尹燕丹　祁媛媛　洪　達(dá)　王傳凱　張曉波　錢(qián)莉玲

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·論著·

早產(chǎn)兒支氣管肺發(fā)育不良危險(xiǎn)因素及2歲時(shí)隨訪結(jié)局

尹燕丹1祁媛媛2洪達(dá)2王傳凱2張曉波2錢(qián)莉玲2

支氣管肺發(fā)育不良；早產(chǎn)兒；危險(xiǎn)因素；隨訪

1　方法

1.1BPD診斷標(biāo)準(zhǔn)[14]在校正胎齡36周或出院回家時(shí)需氧療(FiO2> 21%)≥ 28 d的嬰兒。

1.2BPD組納入標(biāo)準(zhǔn)①胎齡≤ 32周；②出生體重≤ 1 500 g；③生后7 d內(nèi)入我院；④符合BPD診斷。

1.3對(duì)照組納入標(biāo)準(zhǔn)同BPD組納入標(biāo)準(zhǔn)①～③項(xiàng)，非BPD且存活>28 d的嬰兒，樣本量與BPD組1∶1匹配。

1.4BPD組和對(duì)照組共同排除標(biāo)準(zhǔn)排除致死性先天畸形(如中樞神經(jīng)系統(tǒng)畸形等)，膈疝，呼吸系統(tǒng)畸形，除室間隔缺損、房間隔缺損或動(dòng)脈導(dǎo)管未閉(PDA)外的嚴(yán)重先天性心臟病，染色體異常等病例。

1.6隨訪原則隨訪時(shí)點(diǎn)：我院2名呼吸專(zhuān)科醫(yī)生在患兒滿(mǎn)1歲(±1周)和2歲(±1周)時(shí)行電話(huà)隨訪；隨訪項(xiàng)目：以就醫(yī)診斷的支氣管炎、肺炎、喘息發(fā)作次數(shù)，住院次數(shù)，是否患過(guò)敏性疾病(濕疹、喘息、鼻炎)等；暴露吸煙環(huán)境。

2　結(jié)果

2.1一般情況2012年1月至2013年12月入住我院新生兒科病房的BPD組156例符合納入標(biāo)準(zhǔn)進(jìn)入本文分析，納入排除流程如圖1所示，同期符合對(duì)照組納入標(biāo)準(zhǔn)的病例298例，選取了其中156例作為對(duì)照組。

圖1BPD組研究對(duì)象篩選流程

2.4隨訪結(jié)局BPD組住院期間死亡7/156例(4.5%)，出院后1歲以?xún)?nèi)死亡7/149例(4.7%)；非BPD組無(wú)院內(nèi)死亡 ， 出院后1歲以?xún)?nèi)死亡1 例(0.6%)。BDP組和對(duì)照組生后1歲時(shí)點(diǎn)分別隨訪到103/142和140/155例，占存活病例的72.5%和90.3%；BPD組和對(duì)照組～2歲時(shí)點(diǎn)分別隨訪到91/142例，和111/155例，占存活病例的64.1%和71.6%。

BPD組(n=156)對(duì)照組(n=156)χ2/t/ZP母親因素母親年齡/歲30.6±4.529.6±4.71.9990.046先兆子13(8.3)4(2.6)5.3090.025糖尿病10(6.4)12(7.7)1.1960.658胎膜早破49(31.4)53(34.0)0.2330.629產(chǎn)前出血15(9.6)13(8.3)0.1570.692產(chǎn)前體溫≥38.5℃6(3.8)5(3.2)0.0940.759其他15(9.6)9(5.8)1.6250.288陰道產(chǎn)84(53.8)53(34.0)12.5060.000剖宮產(chǎn)72(46.2)103(66.0)產(chǎn)期激素使用83(53.2)88(56.4)0.3240.570新生兒因素胎齡/周28.5±1.630.5±1.5-11.49<0.001出生體重/g1137±2051277±149-6.898<0.0011minApgar評(píng)分[M(P25,P75)]7.0(5.0,8.0)8.0(6.0,9.0)-4.253<0.0015minApgar評(píng)分[M(P25,P75)]8.0(7.0,9.0)9.0(8.0,9.0)-3.897<0.001敗血癥≥72h66(42.3)37(23.7)12.189<0.001動(dòng)脈導(dǎo)管未閉122(78.2)87(55.8)17.754<0.001壞死性小腸結(jié)腸炎27(17.3)19(12.2)1.6320.201早產(chǎn)兒視網(wǎng)膜病變66(43.2)26(16.7)24.664<0.001應(yīng)用肺表面 活性物質(zhì)123(78.8)83(53.2)22.861<0.001呼吸機(jī)相關(guān)性肺炎55(35.3)8(5.1)43.935<0.001機(jī)械通氣≥7d69(44.2)7(4.5)66.867<0.001

