Prophylactic use of inotropic agents for the prevention of low cardiac output syndrome and mortality in adults undergoing cardiac surgery.

As the burden of cardiovascular disease grows, so does the number of cardiac surgeries. Surgery is increasingly performed on older people with comorbidities who are at higher risk of developing perioperative complications such as low cardiac output state (LCOS). Surgery-associated LCOS represents a serious pathology responsible for substantial morbidity and mortality. Prevention of LCOS is a critical and worthwhile aim to further improve the outcome and effectiveness of cardiac surgery. However, guidelines consistently report a lack of evidence for pharmacological LCOS prophylaxis. To assess the benefits and harms of the prophylactic use of any inotropic agent to prevent low cardiac output and associated morbidity and mortality in adults undergoing cardiac surgery. We identified trials (without language restrictions) via systematic searches of CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in October 2022. We checked reference lists from primary studies and review articles for additional references. We also searched two registers of ongoing trials. We included randomised controlled trials (RCTs) enrolling adults who underwent cardiac surgery and were prophylactically treated with one or multiple inotropic agent(s) in comparison to any type of control (i.e. standard cardiac care, placebo, other inotropic agents). We used established methodological procedures according to Cochrane standards. Two review authors independently extracted data and assessed risk of bias according to a pre-defined protocol. On request, we obtained a reply and additional information from only one of the included study authors. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence from the studies that contributed data to the meta-analyses for the pre-specified outcomes. Based on the identified studies, there were seven comparison groups: amrinone versus placebo, dopamine versus placebo, milrinone versus placebo, levosimendan versus dobutamine, levosimendan versus milrinone, levosimendan versus standard cardiac care, and levosimendan versus placebo. We identified 29 eligible studies, including 3307 individuals, and four ongoing studies. In general, confidence in the results of the analysed studies was reduced due to relevant study limitations, imprecision, or inconsistency. Domains of concern encompassed inadequate methods of sequence generation and lack of blinding. The majority of trials were small, with only a few included participants, and investigated the prophylactic use of levosimendan. Our meta-analyses showed that levosimendan as compared to placebo may reduce the risk of LCOS (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.25 to 0.74; I2 = 66%; 1724 participants, 6 studies; GRADE: low) and probably reduces all-cause mortality (RR 0.65, 95% CI 0.43 to 0.97; I2 = 11%; 2347 participants, 14 studies; GRADE: moderate). This translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 to prevent one event of LCOS post surgery and of 44 to prevent one death at 30 days. Subgroup analyses revealed that the beneficial effects of levosimendan were predominantly observed in preoperative drug administration. Our meta-analyses further indicated that levosimendan as compared to placebo may shorten the length of intensive care unit (ICU) stay (mean difference -1.00 days, 95% CI -1.63 to -0.37; 572 participants, 7 studies; GRADE: very low) and the duration of mechanical ventilation (mean difference -8.03 hours, 95% CI -13.17 to -2.90; 572 participants, 7 studies; GRADE: very low) but the evidence is very uncertain. The risk of adverse events did not clearly differ between levosimendan and placebo groups (cardiogenic shock: RR 0.65, 95% CI 0.40 to 1.05; I2 = 0%; 1212 participants, 3 studies; GRADE: high; atrial fibrillation: RR 1.02, 95% CI 0.82 to 1.27; I2 = 60%; 1934 participants, 11 studies; GRADE: very low; perioperative myocardial infarction: RR 0.89, 95% CI 0.61 to 1.31; I2 = 13%; 1838 participants, 8 studies; GRADE: moderate; non-embolic stroke or transient ischaemic attack: RR 0.89, 95% CI 0.58 to 1.38; I2 = 0%; 1786 participants, 8 studies; GRADE: moderate). However, levosimendan as compared to placebo might reduce the number of participants requiring mechanical circulatory support (RR 0.47, 95% CI 0.24 to 0.91; I2 = 74%; 1881 participants, 10 studies; GRADE: low). There was no conclusive evidence on the effect of levosimendan compared to standard cardiac care on LCOS (RR 0.49, 95% CI 0.14 to 1.73; I2 = 59%; 208 participants, 3 studies; GRADE: very low), all-cause mortality (RR 0.37, 95% CI 0.13 to 1.04; I2 = 0%; 208 participants, 3 studies; GRADE: low), adverse events (cardiogenic shock: RR 0.62, 95% CI 0.22 to 1.81; 128 participants, 1 study; GRADE: very low; atrial fibrillation: RR 0.40, 95% CI 0.11 to 1.41; I2 = 60%; 188 participants, 2 studies; GRADE: very low; perioperative myocardial infarction: RR 0.62, 95% CI 0.22 to 1.81; 128 participants, 1 study; GRADE: very low; non-embolic stroke or transient ischaemic attack: RR 0.56, 95% CI 0.27 to 1.18; 128 participants, 1 study; GRADE: very low), length of ICU stay (mean difference 0.33 days, 95% CI -1.16 to 1.83; 80 participants, 2 studies; GRADE: very low), the duration of mechanical ventilation (mean difference -3.40 hours, 95% CI -11.50 to 4.70; 128 participants, 1 study; GRADE: very low), and the number of participants requiring mechanical circulatory support (RR 0.88, 95% CI 0.50 to 1.55; I2 = 0%; 208 participants, 3 studies; GRADE: low). Prophylactic treatment with levosimendan may reduce the incidence of LCOS and probably reduces associated mortality in adult patients undergoing cardiac surgery when compared to placebo only. Conclusions on the benefits and harms of other inotropic agents cannot be drawn due to limited study data. Given the limited evidence available, there is an unmet need for large-scale, well-designed randomised trials. Future studies of levosimendan ought to be designed to derive potential benefit in specific patient groups and surgery types, and the optimal administration protocol.

