Feelisch M, Busse R, editors. The Biology of Nitric Oxide. Physiology and Clinical Aspects. London:Port-land Press,1994:201-203.
[87]Jennings RW, MacGillivray TE, Harrison MR. Nitric oxide inhibits preterm labour in Rhesus monkeys. J Maternal Fetal Med 1993,2:170-175.
[88]Black RS, Flint S, Lees C, Campbell S. Preterm labour and delivery. Eur J Pediatr 1996,155:S2-S7.
[89]Fliegner JR, Gronow M. Treatment of Pre-term Cervical Dilatation withGlyceryl Trinitrate, a Nitric Oxide Donor. Aust NZ J Obstet Gynecol 1997,37:487.
[90]Smith GN, Walker MC, McGrath MJ. Randomized, double-blind, placebo controlled trial assessing nitroglycerin as a tocolytic. Br J Obstet Gynaecol 1999, 106:736-739.
[91]Bisits A, Madsen G, McLean M, O'Callaghan S, Smith R, Giles W. CRH-A biochemical predictor of preterm delivery in a pilot randomized trial of the treatment of preterm labour. Am J Obstet Gynecol 1998,178:862-866.
[92]Lees CC, Lojacono A, Thompson C, Danti L, Black RS, Tanzi P, White IR, Campbell S.Glyceryl trinitrate and ritodrine in tocolysis:An International Multicenter Randomized Study. Obstet Gynecol 1999,94:403-408.
[93]Smith GN, Brien JF. The use of nitroglycerin for uterine relaxation. Obstet Gynecol Survey 1998,53:559-565.
[94]Heymann MA, Bootstaylor B, Roman C, Natuzzi ES, Parer JT, Harrison MR, et al. Glyceryl trinitrate stops active labour in sheep. In:Moncada S, Feelisch M, Busse R, editors. The Biology of Nitric Oxide. Physiology and Clinical Aspects. London: Port-land Press 1994,201-203.
[95]Bootstaylor BS, Roman C, Parer JT, Heymann MA. Fetal and maternal hemody-namic and metabolic effects of maternal nitroglycerin infusions in sheep. Am J Obstet Gynecol 1997,176:644-650.
[96]Giles W, Read M, Falconer J, O'Callaghan S. Ovine fetal blood flow responses to nitric oxide deficiency and nitric oxide donor therapy. Am J Obstet Gynecol 1996, 174:488.
[97]Jennings RW, MacGillivray TE, Harrison MR. Nitric oxide inhibits preterm labour in Rhesus monkeys. J Maternal Fetal Med 1993,2:170-175.
[98]Lees C, Campbell S, Martin J, Moncada S, Brown R, Jauniaux E, et al. Glyceryl trinitrate in management of preterm labour. Author's reply. Lancet 1994, 344:553-554.
[99]Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993,168:1247-1259.