表2BPD危險(xiǎn)因素的Logistic回歸分析

因素Pχ2OR(95%CI)出生胎齡<0.00146.9990.46(0.37～0.58)機(jī)械通氣≥7d<0.00121.9249.47(3.70～24.27)動(dòng)脈導(dǎo)管未閉0.7916.1512.21(1.18～4.12)先兆子0.0225.2414.91(1.26～19.15)

注Logistic回歸模型R2=0.520,P<0.001；變量編碼：先兆子、敗血癥≥72 h、VAP、動(dòng)脈導(dǎo)管未閉、機(jī)械通氣≥7 d,無(wú)均為0,有均為1;出生胎齡未予賦值

隨訪病例失訪病例χ2/tPBPD組(n)9151出生胎齡/周28.6±1.528.4±1.60.4980.619機(jī)械通氣≥7d40(44.4)19(37.3)0.6910.406動(dòng)脈導(dǎo)管未閉74(81.3)38(74.5)0.9090.340先兆子9(9.9)4(7.8)0.0110.918對(duì)照組(n)11144出生胎齡/周30.4±1.430.6±1.6-0.9090.365機(jī)械通氣≥7d5(4.5)2(4.5)0.0001.000動(dòng)脈導(dǎo)管未閉63(56.8)24(54.5)0.0630.802先兆子2(1.8)2(4.5)0.1680.682

注BPD組死亡14例，對(duì)照組死亡1例，死亡病例未納入分析

表4顯示，BPD組1歲以?xún)?nèi)支氣管炎、喘息、 過(guò)敏性疾病的發(fā)生率顯著高于對(duì)照組 (P<0.05 )，其余的隨訪項(xiàng)目?jī)山M間差異無(wú)統(tǒng)計(jì)學(xué)意義；BPD組～2歲支氣管炎、喘息發(fā)生率高于對(duì)照組(P均<0.001)。BPD組1歲以?xún)?nèi)肺炎(P=0.04)、過(guò)敏性疾病(P<0.001)的發(fā)生率顯著高于～2歲組 (P<0.05 )，支氣管炎、喘息的發(fā)生率差異無(wú)統(tǒng)計(jì)學(xué)意義。

表4BPD組和對(duì)照組隨訪結(jié)果比較[n(%)]

隨訪指標(biāo)<1歲BPD組對(duì)照組χ2P～2歲BPD組對(duì)照組χ2P隨訪例數(shù)(n)10314091111支氣管炎50(48.5)26(18.6)24.802<0.00142(46.2)17(15.3)22.999<0.001肺炎27(26.2)31(22.1)0.5410.46213(14.3)1)10(9.0)1.3800.240喘息32(31.1)22(15.7)8.0940.00437(40.7)15(13.5)19.276<0.001過(guò)敏性體質(zhì)(濕疹、喘息、鼻炎)50(48.5)37(26.4)12.627<0.00116(17.6)2)11(9.9)2.5420.111再入院治療17(16.5)24(17.1)0.0170.89611(12.1)11(9.9)0.2440.621暴露吸煙環(huán)境20(19.4)23(16.4)0.3640.54621(23.1)19(17.1)1.1180.290

