王 潛 崔其亮 嚴(yán)彩滿

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·論著·

早產(chǎn)兒補(bǔ)充長鏈多不飽和脂肪酸對支氣管肺發(fā)育不良和壞死性小腸結(jié)腸炎發(fā)生率影響的系統(tǒng)評價(jià)和Meta分析

王 潛 崔其亮 嚴(yán)彩滿

目的 定量評價(jià)早產(chǎn)兒補(bǔ)充長鏈多不飽和脂肪酸(LCPUFA)能否降低壞死性小腸結(jié)腸炎(NEC)、支氣管肺發(fā)育不良(BPD)等的發(fā)生率。方法 計(jì)算機(jī)檢索PubMed、EMBASE、the Cohrane Library、萬方數(shù)據(jù)庫和中國知網(wǎng)，獲得早產(chǎn)兒補(bǔ)充LCPUFA對NEC、BPD、嚴(yán)重感染(敗血癥)和病死率影響的RCT文獻(xiàn)，檢索時(shí)限均從建庫至2015年8月27日。由2名研究者獨(dú)立行文獻(xiàn)篩選、資料提取，采用改良JADAD量表評價(jià)納入文獻(xiàn)的偏倚風(fēng)險(xiǎn)。以相對危險(xiǎn)度(RR)及其95%CI作為效應(yīng)指標(biāo)。采用RevMan 5.3軟件行Meta分析，根據(jù)異質(zhì)性檢驗(yàn)結(jié)果選擇相應(yīng)的效應(yīng)模型合并效應(yīng)量。結(jié)果 15篇RCT文獻(xiàn)(n=2 658)進(jìn)入Meta分析。13篇文獻(xiàn)JADAD評分5～7分，2篇文獻(xiàn)<5分，總體偏倚風(fēng)險(xiǎn)不大。Meta結(jié)果顯示，早產(chǎn)兒補(bǔ)充與未補(bǔ)充LCPUFA組的NEC、BPD、嚴(yán)重感染(敗血癥)和病死率差異均無統(tǒng)計(jì)學(xué)意義，其RR及其95%CI分別為1.16(0.73～1.83)、0.94(0.79～1.13)、1.13(0.93～1.37)和1.15(0.56～2.36)。以胎齡行亞組分析，胎齡≤32周早產(chǎn)兒補(bǔ)充和未補(bǔ)充LCPUFA的NEC發(fā)生率差異有統(tǒng)計(jì)學(xué)意義，RR=0.42(95%CI: 0.19～0.96)，BPD和嚴(yán)重感染(敗血癥)發(fā)生率在胎齡≤32周早產(chǎn)兒補(bǔ)充和未補(bǔ)充LCPUFA間差異均無統(tǒng)計(jì)學(xué)意義。結(jié)論 早產(chǎn)兒補(bǔ)充LCPUFA不能降低BPD、嚴(yán)重感染(敗血癥)的發(fā)生率和病死率，可能降低胎齡≤32周早產(chǎn)兒NEC發(fā)生率。

早產(chǎn)兒； 二十二碳六烯酸； 壞死性小腸結(jié)腸炎； 支氣管肺發(fā)育不良； 敗血癥； 病死率； 系統(tǒng)評價(jià)；Meta分析

早產(chǎn)兒尤其是胎齡≤32周早產(chǎn)兒有較高的壞死性小腸結(jié)腸炎(NEC)、支氣管肺發(fā)育不良(BPD)、嚴(yán)重感染(敗血癥)發(fā)生率和病死率 。長鏈多不飽和脂肪酸(LCPUFA),尤其是二十二碳六烯酸(DHA)和二十碳五烯酸(EPA)是視網(wǎng)膜和中樞神經(jīng)系統(tǒng)細(xì)胞膜的重要組成部分[1,2]。但早產(chǎn)兒在母體內(nèi)脂質(zhì)合成以及貯藏?cái)?shù)量不足，且將α-亞油酸(ALA)合成DHA的能力也十分有限[3,4]。既往新生兒補(bǔ)充LCPUFA尤其是DHA的研究多關(guān)注其促進(jìn)大腦發(fā)育和視覺敏銳度。近年研究提示早產(chǎn)兒補(bǔ)充LCPUFA與炎性反應(yīng)的負(fù)調(diào)節(jié)密切相關(guān)[5]，推測早產(chǎn)兒尤其是胎齡≤32周早產(chǎn)兒補(bǔ)充LCPUFA可抑制炎性反應(yīng)，從而可能降低NEC和BPD等發(fā)生率。為此本研究系統(tǒng)檢索早產(chǎn)兒補(bǔ)充LCPUFA的RCT研究，對NEC、BPD等指標(biāo)行定量綜合。

