中国科技论文统计源期刊　中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖  
医药导报
医药导报, 2018, 37(9): 1119-1126
doi: 10.3870/j.issn.1004-0781.2018.09.022
二甲双胍对妊娠期糖尿病患者新生儿安全性影响的系统评价
Effects of Metformin on Safety of Newborn of Woman with Gestational Diabetes Mellitus:A Systematic Review
张琳, 郑丽, 戴晖, 杨爱华
浙江省南通市妇幼保健院药事科,南通 226010
ZHANG Lin,, ZHENG Li, DAI Hui, YANG Aihua,
Department of Pharmacy,Maternity and Child Health Care Hospital of Nantong City, Zhejiang Province, Nantong 226010,China

作者简介 张琳(1980-),男,山东临沂人,副主任中药师,硕士,研究方向:循证药学及中药质量控制。电话:0513-85116027,E-mail:juezhangyan@163.com。

通信作者 杨爱华(1988-),女,江苏张家港人,主管中药师,硕士,研究方向:临床中药学。电话:0513-89008165,E-mail:yangaihua37@126.com。
中图分类号: R977.15;R969.3     文献标识码: B     文章编号: 1004-0781(2018)09-1119-08
摘要:

目的 系统评价二甲双胍对妊娠期糖尿病(GDM)患者新生儿安全性的影响。方法 计算机检索PubMed数据库、CENTRAL数据库、EMBASE数据库、中国期刊全文数据库(CNKI)、万方数据库、中国生物医学文献数据库(CBM)。收集从建库至2016年7月关于二甲双胍在GDM治疗中对新生儿安全性影响的随机对照临床试验(RCTs)。按纳入及排除标准筛选文献,采用Cochrane系统评价员手册5.1.0版的偏倚风险评估工具评价纳入研究的文献质量。采用RevMan5.3版软件进行荟萃分析。结果 最终纳入11篇RCTs,共2056例患者。与单用胰岛素对照组比较,二甲双胍治疗组(单用或合用胰岛素)可以有效降低新生儿低血糖发生率[RR=0.71,95%CI(0.57,0.88),P=0.002],降低巨大儿发生率[RR=0.66,95%CI(0.47,0.91),P=0.01]、大于胎龄儿的发生率[RR=0.80,95%CI(0.64,0.99),P=0.04]及新生儿重症监护室入住率[R=0.77,95%CI(0.64,0.92),P=0.005],并可显著降低新生儿出生体质量[MD=-85.46,95%CI(-148.22,-22.69),P=0.008],同时不增加小于胎龄儿、新生儿呼吸窘迫综合征、高胆红素血症、肩难产、围产期病死、新生儿畸形等不良反应结局发生率。结论 二甲双胍可能是治疗GDM的一种有效、安全的口服药物。
关键词: 二甲双胍 ; 胰岛素 ; 糖尿病 ; 妊娠期 ; 新生儿 ; Meta分析

Abstract:

Objective To evaluate the effects of metformin on safety of newborn of woman with gestational diabetes mellitus (GDM) treated with metformin. Methods MEDLINE,CENTRAL,EMBASE,CNKI,WANG FANG DATA and CBM were retrieved. Randomized controlled trials (RCTs) that enrolled women with GDM treated with metformin were included. According to the inclusion and exclusion criteria,the quality of the extracted literature were evaluated by the Cochrane Risk of Bias assessment tool of Interventions5.1.0. The included studies were evaluated and analyzed by Meta-analysis with RevMan 5.3. Results Totally,11 RCTs enrolled 2056 pregnant women with GDM. The results of meta-analysis showed that Metformin significantly lowered the risk of neonatal hypoglycemia [RR=0.71,95%CI (0.57,0.88),P=0.002],macrosomia [RR=0.66,95%CI (0.47,0.91),LGA [RR=0.80,95%CI (0.64,0.99),P=0.04],and NICU admission [R=0.77,95%CI (0.64,0.92),P=0.005],and significantly reduce birth weight [MD=-85.46,95%CI (-148.22,-22.69),P=0.008],while did not increase the risk of SGA,NRDS,hyperbilirubinaemia,shoulder dystocia,perinatal fetal mortality,and congenital anomalies. Conclusion Metformin appear to be an effective and safe oral drug for the treatment of GDM.
Key words: Metformin ; Insulin ; Diabetes mellitus ; gestational ; Newborn ; Meta-analysis

