Sympathetic nerve blocks for persistent pain in adults with inoperable abdominopelvic cancer.

BACKGROUND: Persistent visceral pain is an unpleasant sensation coming from one or more organs within the body. Visceral pain is a common symptom in those with advanced cancer. Interventional procedures, such as neurolytic sympathetic nerve blocks, have been suggested as additional treatments that may play a part in optimising pain management for individuals with this condition. OBJECTIVES: To evaluate the benefits and harms of neurolytic sympathetic nerve blocks for persistent visceral pain in adults with inoperable abdominopelvic cancer compared to standard care or placebo and comparing single blocks to combination blocks. SEARCH METHODS: We searched the following databases without language restrictions on 19 October 2022 and ran a top-up search on 31 October 2023: CENTRAL; MEDLINE via Ovid; Embase via Ovid; LILACS. We searched trial registers without language restrictions on 2 November 2022: ClinicalTrials.gov; WHO International Clinical Trials Registry Platform (ICTRP). We searched grey literature, checked reference lists of reviews and retrieved articles for additional studies, and performed citation searches on key articles. We also contacted experts in the field for unpublished and ongoing trials. Our trial protocol was preregistered in the Cochrane Database of Systematic Reviews on 21 October 2022. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) comparing any sympathetic nerve block targeting sites commonly used to treat abdominal pelvic pain from inoperable malignancies in adults to standard care or placebo. DATA COLLECTION AND ANALYSIS: We independently selected trials based on predefined inclusion criteria, resolving any differences via adjudication with a third review author. We used a random-effects model as some heterogeneity was expected between the studies due to differences in the interventions being assessed and malignancy types included in the study population. We chose three primary outcomes and four secondary outcomes of interest. We sought consumer input to refine our review outcomes and assessed extracted data using Cochrane's risk of bias 2 tool (RoB 2). We assessed the certainty of evidence using the GRADE system. MAIN RESULTS: We included 17 studies with 1025 participants in this review. Fifteen studies with a total of 951 participants contributed to the quantitative analysis. Single block versus standard care Primary outcomes No included studies reported our primary outcome, 'Proportion of participants reporting no worse than mild pain after treatment at 14 days'. The evidence is very uncertain about the effect of sympathetic nerve blocks on reducing pain to no worse than mild pain at 14 days when compared to standard care due to insufficient data (very low-certainty evidence). Sympathetic nerve blocks may provide small to 'little to no' improvement in quality of life (QOL) scores at 14 days after treatment when compared to standard care, but the evidence is very uncertain (standardised mean difference (SMD) -0.73, 95% confidence interval (CI) -1.70 to 0.25; I² = 87%; 4 studies, 150 participants; very low-certainty evidence). The evidence is very uncertain about the risk of serious adverse events as defined in our review as only one study contributed data to this outcome. Sympathetic nerve blocks may have an 'increased risk' to 'no additional risk' of harm compared with standard care (very low-certainty evidence). Secondary outcomes Sympathetic nerve blocks showed a small to 'little to no' effect on participant-reported pain scores at 14 days using a 0 to 10 visual analogue scale (VAS) for pain compared with standard care, but the evidence is very uncertain (mean difference (MD) -0.44, 95% CI -0.98 to 0.11; I² = 56%; 5 studies, 214 participants; very low-certainty evidence). There may be a 'moderate to large' to 'little to no' reduction in daily consumption of opioids postprocedure at 14 days with sympathetic nerve blocks compared with standard care, but the evidence is very uncertain (change in daily consumption of opioids at 14 days as oral milligrams morphine equivalent (MME): MD -41.63 mg, 95% CI -78.54 mg to -4.72 mg; I² = 90%; 4 studies, 130 participants; very low-certainty evidence). The evidence is very uncertain about the effect of sympathetic nerve blocks on participant satisfaction with procedure at 0 to 7 days and time to need for retreatment or treatment effect failure (or both) due to insufficient data. Combination block versus single block Primary outcomes There is no evidence about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks on the proportion of participants reporting no worse than mild pain after treatment at 14 days because no studies reported this outcome. There may be a small to 'little to no' effect on QOL score at 14 days after treatment, but the evidence is very uncertain (very low-certainty evidence). The evidence is very uncertain about the risk of serious adverse events with combination sympathetic nerve blocks compared with single sympathetic nerve blocks due to limited reporting in the included studies (very low-certainty evidence). Secondary outcomes The evidence is very uncertain about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks on participant-reported pain score and change in daily consumption of opioids postprocedure, at 14 days. There may be a small to 'little to no' effect, but the evidence is very uncertain (very low-certainty evidence). There is no evidence about the effect on participant satisfaction with procedure at 0 to 7 days and time to need for retreatment or treatment effect failure (or both) due to these outcomes not being measured by the studies. Risk of bias The risk of bias was predominately high for most outcomes in most studies due to significant concerns regarding adequate blinding. Very few studies were deemed as low risk across all domains for any outcome. AUTHORS' CONCLUSIONS: There is limited evidence to support or refute the use of sympathetic nerve blocks for persistent abdominopelvic pain due to inoperable malignancy. We are very uncertain about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks. The certainty of the evidence is very low and these findings should be interpreted with caution.

Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.