1 方法

1.1 文獻(xiàn)納入標(biāo)準(zhǔn) ①RCT研究，干預(yù)組為哺乳期添加DHA、AA等LCPUFA，對照組為未添加或相比較干預(yù)組低劑量添加LCPUFA[5～7]的配方奶；②研究對象為胎齡<37周早產(chǎn)兒，可以行母乳或配方粉喂養(yǎng)；③文獻(xiàn)描述了NEC、BPD和嚴(yán)重感染(敗血癥)的診斷標(biāo)準(zhǔn)；④報(bào)道了本文設(shè)定的結(jié)局指標(biāo)；⑤語種不限。

1.2 文獻(xiàn)排除標(biāo)準(zhǔn) ①非添加DHA、AA為主的LCPUFA；②患嚴(yán)重宮內(nèi)感染、產(chǎn)傷、電解質(zhì)紊亂、遺傳代謝性疾病、嚴(yán)重先天性呼吸道畸形和嚴(yán)重先天性心臟病患兒。

1.3 結(jié)局指標(biāo) NEC、BPD和嚴(yán)重感染(敗血癥)發(fā)生率，病死率(任何原因?qū)е碌乃劳?。

1.4 文獻(xiàn)檢索策略 檢索PubMed、EMBASE、the Cohrane Library、萬方數(shù)據(jù)庫和中國知網(wǎng)，獲得早產(chǎn)兒補(bǔ)充LCPUFA的RCT文獻(xiàn)，檢索時(shí)間均為建庫至2015年8月27日。同時(shí)回溯納入文獻(xiàn)的參考文獻(xiàn)。

英文檢索詞：long chain polyunsaturated fatty acid、docosahexaenoic acid、preterm、premature、randomized controlled trial。

以PubMed數(shù)據(jù)庫為例的檢索式為：(((((((docosahexaenoic acid) OR omega 3) OR LCPUFA) OR long chain poly unsaturated fatty acid) OR DHA) OR fish oil) OR “Fish Oils”[Mesh〗) OR “docosahexaenoic acids”[Mesh])AND (((“premature birth”[Mesh]) OR “infant, extremely premature”[Mesh]) OR “infant, premature”[Mesh]) AND (randomized controlled trial[Publication type]) OR controlled clinical trial[Publication type])。

中文檢索詞：長鏈多不飽和脂肪酸、二十二碳六烯酸、早產(chǎn)、隨機(jī)對照試驗(yàn)。

以萬方數(shù)據(jù)庫為例的檢索式為：“長鏈不飽和脂肪酸”AND “早產(chǎn)” AND“隨機(jī)對照試驗(yàn)”。

1.5 文獻(xiàn)篩選、資料提取和偏倚風(fēng)險(xiǎn)評價(jià) 由王潛、嚴(yán)彩滿獨(dú)立行文獻(xiàn)篩選、提取資料和文獻(xiàn)偏倚風(fēng)險(xiǎn)評價(jià)，并交叉核對，如遇分歧，由崔其亮決定。提取資料包括：①納入研究的基本信息：第一作者、發(fā)表年份和國家；②研究對象的基本特征：各組病例數(shù)、胎齡、出生體重和干預(yù)時(shí)間等；③偏倚風(fēng)險(xiǎn)評價(jià)內(nèi)容；④結(jié)局指標(biāo)。

采用改良版JADAD量表行文獻(xiàn)偏倚風(fēng)險(xiǎn)評價(jià)：隨機(jī)序列的產(chǎn)生、分配隱藏、盲法、退出和理由，其中隨機(jī)序列的產(chǎn)生、分配隱藏和盲法以“否”、“不清楚”和“是”描述，分別賦0、1和2分；退出和理由以“否”和“是”描述，分別評0和1分。>5分為低度偏倚風(fēng)險(xiǎn)。