Gayatri D ，Tongers J ，Efremov L ，Mikolajczyk R ，Sedding D ，Schumann J ... -  《Cochrane Database of Systematic Reviews》

Inotropes for the prevention of low cardiac output syndrome and mortality for paediatric patients undergoing surgery for congenital heart disease: a network meta-analysis.

Paediatric patients undergoing surgery for congenital heart disease (CHD) are at risk for postoperative low cardiac output syndrome (LCOS) and mortality. LCOS affects up to 25% of children after heart surgery. It consists of reduced myocardial function and increases postoperative morbidity, prolongs mechanical ventilation, and lengthens the duration of intensive care unit (ICU) stay. Pharmacological prophylaxis involves inotropes, including catecholamines, phosphodiesterase III inhibitors, or calcium sensitisers, to enhance myocardial contractility. It is unclear whether they are effective in preventing LCOS or death in this vulnerable population. 1. To evaluate the relative benefits and harms of inotropes for the prevention of LCOS and mortality in paediatric patients undergoing surgery for CHD. 2. To generate a clinically useful ranking of prophylactic inotropes for the prevention of LCOS and mortality in paediatric patients undergoing surgery for CHD according to benefits and harms. We searched CENTRAL, MEDLINE, Embase, Web of Science, and clinical trial registries, most recently in December 2023 and April 2024. We also checked reference lists from identified studies and review articles. We did not apply any language restrictions. We included randomised controlled trials comparing inotropes from one drug class (catecholamines, phosphodiesterase type III inhibitors, calcium sensitisers) to another (either alone or in combination) or placebo, in paediatric patients (birth to 18 years of age) undergoing surgery for CHD. Two review authors independently selected studies, extracted data, assessed risk of bias, and rated the certainty of evidence using the CINeMA framework. We performed random-effects network and pairwise meta-analyses comparing the relative effects of each possible pair of medications with each other or placebo. Where meta-analysis was not possible, we provided a narrative description of the results. We ranked the prophylactic medications according to their effects relative to each other. The primary outcomes were all-cause mortality within 30 days, time to death, and LCOS incidence; secondary outcomes were length of ICU stay, length of hospital stay, duration of mechanical ventilation, inotrope score, mechanical circulatory support, and adverse events. We included 13 studies with 937 participants. All except two multicentre studies were conducted at single tertiary care hospitals. Participants comprised children from birth to 14 years of age undergoing surgery for different types of CHD on cardiopulmonary bypass. Five studies compared levosimendan versus milrinone; two compared levosimendan versus placebo; two compared milrinone versus placebo (one comparing two different doses); one compared levosimendan versus dobutamine, another milrinone versus dobutamine. Two studies used combinations of inotropes. Study duration was between less than one year and 5.3 years, with follow-up mostly during ICU or hospital stay. Funding sources included governmental bodies and hospital departments, but also drug manufacturers. We downgraded the certainty of evidence for high risk of bias at study level, or imprecision at comparison level. Primary outcomes Compared to placebo, levosimendan