BACKGROUND: Coagulopathy following cardiac surgery is associated with considerable blood product transfusion and high morbidity and mortality. The treatment of coagulopathy following cardiac surgery is challenging, with the replacement of clotting factors being based on transfusion of fresh frozen plasma (FFP). Prothrombin complex concentrate (PCCs) is an alternative method to replace clotting factors and warrants evaluation. PCCs are also an alternative method to treat refractory ongoing bleeding post-cardiac surgery compared to recombinant factor VIIa (rFVIIa) and also warrants evaluation.   OBJECTIVES: Assess the benefits and harms of PCCs in people undergoing cardiac surgery who have coagulopathic non-surgical bleeding. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase and Conference Proceedings Citation Index-Science (CPCI-S) on the Web of Science on 20 April 2021. We searched Clinicaltrials.gov (www. CLINICALTRIALS: gov), and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/), for ongoing or unpublished trials. We checked the reference lists for additional references. We did not limit the searches by language or publication status. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised trials (NRSs).  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.   MAIN RESULTS: Eighteen studies were included  (4993 participants). Two were RCTs (151 participants) and 16 were NRSs. Both RCTs had low risk of bias (RoB) in almost all domains. Of the 16 NRSs, 14 were retrospective cohort analyses with one prospective study and one case report. The nine studies used in quantitative analysis were judged to have critical RoB, three serious and three moderate.   1. PCC versus standard treatment Evidence from RCTs showed PCCs are likely to reduce the number of units transfused compared to standard care (MD -0.89, 95% CI -1.78 to 0.00; participants = 151; studies = 2; moderate-quality evidence). Evidence from NRSs agreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (MD -1.87 units, 95% CI -2.53 to -1.20; participants = 551; studies = 2; very low-quality evidence). There was no evidence from RCTs showing a difference in the incidence of red blood cell (RBC) transfusion compared to standard care (OR 0.53, 95% CI 0.20 to 1.40; participants = 101; studies = 1; low-quality evidence). Evidence from NRSs disagreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (OR 0.54, 95% CI 0.30 to 0.98; participants = 1046; studies = 4; low-quality evidence). There was no evidence from RCTs showing a difference in the number of thrombotic events with PCC compared to standard care (OR 0.68 95% CI 0.20 to 2.31; participants = 152; studies = 2; moderate-quality evidence). This is supported by NRSs, showing that PCCs may have no effect on the number of thrombotic events compared to standard care but the evidence is very uncertain (OR 1.32, 95% CI 0.87 to 1.99; participants = 1359; studies = 7; very low-quality evidence). There was no evidence from RCTs showing a difference in mortality with PCC compared to standard care  (OR 0.53, 95% CI 0.12 to 2.35; participants = 149; studies = 2; moderate-quality evidence). This is supported by evidence from NRSs, showing that PCCs may have little to no effect on mortality compared to standard care but the evidence is very uncertain (OR 1.02, 95% CI 0.69 to 1.51; participants = 1334; studies = 6; very low-quality evidence). Evidence from RCTs indicated that there was little to no difference in postoperative bleeding (MD -107.05 mLs, 95% CI -278.92 to 64.83; participants = 151, studies = 2; low-quality evidence).  PCCs may have little to no effect on intensive care length of stay (RCT evidence: MD -0.35 hours, 95% CI -19.26 to 18.57; participants = 151; studies = 2; moderate-quality evidence) (NRS evidence: MD -18.00, 95% CI -43.14 to 7.14; participants = 225; studies = 1; very low-quality evidence) or incidence of renal replacement therapy (RCT evidence: OR 0.72, 95% CI 0.14 to 3.59; participants = 50; studies = 1; low-quality evidence) (NRS evidence: OR 1.46, 95% CI 0.71 to 2.98; participants = 684; studies = 2; very low-quality evidence). No studies reported on additional adverse outcomes.   2. PCC versus rFVIIa For this comparison, all evidence was provided from NRSs.  PCC likely results in a large reduction of RBCs transfused intra-operatively in comparison to rFVIIa (MD-4.98 units, 95% CI -6.37 to -3.59; participants = 256; studies = 2; moderate-quality evidence).  PCC may have little to no effect on the incidence of RBC units transfused comparative to rFVIIa; evidence is very uncertain (OR 0.16, 95% CI 0.02 to 1.56; participants = 150; studies = 1; very low-quality evidence). PCC may have little to no effect on the number of thrombotic events comparative to rFVIIa; evidence is very uncertain (OR 0.51, 95% CI 0.23 to 1.16; participants = 407; studies = 4; very low-quality evidence). PCC may have little to no effect on the incidence of mortality (OR 1.07, 95% CI 0.38 to 3.03; participants = 278; studies = 3; very low-quality evidence) or intensive care length of stay comparative to rFVIIa (MD -40 hours, 95% CI -110.41 to 30.41; participants = 106; studies = 1; very low-quality evidence); evidence is very uncertain . PCC may reduce bleeding (MD -674.34 mLs, 95% CI -906.04 to -442.64; participants = 150; studies = 1; very low-quality evidence) and incidence of renal replacement therapy (OR 0.29, 95% CI 0.12 to 0.71; participants = 106; studies = 1; very low-quality evidence) comparative to rFVIIa; evidence is very uncertain. No studies reported on other adverse events.  AUTHORS' CONCLUSIONS: PCCs could potentially be used as an alternative to standard therapy for coagulopathic bleeding post-cardiac surgery compared to FFP as shown by moderate-quality evidence and it may be an alternative to rFVIIa in refractory non-surgical bleeding but this is based on moderate to very low quality of evidence.

Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

BACKGROUND: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines. OBJECTIVES: To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC. SEARCH METHODS: We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021. SELECTION CRITERIA: We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement. MAIN RESULTS: Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting. AUTHORS' CONCLUSIONS: Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.

Antioxidants for male subfertility.

BACKGROUND: The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility. OBJECTIVES: To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men. SEARCH METHODS: The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, and two trial registers were searched on 15 February 2021, together with reference checking and contact with experts in the field to identify additional trials. SELECTION CRITERIA: 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 subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included men with idiopathic infertility and normal semen parameters or fertile men attending a fertility clinic because of female partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes. MAIN RESULTS: We included 90 studies with a total population of 10,303 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing medically assisted reproduction (MAR). Investigators compared and combined 20 different oral antioxidants. The evidence was of 'low' to 'very low' certainty: the main limitation was that out of the 67 included studies in the meta-analysis only 20 studies reported clinical pregnancy, and of those 12 reported on live birth. The evidence is current up to February 2021. Live birth: antioxidants may lead to increased live birth rates (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.07 to 1.91, P = 0.02, 12 RCTs, 1283 men, I2 = 44%, very low-certainty evidence). Results in the studies contributing to the analysis of live birth rate suggest that if the baseline chance of live birth following placebo or no treatment is assumed to be 16%, the chance following the use of antioxidants is estimated to be between 17% and 27%. However, this result was based on only 246 live births from 1283 couples in 12 small or medium-sized studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.22, 95% CI 0.85 to 1.75, 827 men, 8 RCTs, P = 0.27, I2 = 32%). Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 1.89, 95% CI 1.45 to 2.47, P < 0.00001, 20 RCTs, 1706 men, I2 = 3%, low-certainty evidence) compared with placebo or no treatment. This suggests that, in the studies contributing to the analysis of clinical pregnancy, if the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of antioxidants is estimated to be between 20% and 30%. This result was based on 327 clinical pregnancies from 1706 couples in 20 small studies. Adverse events Miscarriage: only six studies reported on this outcome and the event rate was very low. No evidence of a difference in miscarriage rate was found between the antioxidant and placebo or no treatment group (OR 1.46, 95% CI 0.75 to 2.83, P = 0.27, 6 RCTs, 664 men, I2 = 35%, very low-certainty evidence). The findings suggest that in a population of subfertile couples, with male factor infertility, with an expected miscarriage rate of 5%, the risk of miscarriage following the use of an antioxidant would be between 4% and 13%. Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal discomfort when compared with placebo or no treatment (OR 2.70, 95% CI 1.46 to 4.99, P = 0.002, 16 RCTs, 1355 men, I2 = 40%, low-certainty evidence). This suggests that if the chance of gastrointestinal discomfort following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 7%. However, this result was based on a low event rate of 46 out of 1355 men in 16 small or medium-sized studies, and the certainty of the evidence was rated low and heterogeneity was high. We were unable to draw conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. AUTHORS' CONCLUSIONS: In this review, there is very low-certainty evidence from 12 small or medium-sized randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-certainty evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal discomfort, based on very low-certainty evidence. Subfertile couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials studying infertile men and reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Antioxidants for female subfertility.

BACKGROUND: 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. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Probiotic treatment for women with gestational diabetes to improve maternal and infant health and well-being.