1.6 統(tǒng)計(jì)學(xué)方法 采用RevMan 5.2軟件行Meta分析，以RR及其95%CI作為效應(yīng)指標(biāo)。對文獻(xiàn)行異質(zhì)性檢驗(yàn)，若無統(tǒng)計(jì)學(xué)異質(zhì)性(I2<50%)采用固定效應(yīng)模型，若有統(tǒng)計(jì)學(xué)異質(zhì)性(I2≥50%)則采用隨機(jī)效應(yīng)模型。P<0.05為差異具有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 檢索的一般情況 初步檢索到207篇文獻(xiàn)，15篇RCT文獻(xiàn)[5～19]進(jìn)入本文Meta分析(圖1)，共納入2 658例早產(chǎn)兒。15篇RCT文獻(xiàn)來自于歐洲、北美洲和中國臺灣等。8篇文獻(xiàn)的研究對象胎齡≤32周或出生體重<1 500 g[6, 7, 12～15, 17,18]。除文獻(xiàn)[12]外，余14篇文獻(xiàn)早產(chǎn)兒均于生后10 d內(nèi)予LCPUFA干預(yù)，15篇文獻(xiàn)采用補(bǔ)充添加或未添加LCPUFA的配方奶，或?qū)⑼庥^相同的魚油丸或豆油丸混入配方奶中。納入文獻(xiàn)的基本特征見表1。

除文獻(xiàn)[18]外，余文獻(xiàn)均標(biāo)注了干預(yù)組與對照組ω-3 LCPUFA以及ω-6 LCPUFA的濃度，ω-3 LCPUFA以DHA、EPA和ALA為主，ω-6 LCPUFA以AA和LA為主(表2)。

圖1 文獻(xiàn)篩選流程圖

Notes 1) MOSF-2.5Fat/MOSF-3.5Fat/S-2.5Fat/S-3.5Fat; 2) algal-DHA supplement group/fish-DHA supplement group/control group; 3) DHA group/DHA+ARA group/control group; 4) (fish/fungal oil group)/(egg-TG/fish oil)/control group; 5) LCP-enriched formula group/conventional formula group/human milk group. GA: gestational age; NR: not reported; ①: infection (spesis); ②necrotizing enterocolitis; ③bonchopulmonary dysplasia; ④: death

表2 納入文獻(xiàn)LCPUFA的配方(%)

Notes 1) Doses are defined in g/100 g of fatty acid; 2) algal-DHA supplement group/Fish-DHA supplement group/control group; 3) DHA group/DHA+ARA group/control group; 4) (fish/fungal oil group)/(egg-TG/fish oil)/control group; NR: not reported; ND: not done

2.2 文獻(xiàn)偏倚評價(jià)結(jié)果 7篇文獻(xiàn)[5,7～9,12,13,16]描述了隨機(jī)序列的產(chǎn)生方法，余文獻(xiàn)未提及；7篇文獻(xiàn)[5,6,8,10,11,14,17]描述了隨機(jī)序列的分配隱藏，7篇文獻(xiàn)[7,9,12,13,15,16,19]未描述，文獻(xiàn)[18]未采用分配隱藏；11篇文獻(xiàn)[5～11,13～15,17]采用盲法，3篇文獻(xiàn)[12,16,18]未提及，文獻(xiàn)[19]未采用盲法；15篇文獻(xiàn)均描述了失訪。2篇[5,8]文獻(xiàn)評為7分，8篇文獻(xiàn)[6,7,9～11,13,14,17]評為6分，3篇文獻(xiàn)[12，15，16]評為5分，文獻(xiàn)[18,19]評為3分。

2.3 Meta分析結(jié)果

2.3.1 NEC發(fā)生率 10篇文獻(xiàn)[6～14, 19]報(bào)道了兩組NEC發(fā)生率，異質(zhì)性檢驗(yàn)P=0.20，固定效應(yīng)模型Meta分析結(jié)果顯示，干預(yù)組和對照組NEC的發(fā)生率差異無統(tǒng)計(jì)學(xué)意義，RR=1.16,95%CI：0.73～1.83，P=0.54(圖2，胎齡<37周)。