注BPD組，<1歲vs～2歲， 1)P=004, 2)P<0.001

3　討論

隨著近年來(lái)超(極)低出生體重兒存活率升高，BPD的發(fā)生率逐年增多，不僅成為極不成熟早產(chǎn)兒的主要死因，而且對(duì)患兒的近期和遠(yuǎn)期預(yù)后亦影響巨大。BPD導(dǎo)致的心肺功能異?？裳永m(xù)至成年，甚至伴隨終生，與腦性癱瘓和神經(jīng)發(fā)育延遲密切相關(guān)[16]。本研究對(duì)我院新生兒科近2年收治的BPD早產(chǎn)兒行危險(xiǎn)因素分析，顯示低出生胎齡、PDA、機(jī)械通氣≥7 d是發(fā)生BPD的危險(xiǎn)因素，同國(guó)內(nèi)外的多項(xiàng)研究結(jié)果一致[1～5]。其原因可能是出生體重、胎齡與早產(chǎn)兒肺發(fā)育成熟度呈顯著正相關(guān)，且早產(chǎn)兒生后暴露于機(jī)械通氣、高氧、氣壓傷和感染等不利因素，觸發(fā)炎性因子瀑布反應(yīng)，加重氣道、肺血管及間質(zhì)損傷，引起肺損傷[17]。此外出生后PDA可引起肺血流和肺液增加，使肺功能降低和氣體交換減少，肺部感染使得呼吸系統(tǒng)局部解剖結(jié)構(gòu)破壞，對(duì)病原體的清除力降低，均增加了BPD的易感性。

本文2歲隨訪時(shí)點(diǎn)BPD組和對(duì)照組的失訪率分別為35.9%和28.4%，會(huì)對(duì)兩組隨訪結(jié)局造成影響，其中主要的影響可能在于，隨訪與失訪病例的母親因素和新生兒因素的不均衡；為此本文對(duì)兩組上述因素進(jìn)行比較，除BPD組PS使用率差異有統(tǒng)計(jì)學(xué)意義，兩組其余母親和新生兒因素(特別是4項(xiàng)BPD危險(xiǎn)因素)在隨訪和失訪病例間差異無(wú)統(tǒng)計(jì)學(xué)意義。盡管失訪率較高，但對(duì)本文隨訪結(jié)局的影響可能不大。

BPD患兒的遠(yuǎn)期不良結(jié)局包括肺部疾病(如哮喘、肺氣腫、肺動(dòng)脈高壓)[21～23]、心血管功能障礙[24]及生長(zhǎng)發(fā)育遲緩等。本文是國(guó)內(nèi)對(duì)BPD患兒出院后行呼吸道癥狀隨訪的較大樣本研究，顯示在生后1歲以?xún)?nèi)，BPD組支氣管炎的比例顯著高于對(duì)照組，提示BPD患兒在生后1歲以?xún)?nèi)下呼吸道感染的發(fā)生率顯著升高，與林燕等[13]的研究結(jié)果一致。考慮BPD患兒肺發(fā)育不成熟，肺泡數(shù)量減少，肺泡結(jié)構(gòu)簡(jiǎn)單化，肺微血管發(fā)育不良，導(dǎo)致生后通氣、換氣功能降低，也可能與BPD患兒體液免疫和細(xì)胞免疫功能低下有關(guān)[25]。同時(shí)發(fā)現(xiàn)，BPD組喘息的比例顯著高于對(duì)照組，考慮BPD早產(chǎn)兒生后由于肺發(fā)育不成熟，生后接受高壓氧和機(jī)械通氣等治療，引起肺損傷，氣管口徑減小，易出現(xiàn)反復(fù)喘鳴癥狀。Fawke等[26]研究顯示，與哮喘患兒比較，BPD患兒對(duì)β受體激動(dòng)劑反應(yīng)性降低，NO吸入水平降低，提示其氣道結(jié)構(gòu)的異常引起氣流受限，而不是嗜酸性粒細(xì)胞引起的氣道炎癥。同時(shí)Choi等[27]發(fā)現(xiàn)有BPD病史的學(xué)齡前兒童對(duì)5-羥色胺無(wú)反應(yīng)，提示氣道痙攣不能完全解釋BPD患兒的氣流受限，因此BPD不符合哮喘氣道炎癥性反應(yīng)的特征。

