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The history of obstetrics and gynaecology is not a tale of evidence‐based practice. Tradition, expert opinion, and the lure of new technology have frequently superseded evidence as the primary driver for clinical decision making. The proof can be found in a litany of dubious interventions which have gained widespread popularity despite an absence of high quality data attesting to their effectiveness and, in some cases, ample credible evidence demonstrating harm. As a specialty, we have relied on investigations including X‐ray pelvimetry and antenatal stress tests, subjected innumerable women to stilboestrol and thalidomide, and have performed routine episiotomy in all primigravid women 1,. It is no surprise that, in 1979, Archie Cochrane famously awarded obstetrics the ‘wooden spoon’ for being the least evidence‐based specialty.

The field of reproductive medicine is known for its innovations, and where there is innovation there is marketing and engagement with the doctors who are potential prescribers and users of those innovations. Financial connections between drug and device manufacturers with doctors have been extensively debated over the past decade. On one hand, relationships between doctors and industry could be considered synergistic by allowing the development of improved treatments. On the other hand, payment (and other benefits) from industry to doctors may subtly shift the main objective of the collaboration from patients' health to mutual benefits for both doctors and industry. Fertility patients can be considered 'vulnerable' as they face the multiple challenges of seeking to be parents, understanding complex and expensive fertility treatments that are by no means universally successful, and at the same time are under pressure because of their ever-increasing age. They are entitled to receive the most cost-effective treatments. We suggest that specialists in the field of reproductive medicine should be transparent about the receipt of financial benefits, including funding from industry, as it may be influencing both research outcomes and treatments that patients are offered. We also recommend that payments arising from industry-sponsored research should be centralized in institutional funds and not paid directly to researchers. And there should be transparency about the source and the purpose of the payment. Industry sponsorship of medical societies and their educational events should be kept to a minimum and declared quantitatively in societies' websites and scientific programme brochures. Industry sponsorship of scientific meetings should not include the right to host educational symposia or speakers within the programme. All speakers should declare their conflicts of interest (COIs) at their meetings. Guideline groups should require all members to declare their financial COIs before meeting and exclude or limit those members with COI. Governmental authorities should not allow continuing medical education credits to those educational events not complying with the above policies. The crucial role of medical journals as 'gatekeepers' for identifying 'science' must be reaffirmed.

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 assessment TLS 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 assessment It 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, I(2) = 33%, low‐quality evidence) or in miscarriage rates (OR 1.90, 95% CI 0.99 to 3.61, 3 RCTs, N = 826, I(2) = 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, I(2) = 0%, low‐quality evidence). TLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS images All 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, I(2) = 0%); or clinical pregnancy (OR 0.97, 95% CI 0.67 to 1.42, 2 RCTs, N = 463, I(2) = 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 assessment The 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, I(2) = 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, I(2) = 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, I(2) = 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.

Subfertility is common and affects one in six couples, half of whom lack an explanation for their delay in conceiving. Developments in the diagnosis and treatment of subfertility over the past 50 years have been truly remarkable. Indeed, current generations of couples with subfertility are more fortunate than previous generations, as they have many more opportunities to become parents. The timely access to effective treatment for subfertility is important as many couples have a narrow window of opportunity before the age-related effects of subfertility limit the likelihood of success. Assisted reproduction can overcome the barriers to fertility caused by tubal disease and low sperm count, but little progress has been made in reducing the effect of increasing age on ovarian function. The next 5–10 years will likely see further increases in birth rates in women with subfertility, a greater awareness of lifestyle factors and a possible refinement of current assisted reproduction techniques and the development of new ones. Such progress will bring challenging questions regarding the potential benefits and harms of treatments involving germ cell manipulation, artificial gametes, genetic screening of embryos and gene editing of embryos. We hope to see a major increase in fertility awareness, access to safe and cost-effective fertility care in low-income countries and a reduction in the current disparity of access to fertility care.

Hormone therapy (HT) has been used for over 50 years for treating menopausal vasomotor symptoms, and its efficacy is well established. HT consists of oestrogen either alone or combined with a progestogen. Progestogen use reduces the risk of endometrial hyperplasia associated with unopposed oestrogen in women with a uterus. Clinical effects vary according to the type of HT and duration of use. Until about 15 years ago, commonly held expert opinion (supported by strong observational evidence) was that most postmenopausal women could benefit from HT. It was widely used for the management or prevention of chronic conditions such as coronary heart disease (CHD) and osteoporotic fractures, and it was suggested that HT might also help to prevent cognitive decline and dementia. As CHD is the most common cause of death and morbidity in older women, a significant reduction in CHD risk would potentially outweigh any adverse effects of HT. Publication of evidence from the Heart and Estrogen/Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) trials in 2002 raised questions about the safety of HT.1 2 There are nine Cochrane systematic reviews about the effects of HT for perimenopausal and postmenopausal women. We felt it would be useful to include the most important long-term outcomes in a single Cochrane review, for the benefit of women contemplating its use for menopausal symptom relief. We decided to exclude studies shorter than 1 year and to exclude (as outcomes) menopausal symptom control, early-onset side effects and surrogate measures such as endometrial hyperplasia and bone mineral density. We recently published the third update of the review.3 We aimed to assess the effects of long-term HT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognitive function in perimenopausal and postmenopausal women during and after cessation of treatment. We included double-blinded randomised controlled trials (RCTs) …

BackgroundDuring a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle‐stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper‐response are associated with increased chance of cycle cancellation. Hyper‐response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti‐Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes.ObjectivesTo assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI.Search methodsWe searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies.Selection criteriaWe included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm.Data collection and analysisWe used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration.Main resultsWe included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta‐analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT‐algorithm studiesFour trials compared an ORT‐based algorithm to a non‐ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I2=0%, moderate‐quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT‐based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT‐based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs.Authors' conclusionsWe did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate‐quality evidence suggests that ORT‐based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT‐based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.

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 hysterectomy Moderate-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 hysterectomy Women 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 hysterectomy We 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 hysterectomy We 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 hysterectomy We 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 hysterectomy We 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 regimens Single 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.

Background Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. Objectives To assess effects of long-term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment. Search methods We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews. Selection criteria We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route. Data collection and analysis Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods. Main results We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000). Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time. Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use. Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer. One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause. For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms. Authors' conclusions Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented. HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.

Treatment of varicoceles may improve fertility outcomes in subfertile couples where the male has a varicocele. This systematic review evaluates surgical or radiologic interventions for clinical or subclinical varicoceles.

The past three decades have seen considerable change in the understanding of clinical research methods. There has been an acceptance that RCTs are the best way of establishing treatment effectiveness and a recognition that, while single studies are useful, pooling knowledge from a complete body of work is likely to provide the best evidence. Advances in methodology have been mirrored by the many advances in the field of reproductive medicine, such as assisted reproduction, assessment of male fertility, ovulation induction and laparoscopic surgery. Together, they have led to welcome improvements in the outcomes of fertility treatments. In particular, systematic reviews have become important tools enabling clinicians and patients to make health-care decisions based on evidence from all the available high-quality studies. The move towards identifying and aggregating the highest quality evidence has been led by the Cochrane Collaboration, which this year celebrates 20 years of preparing and publishing systematic reviews. This paper outlines the achievements, progress and challenges of this enterprise to date, with a particular focus on systematic reviews of reproductive medicine.

In this paper, a review of evidence provided to the World Health Organization (WHO) guideline development, who prepare global guidance on the management of ovarian stimulation for women undergoing IVF, is presented. The purpose of ovarian stimulation is to facilitate retrieval of multiple oocytes during a single IVF cycle. Availability of multiple oocytes compensates for inefficiencies in subsequent stages of the cycle, which include oocyte maturation, IVF, embryo culture, embryo transfer, and implantation. Multiple embryos can be transferred in most women, and spare embryos can be frozen to allow for future chances of pregnancy without the need for repeated ovarian stimulation and oocyte retrieval. Our evidence synthesis team addressed 10 clinical questions on management of ovarian stimulation for IVF, prepared a narrative review of the evidence and drafted recommendations to be considered through WHO guideline development processes. Our main outcome measures were live birth, clinical pregnancy, and ovarian hyperstimulation syndrome.