BACKGROUND: Gestational diabetes mellitus (GDM) is carbohydrate intolerance first recognised during pregnancy and associated with complications for mothers and babies. Probiotics are naturally occurring micro-organisms, which when ingested in adequate amounts, may confer health benefits. Evidence of the role of probiotics as treatment for GDM is limited. OBJECTIVES: To evaluate the safety and effectiveness of probiotics in treating women with GDM on maternal and infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (24 July 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the use of probiotics versus placebo/standard care for the treatment of GDM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, checked data accuracy, and assessed risk of bias of included trials. The certainty of evidence for selected maternal and infant/child outcomes was assessed using GRADE. MAIN RESULTS: Nine RCTs (695 pregnant women with GDM) comparing probiotics versus placebo were identified. The overall risk of bias in the nine RCTs was low to unclear and the evidence was downgraded for imprecision due to the small numbers of women participating in the trials. The trials were carried out in hospitals and universities in Iran (seven trials), Thailand (one trial) and Ireland (one trial). All trials compared probiotics with placebo. Maternal outcomes We are uncertain if probiotics have any effect compared with placebo on hypertensive disorders of pregnancy, (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.64 to 3.53; participants = 256; studies = 3; low-certainty evidence) and mode of birth as caesareans (average RR 0.64, 95% CI 0.30 to 1.35; participants = 267; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: mode of birth as vaginal/assisted and subsequent development of type 2 diabetes. We are uncertain if probiotics have any effect compared with placebo on induction of labour (RR 1.33, 95% CI 0.74 to 2.37; participants = 127; studies = 1; very low-certainty evidence). For other secondary maternal outcomes, we are uncertain if there are differences between probiotics and placebo for: postpartum haemorrhage; weight gain during pregnancy intervention and total gestational weight gain; fasting plasma glucose and need for extra pharmacotherapy (insulin). Probiotics may be associated with a slight reduction in triglycerides and total cholesterol. In probiotics compared with placebo, there was evidence of reduction in markers for insulin resistance (HOMA-IR) and HOMA-B; and insulin secretion. There was also an increase in quantitative insulin sensitivity check index (QUICKI). Probiotics were associated with minor benefits in relevant bio-markers with evidence of a reduction in inflammatory markers high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and marker of oxidative stress malondialdehyde; and an increase in antioxidant total glutathione, but we are uncertain if there is any difference in total antioxidant capacity. No trials reported secondary outcomes: perineal trauma, postnatal weight retention or return to pre-pregnancy weight and postnatal depression. Infant/child/adult outcomes We are uncertain if probiotics have any effect, compared with placebo, on the risk of large-for-gestational-age babies (RR 0.73, 95% CI 0.35 to 1.52; participants = 174; studies = 2; low-certainty evidence) or infant hypoglycaemia (RR 0.85, 95% CI 0.39 to 1.84; participants = 177; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: perinatal (fetal/neonatal) mortality; or neurosensory disability. For other secondary outcomes, we are uncertain if there is any difference between probiotics and placebo in gestational age at birth, preterm birth, macrosomia, birthweight, head circumference, length, infant hypoglycaemia, and neonatal intensive care unit (NICU) admissions. There was evidence of a reduction in infant hyperbilirubinaemia with probiotics compared with placebo. No trials reported secondary outcomes: infant adiposity, and later childhood adiposity. There were no adverse events reported by any of the trials. AUTHORS' CONCLUSIONS: Low-certainty evidence means we are not certain if there is any difference between probiotic and placebo groups in maternal hypertensive disorders of pregnancy, caesareans; and large-for-gestational-age babies. There were no adverse events reported by the trials. Due to the variability of probiotics used and small sample sizes of trials, evidence from this review has limited ability to inform practice. Well-designed adequately-powered trials are needed to identify whether probiotics may improve maternal blood glucose levels and/or infant/child/adult outcomes; and whether they can be used to treat GDM.

Withdrawal of antihypertensive drugs in older people.

BACKGROUND: Hypertension is an important risk factor for subsequent cardiovascular events, including ischaemic and haemorrhagic stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death. Overall, the use of antihypertensive medications has led to reduction in cardiovascular disease, morbidity rates and mortality rates. However, the use of antihypertensive medications is also associated with harms, especially in older people, including the development of adverse drug reactions, drug-drug interactions and can contribute to increasing medication-related burden. As such, discontinuation of antihypertensives may be considered and appropriate in some older people. OBJECTIVES: To investigate whether withdrawal of antihypertensive medications is feasible, and evaluate the effects of withdrawal of antihypertensive medications on mortality, cardiovascular outcomes, hypertension and quality of life in older people. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2019: the Cochrane Hypertension Specialised Register, CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also conducted reference checking, citation searches and, when appropriate, contacted study authors to identify any additional studies. The searches had no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of withdrawal versus continuation of antihypertensive medications used for hypertension or primary prevention of cardiovascular disease in older adults (defined as 50 years and over). Participants were eligible if they lived in the community, residential aged care facilities, or were based in hospital settings. We sought to include trials looking at the complete withdrawal of the antihypertensive medication, and those focusing on a dose reduction of the antihypertensive medicine. DATA COLLECTION AND ANALYSIS: We compared the intervention of discontinuing or reducing antihypertensive medication to usual treatment using mean differences (MD) and 95% confidence intervals (95% CIs) for continuous variables and we used Peto odds ratios (ORs) and 95% CI for binary variables. Our primary outcomes included: mortality, myocardial infarction, development of adverse drug reactions or adverse drug withdrawal reactions. Secondary outcomes included: blood pressure, hospitalisation, stroke, success of withdrawing from antihypertensives, quality of life, and falls. Two authors independently, and in duplicate, conducted all stages of study selection, data extraction and quality assessment. MAIN RESULTS: Six RCTs met the inclusion criteria and were included in the review (1073 participants). Study duration and follow-up ranged from 4 weeks to 56 weeks. Meta-analysis of studies showed that, in the discontinuation group compared to continuation, the odds for all-cause mortality were 2.08 (95% CI 0.79 to 5.46; low certainty of evidence), for myocardial infarction 1.86 (95% CI 0.19 to 17.98; very low certainty of evidence) and for stroke 1.44 (95% CI 0.25 to 8.35; low certainty of evidence). Blood pressure was higher in the discontinuation group than the continuation group (systolic blood pressure: MD = 9.75 mmHg, 95% CI 7.33 to 12.18; and diastolic blood pressure: MD = 3.5 mmHg, 95% CI 1.82 to 5.18; low certainty of evidence). For the development of adverse events, meta-analysis was not possible; antihypertensive discontinuation did not appear to increase the risk of adverse events and may lead to resolution of adverse drug reactions, although eligible studies had limited reporting of adverse effects of drug withdrawal (very low certainty of evidence). One study reported hospitalisation with an odds ratio of 0.83 for discontinuation compared to continuation (95% CI 0.33 to 2.10; low certainty of evidence). No studies were identified which reported falls. Between 10.5% and 33.3% of participants in the discontinuation group compared to 9% to 15% in the continuation group experienced raised blood pressure or other clinical criteria (as pre-defined by the studies) that would require restarting of therapy/removal from the study. The sources of bias included selective reporting (reporting bias), lack of blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and lack of blinding of participants and personnel (performance bias). AUTHORS' CONCLUSIONS: There is no evidence of an effect of discontinuing compared with continuing antihypertensives used for hypertension or primary prevention of cardiovascular disease in older adults on all-cause mortality and myocardial infarction. The evidence was low to very low certainty mainly due to small studies and low event rates. These limitations mean that we cannot make any firm conclusions about the effect of deprescribing antihypertensives on these outcomes. Future research should focus on populations with the greatest uncertainty of the benefit:risk ratio for use of antihypertensive medications, such as those with frailty, older age groups and those taking polypharmacy, and measure clinically important outcomes such as falls, quality of life and adverse drug events.