國(guó)外Vom Hove等[28]報(bào)道顯示BPD早產(chǎn)兒2歲以?xún)?nèi)的再次入院率為36%，～3歲常由于病毒感染導(dǎo)致頻繁住院，導(dǎo)致呼吸系統(tǒng)疾病惡化[29]；Jeng等[30]報(bào)道也顯示BPD早產(chǎn)兒在生后1歲以?xún)?nèi)有超過(guò)50%的再入院率；國(guó)內(nèi)林燕等[13]報(bào)道顯示BPD 早產(chǎn)兒在生后1歲以?xún)?nèi)再入院率為86%。本研究隨訪結(jié)果顯示，BPD組與對(duì)照組在生后1歲以?xún)?nèi)再住院率均低于20%，且兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義。本研究結(jié)果與上述國(guó)內(nèi)外研究結(jié)果不一致，考慮與本地區(qū)呼吸科床位緊張，也可能與入院收治標(biāo)準(zhǔn)的差異有關(guān)。

本研究同時(shí)對(duì)BPD早產(chǎn)兒在生后2歲行呼吸道疾病發(fā)病情況隨訪，結(jié)果顯示肺炎及過(guò)敏性疾病的發(fā)生率在生后～2歲較1歲以?xún)?nèi)顯著下降，再次入院率、支氣管炎的發(fā)生率有下降趨勢(shì)，但差異無(wú)統(tǒng)計(jì)學(xué)意義，可能與隨著年齡增長(zhǎng)，戶(hù)外活動(dòng)增加，機(jī)體抵抗力逐漸增強(qiáng)有關(guān)。但喘息的發(fā)生率無(wú)明顯下降，反而有升高趨勢(shì)，表明BPD早產(chǎn)兒隨著年齡的增加，雖然呼吸道功能逐漸發(fā)育，但氣道結(jié)構(gòu)的異常尚難在短時(shí)間內(nèi)恢復(fù)，BPD早產(chǎn)兒易出現(xiàn)反復(fù)喘息等癥狀，因此BPD早產(chǎn)兒成年后患慢性阻塞性肺病的風(fēng)險(xiǎn)可能較高。

[1]朱梅英，顧敏貞，劉湲湲，等．極低出生體重兒支氣管肺發(fā)育不良及其危險(xiǎn)因素分析．中國(guó)新生兒科雜志，2009，24(6):343-345

[2] Klinger G，Sokolover N，Boyko V，et al，Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-lowbirthweight infants．Am J Obstet Gynecol，2013，208(2):115-119

[3]早產(chǎn)兒支氣管肺發(fā)育不良調(diào)查協(xié)作組．早產(chǎn)兒支氣管肺發(fā)育不良發(fā)生率及高危因素的多中心回顧性調(diào)查分析．中華兒科雜志，2011，49(9):655-662

[4]鐘美珍，白海濤，劉登禮，等．早產(chǎn)兒支氣管肺發(fā)育不良危險(xiǎn)因素前瞻性隊(duì)列研究．中國(guó)新生兒科雜志，2011，26(6):377-382

[5]田鸞英，Hamvas A．早產(chǎn)兒支氣管肺發(fā)育不良的臨床分析．中國(guó)新生兒科雜志，2009，24(5):277-279

[6] Yen T，Yang H，Hsieh W，et al．Preeclampsia and the risk of bronchopulmonary dysplasia in VLBW infants:a population based study．PLoS One，2013．8(9):e75168

[7] Hansen AR，Barnes CM，F(xiàn)olkman J，et al．Maternal preeclampsia predicts the development of bronchopulmonary dysplasia．J Pediatr，2010，156(4):532-536