妊娠期糖尿病(gestational diabetes mellitus,GDM)是指妊娠期间首次发生或诊断为糖耐量异常[1]。

GDM与多种妊娠并发症和新生儿不良结局相关[2]。GDM患者若血糖得不到较好控制,则其新生儿发生巨大儿、大于胎龄儿(large for gestational age,LGA)、小于胎龄儿(small for gestational age,SGA)、新生儿低血糖发生率及围产期病死率更高[3,4,5,6],子代患成人心血管疾病的风险增加[7,8,9]。为减少以上并发症,有效控制血糖水平是关键,治疗手段包括:饮食控制、运动疗法和药物治疗[10,11,12]。胰岛素能有效控制血糖水平且不透过胎盘组织,常作为GDM的首选药物[13,14,15],但服用不方便、依从性差,需根据患者体质量指数(BMI)、胰岛素水平等调整剂量,且增加妊娠期低血糖、增加孕期体质量风险[16,17]。口服降糖药二甲双胍日益成为替代胰岛素治疗GDM的有效药物[18,19]。英国国家优化卫生与保健研究所在GDM临床指南中推荐使用二甲双胍作为口服降糖药物[20],美国妇产科医师协会在新的GDM临床管理指南中推荐使用格列本脲和二甲双胍作为替代胰岛素治疗药物[21]。但二甲双胍可通过胎盘,脐带动脉血药浓度水平是母体静脉水平的2倍[22],胎儿暴露于二甲双胍的中长期影响是未知的。已有系统评价分析了二甲双胍在GDM治疗中对母婴结局指标的影响[23,24,25],但他们的研究结论不一致,尤其是缺少对子代长期随访数据的分析。近2年来,新增了多个二甲双胍治疗GDM的随机、对照临床研究[26,27],尤其是3个长期随访研究的报道[28,29,30],为进一步客观评价二甲双胍对GDM患者新生儿安全性的影响,笔者对已有随机、对照临床研究进行系统评价,以期为二甲双胍治疗GDM的安全性提供循证依据。

1 资料与方法
1.1 文献检索方法

计算机检索PUBMED、CENTRAL、EMBASE数据库,检索时间均为建库至2016年7月,均采用主题词与自由词相结合的方式检索,语言限定为英文。英文使用检索词包括“metformin”“Diabetes,Gestational”“Gestational Diabetes Mellitus”“Gestational Diabetes”。

1.2 纳入标准

1.2.1 研究对象 临床诊断为GDM患者。

1.2.2 研究类型 ①随机对照试验;②文种限英文;③对同一课题组不同时期的结果报告,采用最新发表的研究。

1.2.3 干预措施 ①对照组:仅使用胰岛素治疗;②治疗组:单独二甲双胍治疗或对照组基础上加用二甲双胍治疗。

1.2.4 结局指标 新生儿低血糖发生率,出生体质量,巨大儿发生率,LGA发生率,SGA发生率,早产率,新生儿呼吸窘迫综合征(neonatal respiratory distress syndrome,NRDS)发生率,高胆红素血症发生率,肩难产发生率,新生儿重症监护室(NICU)入住率,围产期病死率,新生儿畸形率。

1.3 排除标准

①非随机对照试验;②妊娠前已诊断为糖尿病患者,合并多囊卵巢综合征患者;③对照组不是接受胰岛素治疗;④无相关新生儿结局指标;⑤动物实验;⑥重复发表、质量差、报道信息过少的研究及短篇报告。

1.4 文献筛选、资料提取与质量评价

由两名评价员根据纳入和排除标准独立检索数据库,对初步纳入标准的文献进行全文查找,并应用统一表格提取文献数据[20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43],具体内容见表1。按照Cochrane系统评价员手册5.1.0版的偏倚风险评估工具对纳入研究的方法学质量进行评价。评价内容包括:①随机序列的产生;②分配隐藏;③对受试者和干预提供者施盲;④对结果评价施盲;⑤结果数据完整性;⑥选择性结果报告;⑦其他偏倚来源。

1.5 统计学方法

采用Cochrane协作网提供的RevMan5.3版软件进行统计学分析,计数资料采用相对危险度(RR)及其95%置信区间(95%CI)作为研究结果的评价指标,计量资料用均数差(MD)及其95%CI表示。首先采用χ2检验对纳入研究进行异质性检验,检验水准为α=0.1,并采用I2对异质性进行定量分析,I2≥50% 存在异质性。如各研究结果间无异质性,采用固定效应模型进行Meta分析;如各研究结果间有统计学异质性,则进一步分析异质性来源,在排除明显临床异质性的影响后,采用随机效应模型进行Meta分析;如异质性过大,则进行描述性分析。