Background Various hormone therapies (HT) are available to treat menopausal vasomotor symptoms. Bioidentical hormones are chemically identical to those produced by the human body, and several types are well-tested and available on prescription. Many women have opted for bioidentical hormone therapy (BHT) on the assumption that it is safer than other forms of HT. We evaluated the evidence. Objectives To determine the effectiveness and safety of bioidentical hormones compared to placebo or non-bioidentical hormones for the relief of vasomotor symptoms. Search methods In July 2015 we searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS), registers of ongoing trials and the reference lists of articles retrieved. Selection criteria Randomised controlled trials (RCTs) comparing bioidentical hormone therapy (BHT) versus placebo or non-bioidentical hormones. Data collection and analysis We used standard methodological procedures expected by the Cochrane Collaboration. Our primary outcome was vasomotor symptoms (hot flushes and night sweats). We evaluated the overall quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation criteria (GRADE). Main results We included 23 RCTs (5779 participants). Most studies (20/23) included only women with moderate to severe hot flushes. All studies compared unopposed 17 beta-estradiol (beta-estradiol) versus placebo or conjugated equine estrogens (CEE). None of the studies reported night sweats as a separate outcome. BHT patch versus placebo Frequency of hot flushes Four RCTs reported data suitable for analysis. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.68, 95% CI -0.83 to -0.53, four RCTs, 793 women, I2 = 67%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Seven RCTs reported data unsuitable for analysis; all reported a benefit in the intervention group. Symptom intensity Two RCTs reported analysable data. Measured on a 0-100 visual analogue scale (VAS), hot flush intensity was lower in the BHT group (MD -19.94 points, 95% CI -24.86 to -15.02, two RCTs, 393 women, I2 = 54%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. Adverse effects Adverse events (such as headache, vaginal bleeding, breast tenderness and skin reactions) were more common in the intervention group (odds ratio (OR) 2.14, 95% CI 1.29 to 3.54, 9 RCTs, 1822 women, I2 = 73%, low quality evidence). There was moderate heterogeneity, but a consistent direction of effect. In one study, five women in the intervention group developed endometrial hyperplasia. BHT gel versus placebo Hot flush frequency Three RCTs reported this outcome, but the data were unsuitable for analysis. All reported a benefit in the BHT group. Adverse effects Adverse events were more common in the BHT group (OR 1.41, 95% CI 1.09 to 1.83, 3 RCTs, 1086 women, I2 = 0%, moderate quality evidence). Oral BHT versus placebo Hot flush frequency Two studies reported analysable data. There were fewer hot flushes in the BHT group, with a moderate to large effect size (SMD -0.80, 95% CI -1.03 to -0.57, two RCTs, 356 women, I2 = 14%, low quality evidence). Adverse effects There was no evidence of a difference between the groups (OR 1.28, 95% CI 0.84 to 1.96, 3 RCTs, 433 women, I2 = 0%, low quality evidence). Topical BHT emulsion versus placebo Hot flush frequency One study with data unsuitable for analysis reported a benefit in the intervention group. Adverse effects There was no evidence of a difference between the groups (OR 1.46, 95% CI 0.80 to 2.66, one RCT, 200 women, low quality evidence). Intranasal BHT versus placebo Hot flush frequency Only one study reported analysable data. There were fewer hot flushes per day in the BHT group (MD -3.04 95% CI -4.05 to -2.03, one study, 458 women, moderate quality evidence) Adverse effects Adverse events (such as headache, breast tenderness, arthralgia and nausea) were more common in the intervention group (OR 1.96, 95% CI 1.26 to 3.03, one RCT, 458 women, moderate quality evidence). Subgroup analyses Subgroup analyses by dose of BHT suggested that higher doses of BHT may be associated with more effectiveness but also higher risk of adverse effects. BHT patch versus 0.625 mg CEE Two RCTs reported this comparison, but the data were unsuitable for analysis. Hot flush frequency Both RCTs reported no evidence of a difference between the groups. Adverse effects Findings were inconsistent. In one comparison (0.1 mg BHT versus CEE), breast pain and vaginal bleeding were more frequent in the BHT group. Oral BHT versus 0.625 mg CEE Hot flush frequency One study with data unsuitable for analysis reported no evidence of a difference between the groups. Adverse effects There was no evidence of a difference between the groups (OR 1.20, 95% CI 0.50 to 2.87, one RCT, 103 women, very low quality evidence). Authors' conclusions There was low to moderate quality evidence that BHT in various forms and doses is more effective than placebo for treating moderate to severe menopausal hot flushes. There was low to moderate quality evidence of higher rates of adverse effects such as headache, vaginal bleeding, breast tenderness and skin reactions in the BHT group. There was some evidence to suggest that higher doses of BHT are associated with greater effectiveness but also with higher risk of adverse effects. Although all the included studies used unopposed estrogen, it is recommended best practice to use progestogen therapy in women with a uterus taking estrogen in order to avoid endometrial hyperplasia, regardless of the source of the estrogen. No data are yet available about the safety of BHT with regard to long-term outcomes such as heart attack, stroke and breast cancer. There was no good evidence of a difference in effectiveness between BHT and CEE, and findings with regard to adverse effects were inconsistent. The quality of the evidence was too low to reach any firm conclusions. The main limitations in the quality of the evidence were study risk of bias (mainly due to poor reporting of methods), imprecision and lack of data suitable for analysis.

Background Overall survival rates are disappointing for women with early poor prognosis breast cancer. Autologous transplantation of bone marrow or peripheral stem cells (in which the woman is both donor and recipient) has been considered a promising technique because it permits use of much higher doses of chemotherapy. Objectives To compare the effectiveness and safety of high-dose chemotherapy and autograft (either autologous bone marrow or stem cell transplantation) with conventional chemotherapy for women with early poor prognosis breast cancer. Search methods We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (1966 to October 2015), EMBASE (1980 to October 2015), the World Health Organization's International Clinical Trials Registry Search Platform, and ClinicalTrials.gov on the 21 October 2015. Selection criteria Randomised controlled trials (RCTs) comparing high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. Data collection and analysis Two review authors selected RCTs, independently extracted data and assessed risks of bias. We combined data using a Mantel-Haenszel fixed-effect model to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed the quality of the evidence using GRADE methods. Outcomes were survival rates, toxicity and quality of life. Main results We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas. There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women). There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women). Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year. The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. Authors' conclusions There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

Background Dysmenorrhoea refers to painful menstrual cramps and is a common gynaecological complaint. Conventional treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills (OCPs), which both reduce myometrial activity (contractions of the uterus). A suggested alternative approach is dietary supplements. We used the term 'dietary supplement' to include herbs or other botanical, vitamins, minerals, enzymes, and amino acids. We excluded traditional Chinese medicines. Objectives To determine the efficacy and safety of dietary supplements for treating dysmenorrhoea. Search methods We searched sources including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO (all from inception to 23 March 2015), trial registries, and the reference lists of relevant articles. Selection criteria We included randomised controlled trials (RCTs) of dietary supplements for moderate or severe primary or secondary dysmenorrhoea. We excluded studies of women with an intrauterine device. Eligible comparators were other dietary supplements, placebo, no treatment, or conventional analgesia. Data collection and analysis Two review authors independently performed study selection, performed data extraction and assessed the risk of bias in the included trials. The primary outcomes were pain intensity and adverse effects. We used a fixed-effect model to calculate odds ratios (ORs) for dichotomous data, and mean differences (MDs) or standardised mean differences (SMDs) for continuous data, with 95% confidence intervals (CIs). We presented data that were unsuitable for analysis either descriptively or in additional tables. We assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. Main results We included 27 RCTs (3101 women). Most included studies were conducted amongst cohorts of students with primary dysmenorrhoea in their late teens or early twenties. Twenty-two studies were conducted in Iran and the rest were performed in other middle-income countries. Only one study addressed secondary dysmenorrhoea. Interventions included 12 different herbal medicines (German chamomile (Matricaria chamomilla, M recutita, Chamomilla recutita), cinnamon (Cinnamomum zeylanicum, C. verum), Damask rose (Rosa damascena), dill (Anethum graveolens), fennel (Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), ginger (Zingiber officinale), guava (Psidium guajava), rhubarb (Rheum emodi), uzara (Xysmalobium undulatum), valerian (Valeriana officinalis), and zataria (Zataria multiflora)) and five non-herbal supplements (fish oil, melatonin, vitamins B1 and E, and zinc sulphate) in a variety of formulations and doses. Comparators included other supplements, placebo, no treatment, and NSAIDs. We judged all the evidence to be of low or very low quality. The main limitations were imprecision due to very small sample sizes, failure to report study methods, and inconsistency. For most comparisons there was only one included study, and very few studies reported adverse effects. Effectiveness of supplements for primary dysmenorrhoea We have presented pain scores (all on a visual analogue scale (VAS) 0 to 10 point scale) or rates of pain relief, or both, at the first post-treatment follow-up. Supplements versus placebo or no treatment There was no evidence of effectiveness for vitamin E (MD 0.00 points, 95% CI −0.34 to 0.34; two RCTs, 135 women). There was no consistent evidence of effectiveness for dill (MD -1.15 points, 95% CI −2.22 to −0.08, one RCT, 46 women), guava (MD 0.59, 95% CI −0.13 to 1.31; one RCT, 151 women); one RCT, 73 women), or fennel (MD −0.34 points, 95% CI −0.74 to 0.06; one RCT, 43 women). There was very limited evidence of effectiveness for fenugreek (MD −1.71 points, 95% CI −2.35 to −1.07; one RCT, 101 women), fish oil (MD 1.11 points, 95% CI 0.45 to 1.77; one RCT, 120 women), fish oil plus vitamin B1 (MD −1.21 points, 95% CI −1.79 to −0.63; one RCT, 120 women), ginger (MD −1.55 points, 95% CI −2.43 to −0.68; three RCTs, 266 women; OR 5.44, 95% CI 1.80 to 16.46; one RCT, 69 women), valerian (MD −0.76 points, 95% CI −1.44 to −0.08; one RCT, 100 women), vitamin B1 alone (MD −2.70 points, 95% CI −3.32 to −2.08; one RCT, 120 women), zataria (OR 6.66, 95% CI 2.66 to 16.72; one RCT, 99 women), and zinc sulphate (MD −0.95 points, 95% CI −1.54 to −0.36; one RCT, 99 women). Data on chamomile and cinnamon versus placebo were unsuitable for analysis. Supplements versus NSAIDS There was no evidence of any difference between NSAIDs and dill (MD 0.13 points, 95% CI −1.01 to 1.27; one RCT, 47 women), fennel (MD −0.70 points, 95% CI −1.81 to 0.41; one RCT, 59 women), guava (MD 1.19, 95% CI 0.42 to 1.96; one RCT, 155 women), rhubarb (MD −0.20 points, 95% CI −0.44 to 0.04; one RCT, 45 women), or valerian (MD points 0.62 , 95% CI 0.03 to 1.21; one RCT, 99 women), There was no consistent evidence of a difference between Damask rose and NSAIDs (MD −0.15 points, 95% CI −0.55 to 0.25; one RCT, 92 women). There was very limited evidence that chamomile was more effective than NSAIDs (MD −1.42 points, 95% CI −1.69 to −1.15; one RCT, 160 women). Supplements versus other supplements There was no evidence of a difference in effectiveness between ginger and zinc sulphate (MD 0.02 points, 95% CI −0.58 to 0.62; one RCT, 101 women). Vitamin B1 may be more effective than fish oil (MD −1.59 points, 95% CI −2.25 to −0.93; one RCT, 120 women). Effectiveness of supplements for secondary dysmenorrhoea There was no strong evidence of benefit for melatonin compared to placebo for dysmenorrhoea secondary to endometriosis (data were unsuitable for analysis). Safety of supplements Only four of the 27 included studies reported adverse effects in both treatment groups. There was no evidence of a difference between the groups but data were too scanty to reach any conclusions about safety. Authors' conclusions There is no high quality evidence to support the effectiveness of any dietary supplement for dysmenorrhoea, and evidence of safety is lacking. However for several supplements there was some low quality evidence of effectiveness and more research is justified.