[8] Korhonen P，Tammela O，Koivisto AM，et al．Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants．Early Hum Dev，1999，54(3):245-258

[9] Singh SP，Gundavarapu S，Smith KR，et al．Gestational exposure of mice to secondhand cigarette smoke causes bronchopulmonary dysplasia blocked by the nicotinic receptor antagonist mecamylamine．Environ Health Perspect，2013．121 (8):957-964

[10] Hennessy EM．Bracewrll MA，Wood N，et al．Respiratory health in pre-school and school age children following extremely preterm birth．Arch Dis Child，2008，93(12):1037-1043

[11]Smith VC，Zupancic JA，McCormick MC，et al．Rehospitalization in the first year of life among infants with bronchopulmonary dysplasia．J Pediatr，2004，144(6):799-803

[12]陳尚勤，張維溪，張海鄰，等．支氣管肺發(fā)育不良8例患兒6年臨床隨訪．中國(guó)循證兒科雜志，2012，7(1):55-58

[13]林燕，賴(lài)華，徐若梅，等．支氣管肺發(fā)育不良患兒與生后1年內(nèi)下呼吸道感染．四川醫(yī)學(xué)，2010，31(2):182-183

[14]Jobe AH，Bancalari E．Bronchopulmonary dysplasia．Am J Respir Crit Care Med，2001，(163):1723-1729

[15]葉鴻瑁，邵肖梅．實(shí)用新生兒學(xué)．第4 版．人民衛(wèi)生出版社，2011

[16]Baraldi E，F(xiàn)ilippone M，Chronic lung disease after premature birth．N Engl J Med，2007，357(19):1946-1955

[17]Hernandez-Ronquillo L，Tellez-Zenteno JF，Weder-Cisneros N，et al．Risk factors for the development of bronchopulmonary dysplasia; a case-control study．Arch Me Res，2004，35(6):549-555

[18]Gilbert WM，Young AL，Danielson B．Pregnancy outcomes in women with chronic hypertension:a population-based study．J Reprod Med，2007:52(11):1046-1051

[19]Zana-Taieb E．，Butruille L，F(xiàn)ranco-Montoya ML，et al．Effect of two models of intrauterine growth restriction onalveolarization in rat lungs:morphometric and gene expression analysis．PLoS One，2013，8(11):e78326

[20]Kulkarni AV，Mehendale SS，Yadav HR，et al．Circulating angiogenic factors and their association with birth outcomes in preeclampsia．Hypertens Res，2010，33(6):561-567

[21]Wong PM，Lees AN，Louw J，et al，Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia．Eur Respir J，2008，32(2):321-328

[22]Greenough A．Long-term pulmonary outcome in the preterm infant．Neonatology，2008，93(4):324-327

[23]Khemani E，McElhinney DB，Rhein L，et al．Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia:clinical features and outcomes in the surfactant era．Pediatrics，2007，120(6):1260-1269

[24]Mourani PM，Ivy DD，Rosenberg AA，et al，Left ventricular diastolic dysfunction in bronchopulmonary dysplasia．J Pediatr，2008，152(2):291-293

[25]Ballow M，Cates KL，Rowe JC，et al．Development of the immune system in very low birth weight (less than 1500 g)premature infants:concentrations of plasma immunoglobulins and patterns of infections．Pediatr Res，1986，20:899-904

[26]Fawke J，Lum S，Kirkby J，et al．Lung function and respiratory symptoms at 11 years in children born extremely preterm:the EPICure study．Am J Respir Crit Care Med，2010，182(2):237-245

[27]Choi SH，Kim DK，Yu J，et al．Bronchial responsiveness to methacholine and adenosine 5'-monophosphate in young children with asthma:their relationship with blood eosinophils and serum eosinophil cationic protein．Allergy，2007，62(10):1119-1124