The use of specialised preterm birth clinics for women at high risk of spontaneous preterm birth: a systematic review.

BACKGROUND: Specialised preterm birth clinics care for women at high risk of spontaneous preterm birth. This systematic review assesses current practice within preterm birth clinics globally. METHODS: A comprehensive search strategy was used to identify all studies on preterm birth clinics on the MEDLINE, Embase, PsycINFO, CENTRAL and CINAHL databases. There were no restrictions to study design. Studies were limited to the English language and publications from 1998 onwards. Two reviewers assessed studies for inclusion, performed data extraction and reviewed methodological quality. Primary outcomes were referral criteria, investigations and interventions offered in preterm birth clinics. Secondary outcomes were the timing of planned first and last appointments and frequency of review. RESULTS: Thirty-two records fulfilled eligibility criteria and 20 studies were included in the main analysis following grouping of records describing the same study or clinic. Studies were of mixed study design and methodological quality. A total of 39 clinics were described; outcome data was not available for all clinics. Referral criteria included previous spontaneous preterm birth (38/38, 100%), previous mid-trimester loss (34/38, 89%) and previous cervical surgery (33/38, 87%). All clinics offered transvaginal cervical length scans. Additional investigations varied, including urogenital swabs (16/28, 57%) and fetal fibronectin (8/28, 29%). The primary treatment of choice for a sonographic short cervix was cervical cerclage in 10/33 (30%) clinics and vaginal progesterone in 6/33 (18%), with 10/33 (30%) using multiple first-line options and 6/33 (18%) using a combination of treatments. The majority of clinics planned timing of first review for 12-16 weeks (30/35, 86%) and the frequency of review was usually determined by clinical findings (18/24, 75%). There was a wide variation in gestational age at clinic discharge between 24 and 37 weeks. CONCLUSIONS: There is variation in the referral criteria, investigations and interventions offered in preterm birth clinics and in the timing and frequency of review. Consistency in practice may improve with the introduction of consensus guidelines and national preterm birth prevention programmes. TRIAL REGISTRATION: Systematic review registration number: CRD42019131470.

Interventions to reduce shoulder pain following gynaecological laparoscopic procedures.

BACKGROUND: Laparoscopy is a common procedure used to diagnose and treat various gynaecological conditions. Shoulder-tip pain (STP) as a result of the laparoscopy occurs in up to 80% of women, with potential for significant morbidity, delayed discharge and readmission. Interventions at the time of gynaecological laparoscopy have been developed in an attempt to reduce the incidence and severity of STP. OBJECTIVES: To determine the effectiveness and safety of methods for reducing the incidence and severity of shoulder-tip pain (STP) following gynaecological laparoscopy. SEARCH METHODS: We searched the following databases: Cochrane Gynaecology and Fertility (CGF) Specialised Register, the Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO and CINAHL from inception to 8 August 2018. We also searched the reference lists of relevant articles and registers of ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions used during or immediately after gynaecological laparoscopy to reduce the incidence or severity of STP. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes: incidence or severity of STP and adverse events of the interventions; secondary outcomes: analgesia usage, delay in discharge, readmission rates, quality-of-life scores and healthcare costs. MAIN RESULTS: We included 32 studies (3284 women). Laparoscopic procedures in these studies varied from diagnostic procedures to complex operations. The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias, imprecision and inconsistency.Specific technique versus "standard" technique for releasing the pneumoperitoneumUse of a specific technique of releasing the pneumoperitoneum (pulmonary recruitment manoeuvre, extended assisted ventilation or actively aspirating intra-abdominal gas) reduced the severity of STP at 24 hours (standardised mean difference (SMD) -0.66, 95% confidence interval (CI) -0.82 to -0.50; 5 RCTs; 670 participants; I2 = 0%, low-quality evidence) and reduced analgesia usage (SMD -0.53, 95% CI -0.70 to -0.35; 4 RCTs; 570 participants; I2 = 91%, low-quality evidence). There appeared to be little or no difference in the incidence of STP at 24 hours (odds ratio (OR) 0.87, 95% CI 0.41 to 1.82; 1 RCT; 118 participants; low-quality evidence).No adverse events occurred in the only study assessing this outcome.Fluid instillation versus no fluid instillationFluid instillation is probably associated with a reduction in STP incidence (OR 0.38, 95% CI 0.22 to 0.66; 2 RCTs; 220 participants; I2 = 0%, moderate-quality evidence) and severity (mean difference (MD) (0 to 10 visual analogue scale (VAS) scale) -2.27, 95% CI -3.06 to -1.48; 2 RCTs; 220 participants; I2 = 29%, moderate-quality evidence) at 24 hours, and may reduce analgesia usage (MD -12.02, 95% CI -23.97 to -0.06; 2 RCTs; 205 participants, low-quality evidence).No study measured adverse events.Intraperitoneal drain versus no intraperitoneal drainUsing an intraperitoneal drain may reduce the incidence of STP at 24 hours (OR 0.30, 95% CI 0.20 to 0.46; 3 RCTs; 417 participants; I2 = 90%, low-quality evidence) and may reduce analgesia use within 48 hours post-operatively (SMD -1.84, 95% CI -2.14 to -1.54; 2 RCTs; 253 participants; I2 = 90%). We are uncertain whether it reduces the severity of STP at 24 hours, as the evidence was very low quality (MD (0 to 10 VAS scale) -1.85, 95% CI -2.15 to -1.55; 3 RCTs; 320 participants; I2 = 70%).No study measured adverse events.Subdiaphragmatic intraperitoneal local anaesthetic versus control (no fluid instillation, normal saline or Ringer's lactate)There is probably little or no difference between the groups in incidence of STP (OR 0.72, 95% CI 0.42 to 1.23; 4 RCTs; 336 participants; I2 = 0%; moderate-quality evidence) and there may be no difference in STP severity (MD -1.13, 95% CI -2.52 to 0.26; 1 RCT; 50 participants; low-quality evidence), both measured at 24 hours. However, the intervention may reduce post-operative analgesia use (SMD-0.57, 95% CI -0.94 to -0.21; 2 RCTs; 129 participants; I2 = 51%, low-quality evidence).No adverse events occurred in any study.Local anaesthetic into peritoneal cavity (not subdiaphragmatic) versus normal salineLocal anaesthetic into the peritoneal cavity may reduce the incidence of STP at 4 to 8 hours post-operatively (OR 0.23, 95% CI 0.06 to 0.93; 2 RCTs; 157 participants; I2 = 56%; low-quality evidence). Our other outcomes of interest were not assessed.Warmed, or warmed and humidified CO2 versus unwarmed and unhumidified CO2There may be no difference between these interventions in incidence of STP at 24 to 48 hours (OR 0.81 95% CI 0.45 to 1.49; 2 RCTs; 194 participants; I2 = 12%; low-quality evidence) or in analgesia usage within 48 hours (MD -4.97 mg morphine, 95% CI -11.25 to 1.31; 1 RCT; 95 participants; low-quality evidence); there is probably little or no difference in STP severity at 24 hours (MD (0 to 10 VAS scale) 0.11, 95% CI -0.75 to 0.97; 2 RCTs; 157 participants; I2 = 50%; moderate-quality evidence).No study measured adverse events.Gasless laparoscopy versus CO2 insufflationGasless laparoscopy may be associated with increased severity of STP within 72 hours post-operatively when compared with standard treatment (MD 3.8 (0 to 30 VAS scale), 95% CI 0.76 to 6.84; 1 RCT; 54 participants, low-quality evidence), and there may be no difference in the risk of adverse events (OR 2.56, 95% CI 0.25 to 26.28; 1 RCT; 54 participants; low-quality evidence).No study measured the incidence of STP. AUTHORS' CONCLUSIONS: There is low to moderate-quality evidence that the following interventions are associated with a reduction in the incidence or severity, or both, of STP, or a reduction in analgesia requirements for women undergoing gynaecological laparoscopy: a specific technique for releasing the pneumoperitoneum; intraperitoneal fluid instillation; an intraperitoneal drain; and local anaesthetic applied to the peritoneal cavity (not subdiaphragmatic).There is low to moderate-quality evidence that subdiaphragmatic intraperitoneal local anaesthetic and warmed and humidified insufflating gas may not make a difference to the incidence or severity of STP.There is low-quality evidence that gasless laparoscopy may increase the severity of STP, compared with standard treatment.Few studies reported data on adverse events. Some potentially useful interventions have not been studied by RCTs of gynaecological laparoscopy.