Background A wide variety of grafts have been introduced with the aim of improving the outcomes of traditional native tissue repair (colporrhaphy) for vaginal prolapse. Objectives To determine the safety and effectiveness of transvaginal mesh or biological grafts compared to native tissue repair for vaginal prolapse. Search methods We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ongoing trials registers, and handsearching of journals and conference proceedings (6 July 2015). We also contacted researchers in the field. Selection criteria Randomised controlled trials (RCTs) comparing different types of vaginal repair (mesh, biological graft, or native tissue). Data collection and analysis Two review authors independently selected trials, assessed risk of bias, and extracted data. The primary outcomes were awareness of prolapse, repeat surgery, and recurrent prolapse on examination. Main results We included 37 RCTs (4023 women). The quality of the evidence ranged from very low to moderate. The main limitations were poor reporting of study methods, inconsistency, and imprecision. Permanent mesh versus native tissue repair Awareness of prolapse at one to three years was less likely after mesh repair (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.54 to 0.81, 12 RCTs, n = 1614, I2 = 3%, moderate-quality evidence). This suggests that if 19% of women are aware of prolapse after native tissue repair, between 10% and 15% will be aware of prolapse after permanent mesh repair. Rates of repeat surgery for prolapse were lower in the mesh group (RR 0.53, 95% CI 0.31 to 0.88, 12 RCTs, n = 1675, I2 = 0%, moderate-quality evidence). There was no evidence of a difference between the groups in rates of repeat surgery for continence (RR 1.07, 95% CI 0.62 to 1.83, 9 RCTs, n = 1284, I2 = 21%, low-quality evidence). More women in the mesh group required repeat surgery for the combined outcome of prolapse, stress incontinence, or mesh exposure (RR 2.40, 95% CI 1.51 to 3.81, 7 RCTs, n = 867, I2 = 0%, moderate-quality evidence). This suggests that if 5% of women require repeat surgery after native tissue repair, between 7% and 18% in the permanent mesh group will do so. Eight per cent of women in the mesh group required repeat surgery for mesh exposure. Recurrent prolapse on examination was less likely after mesh repair (RR 0.40, 95% CI 0.30 to 0.53, 21 RCTs, n = 2494, I2 = 73%, low-quality evidence). This suggests that if 38% of women have recurrent prolapse after native tissue repair, between 11% and 20% will do so after mesh repair. Permanent mesh was associated with higher rates of de novo stress incontinence (RR 1.39, 95% CI 1.06 to 1.82, 12 RCTs, 1512 women, I2 = 0%, low-quality evidence) and bladder injury (RR 3.92, 95% CI 1.62 to 9.50, 11 RCTs, n = 1514, I2 = 0%, moderate-quality evidence). There was no evidence of a difference between the groups in rates of de novo dyspareunia (RR 0.92, 95% CI 0.58 to 1.47, 11 RCTs, n = 764, I2 = 21%, low-quality evidence). Effects on quality of life were uncertain due to the very low-quality evidence. Absorbable mesh versus native tissue repair There was very low-quality evidence for the effectiveness of either form of repair at two years on the rate of awareness of prolapse (RR 1.05, 95% CI 0.77 to 1.44, 1 RCT, n = 54). There was very low-quality evidence for the effectiveness of either form of repair on the rate of repeat surgery for prolapse (RR 0.47, 95% CI 0.09 to 2.40, 1 RCT, n = 66). Recurrent prolapse on examination was less likely in the mesh group (RR 0.71, 95% CI 0.52 to 0.96, 3 RCTs, n = 292, I2 = 21%, low-quality evidence) The effect of either form of repair was uncertain for urinary outcomes, dyspareunia, and quality of life. Biological graft versus native tissue repair There was no evidence of a difference between the groups at one to three years for the outcome awareness of prolapse (RR 0.97, 95% CI 0.65 to 1.43, 7 RCTs, n = 777, low-quality evidence). There was no evidence of a difference between the groups for the outcome repeat surgery for prolapse (RR 1.22, 95% CI 0.61 to 2.44, 5 RCTs, n = 306, I2 = 8%, low-quality evidence). The effect of either approach was very uncertain for recurrent prolapse (RR 0.94, 95% CI 0.60 to 1.47, 7 RCTs, n = 587, I2 = 59%, very low-quality evidence). There was no evidence of a difference between the groups for dyspareunia or quality of life outcomes (very low-quality evidence). Authors' conclusions While transvaginal permanent mesh is associated with lower rates of awareness of prolapse, repeat surgery for prolapse, and prolapse on examination than native tissue repair, it is also associated with higher rates of repeat surgery for prolapse or stress urinary incontinence or mesh exposure (as a composite outcome), and with higher rates of bladder injury at surgery and de novo stress urinary incontinence. The risk-benefit profile means that transvaginal mesh has limited utility in primary surgery. While it is possible that in women with higher risk of recurrence the benefits may outweigh the risks, there is currently no evidence to support this position. Limited evidence suggests that absorbable mesh may reduce rates of recurrent prolapse on examination compared to native tissue repair, but there was insufficient evidence on absorbable mesh for us to draw any conclusions for other outcomes. There was also insufficient evidence for us to draw any conclusions regarding biological grafts compared to native tissue repair. In 2011, many transvaginal permanent meshes were voluntarily withdrawn from the market, and the newer, lightweight transvaginal permanent meshes still available have not been evaluated within a RCT. In the meantime, these newer transvaginal meshes should be utilised under the discretion of the ethics committee.

Item does not contain fulltext Follicle-stimulating hormone (FSH) given as a weekly injection in a medium dose is as safe and effective as a daily FSH injection for women undergoing assisted reproduction.

A policy of repeated single embryo transfer (SET) may minimize the risk of multiple pregnancy without substantially reducing live birth rates. We need more evidence on policies for repeated SET, including the best way to use available embryos within a single in vitro fertilization cycle until success is achieved or the supply of embryos is exhausted.

In women with polycystic ovary syndrome, metformin treatment before or during assisted reproductive technology cycles increases clinical pregnancy rates and decreases the risk of ovarian hyperstimulation syndrome. However, there is no conclusive evidence of a benefit in live birth rates.

BACKGROUND: As many as one in six couples will encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months. Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex, and each ART cycle consists of several steps. If one of these steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step of the ART cycle is supported by good evidence from well‐designed studies. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews on procedures and treatment options available to couples with subfertility undergoing assisted reproductive technology (ART) procedures. METHODS: Published Cochrane systematic reviews of couples undergoing ART procedures (in vitro fertilisation or intracytoplasmic sperm injection) were eligible for inclusion in the overview. We also identified Cochrane reviews in preparation, for future inclusion. The primary outcome of the overview was live birth or the composite outcome live birth or ongoing pregnancy, as reported by the included reviews. Our secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage, and ovarian hyperstimulation syndrome. We excluded studies of intrauterine insemination and ovulation induction. We undertook selection of systematic reviews, data extraction, and quality assessment in duplicate. We assessed review quality by using the AMSTAR tool. We organised reviews by their relevance to specific stages in the ART cycle. We summarised their findings in the text and reported data for each outcome in 'Additional tables'. MAIN RESULTS: We included 68 systematic reviews published in the Cochrane Library up to May 2018. All were of high quality. These reviews identified 38 interventions that were effective (n = 23) or promising (n = 15), and they identified 19 interventions that were ineffective (n = 2) or possibly ineffective (n = 17). For 15 interventions, review authors were unable to draw conclusions owing to lack of evidence. We identified an additional 11 protocols and four titles for future inclusion in this overview. AUTHORS' CONCLUSIONS: This overview provides the most up‐to‐date evidence on ART cycles from systematic reviews of randomised controlled trials. Fertility treatments are costly, and the stakes are high. Using the best available evidence to optimise outcomes is best practice. Evidence from this overview could be used to develop clinical practice guidelines and protocols that can be applied in daily clinical practice to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.