likely results in a large reduction in mortality (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.15 to 2.13) and milrinone likely results in no difference (RR 0.97, 95% CI 0.11 to 8.49), whereas for dobutamine, no effect was estimable; all moderate-certainty evidence (9 studies, 557 participants, 14 events). LCOS was largely reduced with levosimendan (RR 0.45, 95% CI 0.24 to 0.83; high-certainty evidence), likely largely reduced with milrinone (RR 0.46, 95% CI 0.24 to 0.89; moderate-certainty evidence), and may be reduced with low-dose milrinone (RR 0.7, 95% CI 0.39 to 1.28; low-certainty evidence), compared with placebo (5 studies, 513 participants, 85 events). Secondary outcomes The length of ICU stay may be no different with levosimendan (ratio of means (ROM) 1.12, 95% CI 0.77 to 1.63; low-certainty evidence), and is likely no different with milrinone (ROM 1.13, 95% CI 0.75 to 1.69) or with dobutamine (ROM 1.11, 95% CI 0.66 to 1.86), compared with placebo (9 studies, 577 participants); both moderate-certainty evidence. The length of hospital stay, compared with placebo, is likely no different with levosimendan (ROM 1.03, 95% CI 0.84 to 1.27) or with milrinone (ROM 1, 95% CI 0.78 to 1.3), but is likely reduced with dobutamine (ROM 0.68, 95% CI 0.37 to 1.26); all moderate-certainty evidence (7 studies, 297 participants). The duration of mechanical ventilation, compared with placebo, is likely increased with levosimendan (ROM 1.17, 95% CI 0.65 to 2.12) or with milrinone (ROM 1.25, 5% CI 0.67 to 2.36) and is likely no different with dobutamine (ROM 1.04, 95% CI 0.45 to 2.38); all moderate-certainty evidence (9 studies, 577 participants). There is moderate-certainty evidence that adverse events are likely increased with levosimendan (incidence rate ratio (IRR) 1.23, 95% CI 0.78 to 1.96) or dobutamine (IRR 1.24, 95% CI 0.75 to 2.03) and low-certainty evidence that they may be increased with milrinone (IRR 1.31, 95% CI 0.96 to 1.79) and decreased with low-dose milrinone (IRR 0.84, 95% CI 0.47 to 1.5), compared with placebo (8 studies, 706 participants, 380 events). Levosimendan likely results in a large reduction in mortality compared to placebo in paediatric patients undergoing surgery for congenital heart disease, whereas milrinone likely results in no difference, and the effect of dobutamine is unknown. Low cardiac output syndrome (LCOS) is largely reduced with levosimendan, likely largely reduced with milrinone, and may be reduced with low-dose milrinone, compared to placebo. The length of ICU stay may be no different with levosimendan and is likely no different with milrinone or with dobutamine, compared to placebo. The length of hospital stay is likely no different with levosimendan or with milrinone, but is likely reduced with dobutamine, compared to placebo. The duration of mechanical ventilation is likely increased with levosimendan or with milrinone and is likely no different with dobutamine, compared to placebo. Adverse events are likely increased with levosimendan or dobutamine, and may be increased with milrinone and decreased with low-dose milrinone, compared to placebo. The evidence is based on few, heterogeneous studies, with small numbers of patients and short follow-up periods. Future research should include large numbers of patients, consistently report all co-interventions, and ensure the longest possible follow-up.

Burkhardt BE ，Hummel J ，Rücker G ，Stiller B ... -  《-》

Interventions to prevent surgical site infection in adults undergoing cardiac surgery.