Time-lapse systems for embryo incubation and assessment in assisted reproduction.

BACKGROUND: Embryo incubation and assessment is a vital step in assisted reproductive technology (ART). Traditionally, embryo assessment has been achieved by removing embryos from a conventional incubator daily for quality assessment by an embryologist, under a microscope. In recent years time-lapse systems (TLS) have been developed which can take digital images of embryos at frequent time intervals. This allows embryologists, with or without the assistance of embryo selection software, to assess the quality of the embryos without physically removing them from the incubator.The potential advantages of a TLS include the ability to maintain a stable culture environment, therefore limiting the exposure of embryos to changes in gas composition, temperature, and movement. A TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through continuously monitoring embryo development. Use of a TLS often adds significant extra cost to ART treatment. OBJECTIVES: To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART. SEARCH METHODS: We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trials registers on 7 January 2019 and checked references of appropriate papers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing TLS, with or without embryo selection software, versus conventional incubation with morphological assessment; and TLS with embryo selection software versus TLS without embryo selection software among couples undergoing ART. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy, miscarriage and stillbirth, and cumulative live birth or ongoing pregnancy rate. The secondary outcomes were clinical pregnancy and cumulative clinical pregnancy. We assessed the quality of the evidence using GRADE methodology. We made the following comparisons.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentTLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS images TLS utilising embryo selection software versus conventional incubation and assessment MAIN RESULTS: We included nine RCTs (N = 2955 infertile couples). The quality of the evidence ranged from very low to low. The main limitations were high risk of bias in the included studies, imprecision, indirectness, and inconsistency. There were no data on cumulative live birth or ongoing pregnancy rate or cumulative clinical pregnancy rate.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentIt is unclear whether there is any difference between interventions in rates of live birth or ongoing pregnancy (odds ratio (OR) 0.91, 95% confidence interval (CI) 0.67 to 1.23, 3 RCTs, N = 826, I2 = 33%, low-quality evidence) or in miscarriage rates (OR 1.90, 95% CI 0.99 to 3.61, 3 RCTs, N = 826, I2 = 0%, low-quality evidence). The evidence suggests that if the rate of live birth or ongoing pregnancy associated with conventional incubation and assessment is 35%, the rate with the use of TLS with conventional morphological assessment of still TLS images would be between 27% and 40%, and if the miscarriage rate with conventional incubation is 4%, the rate associated with conventional morphological assessment of still TLS images would be between 4% and 14%. It is unclear whether there is a difference between the interventions in rates of stillbirth (OR 1.00, 95% CI 0.13 to 7.49, 1 RCT, N = 76, low-quality evidence) or clinical pregnancy (OR 1.06, 95% CI 0.79 to 1.41, 4 RCTs, N = 875, I2 = 0%, low-quality evidence).TLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS imagesAll findings for this comparison were very uncertain due to the very low-quality of the evidence. No data were available on live birth, but one RCT reported ongoing pregnancy. It is unclear whether there is any difference between the interventions in rates of ongoing pregnancy (OR 0.61, 95% CI 0.32 to 1.20, 1 RCT, N = 163); miscarriage (OR 1.39, 95% CI 0.64 to 3.01, 2 RCTs, N = 463, I2 = 0%); or clinical pregnancy (OR 0.97, 95% CI 0.67 to 1.42, 2 RCTs, N = 463, I2 = 0%). The evidence suggests that if the rate of ongoing pregnancy associated with TLS with conventional morphological assessment of still TLS images is 47%, the rate associated with TLS utilising embryo selection software would be between 22% and 52%, and if the miscarriage rate associated with conventional morphological assessment of still TLS images is 5%, the rate associated with TLS utilising embryo selection software would be between 4% and 15%. No studies reported stillbirth.TLS utilising embryo selection software versus conventional incubation and assessmentThe findings for this comparison were also very uncertain due to the very low quality of the evidence. It is unclear whether there is any difference between the interventions in rates of live birth (OR 1.12, 95% CI 0.92 to 1.36, 3 RCTs, N = 1617, I2 = 84%). There was very low-quality evidence that TLS might reduce miscarriage rates (OR 0.63, 95% CI 0.45 to 0.89, 3 RCTs, N = 1617, I2 = 0%). It is unclear whether there is any difference between the interventions in rates of clinical pregnancy (OR 0.95, 95% CI 0.78 to 1.16, 3 RCTs, N = 1617, I2 = 89%). The evidence suggests that if the rate of live birth associated with conventional incubation and assessment is 48%, the rate with TLS utilising embryo selection software would be between 46% and 55%, and if the miscarriage rate with conventional incubation and assessment is 11%, the rate associated with TLS would be between 5% and 10%. No stillbirths occurred in the only study reporting this outcome. AUTHORS' CONCLUSIONS: There is insufficient good-quality evidence of differences in live birth or ongoing pregnancy, miscarriage and stillbirth, or clinical pregnancy to choose between TLS, with or without embryo selection software, and conventional incubation. As the evidence is of low or very low-quality, our findings should be interpreted with caution.

Antioxidants for male subfertility.