Item does not contain fulltext Polycystic ovary syndrome (PCOS) is a common cause of anovulatory subfertility. We evaluated the effectiveness and safety of aromatase inhibitors compared with other methods of ovulation induction in women with anovulatory PCOS.

Background Ten per cent to 15% of couples have difficulty in conceiving. A proportion of these couples will ultimately require assisted reproduction. Prior to controlled ovarian hyperstimulation (COH) a baseline ultrasound is performed to detect the presence of ovarian cysts. Previous research has suggested that there is a relationship between the presence of an ovarian cyst prior to COH and poor outcome of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Objectives The aim of this review was to determine the effectiveness and safety of functional ovarian cyst aspiration prior to ovarian stimulation versus a conservative approach in women with an ovarian cyst who were undergoing IVF or ICSI. Search methods We searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, Google Scholar and PubMed. The evidence was current to April 2014 and no language restrictions were applied. Selection criteria We included all randomized controlled trials (RCTs) comparing functional ovarian cyst aspiration versus conservative management of ovarian cysts that have been seen on transvaginal ultrasound (TVS) prior to COH for IVF or ICSI. Ovarian cysts were defined as simple, functional ovarian cysts > 20 mm in diameter. Oocyte donors and women undergoing donor oocyte cycles were excluded. Data collection and analysis Study selection, data extraction and risk of bias assessments were conducted independently by two review authors. The primary outcome measures were live birth rate and adverse events. The overall quality of the evidence for each comparison was rated using GRADE methods. Main results Three studies were eligible for inclusion (n = 339), all of which used agonist protocols. Neither live birth rate nor adverse events were reported by any of the included studies. There was insufficient evidence to determine whether there was a difference in the clinical pregnancy rate between the group who underwent ovarian cyst aspiration and the conservatively managed group (OR 1.19, 95% CI 0.33 to 4.29, two RCTs, 159 women, I2 = 0%, very low quality evidence). This suggested that if the clinical pregnancy rate in women with conservative management was assumed to be 6%, the chance following cyst aspiration would be between 2% and 22%. There was no evidence of a difference between the groups in the mean number of follicles recruited (0.55 follicles, 95% CI -0.48 to 1.59, 2 studies, 159 women, I2 = 0%, very low quality evidence) mean number of oocytes collected (0.41 oocytes, 95% CI -0.04 to 0.85, 3 studies, 339 women, I2 = 0%, low quality evidence) or cancellation rate (OR 0.99, 95% CI 0.42 to 2.33, one RCT, 122 women, very low quality evidence). The main limitations of the evidence were imprecision, risk of bias associated with poor reporting of study methods, and inconsistent reporting of study findings in one RCT which meant that some of the data could not be used. Authors' conclusions There is insufficient evidence to determine whether drainage of functional ovarian cysts prior to controlled ovarian hyperstimulation influences rates of live birth, clinical pregnancy, number of follicles recruited, or number of oocytes collected in women with a functional ovarian cyst. The findings of this review do not provide supportive evidence for this approach, particularly in view of the requirement for anaesthesia, extra cost, psychological stress and risk of surgical complications.

Background Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone therapy has traditionally been used as a highly effective treatment, but concerns about increased risk of some chronic diseases have markedly increased the interest of women in alternative treatments. Some of the most popular of these treatments are foods or supplements enriched with phytoestrogens—plant-derived chemicals that have estrogenic action. Objectives To assess the efficacy, safety and acceptability of food products, extracts and dietary supplements containing high levels of phytoestrogens when compared with no treatment, placebo or hormone therapy for the amelioration of vasomotor menopausal symptoms (such as hot flushes and night sweats) in perimenopausal and postmenopausal women. Search methods Searches targeted the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials (29 July 2013), the Cochrane Register of Controlled Trials (CENTRAL; 29 July 2013), MEDLINE (inception to 29 July 2013), EMBASE (inception to 29 July 2013), AMED (1985 to 29 July 2013), PsycINFO (inception to 29 July 2013) and CINAHL (inception to 29 July 2013). Attempts were made to access grey literature by sending letters to pharmaceutical companies and performing searches of ongoing trial registers. Reference lists of included trials were also searched. Selection criteria Studies were included if they were randomised, included perimenopausal or postmenopausal participants with vasomotor symptoms (hot flushes or night sweats), lasted at least 12 weeks and provided interventions such as foods or supplements with high levels of phytoestrogens (not combined with other herbal treatments). Trials that included women who had breast cancer or a history of breast cancer were excluded. Data collection and analysis Selection of trials, extraction of data and assessment of quality were undertaken by at least two review authors. Most trials were too dissimilar for their results to be combined in a meta-analysis, so these findings are provided in narrative 'Summary of results' tables. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts, genistein extracts and other types of phytoestrogens. Five trials used Promensil, a red clover extract; results of these trials were combined in a meta-analysis, and summary effect measures were calculated. Main results A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I2 = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I2 = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years. Authors' conclusions No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.

The addition of adherence compounds to embryo transfer medium may improve fertility outcomes in women undergoing assisted reproductive technologies.

It is suggested that heparin given in the peri-implantation period may improve clinical outcomes in women undergoing assisted reproduction techniques (ART). This systematic review evaluates the use of heparin in subfertile women undergoing ART.

BACKGROUND: Transfer of more than one embryo during in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) increases multiple pregnancy rates resulting in an increased risk of maternal and perinatal morbidity. Elective single embryo transfer offers a means of minimising this risk, but this potential gain needs to be balanced against the possibility of jeopardising the overall live birth rate (LBR). OBJECTIVES: To evaluate the effectiveness and safety of different policies for the number of embryos transferred in infertile couples undergoing assisted reproductive technology cycles. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialised register of controlled trials, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to March 2020. We handsearched reference lists of articles and relevant conference proceedings. We also communicated with experts in the field regarding any additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different policies for the number of embryos transferred following IVF or ICSI in infertile women. Studies of fresh or frozen and thawed transfer of one to four embryos at cleavage or blastocyst stage were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial eligibility and risk of bias. The primary outcomes were LBR and multiple pregnancy rate. The secondary outcomes were clinical pregnancy and miscarriage rates. We analysed data using risk ratios (RR), Peto odds ratio (Peto OR) and a fixed effect model. MAIN RESULTS: We included 17 RCTs in the review (2505 women). The main limitation was inadequate reporting of study methods and moderate to high risk of performance bias due to lack of blinding. A majority of the studies had low numbers of participants. None of the trials compared repeated single embryo transfer (SET) with multiple embryo transfer. Reported results of multiple embryo transfer below refer to double embryo transfer. Repeated single embryo transfer versus multiple embryo transfer in a single cycle Repeated SET was compared with double embryo transfer (DET) in four studies of cleavage‐stage transfer. In these studies the SET group received either two cycles of fresh SET (one study) or one cycle of fresh SET followed by one frozen SET (three studies). The cumulative live birth rate after repeated SET may be little or no different from the rate after one cycle of DET (RR 0.95, 95% CI (confidence interval) 0.82 to 1.10; I² = 0%; 4 studies, 985 participants; low‐quality evidence). This suggests that for a woman with a 42% chance of live birth following a single cycle of DET, the repeated SET would yield pregnancy rates between 34% and 46%. The multiple pregnancy rate associated with repeated SET is probably reduced compared to a single cycle of DET (Peto OR 0.13, 95% CI 0.08 to 0.21; I² = 0%; 4 studies, 985 participants; moderate‐quality evidence). This suggests that for a woman with a 13% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 3%. The clinical pregnancy rate (RR 0.99, 95% CI 0.87 to 1.12; I² = 47%; 3 studies, 943 participants; low‐quality evidence) after repeated SET may be little or no different from the rate after one cycle of DET. There may be little or no difference in the miscarriage rate between the two groups. Single versus multiple embryo transfer in a single cycle A single cycle of SET was compared with a single cycle of DET in 13 studies, 11 comparing cleavage‐stage transfers and three comparing blastocyst‐stage transfers.One study reported both cleavage and blastocyst stage transfers. Low‐quality evidence suggests that the live birth rate per woman may be reduced in women who have SET in comparison with those who have DET (RR 0.67, 95% CI 0.59 to 0.75; I² = 0%; 12 studies, 1904 participants; low‐quality evidence). Thus, for a woman with a 46% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 27% and 35%. The multiple pregnancy rate per woman is probably lower in those who have SET than those who have DET (Peto OR 0.16, 95% CI 0.12 to 0.22; I² = 0%; 13 studies, 1952 participants; moderate‐quality evidence). This suggests that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 2% and 4%. Low‐quality evidence suggests that the clinical pregnancy rate may be lower in women who have SET than in those who have DET (RR 0.70, 95% CI 0.64 to 0.77; I² = 0%; 10 studies, 1860 participants; low‐quality evidence). There may be little or no difference in the miscarriage rate between the two groups. AUTHORS' CONCLUSIONS: Although DET achieves higher live birth and clinical pregnancy rates per fresh cycle, the evidence suggests that the difference in effectiveness may be substantially offset when elective SET is followed by a further transfer of a single embryo in fresh or frozen cycle, while simultaneously reducing multiple pregnancies, at least among women with a good prognosis. The quality of evidence was low to moderate primarily due to inadequate reporting of study methods and absence of masking those delivering, as well as receiving the interventions.