2 结果
2.1 文献检索结果及质量评价

2.1.1 文献检索结果 初检出282篇文献,阅读文章题名和摘要及查重后余35篇供进一步筛选。通过对全文的阅读,根据纳入与排除标准,9篇因研究类型不符而排除,6篇因研究对象为2型糖尿病患者被排除,5篇无相关结局指标被排除,4篇因对照组不符或无对照组被排除。最终纳入11篇研究[26-27,31-39]。

2.1.2 纳入研究的基本特征及质量评价 在纳入的11篇文献中,二甲双胍治疗组(单用或合用胰岛素)1024例,单用胰岛素对照组1032例。其中来自伊朗3项研究,芬兰、巴基斯坦各2项研究,美国、巴西与埃及各1项研究,新西兰与澳大利亚1项。所有研究均报告了新生儿结局指标,纳入文献的详细特征见表1。所有研究均报告了GDM诊断标准和开始治疗标准,具体标准情况见表2。所有纳入研究报告了随机方法,但只有7项研究正确描述了分配隐藏[26,32-35,38-39];受医学伦理学限制,只有2项研究设置了双盲[32,38];只有2项研究进行了意向性分析(ITT)[31,33];所有研究均无选择性报道。

表1 纳入文献的基本特征
Tab.1 Basic characteristics of the included studies
文献第一作者和发表年 国家 样本量/例 患者年龄/岁 BMI
治疗组 对照组 治疗组 对照组 治疗组 对照组
MOORE 2007[33] USA 32 31 27.1±4.7 27.7±6.7 NR NR
ROWAN 2008[31] New Zealand,Australia 363 370 33.5±5.4 33.0±5.1 NR NR
IJAS 2011[34] Finland 47 50 32.3±5.6 31.7±6.1 31.5±6.5 30.80±5.40
NIROMANESH 2012[35] Iran 80 80 30.7±5.5 31.8±5.1 28.1±4.0 27.10±2.10
HASSAN 2012[36] Pakistan 75 75 30.29±3.06 30.9±3.6 29.17±1.94 28.70±2.70
SPAULONCI 2013[37] Brazil 47 47 31.93±6.02 32.8±4.7 31.96±4.75 31.40±5.70
MESDAGHINIA 2013[38] Iran 100 100 29.6±5.3 30.2±5.9 27.6 28.46
TETTTI 2013[39] Finland 110 107 31.9±5.0 32.1±5.4 29.4±5.9 28.90±4.70
SAFURA 2014[32] Iran 50 50 24.6±6.3 32.1±5.4 29.4±5.9 28.90±4.70
AINUDDIN 2015[27] Pakistan 43 75 30.6±2.9 31.0±4.0 NR NR
ASHOUSH 2016[26] Egypt 47 48 31.6±2.8 32.1±3.2 31.1±1.3 31.40±1.50
文献第一作者和发表年 干预措施 纳入时的妊娠周数 结局指标
二甲双胍/
(mg·d-1)		 胰岛素 治疗组 对照组
MOORE 2007[33] 1000~2000 0.7 U·kg-1·d-1 27.80±6.50 28.90±5.00 b,f,i
ROWAN 2008[31] 500~2500 30~90 U·d-1 30.20±3.30 30.10±3.20 a,b,c,d,f,g,h,i,j,k
IJAS 2011[34] 750~2250 30(I),43(M) 30.00±4.90 30.00±4.00 a,b,c,e,f,g,h,i,j
NIROMANESH 2012[35] 1000~2500 NR 28.70±3.70 28.60±3.60 a,b,c,d,e,f,g,h,i,j,k
HASSAN 2012[36] 500~3000 NR 29.53±1.33 29.20±1.48 b,d,e,f,h,i,j,k
SPAULONCI 2013[37] 1700~2550 NR 32.18±3.70 32.05±3.50 a,b,c,d,e,f,h,i,k
MESDAGHINIA 2013[38] 500~2500 0.5 U·kg-1·d-1 27.90±3.20 28.90±3.80 a,b,c,e,f,g,i,k
TETTTI 2013[39] 500~2000 11(M),10(I) 30.30±2.00 30.40±1.80 a,b,c,e,f,h,i,j
SAFURA 2014[32] 500~1500 NR 27.60±3.30 26.70±3.50 a,b,d,e,f,g,h,i,k
AINUDDIN 2015[27] 500~2500 49.4(I),13.6(M) 29.90±1.10 29.20±1.50 b,c,d,f,g,i,j,k
ASHOUSH 2016[26] 1000~2500 0.7 U·kg-1·d-1 29.80±1.40 29.70±1.90 a,b,e,j