BACKGROUND: The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility. This review did not examine the use of antioxidants in normospermic men. OBJECTIVES: To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men. SEARCH METHODS: The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers were searched on 1 February 2018, together with reference checking and contact with study authors and experts in the field to identify additional trials. SELECTION CRITERIA: 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 subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included fertile men attending a fertility clinic because of female partner infertility. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes. MAIN RESULTS: We included 61 studies with a total population of 6264 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing assisted reproductive techniques (ART). Investigators compared and combined 18 different oral antioxidants. The evidence was of 'low' to 'very low' quality: the main limitation was that out of the 44 included studies in the meta-analysis only 12 studies reported on live birth or clinical pregnancy. The evidence is current up to February 2018.Live birth: antioxidants may lead to increased live birth rates (OR 1.79, 95% CI 1.20 to 2.67, P = 0.005, 7 RCTs, 750 men, I2 = 40%, low-quality evidence). Results suggest that if in the studies contributing to the analysis of live birth rate, the baseline chance of live birth following placebo or no treatment is assumed to be 12%, the chance following the use of antioxidants is estimated to be between 14% and 26%. However, this result was based on only 124 live births from 750 couples in seven relatively small studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.38, 95% CI 0.89 to 2.16; participants = 540 men, 5 RCTs, P = 0.15, I2 = 0%).Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 2.97, 95% CI 1.91 to 4.63, P < 0.0001, 11 RCTs, 786 men, I2 = 0%, low-quality evidence) compared to placebo or no treatment. This suggests that if in the studies contributing to the analysis of clinical pregnancy, the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 7%, the chance following the use of antioxidants is estimated to be between 12% and 26%. This result was based on 105 clinical pregnancies from 786 couples in 11 small studies.Adverse eventsMiscarriage: only three studies reported on this outcome and the event rate was very low. There was no difference in miscarriage rate between the antioxidant and placebo or no treatment group (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low-quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, the chance following the use of an antioxidant would result in the risk of a miscarriage between 1% and 13%.Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal upsets when compared to placebo or no treatment (OR 2.51, 95% CI 1.25 to 5.03, P = 0.010, 11 RCTs, 948 men, I2 = 50%, very low-quality evidence). This suggests that if the chance of gastrointestinal upsets following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 9%. However, this result was based on a low event rate of 35 out of 948 men in 10 small or medium-sized studies, and the quality of the evidence was rated very low and was high in heterogeneity.We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. AUTHORS' CONCLUSIONS: In this review, there is low-quality evidence from seven small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-quality evidence suggests that clinical pregnancy rates may also increase. Overall, there is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal upsets but the evidence is of very low quality. Subfertilte couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.

Diabetic eye disease and screening attendance by ethnicity in New Zealand: A systematic review.

To examine differences in incidence, prevalence and screening for diabetic retinopathy in New Zealand, we searched MEDLINE, EMBASE and CINAHL up to 6 December 2018 for observational studies reporting diabetic eye disease or attendance at retinal screening, disaggregated by ethnicity. Two authors separately screened and selected studies, and extracted data. None of the 11 included studies reported data on visual impairment from diabetic retinopathy. All nine studies reporting diabetic eye disease by ethnicity found Pacific people and Maori had higher rates of sight-threatening disease and lower rates of screening attendance compared to Europeans. Data for Asian people were infrequently reported, but when they were, they also fared worse than Europeans. This review highlights that equity-focused strategies are needed to address ethnic disparities in eye health among New Zealanders with diabetes. The review also identifies how research methods can be strengthened to enable future calculation of robust disease prevalence estimates.

Maternal folic acid supplementation for the prevention of preeclampsia: A systematic review and meta-analysis.

BACKGROUND: Preeclampsia is a significant contributor to maternal and neonatal morbidity and mortality. Folic acid supplementation is recommended periconceptionally for the prevention of neural tube defects. Epidemiological evidence suggests that maternal folic acid supplementation may play a role in preventing other adverse birth outcomes. This systematic review aimed to investigate the effect of maternal folic acid supplementation during pregnancy on risk of preeclampsia and gestational hypertension. METHODS: Multiple scientific databases and grey literature were searched for relevant studies. Studies were reviewed according to pre-specified inclusion and exclusion criteria. Study characteristics were summarised and study quality was assessed. A meta-analysis of observational studies was conducted to examine the effect of maternal folic acid supplementation on preeclampsia risk. RESULTS: Meta-analysis of eight observational studies showed significantly lower odds of preeclampsia with folic acid supplementation in comparison to no folic acid supplementation: OR = 0.78 (95% CI 0.63, 0.98), with moderately high heterogeneity between studies. Subgroup analysis showed no significant subgroup difference between folic acid supplementation taken by itself, in comparison to folic acid taken in or alongside a multivitamin. CONCLUSION: Low level evidence is available for a modest association between maternal folic acid supplementation and reduction in preeclampsia risk. Future studies should differentiate between early and late onset and mild vs severe preeclampsia, and should control for relevant confounders including the presence of multivitamin supplements. The protocol for this systematic review was prospectively registered with PROSPERO (CRD42015029310).

Time-lapse systems for embryo incubation and assessment in assisted reproduction.