Background Intrauterine insemination (IUI) is a common treatment for couples with subfertility that does not involve the fallopian tubes. It is used to bring the sperm close to the released oocyte. Another method of introducing sperm is fallopian tube sperm perfusion (FSP). Fallopian tube sperm perfusion ensures the presence of higher sperm densities in the fallopian tubes at the time of ovulation than does standard IUI. These treatments are often used in combination with ovarian hyperstimulation. Objectives To compare intrauterine insemination versus fallopian tube sperm perfusion in the treatment of non-tubal subfertility, for live birth and pregnancy outcomes. Search methods We searched the Menstrual Disorders and Subfertility Group Trials Register, MEDLINE, CINAHL and EMBASE from inception to September 2013. We also searched study reference lists and trial registers. Selection criteria Randomised controlled trials (RCTs) comparing IUI with FSP in couples with non-tubal subfertility were included. Data collection and analysis Two review authors independently selected studies for inclusion, assessed study quality and extracted the data. If studies were sufficiently similar, data were combined using a fixed-effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). A random-effects model was used if substantial statistical heterogeneity was detected. Studies that included participants with unexplained or mixed (non-tubal) subfertility were analysed separately from studies restricted to participants with mild or moderate male factor subfertility. The overall quality of evidence for the main outcomes was summarised using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Main results The review included 16 RCTs. Fourteen RCTs (1745 women) were included in the meta-analysis. Only three studies reported live birth per couple. No evidence of a statistically significant difference was noted between IUI and FSP in live birth (OR 0.94, 95% CI 0.59 to 1.49, three RCTs, 633 women, I-2 = 0%, low-quality evidence) or clinical pregnancy (OR 0.75, 95% CI 0.49 to 1.12, 14 RCTs, 1745 women, I-2 = 52%, low-quality evidence). These findings suggest that for a couple with a 13% chance of live birth using FSP, the chance when using IUI will be between 8% and 19%; and that for a couple with a 19% chance of pregnancy using FSP, the chance of pregnancy when using IUI will be between 10% and 20%. Nor was evidence found of a statistically significant difference between IUI and FSP in per-pregnancy of multiple pregnancy (OR 0.96, 95% CI 0.44 to 2.07, eight RCTs, 197 women, I-2 = 0%, low-quality evidence), miscarriage (OR 1.23, 95% CI 0.60 to 2.53, seven RCTs, 199 women, I-2 = 0%, low-quality evidence) or ectopic pregnancy (OR 1.71, 95% CI 0.42 to 6.88, four RCTs, 111 women, I-2 = 0%, very low quality evidence). Substantial heterogeneity was noted for the outcome of clinical pregnancy (I-2 = 54%), for which no clear explanation was provided. Authors' conclusions Currently no clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety for treating couples with non-tubal subfertility. However, a high level of uncertainty is evident in the findings, and additional research may be useful.

BACKGROUND: Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well‐being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo. OBJECTIVES: The objective of this review is to assess which hormone therapy regimens provide effective protection against the development of endometrial hyperplasia or carcinoma. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2012), The Cochrane Library (Issue 1, 2012), MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), Current Contents (1993 to May 2008), Biological Abstracts (1969 to 2008), Social Sciences Index (1980 to May 2008), PsycINFO (1972 to January 2012) and CINAHL (1982 to May 2008). Attempts were made to identify trials from citation lists of reviews and studies retrieved, and drug companies were contacted for unpublished data. SELECTION CRITERIA: Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen‐progestogen therapy, sequential estrogen‐progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted. DATA COLLECTION AND ANALYSIS: In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta‐analysis for many outcomes. MAIN RESULTS: Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low‐dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events). AUTHORS' CONCLUSIONS: Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia.

BACKGROUND: Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess effects of long‐term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment. SEARCH METHODS: We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews. SELECTION CRITERIA: We included randomised double‐blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods. MAIN RESULTS: We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well‐conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow‐up: from 5 per 1000 to between 6 and 13 per 1000). Oestrogen‐only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow‐up time. Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long‐term use. Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen‐only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer. One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen‐only HT versus similar‐sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause. For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms. AUTHORS' CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short‐term use of low‐dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen‐only HT is well documented. HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non‐oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long‐term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.

Background Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. However, women with PCOS who are treated with medical ovulation induction, with drugs such as gonadotrophins, often have an over-production of follicles which may result in ovarian hyperstimulation syndrome and multiple pregnancies. Moreover, gonadotrophins, though effective, are costly and time-consuming and their use requires intensive monitoring. Surgical therapy with laparoscopic ovarian 'drilling' (LOD) may avoid or reduce the need for medical ovulation induction, or may facilitate its usefulness. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with traditional surgical approaches. Many uncontrolled observational studies have claimed that ovarian drilling is followed, at least temporarily, by a high rate of spontaneous ovulation and conception, or that subsequent medical ovulation induction becomes easier. Objectives To determine the effectiveness and safety of laparoscopic ovarian drilling compared with ovulation induction for subfertile women with clomiphene-resistant PCOS. Search methods We used the search strategy of the Menstrual Disorders and Subfertility Group (MDSG) to search the MDSG Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO. The keywords included polycystic ovary syndrome, laparoscopic ovarian drilling, electrocautery and diathermy. Searches were conducted in September 2011, and a further search of the MDSG Trials Register was made on 14 May 2012. Selection criteria We included randomised controlled trials of subfertile women with clomiphene-resistant PCOS who undertook laparoscopic ovarian drilling in order to induce ovulation. Data collection and analysis This is an update of a previously updated review. There were nine RCTs in the previous version; an additional 16 trials were added in the current (2012) update. All trials were assessed for quality. The primary outcomes were live birth and multiple pregnancy. The secondary outcomes were rate of miscarriage, ovulation and pregnancy rates, ovarian hyperstimulation syndrome (OHSS), quality of life and cost. Main results Nine trials, including 1210 women, reported on the primary outcome of live birth rate per couple. Live births were reported in 34% of women in the LOD groups and 38% in other medical treatment groups. There were five different comparisons with LOD and there was no evidence of a difference in live births when compared with clomiphene citrate + tamoxifen (OR 0.81; 95% CI 0.42 to 1.53; P = 0.51, 1 trial, n = 150), gonadotrophins (OR 0.97; 95% CI 0.59 to 1.59; P = 0.89, I(2) = 0%, 2 trials, n = 318), aromatase inhibitors (OR 0.84; 95% CI 0.54 to 1.31; P = 0.44, I(2) = 0%, 2 trials, n = 407) or clomiphene citrate (OR 1.21; 95%CI 0.64 to 2.32; 1 trial, n=176, P= 0.05). There was evidence of significantly fewer live births following LOD compared with clomiphene citrate + metformin (OR 0.44; 95% CI 0.24 to 0.82; P = 0.01, I(2) = 78%, 2 trials, n = 159); the high heterogeneity in this subgroup could not be explained by population differences or differences in quality of the trials.Thirteen trials reported on multiple pregnancies (n= 1305 women). There were no cases of multiple pregnancies in either group for clomiphene citrate or aromatase inhibitors compared with LOD. The rate of multiple pregnancies was significantly lower in the LOD group compared with trials using gonadotrophins (OR 0.13; 95% CI 0.03 to 0.52; P=0.004, I(2) = 0%, 5 trials, n = 166). Authors' conclusions There was no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive. However, there are ongoing concerns about the long-term effects of LOD on ovarian function.

Background Traditionally Chinese herbal medicine (CHM) has been used widely in Chinese hospitals to treat ectopic pregnancy. Many studies have been published supporting its use but the evidence has not been systematically reviewed. This is and update of the review published in 2007. Objectives To determine the effectiveness and safety of CHM in the treatment of ectopic pregnancy. Search strategy Computerised databases (CENTRAL (The Cochrane Library), MEDLINE, EMBASE, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP, Traditional Chinese Medicine Database System) were searched from their inception to November 2010 for relevant trials. Selection criteria Randomised controlled trials (RCT) on the use of CHM for the treatment of ectopic pregnancy. Data collection and analysis Original authors of the identified studies were contacted to determine the trial design and identify authentic RCTs. Two review authors extracted and analysed the data. Main results The search identified 281 trials. Only two studies involving a total of 157 participants were confirmed to be authentic RCTs (Li 2004c; Zhao 2000). Both were of poor methodological quality with a high risk of conflicted interest and potential for bias in favour of the intervention. We could not reach a definitive conclusion from the results. The pooled result showed that adding a Western medicine to CHM resulted in a significantly higher treatment success rate than with CHMalone (RR 1.33, 95% CI 1.08 to 1.63). When CHM plus Western medicine was compared to CHM alone for the time to disappearance of abdominal pain, again the results favoured the arm that included Western medicine (RR -2.09, 95% CI -4.14 to -0.04). Results were inconsistent for the time required for human chorionic gonadotropin (beta-hCG) to return to normal. One study favoured CHM plus Western medicine over Western medicine (with or without placebo) (MD -6.68, 95% CI -11.49 to -1.87); when CHM plus Western medicine was compared to CHM alone the results favoured the arm that included Western medicine (MD -8.12, 95% CI -10.89 to -5.53). Authors' conclusions We have not found any well-designed trials investigating Chinese herbal medicines in the treatment of ectopic pregnancy. We cannot support or refute any CHM preparation for clinical use on the basis of evidence from randomised controlled trials.