Surgical site infection (SSI) is a common type of hospital-acquired infection and affects up to a third of patients following surgical procedures. It is associated with significant mortality and morbidity. In the United Kingdom alone, it is estimated to add another £30 million to the cost of adult cardiac surgery. Although generic guidance for SSI prevention exists, this is not specific to adult cardiac surgery. Furthermore, many of the risk factors for SSI are prevalent within the cardiac surgery population. Despite this, there is currently no standard of care for SSI prevention in adults undergoing cardiac surgery throughout the preoperative, intraoperative and postoperative periods of care, with variations in practice existing throughout from risk stratification, decontamination strategies and surveillance. Primary objective: to assess the clinical effectiveness of pre-, intra-, and postoperative interventions in the prevention of cardiac SSI. (i) to evaluate the effects of SSI prevention interventions on morbidity, mortality, and resource use; (ii) to evaluate the effects of SSI prevention care bundles on morbidity, mortality, and resource use. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (Ovid, from inception) and Embase (Ovid, from inception) on 31 May 2021. gov and the WHO International Clinical Trials Registry Platform (ICTRP) were also searched for ongoing or unpublished trials on 21 May 2021. No language restrictions were imposed. We included RCTs evaluating interventions to reduce SSI in adults (≥ 18 years of age) who have undergone any cardiac surgery. We followed the methods as per our published Cochrane protocol. Our primary outcome was surgical site infection. Our secondary outcomes were all-cause mortality, reoperation for SSI, hospital length of stay, hospital readmissions for SSI, healthcare costs and cost-effectiveness, quality of life (QoL), and adverse effects. We used the GRADE approach to assess the certainty of evidence. A total of 118 studies involving 51,854 participants were included. Twenty-two interventions to reduce SSI in adults undergoing cardiac surgery were identified. The risk of bias was judged to be high in the majority of studies. There was heterogeneity in the study populations and interventions; consequently, meta-analysis was not appropriate for many of the comparisons and these are presented as narrative summaries. We focused our reporting of findings on four comparisons deemed to be of great clinical relevance by all review authors. Decolonisation versus no decolonisation Pooled data from three studies (n = 1564) using preoperative topical oral/nasal decontamination in all patients demonstrated an uncertain direction of treatment effect in relation to total SSI (RR 0.98, 95% CI 0.70 to 1.36; I2 = 0%; very low-certainty evidence). A single study reported that decolonisation likely results in little to no difference in superficial SSI (RR 1.35, 95% CI 0.84 to 2.15; moderate-certainty evidence) and a reduction in deep SSI (RR 0.36, 95% CI 0.17 to 0.77; high-certainty evidence). The evidence on all-cause mortality from three studies (n = 1564) is very uncertain (RR 0.66, 95% CI 0.24 to 1.84; I2 = 49%; very low-certainty evidence). A single study (n = 954) demonstrated that decolonisation may result in little to no difference in hospital readmission for SSI (RR 0.80, 95% CI 0.44 to 1.45; low-certainty evidence). A single study (n = 954) reported one case of temporary discolouration of teeth in the decolonisation arm (low-certainty-evidence. Reoperation for SSI was not reported. Tight glucose control versus standard glucose control Pooled data from seven studies (n = 880) showed that tight glucose control may reduce total SSI, but the evidence is very uncertain (RR 0.41, 95% CI 0.19 to 0.85; I2 = 29%; numbers need to treat to benefit (NNTB) = 13; very-low certainty evidence). Pooled data from seven studies (n = 3334) showed tight glucose control may reduce all-cause mortality, but the evidence is very uncertain (RR 0.61, 95% CI 0.41 to 0.91; I2 = 0%; very low-certainty evidence). Based on four studies (n = 2793), there may be little to no difference in episodes of hypoglycaemia between tight control vs. standard control, but the evidence is very uncertain (RR 2.12, 95% CI 0.51 to 8.76; I2 = 72%; very low-certainty evidence). No studies reported superficial/deep SSI, reoperation for SSI, or hospital readmission for SSI. Negative pressure wound therapy (NPWT) versus standard dressings NPWT was assessed in two studies (n = 144) and it may reduce total SSI, but the evidence is very uncertain (RR 0.17, 95% CI 0.03 to 0.97; I2 = 0%; NNTB = 10; very low-certainty evidence). A single study (n = 80) reported reoperation for SSI. The relative effect could not be estimated. The certainty of evidence was judged to be very low. No studies reported superficial/deep SSI, all-cause mortality, hospital readmission for SSI, or adverse effects. Topical antimicrobials versus no topical antimicrobials Five studies (n = 5382) evaluated topical gentamicin sponge, which may reduce total SSI (RR 0.62, 95% CI 0.46 to 0.84; I2 = 48%; NNTB = 32), superficial SSI (RR 0.60, 95% CI 0.37 to 0.98; I2 = 69%), and deep SSI (RR 0.67, 95% CI 0.47 to 0.96; I2 = 5%; low-certainty evidence. Four studies (n = 4662) demonstrated that topical gentamicin sponge may result in little to no difference in all-cause mortality, but the evidence is very uncertain (RR 0.96, 95% CI 0.65 to 1.42; I2 = 0%; very low-certainty evidence). Reoperation for SSI, hospital readmission for SSI, and adverse effects were not reported in any included studies. This review provides the broadest and most recent review of the current evidence base for interventions to reduce SSI in adults undergoing cardiac surgery. Twenty-one interventions were identified across the perioperative period. Evidence is of low to very low certainty primarily due to significant heterogeneity in how interventions were implemented and the definitions of SSI used. Knowledge gaps have been identified across a number of practices that should represent key areas for future research. Efforts to standardise SSI outcome reporting are warranted.