2.3.2 BPD發(fā)生率 10篇文獻(xiàn)[5, 6, 9～11, 13～17]報(bào)道了兩組BPD發(fā)生率，異質(zhì)性檢驗(yàn)P=0.30，采用固定效應(yīng)模型合并結(jié)果，Meta分析結(jié)果顯示，干預(yù)組和對照組BPD的發(fā)生率差異無統(tǒng)計(jì)學(xué)意義，RR=0.94, 95%CI：0.79～1.13，P=0.53(圖3，胎齡<37周)。

2.3.3 嚴(yán)重感染(敗血癥)發(fā)生率 9篇文獻(xiàn)[6, 8～14, 16, 18]報(bào)道了兩組嚴(yán)重感染(敗血癥)發(fā)生率，異質(zhì)性檢驗(yàn)P=0.90，采用固定效應(yīng)模型合并結(jié)果，Meta分析結(jié)果顯示，干預(yù)組和對照組嚴(yán)重感染(敗血癥)的發(fā)生率差異無統(tǒng)計(jì)學(xué)意義，RR=1.13, 95%CI:0.93～1.37，P=0.23(圖4，胎齡<37周)。

2.3.4 病死率 4篇文獻(xiàn)[8, 10, 11, 14]報(bào)道了病死率，異質(zhì)性檢驗(yàn)P=0.35，采用固定效應(yīng)模型合并結(jié)果，Meta分析結(jié)果顯示，干預(yù)組和對照組病死率差異無統(tǒng)計(jì)學(xué)意義，RR=1.15, 95%CI:0.56～2.36，P=0.71(圖5)。

2.3.5 亞組分析 圖2顯示，胎齡≤32周早產(chǎn)兒補(bǔ)充和未補(bǔ)充LCPUFA的NEC發(fā)生率差異有統(tǒng)計(jì)學(xué)意義，RR=0.42(95%CI: 0.19～0.96)；圖3和4顯示，BPD和嚴(yán)重感染(敗血癥)發(fā)生率在胎齡≤32周早產(chǎn)兒補(bǔ)充和未補(bǔ)充LCPUFA間差異均無統(tǒng)計(jì)學(xué)意義。

圖3 LCPUFA干預(yù)組和對照組BPD發(fā)生率的Meta分析

圖4 LCPUFA干預(yù)組和對照組嚴(yán)重感染(敗血癥)發(fā)生率的Meta分析

圖5 LCPUFA干預(yù)組和對照組病死率的Meta分析

Fig 5 Meta-analysis of the mortality in LCPUFA and control groups

2.4 發(fā)表偏倚 以報(bào)道NEC發(fā)生率的文獻(xiàn)繪制漏斗圖(圖6)，顯示漏斗圖對稱，提示發(fā)表偏倚的可能性不大。

圖6 NEC文獻(xiàn)發(fā)表偏倚的漏斗圖

Fig 6 Funnel plot of studies regarding NEC

3 討論

本文Meta分析納入的15篇RCT文獻(xiàn)，采用改良JADAD量表行偏倚風(fēng)險(xiǎn)評價(jià)，7篇文獻(xiàn)描述隨機(jī)序列產(chǎn)生的方法，8篇文獻(xiàn)采用分配隱藏，11篇文獻(xiàn)采用盲法，均報(bào)道了失訪情況，13篇文獻(xiàn)評分在5～7分，2篇文獻(xiàn)<5分，因此本文納入文獻(xiàn)的偏倚風(fēng)險(xiǎn)較低。

以DHA為主的LCPUFA廣泛存在于大腦皮質(zhì)(足月兒約23%)、肌肉和脂肪組織[20]，早產(chǎn)兒體內(nèi)DHA貯存量低于足月兒10%[21]。研究表明，極早產(chǎn)兒每日DHA的需求量40～60 mg·kg-1。ALA是體內(nèi)代謝DHA的關(guān)鍵脂肪酸，可通過去飽和-延伸途徑合成DHA和EPA[22]。由于早產(chǎn)兒體內(nèi)脂肪貯存量少、生長發(fā)育的需求量大和體內(nèi)合成功能不足等因素，可導(dǎo)致早產(chǎn)兒缺乏DHA。有研究顯示，早產(chǎn)兒尤其行機(jī)械通氣、長期氧療者的炎性反應(yīng)生物標(biāo)志物水平高于正常足月兒，而持續(xù)的氧化應(yīng)激以及炎性反應(yīng)是BPD、NEC等新生兒疾病發(fā)生不可忽視的原因[23～25]。補(bǔ)充LCPUFA尤其是DHA與EPA對炎性反應(yīng)有非常重要的調(diào)節(jié)作用[26～33]。