Hormone therapy (HT) is widely used for controlling menopausal symptoms and has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of the original Cochrane review first published in 2005.To assess the effect of long-term HT on mortality, cardiovascular outcomes, cancer, gallbladder disease, cognition, fractures and quality of life.We searched the following databases to November 2007: Trials Register of the Cochrane Menstrual Disorders and Subfertility Group, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Biological Abstracts. Also relevant non-indexed journals and conference abstracts.Randomised double-blind trials of HT versus placebo, taken for at least one year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via oral, transdermal, subcutaneous or transnasal routes.Two authors independently assessed trial quality and extracted data.Nineteen trials involving 41,904 women were included. In relatively healthy women, combined continuous HT significantly increased the risk of venous thrombo-embolism or coronary event (after one year's use), stroke (after three years), breast cancer and gallbladder disease. Long-term oestrogen-only HT significantly increased the risk of venous thrombo-embolism, stroke and gallbladder disease (after one to two years, three years and seven years' use respectively), but did not significantly increase the risk of breast cancer. The only statistically significant benefits of HT were a decreased incidence of fractures and (for combined HT) colon cancer, with long-term use. Among women aged over 65 who were relatively healthy (i.e. generally fit, without overt disease) and taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thrombo-embolism.One trial analysed subgroups of 2839 relatively healthy 50 to 59 year old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thrombo-embolism in women taking combined continuous HT: their absolute risk remained low, at less than 1/500. However, this study was not powered to detect differences between groups of younger women.HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women.

Background Traditional Chinese herbal medicine (CHM) has been used widely in Chinese hospitals to treat ectopic pregnancy. Many studies have been published supporting its use but the evidence has not been systematically reviewed. Objectives To determine the effectiveness and safety of CHM in the treatment of ectopic pregnancy. Search strategy Computerised databases (CENTRAL (The Cochrane Library), MEDLINE, EMBASE, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP, Traditional Chinese Medicine Database System) were searched from their inception to March 2006 for relevant trials. Selection criteria Randomised controlled trials (RCT) on the use of CHM for the treatment of ectopic pregnancy. Data collection and analysis Original authors of the identified studies were contacted to determine the trial design and identify authentic RCTs. Two review authors extracted and analysed the data. Main results The search identified 166 trials. Only two studies involving a total of 157 participants were confirmed to be authentic RCTs ( Li 2004c; Zhao 2000). Both were of poor methodological quality with a high risk of conflicted interest and potential for bias in favour of the intervention. We could not reach a definitive conclusion from the results. The pooled result showed that adding a Western medicine to CHM resulted in a significantly higher treatment success rate than with CHM alone (RR 1.33, 95% CI 1.08 to 1.63). When CHM plus Western medicine was compared to CHM alone for the time to disappearance of abdominal pain, again the results favoured the arm that included Western medicine (RR -2.09, 95% CI -4.14 to -0.04). Results were inconsistent for the time required for human chorionic gonadotropin (beta-hCG) to return to normal. One study favoured CHM plus Western medicine over Western medicine (with or without placebo) (WMD -6.68, 95% CI -11.49 to -1.87); when CHM plus Western medicine was compared to CHM alone the results favoured the arm that included Western medicine (WMD -8.12, 95% CI -10.89 to -5.53). Authors' conclusions We have not found any well-designed trials investigating traditional Chinese herbal medicines in the treatment of ectopic pregnancy. We cannot support or refute any CHM preparation for clinical use on the basis of evidence from randomised controlled trials.

Background Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone replacement therapy has traditionally been used as a very effective treatment but concerns over increased risks of some chronic diseases have markedly increased the interest of women in alternatives. Some of the most popular of these are treatments based on foods or supplements enriched with phytoestrogens, plant-derived chemicals that have oestrogenic action. Objectives To assess the efficacy, safety and acceptability of foods and supplements based on high levels of phytoestrogens for reducing hot flushes and night sweats in postmenopausal women. Search methods Searches were undertaken of the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials, Cochrane Register of Controlled Trials (CENTRAL) (March 2007), MEDLINE (1966 to March 2007), EMBASE (1980 to March 2007), AMED (1985 to March 2007), PsycINFO (1986 to March 2007) and CINAHL (1982 to March 2007). Attempts were made to access grey literature by letters to pharmaceutical companies and searches of ongoing trial registers. Reference lists of included trials were also searched. Selection criteria Studies were included if they were randomised, had peri- or postmenopausal participants with vasomotor symptoms, a duration of at least 12 weeks and where the intervention was a food or supplement with high levels of phytoestrogens (and not combined with other herbal treatments). Trials of women who had breast cancer or a history of breast cancer were excluded. Data collection and analysis Selection of trials, data extraction and quality assessment were undertaken by at least two authors. Most of the trials were too dissimilar to combine in meta-analysis and their results are provided in table format. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts and other types of phytoestrogen. Five trials used Promensil, a red clover extract; these trials were combined in a meta-analysis and summary effect measures were calculated. Main results Thirty trials comparing phytoestrogens with control met the inclusion criteria. Very few trials had data suitable for combining in meta-analysis. Of the five trials with data suitable for pooling that assessed daily frequency of hot flushes, there was no significant difference overall in the frequency of hot flushes between Promensil (a red clover extract) and placebo (WMD=-0.6, 95% CI -1.8 to 0.6). There was no evidence of a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (WMD=20.2, 95% CI -12.1 to 52.4). Individual results from the remaining trials were compared. Some of the trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared to placebo but many of the trials were of low quality and were underpowered. There was a strong placebo effect in most trials with a reduction in frequency ranging from 1% to 59% with placebo. There was no indication that the discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. There was also no evidence that the treatments caused oestrogenic stimulation of the endometrium (an adverse effect) when used for up to two years. Authors' conclusions There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments.

Summary Background High dose chemotherapy with autologous transplantation of bone marrow or peripheral stem cells (autograft) has been considered promising for treating poor prognosis breast cancer. We reviewed the relevant evidence. Methods We included randomised controlled trials comparing high dose chemotherapy and autograft with conventional chemotherapy for women with early poor prognosis breast cancer. We searched medical databases (Cochrane Library, MEDLINE, EMBASE), websites (co-operative cancer research groups, American Society of Clinical Oncologists) and citations of articles found, to September 2006. Where appropriate, data were pooled to obtain a relative risk, using a fixed effects model. Clinical, methodological and statistical heterogeneity were examined with sensitivity analyses. Findings Thirteen trials with 5064 women were included. There was a significant benefit in event-free survival for the high dose group at three years (RR 1.19 (95% CI 1.06, 1.19)) and four years (RR 1.24 (95% CI 1.03, 1.50)) and at five years this benefit approached statistical significance (RR 1.06 (95% CI 1.00, 1.13)). Overall survival rates were not significantly different at any stage of follow up. There were significantly more treatment-related deaths on the high dose arm (RR 8.58 (95% CI 4.13, 17.80)). Morbidity was higher in the high dose group but there was no significant difference in the incidence of second cancers. The high dose group reported significantly worse quality of life immediately after treatment, but there were few differences by one year. Interpretation There is insufficient evidence supporting routine use of high dose chemotherapy with autograft for treating early poor prognosis breast cancer.

Background There is a hypothesis that high dose chemotherapy with autologous bone marrow or stem cell transplantation (autograft) may improve survival for women with metastatic breast cancer. Objectives To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell transplantation with conventional chemotherapy for women with metastatic breast cancer. Search strategy We used the Cochrane Breast Cancer Group search strategy, adding these terms: bone marrow transplantation, stem cell transplantation, autologous stem cell support. The following databases were searched: MEDLINE (until August 2002), EMBASE (until July 2002), ASCO (American Society of Clinical Oncology) (1995-2002) and the COCHRANE LIBRARY (Issue 3 2002). We searched the Cochrane Breast Cancer Group database and cooperative research groups' websites for unpublished trials. Selection criteria Randomised controlled trials comparing the effectiveness of high dose chemotherapy and autograft with conventional chemotherapy for women with metastatic breast cancer. Studies included one or more of the following outcomes: treatment related mortality, overall or progression-free survival at 1, 2, 3, 5 or 7 years, morbidity, quality of life measures, time to tumour progression, overall survival time. Data collection and analysis Five randomised controlled trials met the inclusion criteria. Two independent reviewers extracted data. Main results In total 382 women were randomised to receive high dose chemotherapy with autograft and 358 were randomised to receive conventional treatment. There were ten treatment related deaths among the high dose group and none reported in the control (conventional dose) group (RR 5.70, 95%CI (1.30, 25)). There was no statistically significant difference in overall survival between the high dose and control groups (at one year: RR 0.99, 95% CI (0.91, 1.08); three years: RR 1.16 95% CI (0.90, 1.51); five years: RR 1.28, 95% CI (0.72, 2.27)). At one and two years of follow up, a statistically significant difference in progression free survival was reported, favouring the high dose group (one year: RR 1.81, 95% CI (1.39,2.34); two years: RR 1.96, 95% CI (1.32, 2.90 ). However this difference was not evident at three or five years (three years: RR 1.44, 95% CI (0.85, 2.44); five years: RR 1.21, 95% CI (0.40, 3.69). Toxicity was more severe in the high dose group. None of the trials has completed follow up and further data are awaited. Reviewer's conclusions Although there is evidence that high dose chemotherapy and autograft improves progression free survival at one and two years' follow up compared to conventional chemotherapy, there is no evidence of benefit in overall survival.