Cardiothoracic Interdisciplinary Research Network ，Rogers LJ ，Vaja R ，Bleetman D ，Ali JM ，Rochon M ，Sanders J ，Tanner J ，Lamagni TL ，Talukder S ，Quijano-Campos JC ，Lai F ，Loubani M ，Murphy GJ ... -  《Cochrane Database of Systematic Reviews》

Fenoldopam for preventing and treating acute kidney injury.

Fenoldopam is a short-acting benzazepine selective dopaminergic A1 (DA1) receptor agonist with increased activity at the D1 receptor compared with dopamine. Activation of the DA1 receptors increases kidney blood flow because of dilatation of the afferent and efferent arterioles. Previous reviews have been published on the efficacy and safety of fenoldopam for acute kidney injury (AKI); however, they either combined data on its effect on both prevention and treatment of AKI, focused on only those undergoing cardiac surgery and/or excluded children. This review aimed to assess the benefits and harms of fenoldopam for the prevention or treatment of AKI in children and adults. We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) evaluating fenoldopam for the prevention or treatment of AKI in children and adults following surgery, radiocontrast exposure or sepsis. Two authors independently assessed studies for eligibility, assessed the studies for risk of bias and extracted data from the studies. Dichotomous outcomes were presented as relative risk (RR) with 95% confidence intervals (CI). For continuous outcomes, the mean difference (MD) with 95% CI was used. Statistical analysis was performed using the random-effects model. We assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We identified 25 RCTs, including 3339 randomised participants. Twenty-three studies used fenoldopam for preventing AKI and two for the treatment of AKI. Nine studies included participants undergoing cardiac surgery, and one included children. The risks of bias for sequence generation and concealment were low in 11 and 13 studies, respectively. Only 13 and 18 studies were at low risk of performance bias and detection bias, respectively. The risk of attrition bias and selective reporting were judged to be at low risk of bias in 17 and 10 studies, respectively. We included data in the meta-analyses from eight of the 14 studies comparing fenoldopam with placebo or saline, all six studies comparing fenoldopam with dopamine, all five studies comparing fenoldopam with N-acetylcysteine (NAC) for the prevention of AKI and from the two studies comparing fenoldopam with placebo or saline for the treatment of AKI. Compared with placebo or saline fenoldopam probably results in fewer participants developing AKI (RR 0.72, 95% CI 0.53 to 0.98; 8 studies, 1147 participants; I2 = 48%; moderate certainty) but may make little or no difference to the number requiring kidney replacement therapy (KRT) (RR 0.81, 95% CI 0.31 to 2.15; 7 studies, 835 participants; I2 = 17%), risk of death (RR 0.76, 95% CI: 0.58 to 1.00; 7 studies, 944 participants; I2 = 0%) or change in urine output (SMD 0.20, 95% CI -0.44 to 0.84; 2 studies, 58 participants; I2 = 34%; all low certainty). Fenoldopam may result in a shorter stay in the ICU (MD -1.81 days; 95% CI -2.41 to -1.21; 4 studies, 403 participants; I2 = 0%). It is uncertain whether adverse events (hypotension, myocardial infarction, drug intolerance, cardiac arrhythmias) differed between the treatment groups as the certainty of the evidence was very low. In patients undergoing cardiac surgery, fenoldopam, compared to placebo or saline, may make little or no difference to the prevention of AKI, the need for KRT or death. Compared with dopamine, fenoldopam may make little or no difference to the prevention of AKI (RR 0.62, 95% CI 0.23 to 1.68; 4 studies, 398 participants; I2 = 78%), the number requiring KRT (RR 0.74, 95% CI 0.29 to 1.87; 4 studies, 434 participants; I2 = 0%) or the risk of death (RR 1.27, 95% CI 0.36 to 4.50; 2 studies, 174 participants; I2 = 0%) (all low certainty). It is uncertain whether participants receiving fenoldopam were more likely to develop hypotension compared with those receiving dopamine (RR 3.00, 95% CI 1.06 to 8.52; 1 study, 80 participants; very low certainty). Change in urine output was not reported. It is uncertain whether fenoldopam compared with NAC prevents AKI (RR 1.68, 95% CI 0.79 to 3.56; 3 studies, 359 participants; I2 = 38%), reduces the need for KRT (RR 0.96, 95% CI 0.15 to 6.26; 2 studies, 137 participants; I2 = 0%), or the risk of death (RR 1.05, 95% CI 0.07 to 15.66; 1 study, 39 participants) (all very low certainty). It is uncertain whether hypotension was more frequent with fenoldopam (RR 5.10, 95% CI 0.25, 104.94; 1 study, 192 participants; very low certainty). Change in urine output was not reported. In participants with established AKI, it is uncertain whether fenoldopam compared to placebo or half saline reduces the numbers needing KRT (RR: 0.91, 95% CI 0.54 to 1.54; 2 studies, 822 participants; I2 = 58%; very low certainty) or the risk of death (RR 0.81, 95% CI 0.44 to 1.48; 2 studies, 822 participants; I2 = 66%; very low certainty), or if it increases the risk of hypotension (RR 1.65, 95% CI 1.22 to 2.22; 2 studies, 822 participants; I2 = 0%; very low certainty). Fenoldopam administration in patients at risk of AKI is probably associated with a lower risk of developing AKI and shorter ICU stay when compared with placebo or saline, but has little or no effect on the need for KRT or the risk of death. In those undergoing cardiac surgery, fenoldopam may not confer any benefits compared with placebo or saline. Furthermore, it remains unclear whether fenoldopam is more or less effective than either dopamine or NAC in reducing the risk for AKI or the need for KRT. Further well-designed and adequately powered studies are required to evaluate the efficacy and safety of fenoldopam in preventing or treating AKI.