BACKGROUND: Embryo incubation and assessment is a vital step in assisted reproductive technology (ART). Traditionally, embryo assessment has been achieved by removing embryos from a conventional incubator daily for quality assessment by an embryologist, under a light microscope. Over recent years time-lapse systems have been developed which can take digital images of embryos at frequent time intervals. This allows embryologists, with or without the assistance of embryo selection software, to assess the quality of the embryos without physically removing them from the incubator.The potential advantages of a time-lapse system (TLS) include the ability to maintain a stable culture environment, therefore limiting the exposure of embryos to changes in gas composition, temperature and movement. A TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through continuously monitoring embryo development. Use of a TLS often adds significant extra cost onto an in vitro fertilisation (IVF) cycle. OBJECTIVES: To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART. SEARCH METHODS: We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, CINAHL and two trials registers on 2 August 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in the following comparisons: comparing a TLS, with or without embryo selection software, versus conventional incubation with morphological assessment; and TLS with embryo selection software versus TLS without embryo selection software among couples undergoing ART. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth, miscarriage and stillbirth. Secondary outcomes were clinical pregnancy and cumulative clinical pregnancy. We reported quality of the evidence for important outcomes using GRADE methodology. We made the following comparisons.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentTLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS images TLS utilising embryo selection software versus conventional incubation and assessment MAIN RESULTS: We included eight RCTs (N = 2303 women). The quality of the evidence ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding of participants and researchers, and indirectness secondary to significant heterogeneity between interventions in some studies. There were no data on cumulative clinical pregnancy.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentThere is no evidence of a difference between the interventions in terms of live birth rates (odds ratio (OR) 0.73, 95% CI 0.47 to 1.13, 2 RCTs, N = 440, I2 = 11% , moderate-quality evidence) and may also be no evidence of difference in miscarriage rates (OR 2.25, 95% CI 0.84 to 6.02, 2 RCTs, N = 440, I2 = 44%, low-quality evidence). The evidence suggests that if the live birth rate associated with conventional incubation and assessment is 33%, the rate with use of TLS with conventional morphological assessment of still TLS images is between 19% and 36%; and that if the miscarriage rate with conventional incubation is 3%, the rate associated with conventional morphological assessment of still TLS images would be between 3% and 18%. There is no evidence of a difference between the interventions in the stillbirth rate (OR 1.00, 95% CI 0.13 to 7.49, 1 RCT, N = 76, low-quality evidence). There is no evidence of a difference between the interventions in clinical pregnancy rates (OR 0.88, 95% CI 0.58 to 1.33, 3 RCTs, N = 489, I2 = 0%, moderate-quality evidence).TLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS imagesNo data were available on live birth or stillbirth. We are uncertain whether TLS utilising embryo selection software influences miscarriage rates (OR 1.39, 95% CI 0.64 to 3.01, 2 RCTs, N = 463, I2 = 0%, very low-quality evidence) and there may be no difference in clinical pregnancy rates (OR 0.97, 95% CI 0.67 to 1.42, 2 RCTs, N = 463, I2 = 0%, low-quality evidence). The evidence suggests that if the miscarriage rate associated with assessment of still TLS images is 5%, the rate with embryo selection software would be between 3% and 14%.TLS utilising embryo selection software versus conventional incubation and assessmentThere is no evidence of a difference between TLS utilising embryo selection software and conventional incubation improving live birth rates (OR 1.21, 95% CI 0.96 to 1.54, 2 RCTs, N = 1017, I2 = 0%, very low-quality evidence). We are uncertain whether TLS influences miscarriage rates (OR 0.73, 95% CI 0.49 to 1.08, 3 RCTs, N = 1351, I2 = 0%, very low-quality evidence). The evidence suggests that if the live birth rate associated with no TLS is 38%, the rate with use of conventional incubation would be between 36% and 58%, and that if miscarriage rate with conventional incubation is 9%, the rate associated with TLS would be between 4% and 10%. No data on stillbirths were available. It was uncertain whether the intervention influenced clinical pregnancy rates (OR 1.17, 95% CI 0.94 to 1.45, 3 RCTs, N = 1351, I2 = 42%, very low-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence of differences in live birth, miscarriage, stillbirth or clinical pregnancy to choose between TLS, with or without embryo selection software, and conventional incubation. The studies were at high risk of bias for randomisation and allocation concealment, the result should be interpreted with extreme caution.

Inositol for subfertile women with polycystic ovary syndrome.

BACKGROUND: Subfertile women are highly motivated to try different adjunctive therapies to have a baby, and the widespread perception is that dietary supplements such as myo-inositol (MI) and D-chiro-insoitol (DCI) are associated with only benefit, and not with harm. Many fertility clinicians currently prescribe MI for subfertile women with polycystic ovary syndrome (PCOS) as pre-treatment to in vitro fertilisation (IVF) or for ovulation induction; however no high-quality evidence is available to support this practice. This review assessed the evidence for the effectiveness of inositol in subfertile women with a diagnosis of PCOS. OBJECTIVES: To evaluate the effectiveness and safety of oral supplementation of inositol for reproductive outcomes among subfertile women with PCOS who are trying to conceive. SEARCH METHODS: We searched the following databases (to July 2018): Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. We also checked reference lists and searched the clinical trials registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose, or combination of oral inositol versus placebo, no treatment/standard treatment, or treatment with another antioxidant, or with a fertility agent, or with another type of inositol, among subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed risk of bias. The primary outcomes were live birth and adverse effects; secondary outcomes included clinical pregnancy rates and ovulation rates. We pooled studies using a fixed-effect model, and we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We assessed the overall quality of the evidence by applying GRADE criteria. MAIN RESULTS: We included 13 trials involving 1472 subfertile women with PCOS who were receiving myo-inositol as pre-treatment to IVF (11 trials), or during ovulation induction (two trials). These studies compared MI versus placebo, no treatment/standard, melatonin, metformin, clomiphene citrate, or DCI. The evidence was of 'low' to 'very low' quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency, and lack of reporting of clinically relevant outcomes such as live birth and adverse events.We are uncertain whether MI improves live birth rates when compared to standard treatment among women undergoing IVF (OR 2.42, 95% CI 0.75 to 7.83; P = 0.14; 2 RCTs; 84 women; I² = 0%). Very low-quality evidence suggests that for subfertile women with PCOS undergoing pre-treatment to IVF who have an expected live birth rate of 12%, the rate among women using MI would be between 9% and 51%.We are uncertain whether MI may be associated with a decrease in miscarriage rate when compared to standard treatment (OR 0.40, 95% CI 0.19 to 0.86; P = 0.02; 4 RCTs; 535 women; I² = 66%; very low-quality evidence). This suggests that among subfertile women with PCOS with an expected miscarriage rate of 9% who are undergoing pre-treatment to IVF, the rate among women using MI would be between 2% and 8%; however this meta-analysis is based primarily on one study, which reported an unusually high miscarriage rate in the control group, and this has resulted in very high heterogeneity. When we removed this trial from the sensitivity analysis, we no longer saw the effect, and we noted no conclusive differences between MI and standard treatment.Low-quality evidence suggests that MI may be associated with little or no difference in multiple pregnancy rates when compared with standard treatment (OR 1.04, 95% CI 0.63 to 1.71; P = 0.89; 2 RCTs; 425 women). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected multiple pregnancy rate of 18%, the rate among women using inositol would be between 12% and 27%.We are uncertain whether MI may be associated with an increased clinical pregnancy rate when compared to standard treatment (OR 1.27, 95% CI 0.87 to 1.85; P = 0.22; 4 RCTs; 535 women; I² = 0%; very low-quality evidence). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected clinical pregnancy rate of 26%, the rate among women using MI would be between 24% and 40%. Ovulation rates were not reported for this comparison.Other comparisons included only one trial in each, so for the comparisons MI versus antioxidant, MI versus an insulin-sensitising agent, MI versus an ovulation induction agent, and MI versus another DCI, meta-analysis was not possible.No pooled evidence was available for women with PCOS undergoing ovulation induction, as only single trials performed comparison of the insulin-sensitising agent and the ovulation induction agent. AUTHORS' CONCLUSIONS: In light of available evidence of very low quality, we are uncertain whether MI improves live birth rate or clinical pregnancy rate in subfertile women with PCOS undergoing IVF pre-treatment taking MI compared to standard treatment. We are also uncertain whether MI decreases miscarriage rates or multiple pregnancy rates for these same women taking MI compared to standard treatment. No pooled evidence is available for use of MI versus placebo, another antioxidant, insulin-sensitising agents, ovulation induction agents, or another type of inositol for women with PCOS undergoing pre-treatment to IVF. No pooled evidence is available for use of MI in women undergoing ovulation induction.

Clinical trial registration in fertility trials - a case for improvement?