Neonatal outcome index:a.incidence of preterm birth;b.birth weight;c.incidence that greater than gestational age;d.incidence that less than gestational age;e.incidence of giant baby;f.incidence of neonatal hypoglycemia;g.incidence of difficult labor;h.incidence of hypobilirubinemia;i.incidence of NICU;j.duration of pregnancy;k.incidence of neonatal respiratory distress syndrome;NR.failed to report

新生儿结局指标:a.早产发生率 ;b.出生体质量;c.大于胎龄儿发生率;d.小于胎龄儿发生率;e.巨大儿发生率;f. 新生儿低血糖发生率;g.肩难产发生率;h.低胆红素血症发生率; i.入住NICU发生率;j.妊娠时限;k.新生儿呼吸窘迫综合征发生率;NR.未报告

表1 纳入文献的基本特征

Tab.1 Basic characteristics of the included studies

表2 GDM诊断标准和纳入标准
Tab.2 Criteria for diagnosis and inclusion of GDM
文献第一作者和发表年 GDM诊断标准 GDM纳入标准
标准 糖负荷/
g		 空腹血糖 餐后1 h血糖 餐后2 h血糖 餐后3 h血糖 空腹血糖 餐后2 h血糖
(mmol·L-1) (mmol·L-1)
MOORE 2007[33] NDDG 100 5.88 10.64 9.24 8.12 5.88 6.72
ROWAN 2008[31] ADIPS 75 5.54 — 7.06 — 5.44 6.75
IJAS 2011[34] NR 75 5.34 11.09 9.68 — 5.34 6.75(1.5 h)
NIROMANESH 2012[35] ADA 100 5.34 10.08 8.67 — 5.32 6.72
HASSAN 2012[36] WHO 2006 75 5.32 10.08 8.68 — 5.60 7.06
SPAULONCI 2013[37] ADA 100 5.32 10.08 8.68 7.84 5.32 6.72
MESDAGHINIA 2013[38] ADA 100 5.32 10.08 8.68 7.84 5.32 6.72
TETTTI 2013[39] ADA 75 5.34 10.08 8.67 — 5.54 7.86(1 h)
SAFURA 2014[34] ADIPS 75 5.54 — 7.06 — 5.32 6.72
AINUDDIN 2015[27] ADA 75 5.32 10.08 8.68 — 5.32 8.68
ASHOUSH 2016[26] ADA 75 5.34 10.08 8.67 — 5.60 7.84

NDDG:National Diabetes Data Group;ADIPS:Australasian Diabetes in Pregnancy Society;ADA:American Diabetes Association;WHO:World Health Organization;NR:failed to report

NDDG:美国国家糖尿病资料组;ADIPS:澳大利亚妊娠糖尿病协会;ADA:美国糖尿病协会;WHO:世界卫生组织;NR:未报告

表2 GDM诊断标准和纳入标准

Tab.2 Criteria for diagnosis and inclusion of GDM

3 Meta分析结果
3.1 新生儿主要结局指标

新生儿主要结局指标包括新生儿低血糖发生率,出生体质量,巨大儿发生率,LGA发生率,SGA发生率,新生儿呼吸窘迫综合征发生率,NICU入住率。除出生体质量外,其余指标均采用固定效应模型分析。纳入研究均报告了新生儿低血糖发生率与出生体质量情况,汇总结果显示与单用胰岛素比较,二甲双胍可以显著降低新生儿低血糖发生率[RR=0.71,95%CI(0.57,0.88),P=0.002],新生儿出生体质量[MD=-85.46,95%CI(-148.22,-22.69),P=0.008],巨大儿发生率[RR=0.66,95%CI(0.47,0.91),P=0.01],LGA发生率[RR=0.80,95%CI(0.64,0.99),P=0.04],NICU入住率[RR=0.77,95%CI(0.64,0.92),P=0.005],两组间差异具有统计学意义。而SGA发生率[RR=1.07,95%CI(0.75,1.53),P=0.72],NRDS发生率[RR=0.76,95%CI(0.50,1.15),P=0.19],二甲双胍治疗组(单用或合用胰岛素)与单用胰岛素对照组差异无统计学意义,见图1,2。


图1 2组新生儿主要结局指标比较森林图

Fig.1 Forest plots of primary outcomes in two groups of neonates


图2 2组新生儿出生体质量比较森林图

Fig.2 Forest plots of birth weight in two groups of neonates

3.2 新生儿次要结局指标

新生儿次要结局指标包括低胆红素血症发生率、早产率、肩难产发生率、围产期病死率、新生儿畸形率。所有指标均采用固定效应模型分析。汇总结果显示,高胆红素血症发生率[RR=0.86,95%CI(0.63,1.17),P=0.33],围产期病死率[RR=0.99,95%CI(0.14,7.19),P=1.0],早产率[RR=1.20,95%CI(0.86,1.68),P=0.28],肩难产发生率[RR=0.55,95%CI(0.28,1.11),P=0.10],新生儿畸形率[RR=1.20,95%CI(0.86,1.68),P=0.28],二甲双胍治疗组(单用或合用胰岛素)与单用胰岛素对照组差异无统计学意义,见图3。