Background Dysmenorrhoea is a common gynaecological complaint consisting of painful cramps accompanying menstruation, which in the absence of any underlying abnormality is known as primary dysmenorrhoea. Research has shown that women with dysmenorrhoea have high levels of prostaglandins, hormones known to cause cramping abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs which act by blocking prostaglandin production. Objectives The purpose of this review is to compare all nonsteroidal anti-inflammatory drugs used in the treatment of primary dysmenorrhoea with placebo, with paracetamol and with each other to evaluate their effectiveness and safety. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (11 April 2003), Cochrane Central Register of Controlled Trials (1st quarter 2003), MEDLINE (1966-April 2003), and EMBASE (1980 - Week 15 2003). Attempts were also made to identify trials from the National Research Register and the Clinical Trials Register. Citation lists of relevant publications, review articles, abstracts of major scientific meetings and included studies were also searched. Selection criteria All randomised controlled comparisons of NSAID therapies versus placebo, versus other NSAIDs or versus paracetamol when used to treat primary dysmenorrhoea. Data collection and analysis Two reviewers independently assessed trials for quality and extracted data, calculating odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Crossover trial data were presented in additional tables and other data were summarised descriptively. Main results In women with dysmenorrhoea, NSAIDs were found significantly more effective for pain relief than placebo (OR 7.91, 95% CI 5.65 to 11.09), though overall adverse effects were also significantly more common (OR 1.52 95% CI 1.09 to 2.12). When NSAIDs were compared with each other or with paracetamol, there was little evidence of the superiority of any individual NSAID with regard to either efficacy or safety. However the available evidence had little power to detect such differences, as most individual comparisons were based on very few small trials, most of which were unsuitable for meta-analysis. Authors' conclusions NSAIDs are an effective treatment for dysmenorrhoea, though women using them need to be aware of the significant risk of adverse effects. There is insufficient evidence to determine which (if any) individual NSAID is the most safe and effective for the treatment of dysmenorrhoea.

Background Heavy menstrual bleeding significantly impairs the quality of life of many otherwise healthy women. Perception of heavy menstrual bleeding is subjective and management usually depends upon what symptoms are acceptable to the individual. Surgical options include conservative surgery (uterine resection or ablation) and hysterectomy. Medical treatment options include oral medication and a hormone-releasing intrauterine device (LNG-IUS). Objectives To compare the effectiveness, safety and acceptability of surgery versus medical therapy for heavy menstrual bleeding. Search methods We searched the following databases from inception to January 2016: Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and clinical trials registers (clinical trials.gov and ICTRP). We also searched the reference lists of retrieved articles. Selection criteria Randomised controlled trials (RCTs) comparing conservative surgery or hysterectomy versus medical therapy (oral or intrauterine) for heavy menstrual bleeding. Data collection and analysis Two review authors independently selected the studies, assessed their risk of bias and extracted the data. Our primary outcomes were menstrual bleeding, satisfaction rate and adverse events. Where appropriate we pooled the data to calculate pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), using a fixed-effect model. We assessed heterogeneity with the I2 statistic and evaluated the quality of the evidence using GRADE methods. Main results We included 15 parallel-group RCTs (1289 women). Surgical interventions included hysterectomy and endometrial resection or ablation. Medical interventions included oral medication and the levonorgestrel-releasing intrauterine device (LNG-IUS). The overall quality of the evidence for different comparisons ranged from very low to moderate. The main limitations were lack of blinding, attrition and imprecision. Moreover, it was difficult to interpret long-term study findings as many women randomised to medical interventions subsequently underwent surgery. Surgery versus oral medication Surgery (endometrial resection) was more effective in controlling bleeding at four months (RR 2.66, 95% CI 1.94 to 3.64, one RCT, 186 women, moderate quality evidence) and also at two years (RR 1.29, 95% CI 1.06 to 1.57, one RCT, 173 women, low quality evidence). There was no evidence of a difference between the groups at five years (RR 1.14, 95% CI 0.97 to 1.34, one RCT, 140 women, very low quality evidence). Satisfaction with treatment was higher in the surgical group at two years (RR 1.40, 95% CI 1.13 to 1.74, one RCT, 173 women, moderate quality evidence), but there was no evidence of a difference between the groups at five years (RR 1.13, 95% CI 0.94 to 1.37, one RCT, 114 women, very low quality evidence). There were fewer adverse events in the surgical group at four months (RR 0.26, 95 CI 0.15 to 0.46, one RCT, 186 women). These findings require cautious interpretation, as 59% of women randomised to the oral medication group had had surgery within two years and 77% within five years. Surgery versus LNG-IUS When hysterectomy was compared with LNG-IUS, the hysterectomy group were more likely to have objective control of bleeding at one year (RR 1.11, 95% CI 1.05 to 1.19, one RCT, 223 women, moderate quality evidence). There was no evidence of a difference in quality of life between the groups at five or 10 years, but by 10 years 46% of women originally assigned to LNG-IUS had undergone hysterectomy. Adverse effects associated with hysterectomy included surgical complications such as bladder or bowel perforation and vesicovaginal fistula. Adverse effects associated with LNG-IUS were ongoing bleeding and hormonal symptoms. When conservative surgery was compared with LNG-IUS, at one year the surgical group were more likely to have subjective control of bleeding (RR 1.19, 95% CI 1.07 to 1.32, five RCTs, 281 women, low quality evidence, I2 = 15%). Satisfaction rates were higher in the surgical group at one year (RR 1.16, 95% CI 1.04, to 1.28, six RCTs, 442 women, I2 = 27%), but this finding was sensitive to the choice of statistical model and use of a random-effects model showed no conclusive evidence of a difference between the groups. There was no evidence of a difference between the groups in satisfaction rates at two years (RR 0.93, 95% CI 0.81 to 1.08, two RCTs, 117 women, I2 = 1%). At one year there were fewer adverse events (such as bleeding and spotting) in the surgical group (RR 0.36, 95% CI 0.15 to 0.82, three RCTs, moderate quality evidence). It was unclear what proportion of women assigned to LNG-IUS underwent surgery over long-term follow-up, as there were few data beyond one year. Authors' conclusions Surgery, especially hysterectomy, reduces menstrual bleeding more than medical treatment at one year. There is no conclusive evidence of a difference in satisfaction rates between surgery and LNG-IUS, though adverse effects such as bleeding and spotting are more likely to occur with LNG-IUS. Oral medication suits a minority of women in the long term, and the LNG-IUS device provides a better alternative to surgery in most cases. Although hysterectomy is a definitive treatment for heavy menstrual bleeding, it can cause serious complications for a minority of women. Most women may be well advised to try a less radical treatment as first-line therapy. Both LNG-IUS and conservative surgery appear to be safe, acceptable and effective.

We considered whether to include Schierbeck and colleagues’ trial in our 2012 Cochrane review of long term hormone therapy for perimenopausal and postmenopausal women.1 2 However, it …

BACKGROUND: The first‐line treatment in donor sperm treatment consists of inseminations that can be done by intrauterine insemination (IUI) or by intracervical insemination (ICI). OBJECTIVES: To compare the effectiveness and safety of intrauterine insemination (IUI) and intracervical insemination (ICI) in women who start donor sperm treatment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL in October 2016, checked references of relevant studies, and contacted study authors and experts in the field to identify additional studies. We searched PubMed, Google Scholar, the Grey literature, and five trials registers on 15 December 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on IUI versus ICI in natural cycles or with ovarian stimulation, and RCTs comparing different cointerventions in IUI and ICI. We included cross‐over studies if pre‐cross‐over data were available. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We collected data on primary outcomes of live birth and multiple pregnancy rates, and on secondary outcomes of clinical pregnancy, miscarriage, and cancellation rates. MAIN RESULTS: We included six RCTs (708 women analysed) on ICI and IUI in donor sperm treatment. Two studies compared IUI and ICI in natural cycles, two studies compared IUI and ICI in gonadotrophin‐stimulated cycles, and two studies compared timing of IUI and ICI. There was very low‐quality evidence; the main limitations were risk of bias due to poor reporting of study methods, and serious imprecision. IUI versus ICI in natural cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in natural cycles (odds ratio (OR) 3.24, 95% confidence interval (CI) 0.12 to 87.13; 1 RCT, 26 women; very low‐quality evidence). There was only one live birth in this study (in the IUI group). IUI resulted in higher clinical pregnancy rates (OR 6.18, 95% CI 1.91 to 20.03; 2 RCTs, 76 women; I² = 48%; very low‐quality evidence). No multiple pregnancies or miscarriages occurred in this study. IUI versus ICI in gonadotrophin‐stimulated cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in gonadotrophin‐stimulated cycles (OR 2.55, 95% CI 0.72 to 8.96; 1 RCT, 43 women; very low‐quality evidence). This suggested that if the chance of a live birth following ICI in gonadotrophin‐stimulated cycles was assumed to be 30%, the chance following IUI in gonadotrophin‐stimulated cycles would be between 24% and 80%. IUI may result in higher clinical pregnancy rates than ICI (OR 2.83, 95% CI 1.38 to 5.78; 2 RCTs, 131 women; I² = 0%; very low‐quality evidence). IUI may be associated with higher multiple pregnancy rates than ICI (OR 2.77, 95% CI 1.00 to 7.69; 2 RCTs, 131 women; I² = 0%; very low‐quality evidence). This suggested that if the risk of multiple pregnancy following ICI in gonadotrophin‐stimulated cycles was assumed to be 10%, the risk following IUI would be between 10% and 46%. We found insufficient evidence to determine whether there was any clear difference between the groups in miscarriage rates in gonadotrophin‐stimulated cycles (OR 1.97, 95% CI 0.43 to 9.04; 2 RCTs, overall 67 pregnancies; I² = 50%; very low‐quality evidence). Timing of IUI and ICI We found no studies that reported on live birth rates. We found a higher clinical pregnancy rate when IUI was timed one day after a rise in blood levels of luteinising hormone (LH) compared to IUI two days after a rise in blood levels of LH (OR 2.00, 95% CI 1.14 to 3.53; 1 RCT, 351 women; low‐quality evidence). We found insufficient evidence to determine whether there was any clear difference in clinical pregnancy rates between ICI timed after a rise in urinary levels of LH versus a rise in basal temperature plus cervical mucus scores (OR 1.31, 95% CI 0.42 to 4.11; 1 RCT, 56 women; very low‐quality evidence). Neither of these studies reported multiple pregnancy or miscarriage rates as outcomes. AUTHORS' CONCLUSIONS: There was insufficient evidence to determine whether there was a clear difference in live birth rates between IUI and ICI in natural or gonadotrophin‐stimulated cycles in women who started with donor sperm treatment. There was insufficient evidence available for the effect of timing of IUI or ICI on live birth rates. Very low‐quality data suggested that in gonadotrophin‐stimulated cycles, IUI may be associated with a higher clinical pregnancy rate than ICI, but also with a higher risk of multiple pregnancy rate. We concluded that the current evidence was too limited to choose between IUI or ICI, in natural cycles or with ovarian stimulation, in donor sperm treatment.