STUDY QUESTION: What is the prevalence and source of prospectively and retrospectively registered and unregistered trials in fertility treatments? SUMMARY ANSWER: Trial registration is low and does not appear to be changing over the 5 years studied. WHAT IS KNOWN ALREADY: Trial registration is associated with lower risk of bias than in unregistered trials. STUDY DESIGN, SIZE, DURATION: The Cochrane Gynaecology and Fertility Group's specialised register was searched on 5 November 2015 for randomised controlled trials (RCTs) published from January 2010 to December 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible trials included randomised women or men for fertility treatments, were published in full text, and written in English. Two reviewers independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. MAIN RESULTS AND ROLE OF CHANCE: Of 693 eligible RCTS, only 44% were registered trials. Of 309 registered trials, 21.7% were prospectively registered, 15.8% were registered within 6 months of first patient enrolment and 62.5% were retrospectively registered trials. Prospective trial registration by country varied from 0% to 100%. The highest frequency of prospective trial registration amongst the top 10 publishing countries was 31% in the Netherlands. LIMITATIONS, REASONS FOR CAUTION: Only English language trials were included in this review. WIDER IMPLICATIONS OF THE FINDINGS: Prospective trial registration is still low. Journals, funders and ethics committees could have a greater role to increase trial registration. STUDY FUNDING/COMPETING INTERESTS: University of Auckland. No competing interests.

Antioxidants for female subfertility.

BACKGROUND: 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. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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, I2 = 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, I2 = 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, I2 = 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, I2 = 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, I2 = 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, I2 = 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, I2 = 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.

Antibiotic prophylaxis for elective hysterectomy.

BACKGROUND: Elective hysterectomy is commonly performed for benign gynaecological conditions. Hysterectomy can be performed abdominally, laparoscopically, or vaginally, with or without laparoscopic assistance. Antibiotic prophylaxis consists of administration of antibiotics to reduce the rate of postoperative infection, which otherwise affects 40%-50% of women after vaginal hysterectomy, and more than 20% after abdominal hysterectomy. No Cochrane review has systematically assessed evidence on this topic. OBJECTIVES: To determine the effectiveness and safety of antibiotic prophylaxis in women undergoing elective hysterectomy. SEARCH METHODS: We searched electronic databases to November 2016 (including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as clinical trials registers, conference abstracts, and reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing use of antibiotics versus placebo or other antibiotics as prophylaxis in women undergoing elective hysterectomy. DATA COLLECTION AND ANALYSIS: We used Cochrane standard methodological procedures. MAIN RESULTS: We included in this review 37 RCTs, which performed 20 comparisons of various antibiotics versus placebo and versus one another (6079 women). The quality of the evidence ranged from very low to moderate. The main limitations of study findings were risk of bias due to poor reporting of methods, imprecision due to small samples and low event rates, and inadequate reporting of adverse effects. Any antibiotic versus placebo Vaginal hysterectomyModerate-quality evidence shows that women who received antibiotic prophylaxis had fewer total postoperative infections (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.19 to 0.40; five RCTs, N = 610; I2 = 85%), less urinary tract infection (UTI) (RR 0.58, 95% CI 0.43 to 0.77; eight RCTs, N = 1790; I2 = 44%), fewer pelvic infections (RR 0.28, 95% CI 0.20 to 0.39; 11 RCTs, N = 2010; I2 = 57%), and fewer postoperative fevers (RR 0.43, 95% CI 0.34 to 0.54; nine RCTs, N = 1879; I2 = 48%) than women who did not receive such prophylaxis. This suggests that antibiotic prophylaxis reduces the average risk of postoperative infection from about 34% to 7% to 14%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.20, 95% CI 0.01 to 4.10; one RCT, N = 146; very low-quality evidence).Data were insufficient for comparison of adverse effects. Abdominal hysterectomyWomen who received antibiotic prophylaxis of any class had fewer total postoperative infections (RR 0.16, 95% CI 0.06 to 0.38; one RCT, N = 345; low-quality evidence), abdominal wound infections (RR 0.64, 95% CI 0.45 to 0.92; 11 RCTs, N = 2434; I2 = 0%; moderate-quality evidence), UTIs (RR 0.39, 95% CI 0.29 to 0.51; 11 RCTs, N = 2547; I2 = 26%; moderate-quality evidence), pelvic infections (RR 0.50, 95% CI 0.35 to 0.71; 11 RCTs, N = 1883; I2 = 11%; moderate-quality evidence), and postoperative fevers (RR 0.60, 95% CI 0.51 to 0.70; 11 RCTs, N = 2581; I2 = 51%; moderate-quality evidence) than women who did not receive prophylaxis, suggesting that antibiotic prophylaxis reduces the average risk of postoperative infection from about 16% to 1% to 6%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.44, 95% CI 0.12 to 1.69; two RCTs, N = 476; I2 = 29%; very low-quality evidence).It is unclear whether rates of adverse effects differed between groups (RR 1.80, 95% CI 0.62 to 5.18; two RCTs, N = 430; I2 = 0%; very low-quality evidence). Head-to-head comparisons between antibiotics Vaginal hysterectomyWe identified four comparisons: cephalosporin versus penicillin (two RCTs, N = 470), cephalosporin versus tetracycline (one RCT, N = 51), antiprotozoal versus lincosamide (one RCT, N = 80), and cephalosporin versus antiprotozoal (one RCT, N = 78). Data show no evidence of differences between groups for any of the primary outcomes, except that fewer cases of total postoperative infection and postoperative fever were reported in women who received cephalosporin than in those who received antiprotozoal.Only one comparison (cephalosporin vs penicillin; two RCTs, N = 451) yielded data on adverse effects and showed no differences between groups. Abdominal hysterectomyWe identified only one comparison: cephalosporin versus penicillin (N = 220). Data show no evidence of differences between groups for any of the primary outcomes. Adverse effects were not reported. Combined antibiotics versus single antibiotics Vaginal hysterectomyWe identified three comparisons: cephalosporin plus antiprotozoal versus cephalosporin (one RCT, N = 78), cephalosporin plus antiprotozoal versus antiprotozoal (one RCT, N = 78), and penicillin plus antiprotozoal versus penicillin (one RCT, N = 230). Data were unavailable for most outcomes, including adverse effects. We found no evidence of differences between groups, except that fewer women receiving cephalosporin with antiprotozoal received a diagnosis of total postoperative infection, UTI, or postoperative fever compared with women receiving antiprotozoal. Abdominal hysterectomyWe identified one comparison (penicillin plus antiprotozoal vs penicillin only; one RCT, N = 230). Whether differences between groups occurred was unclear. Adverse effects were not reported. Comparison of cephalosporins in different regimensSingle small trials addressed dose comparisons and provided no data for most outcomes, including adverse effects. Whether differences between groups occurred was unclear. No trials compared route of administration.The quality of evidence for all head-to-head and dose comparisons was very low owing to very serious imprecision and serious risk of bias related to poor reporting of methods. AUTHORS' CONCLUSIONS: Antibiotic prophylaxis appears to be effective in preventing postoperative infection in women undergoing elective vaginal or abdominal hysterectomy, regardless of the dose regimen. However, evidence is insufficient to show whether use of prophylactic antibiotics influences rates of adverse effects. Similarly, evidence is insufficient to show which (if any) individual antibiotic, dose regimen, or route of administration is safest and most effective. The most recent studies included in this review were 14 years old at the time of our search. Thus findings from included studies may not reflect current practice in perioperative and postoperative care and may not show locoregional antimicrobial resistance patterns.