Showell Marian G, Mackenzie-Proctor Rebecca, Jordan Vanessa, Hart Roger J
Department of Obstetrics and Gynaecology, University of Auckland, Park Road Grafton, Auckland, New Zealand, 1142.
Cochrane Database Syst Rev. 2017 Jul 28;7(7):CD007807. doi: 10.1002/14651858.CD007807.pub3.
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.
We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers.
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria.
We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant.Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn.Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
AUTHORS' CONCLUSIONS: In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
如果一对夫妇尝试受孕超过一年仍未成功，可认为他们存在生育问题。这可能影响多达四分之一计划要孩子的夫妇。据估计，40%至50%的夫妇生育力低下可能是由影响女性的因素导致的。抗氧化剂被认为可以减轻这些情况所带来的氧化应激。目前，有限的证据表明抗氧化剂可提高生育力，相关试验对该领域的探索结果各异。本综述评估不同抗氧化剂对女性生育力低下有效性的证据。
确定与安慰剂、不治疗/标准治疗或另一种抗氧化剂相比，补充口服抗氧化剂是否能改善生育力低下女性的生育结局。
我们检索了以下数据库（从创建至2016年9月），无语言或日期限制：Cochrane妇科与生育组（CGFG）专业注册库、Cochrane系统评价中心注册库（CENTRAL CRSO）、MEDLINE、Embase、PsycINFO、CINAHL和AMED。我们检查了相关研究的参考文献列表，并在临床试验注册库中搜索正在进行的试验。
我们纳入了随机对照试验（RCT），这些试验比较了在生殖诊所就诊的女性中，任何类型、剂量或组合的口服抗氧化剂补充剂与安慰剂、不治疗或另一种抗氧化剂治疗。我们排除了仅比较抗氧化剂与生育药物的试验，以及仅纳入因男性伴侣不育而在生育诊所就诊的可育女性的试验。
两位综述作者独立选择符合条件的研究，提取数据并评估纳入研究的偏倚风险。主要综述结局是活产；次要结局包括临床妊娠率和不良事件。我们使用固定效应模型对研究进行合并，并计算活产、临床妊娠和不良事件二分结局的比值比（OR）及95%置信区间（CI）。我们应用GRADE标准评估证据的总体质量。
我们纳入了50项试验，涉及6510名女性。研究者比较了口服抗氧化剂，包括抗氧化剂组合、N-乙酰半胱氨酸、褪黑素、L-精氨酸、肌醇、D-手性肌醇、肉碱、硒、维生素E、复合维生素B、维生素C、维生素D+钙、辅酶Q10、己酮可可碱和ω-3多不饱和脂肪酸与安慰剂、不治疗/标准治疗或另一种抗氧化剂。极低质量的证据表明，与安慰剂或不治疗/标准治疗相比，抗氧化剂可能与活产率增加相关（OR 2.13，95%CI 1.45至3.12，P>0.001，8项RCT，651名女性，I=47%）。这表明，在预期活产率为20%的生育力低下女性中，使用抗氧化剂的女性活产率在26%至43%之间。极低质量的证据表明，与安慰剂或不治疗/标准治疗相比，抗氧化剂可能与临床妊娠率增加相关（OR 1.52，95%CI 1.31至1.76，P<0.001，26项RCT，4271名女性，I=66%）。这表明，在预期临床妊娠率为22%的生育力低下女性中，使用抗氧化剂的女性临床妊娠率在27%至33%之间。异质性中等偏高。没有足够的证据确定两组在流产率上是否存在差异（OR 0.79，95%CI 0.58至1.08，P=0.14，18项RCT，2834名女性，I=23%，极低质量证据）。这表明，在预期流产率为7%的生育力低下女性中，使用抗氧化剂预计会导致流产率在4%至7%之间。也没有足够的证据确定两组在多胎妊娠率上是否存在差异（OR 1.00，95%CI 0.73至1.38，P=0.98，8项RCT，2163名女性，I=4%，极低质量证据）。这表明，在预期多胎妊娠率为8%的生育力低下女性中，使用抗氧化剂预计会导致多胎妊娠率在6%至11%之间。同样，没有足够的证据确定两组在胃肠道紊乱率上是否存在差异（OR 1.55，95%CI 0.47至5.10，P=0.47，3项RCT，343名女性，I=0%，极低质量证据）。这表明，在预期胃肠道紊乱率为2%的生育力低下女性中，使用抗氧化剂预计会导致紊乱率在1%至11%之间。荟萃分析中有35项试验报告了总体不良事件，但没有足够的证据得出任何结论。只有一项试验报告了抗氧化剂与抗氧化剂比较中的活产、临床妊娠或不良反应情况，无法得出结论。极低质量的证据表明，与安慰剂或不治疗相比，己酮可可碱可能与临床妊娠率增加相关（OR 2.07，95%CI 1.20至3.56，P=0.009，3项RCT，276名女性，I=0%）。这表明，在预期临床妊娠率为25%的生育力低下女性中，使用己酮可可碱的女性临床妊娠率在28%至53%之间。没有足够的证据确定两组在流产率（OR 1.34，95%CI 0.46至3.90，P=0.58，3项RCT，276名女性，I=0%）或多胎妊娠率（OR 0.78，95%CI 0.20至3.09，一项RCT，112名女性，极低质量证据）上是否存在差异。这表明，在预期流产率为4%的生育力低下女性中