本文Meta分析結(jié)果顯示，早產(chǎn)兒補(bǔ)充LCPUFA不能降低BPD、嚴(yán)重感染(敗血癥)的發(fā)生率和病死率；但以胎齡行亞組分析顯示，補(bǔ)充LCPUFA可能降低胎齡≤32周早產(chǎn)兒NEC發(fā)生率，RR=0.42(95%CI:0.19～0.96)，與多項(xiàng)觀察性研究的結(jié)果相近[34～36]。但本文亞組分析的NEC的文獻(xiàn)為4篇，結(jié)局事件的發(fā)生例數(shù)少，且結(jié)果存在顯著的不精確性，因此仍需補(bǔ)充研究進(jìn)一步明確。

本文分析的4個指標(biāo)異質(zhì)性檢驗(yàn)P均>0.1，提示文獻(xiàn)間具同質(zhì)性；但本文納入文獻(xiàn)間存在一定的臨床異質(zhì)性，如干預(yù)組中的LCPUFA或來源于魚油或海藻油，而喂養(yǎng)載體或?yàn)槟溉榛蚺浞侥?，但限于文獻(xiàn)量有限，未行分層分析。4篇文獻(xiàn)對照組為添加較低濃度的LCPUFA，可能對結(jié)果有一定影響。

結(jié)論：早產(chǎn)兒補(bǔ)充LCPUFA不能降低BPD、嚴(yán)重感染(敗血癥)的發(fā)生率和病死率，可能降低胎齡≤32周早產(chǎn)兒NEC發(fā)生率。

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(本文編輯：丁俊杰)

The impact of LCPUFA supplement on incidence of necrotizing enterocolitis and bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis

WANGQian,CUIQi-liang,YANCai-man

(TheThirdAffiliatedHospitalofGuangzhouMedicalUniversity,Guangzhou510630,China)

CUI Qi-liang，E-mail:gycuiqiliang@126.com

ObjectiveTo compare the incidence of necrotizing enterocolitis(NEC), bronchopulmonary dysplasia(BPD) and other neonatal disease between preterm infants received LCPUFA-supplemented formula and regular formula.MethodsThe databases of PubMed,EMBASE,the Cohrane Library, CNKI and Wanfang database were searched from establishment to Augest, 2015, to collect relevant studies investigating the impact of preterm infants given LCPUFA on the incidence of NEC, BPD, sepsis and mortality. Two reviewers independently screened literatures, extracted data,and assessed the risk bias of included studies by modified JADAD scale, including randomization, concealing, blinding and loss of follow up. The outcomes were expressed as risk ratio(RR) with 95% CI.The meta-analysis was performed using RevMan 5.3 software.A fixed-effect model or a random-effect model would be used according to the heterogeneity test results.ResultsFifteen RCTs (2 658 infants) were included into this meta-analysis. The JADAD score of 13 RCTs ranged from 5 to 7, whearas 2 RCTs < 5, which indicated the risk of bias of included studies was low. The meta-analysis showed that LCPUFA could not significantly decrease the incidence of NEC, BPD, sepsis or death, the correponding RR(95%CI) was 1.16(0.73-1.83), 0.94(0.79-1.13), 1.13(0.93-1.37) and 1.15(0.56-2.36), respectively. Subgroup analysis found that preterm infants with gestational age ≤32 weeks receiving LCPUFA had lower incidence of NEC (RR,0.42,95% CI: 0.19-0.96). The incidences of BPD and sepsis did not significantly differ in infants reveiving and non-reveiving LCPUFA in the gestational age ≤32 weeks. ConclusionPreterm infants received LCPUFA-supplemented formula could not decrease the incidence of BPD, sepsis and death, however may decrease the incidence of NEC in infants with gestational age less than 32 weeks.

Preterm infant； Docosahexaenoic acid； Necrotizing enterocolitis； Bronchopulmonary dysplasia； Sepsis； Mortality； Systematic review； Meta analysis

廣州醫(yī)科大學(xué)附屬第三醫(yī)院 廣州，510630

崔其亮，E-mail:gycuiqiliang@126.com

10.3969/j.issn.1673-5501.2015.06.005

2015-08-15

2015-11-16)