Brown Julie, Martis Ruth, Hughes Brenda, Rowan Janet, Crowther Caroline A
Liggins Institute, The University of Auckland, Park Rd, Grafton, Auckland, New Zealand, 1142.
Pharmacy, Auckland City Hospital, Auckland, New Zealand.
Cochrane Database Syst Rev. 2017 Jan 25;1(1):CD011967. doi: 10.1002/14651858.CD011967.pub2.
Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies.
To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM.
We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies.
We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.Women with pre-existing type 1 or type 2 diabetes were excluded.
Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy.
We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard careThere was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamideThere was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I = 61%, Tau = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I = 54%, Tau = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarboseThere was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes).
AUTHORS' CONCLUSIONS: There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit.
妊娠期糖尿病（GDM）是一个重大的公共卫生问题，全球发病率呈上升趋势。妊娠期糖尿病是指在孕期首次被识别出的葡萄糖耐量异常，通常在产后缓解，且与母亲及其婴儿的短期和长期并发症相关。治疗选择可包括口服抗糖尿病药物疗法。
评估口服抗糖尿病药物疗法治疗妊娠期糖尿病女性的效果。
我们检索了Cochrane妊娠与分娩试验注册库（2016年5月14日）、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台（2016年5月14日）以及检索到的研究的参考文献列表。
我们纳入了已发表和未发表的随机对照试验，这些试验评估了口服抗糖尿病药物疗法治疗妊娠期糖尿病孕妇的效果。我们纳入了比较口服抗糖尿病药物疗法与以下情况的研究：1）安慰剂/标准治疗，2）另一种口服抗糖尿病药物疗法，3）联合口服抗糖尿病药物疗法。以胰岛素作为对照的试验被排除，因为它们是另一项Cochrane系统评价的主题。患有孕前1型或2型糖尿病的女性被排除。
两位综述作者独立评估试验是否纳入及试验质量。两位综述作者独立提取数据，并检查数据的准确性。
我们纳入了11项研究（19篇出版物）（1487名女性及其婴儿）。八项研究的数据可纳入荟萃分析。这些研究在巴西、印度、以色列、英国、南非和美国进行。这些研究在妊娠期糖尿病的诊断标准和血糖控制的治疗目标方面存在差异。由于方法学报告不充分，总体偏倚风险“不清楚”。使用GRADE方法，证据质量从中等质量到极低质量不等。由于偏倚风险（报告偏倚、缺乏盲法）、不一致性、间接性、不精确性以及口服抗糖尿病疗法与安慰剂相比的可推广性，证据被降级。口服抗糖尿病药物疗法与安慰剂/标准治疗相比：在妊娠期高血压疾病方面，没有证据表明格列本脲组与安慰剂组之间存在差异（风险比（RR）1.24，95%置信区间（CI）0.81至1.90；一项研究，375名女性，极低质量证据）；剖宫产（RR 1.03，95% CI 0.79至1.34；一项研究，375名女性，极低质量证据）；会阴创伤（RR 0.98，95% CI 0.06至15.62；一项研究，375名女性，极低质量证据）或引产（RR 1.18，95% CI 0.79至1.76；一项研究，375名女性；极低质量证据）。没有报告2型糖尿病或其他预先指定的GRADE孕产妇结局（恢复孕前体重、产后抑郁）的数据。对于婴儿，没有证据表明母亲接受格列本脲治疗的婴儿与安慰剂组婴儿相比，大于胎龄儿（LGA）出生风险存在差异（RR 0.89，95% CI 0.51至1.58；一项研究，375名，低质量证据）。没有报告其他婴儿主要结局或GRADE结局（围产期死亡率、死亡或严重发病综合结局、儿童期后期神经感觉残疾、新生儿低血糖、肥胖、糖尿病）的数据。二甲双胍与格列本脲相比：在妊娠期高血压疾病风险方面，没有证据表明二甲双胍治疗组与格列本脲治疗组之间存在差异（RR 0.70，95% CI 0.38至1.30；三项研究，508名女性，中等质量证据）；剖宫产（平均RR 1.20，95% CI 1.20；95% CI 0.83至1.72，四项研究，554名女性，I = 61%，Tau = 0.07，低质量证据）；引产（0.81，95% CI 0.61至1.07；一项研究，159名女性；低质量证据）或会阴创伤（RR 1.67，95% CI 0.22至12.52；两项研究，158名女性；低质量证据）。没有报告2型糖尿病或其他预先指定的GRADE孕产妇结局（恢复孕前体重、产后抑郁）的数据。对于婴儿，没有证据表明暴露于二甲双胍和格列本脲的组之间在LGA出生风险方面存在差异（平均RR 0.67，95% CI至1.83；两项研究，246名婴儿，I = 54%，Tau = 0.30，低质量证据）。二甲双胍与死亡或严重发病综合结局的降低相关（RR 0.54，95% CI 0.31至0.94；一项研究，159名婴儿，低质量证据）。在新生儿低血糖方面，两组之间没有明显差异（RR 0.86，95% CI 0.42至1.77；四项研究，554名婴儿，低质量证据）或围产期死亡率（RR 0.92，95% CI 0.06至14.55，两项研究，359名婴儿）。没有报告儿童期后期神经感觉残疾或肥胖或糖尿病的数据。格列本脲与阿卡波糖相比：一项研究（43名女性）中，在任何孕产妇或婴儿主要结局方面，没有证据表明格列本脲与阿卡波糖之间存在差异（剖宫产，RR 0.95，95% CI 0.53至1.70；低质量证据；围产期死亡率 - 无事件发生；低质量证据；LGA，RR至10.46；低质量证据）。在新生儿低血糖方面，没有证据表明格列本脲与阿卡波糖之间存在差异（RR 6.33，95% CI 0.87至46.32；低质量证据）。没有报告其他预先指定的GRADE或主要孕产妇结局（妊娠期高血压疾病、2型糖尿病的发生、会阴创伤、恢复孕前体重、产后抑郁、引产）或新生儿结局（死亡或严重发病综合结局、肥胖或糖尿病）的数据。
将口服抗糖尿病药物疗法与安慰剂/标准治疗（生活方式建议）进行比较的数据不足，无法为临床实践提供信息。由于本综述中主要和次要结局的数据报告有限，没有足够的高质量证据能够就一种口服抗糖尿病药物疗法相对于另一种疗法的益处得出任何有意义的结论。本综述的短期和长期临床结局报告不充分或未报告。目前口服抗糖尿病药物疗法的选择似乎基于临床偏好、可获得性和国家临床实践指南。一种口服抗糖尿病药物疗法与另一种疗法相比，或与安慰剂/标准治疗相比的益处和潜在危害仍不清楚，需要进一步研究。未来的试验应尝试报告本综述中建议的核心结局，特别是迄今为止报告不足的女性和婴儿的长期结局、女性的经历以及成本效益。