Esezobor CI ，Bhatt GC ，Effa EE ，Hodson EM ... -  《Cochrane Database of Systematic Reviews》

Antioxidants for female subfertility.

M.G. Showell, R. Mackenzie‐Proctor, V. Jordan, and R.J. Hart, “Antioxidants for Female Subfertility,” Cochrane Database of Systematic Reviews, no. 8 (2020): CD007807, https://doi.org/10.1002/14651858.CD007807.pub4 This Editorial Note is for the above article, published online on August 27, 2020, in Cochrane Library (cochranelibrary.com), and has been issued by the Publisher, John Wiley & Sons Ltd, in agreement with Cochrane. The Editorial note has been agreed due to concerns discovered by the Cochrane managing editor regarding the retraction of six studies in the Review (Badawy et al. 2006, 10.1016/j.fertnstert.2006.02.097; El Refaeey et al. 2014, 10.1016/j.rbmo.2014.03.011; El Sharkwy & Abd El Aziz 2019a, https://doi.org/10.1002/ijgo.12902; Gerli et al. 2007, https://doi.org/10.26355/eurrev_202309_33752, full text: https://europepmc.org/article/MED/18074942; Ismail et al. 2014, http://dx.doi.org/10.1016/j.ejogrb.2014.06.008; Hashemi et al. 2017, https://doi.org/10.1080/14767058.2017.1372413). In addition, expressions of concern have been published for two studies (Jamilian et al. 2018, https://doi.org/10.1007/s12011-017-1236-3; Zadeh Modarres 2018, https://doi.org/10.1007/s12011-017-1148-2). The retracted studies will be moved to the Excluded Studies table, and their impact on the review findings will be investigated and acted on accordingly in a future update. Initial checks indicate that removal of the six retracted studies did not make an appreciable difference to the results. Likewise, the studies for which Expressions of Concern were issued will be moved to the Awaiting classification table; they did not report any review outcomes, so removal will have no impact on the review findings. 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 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial 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. We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Showell MG ，Mackenzie-Proctor R ，Jordan V ，Hart RJ ... -  《Cochrane Database of Systematic Reviews》