[28]Vom Hove M，Prenzel F，UhligH，et al．Pulmonary outcome in former preterm，very low birth weight children with bronchopulmonary dysplasia:a case-control follow-up at school age．J Pediatr，2014，164(1):40-45

[29]Perez PG，Navarro MM．Bronchopulmonary dysplasia and prematurity．Short and long-term respiratory changes．An Pediatr(Barc )，2010，72(1):79．e1-16

[30]Jeng SF，Hsu CH，Tsao PN，et al．Bronchopulmonary dysplasia predicts adverse developmental and clinical outcomes in very-low-birth weight infants．Dev Med Child Neurol，2008，50(1):51-57

(本文編輯：丁俊杰)

Study on risk factors and follow-up outcome at 2 years in preterm infants with bronchopulmonary dysplasia

YINYan-dan1,QIYuan-yuan2,HONGDa2,WANGChuan-kai2,ZHANGXiao-bo2,QIANLi-ling

2(1TaizhouMunicipalHospital,ZhejiangProvince,Taizhou318000; 2DepartmentofPneumology,Children′sHospitalofFudanUniversity,Shanghai201102,China)

QIAN Li-ling，E-mail:llqian@126.com; ZHANG Xiao-bo,E-mail:zhangxiaobo0307@163.com

Objective To investigate the main risk factors and long term outcome of preterm infants with bronchopulmonary dysplasia (BPD).MethodsChildren with BPD were collected from neonatal intensive care units (NICU) in Children′s Hospital Fudan University, from January 1, 2012 to December 31, 2013. All babies with gestational age ≤ 32 weeks, birth weight ≤1 500 g, and admission within 7 days after birth were included in this study. In the same period，according to the inclusion criteria, the same sample size of non BPD was collected as control group. Univariate and multiple logistic regression analyses were used to determine factors associated with the risk of BPD. At the same time ,the incidence of bronchitis,pneumonia,wheezing and rehospitalization were analyzed during the first two years of life.ResultsThere were 156 cases in BPD group and matched 156 infants without BPD in control group. Mother′s information including age, the proportion of preeclampsia and vaginal delivery was significantly higher in BPD group than that in control group(P=0.046,0.025 and <0.001). Birth gestational age and birth weight of BPD group were significantly lower than those of control grouop ( P <0.001 ).Infant information including 1 min Apgar score, 5 min Apgar score, sepsis ≥72 h , patent ductus arteriosus ( PDA ), retinopathy of prematurity ( ROP ) , ventilator associated pneumonia ( VAP ) , the application of PS and mechanical ventilation ≥7 d was significantly higher in BPD group than that in control group. The factors increasing the risk of BPD determined by multivariate logistic analysis were: gestational age (OR=0.46，95%CI:0.37-0.58), mechanical ventilation ≥7 d(OR= 9.47，95%CI:3.70-24.27), PDA (OR= 2.21，95%CI:1.18-4.12 ) and preeclampsia( OR= 4.91，95%CI:1.26-19.15). In the first year of life, the incidence of bronchitis and wheezing in preterm-born children with a history of BPD was significantly higher than that in preterm-born children without BPD, but there was no significant difference in rehospitalization between the two groups. The incidence of pneumonia of BPD group was significantly decreased in the second year of life, while there was no significant difference in bronchitis, wheezing and rehospitalization compared to the first year of life.ConclusionLow gestational age, mechanical ventilation ≥7 d, patent ductus arteriosus, preeclampsia were highest risk factors for BPD. Among premature infants, BPD substantially increased the risk of lower respiratory tract infection during the first year of life.

Bronchopulmonary dysplasia; Premature infants;Risk factors; Follow-up

10.3969/j.issn.1673-5501.2016.02.006

1 浙江省臺(tái)州市立醫(yī)院 臺(tái)州，318000；2 復(fù)旦大學(xué)附屬兒科醫(yī)院呼吸科上海，201102

錢(qián)莉玲，E-mail:llqian@126.com；張曉波，E-mail:zhangxiaobo0307@163.com

2016-01-13

2016-03-20)