图3 2组新生儿次要结局指标比较森林图

Fig.3 Forest plots of secondary outcomes in two groups of neonates

3.3 敏感性及发表偏倚分析

所有纳入研究均报告了新生儿低血糖发生率,以其为研究指标将固定效应模型换成随机效应模型计算合并效应量,再进行Meta分析,所得合并效应量RR值分别为0.564,95%CI(0.431,0.739)与0.584,95%CI(0.444,0.769),P=0.506,两者比较差异无统计学意义,表明结果敏感性低。利用漏斗图评价新生儿低血糖发生率的发表偏倚,结果显示漏斗图各点分布基本对称,提示本研究所纳入的文献不存在发表偏倚,见图4。


图4 新生儿低血糖发生率发表偏倚漏斗图

Fig.4 Funnel plots for publication bias analysis on the hypoglycemia incidence of neonates

4 讨论
4.1 主要发现

汇总结果显示,与单用胰岛素对照组比较,二甲双胍治疗组可以显著降低新生儿低血糖发生率(P=0.002),NICU入住率(P=0.005),进一步证实了以往发表的Meta分析结论[24,25]。二甲双胍治疗组同时可以显著降低新生儿体质量(P=0.008),巨大儿发生率(P=0.01)、LGA发生率(P=0.04)。其中对新生儿体质量的影响与Juan Gui 和Kitwitee的Meta汇总结果不一致[25,41],两个Meta分析结果显示,虽然二甲双胍治疗组与单用胰岛素组比较可以降低新生儿体质量,但差异无统计学意义。而对巨大儿发生率和LGA发生率的影响与文献[42,43]的汇总结果不一致,虽然与对照组比较可以降低发生率,但两组间差异无统计学意义。引起不一致的原因可能是笔者新纳入了多篇新的临床研究,扩大了统计样本量。

对GDM子代的长期影响。作为胰岛素的增敏剂,二甲双胍可透过胎盘,GDM患者胎儿较长时间暴露于其环境中,对其子代的成长有无不良影响,因目前研究数据有限,并无确切结论。ROWAN等[28]经过2年的随访研究表明,在总脂肪和向心性肥胖方面,二甲双胍暴露组与胰岛素暴露组无差异,但二甲双胍组皮下脂肪沉积增加。IJAS等[29]经过18个月的随访研究研究表明,与胰岛素暴露组相比,二甲双胍暴露组的子代体质量更重和身高更高,但体质量指数差异无统计学意义。二甲双胍对GDM子代的安全性评价需更多、更长时间的随访研究。

4.2 局限性

首先纳入研究样本量普遍较小,只有3项研究样本量超过200例[31,38-39];其次纳入研究来自不同国家,且GDM诊断标和纳入标准不统一,干预措施不同,这些都是造成临床异质性和方法学异质性的潜在来源;由于受医学伦理学限制,纳入11项研究中只有2项研究实施了双盲,只有7项研究描述了分配隐藏,这些都是方法学异质性的潜在来源;此外,所有纳入研究均为英文,无其他语种文献,可能会导致以其他语种形式发表的研究未纳入的语种偏倚风险;由于缺少长时间随访数据的纳入,这些均限制了对新生儿安全性的评价结论。以上因素均有可能影响本文Meta分析结果。

4.3 研究结论

与单用胰岛素对照组比较,二甲双胍治疗组可有效降低新生儿低血糖、巨大儿、LGA、NICU不良妊娠结局发生率,未增加SGA、NRDS、高胆红素血症、肩难产、围产期死亡、新生儿畸形等不良反应结局发生率。二甲双胍可能是替代胰岛素治疗GDM的一种有效、安全口服药物。但目前中国相关指南中并未推荐任何口服药物应用于GDM的治疗,本文纳入的研究都来自于国外,得出的结果是否能应用于中国人群,尚需高质量、大样本的临床研究验证。

The authors have declared that no competing interests exist.
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DOI:10.1007/s00404-014-3566-0      URL    
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关键词（key words）
二甲双胍
胰岛素
糖尿病
妊娠期
新生儿
Meta分析
Metformin
Insulin
Diabetes mellitus
gestational
Newborn
Meta-analysis
作者
张琳
郑丽
戴晖
杨爱华
ZHANG Lin
ZHENG Li
DAI Hui
YANG Aihua