Background Premenstrual syndrome (PMS) is a common cause of physical, psychological and social problems in women of reproductive age. The key characteristic of PMS is the timing of symptoms, which occur only during the two weeks leading up to menstruation (the luteal phase of the menstrual cycle). Selective serotonin reuptake inhibitors (SSRIs) are increasingly used as first line therapy for PMS. SSRIs can be taken either in the luteal phase or else continuously (every day). SSRIs are generally considered to be effective for reducing premenstrual symptoms but they can cause adverse effects. Objectives The objective of this review was to evaluate the effectiveness and safety of SSRIs for treating premenstrual syndrome. Search methods Electronic searches for relevant randomised controlled trials (RCTs) were undertaken in the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, and CINAHL (February 2013). Where insufficient data were presented in a report, attempts were made to contact the original authors for further details. Selection criteria Studies were considered in which women with a prospective diagnosis of PMS, PMDD or late luteal phase dysphoric disorder (LPDD) were randomised to receive SSRIs or placebo for the treatment of premenstrual syndrome. Data collection and analysis Two review authors independently selected the studies, assessed eligible studies for risk of bias, and extracted data on premenstrual symptoms and adverse effects. Studies were pooled using random-effects models. Standardised mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for premenstrual symptom scores, using separate analyses for different types of continuous data (that is end scores and change scores). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Analyses were stratified by type of drug administration (luteal or continuous) and by drug dose (low, medium, or high). We calculated the number of women who would need to be taking a moderate dose of SSRI in order to cause one additional adverse event (number needed to harm: NNH). The overall quality of the evidence for the main findings was assessed using the GRADE working group methods. Main results Thirty-one RCTs were included in the review. They compared fluoxetine, paroxetine, sertraline, escitalopram and citalopram versus placebo. SSRIs reduced overall self-rated symptoms significantly more effectively than placebo. The effect size was moderate when studies reporting end scores were pooled (for moderate dose SSRIs: SMD -0.65, 95% CI -0.46 to -0.84, nine studies, 1276 women; moderate heterogeneity (I2 = 58%), low quality evidence). The effect size was small when studies reporting change scores were pooled (for moderate dose SSRIs: SMD -0.36, 95% CI -0.20 to -0.51, four studies, 657 women; low heterogeneity (I2=29%), moderate quality evidence). SSRIs were effective for symptom relief whether taken only in the luteal phase or continuously, with no clear evidence of a difference in effectiveness between these modes of administration. However, few studies directly compared luteal and continuous regimens and more evidence is needed on this question. Withdrawals due to adverse effects were significantly more likely to occur in the SSRI group (moderate dose: OR 2.55, 95% CI 1.84 to 3.53, 15 studies, 2447 women; no heterogeneity (I2 = 0%), moderate quality evidence). The most common side effects associated with a moderate dose of SSRIs were nausea (NNH = 7), asthenia or decreased energy (NNH = 9), somnolence (NNH = 13), fatigue (NNH = 14), decreased libido (NNH = 14) and sweating (NNH = 14). In secondary analyses, SSRIs were effective for treating specific types of symptoms (that is psychological, physical and functional symptoms, and irritability). Adverse effects were dose-related. The overall quality of the evidence was low to moderate, the main weakness in the included studies being poor reporting of methods. Heterogeneity was low or absent for most outcomes, though (as noted above) there was moderate heterogeneity for one of the primary analyses. Authors' conclusions SSRIs are effective in reducing the symptoms of PMS, whether taken in the luteal phase only or continuously. Adverse effects are relatively frequent, the most common being nausea and asthenia. Adverse effects are dose-dependent.

Background Dysmenorrhoea is a common gynaecological problem consisting of painful cramps accompanying menstruation, which in the absence of any underlying abnormality is known as primary dysmenorrhoea. Research has shown that women with dysmenorrhoea have high levels of prostaglandins, hormones known to cause cramping abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that act by blocking prostaglandin production. They inhibit the action of cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins. The COX enzyme exists in two forms, COX-1 and COX-2. Traditional NSAIDs are considered 'non-selective' because they inhibit both COX-1 and COX-2 enzymes. More selective NSAIDs that solely target COX-2 enzymes (COX-2-specific inhibitors) were launched in 1999 with the aim of reducing side effects commonly reported in association with NSAIDs, such as indigestion, headaches and drowsiness. Objectives To determine the effectiveness and safety of NSAIDs in the treatment of primary dysmenorrhoea. Search methods We searched the following databases in January 2015: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, November 2014 issue), MEDLINE, EMBASE and Web of Science. We also searched clinical trials registers (ClinicalTrials.gov and ICTRP). We checked the abstracts of major scientific meetings and the reference lists of relevant articles. Selection criteria All randomised controlled trial (RCT) comparisons of NSAIDs versus placebo, other NSAIDs or paracetamol, when used to treat primary dysmenorrhoea. Data collection and analysis Two review authors independently selected the studies, assessed their risk of bias and extracted data, calculating odds ratios (ORs) for dichotomous outcomes and mean differences for continuous outcomes, with 95% confidence intervals (CIs). We used inverse variance methods to combine data. We assessed the overall quality of the evidence using GRADE methods. Main results We included 80 randomised controlled trials (5820 women). They compared 20 different NSAIDs (18 non-selective and two COX-2-specific) versus placebo, paracetamol or each other. NSAIDs versus placebo Among women with primary dysmenorrhoea, NSAIDs were more effective for pain relief than placebo (OR 4.37, 95% CI 3.76 to 5.09; 35 RCTs, I2 = 53%, low quality evidence). This suggests that if 18% of women taking placebo achieve moderate or excellent pain relief, between 45% and 53% taking NSAIDs will do so. However, NSAIDs were associated with more adverse effects (overall adverse effects: OR 1.29, 95% CI 1.11 to 1.51, 25 RCTs, I2 = 0%, low quality evidence; gastrointestinal adverse effects: OR 1.58, 95% CI 1.12 to 2.23, 14 RCTs, I2 = 30%; neurological adverse effects: OR 2.74, 95% CI 1.66 to 4.53, seven RCTs, I2 = 0%, low quality evidence). The evidence suggests that if 10% of women taking placebo experience side effects, between 11% and 14% of women taking NSAIDs will do so. NSAIDs versus other NSAIDs When NSAIDs were compared with each other there was little evidence of the superiority of any individual NSAID for either pain relief or safety. However, the available evidence had little power to detect such differences, as most individual comparisons were based on very few small trials. Non-selective NSAIDs versus COX-2-specific selectors Only two of the included studies utilised COX-2-specific inhibitors (etoricoxib and celecoxib). There was no evidence that COX-2-specific inhibitors were more effective or tolerable for the treatment of dysmenorrhoea than traditional NSAIDs; however data were very scanty. NSAIDs versus paracetamol NSAIDs appeared to be more effective for pain relief than paracetamol (OR 1.89, 95% CI 1.05 to 3.43, three RCTs, I2 = 0%, low quality evidence). There was no evidence of a difference with regard to adverse effects, though data were very scanty. Most of the studies were commercially funded (59%); a further 31% failed to state their source of funding. Authors' conclusions NSAIDs appear to be a very effective treatment for dysmenorrhoea, though women using them need to be aware of the substantial risk of adverse effects. There is insufficient evidence to determine which (if any) individual NSAID is the safest and most effective for the treatment of dysmenorrhoea. We rated the quality of the evidence as low for most comparisons, mainly due to poor reporting of study methods.