Identifying employee, workplace and population characteristics associated with COVID-19 outbreaks in the workplace: a population-based study.

OBJECTIVES: To identify risk factors that contribute to outbreaks of COVID-19 in the workplace and quantify their effect on outbreak risk. METHODS: We identified outbreaks of COVID-19 cases in the workplace and investigated the characteristics of the individuals, the workplaces, the areas they work and the mode of commute to work, through data linkages based on Middle Layer Super Output Areas in England between 20 June 2021 and 20 February 2022. We estimated population-level associations between potential risk factors and workplace outbreaks, adjusting for plausible confounders identified using a directed acyclic graph. RESULTS: For most industries, increased physical proximity in the workplace was associated with increased risk of COVID-19 outbreaks, while increased vaccination was associated with reduced risk. Employee demographic risk factors varied across industry, but for the majority of industries, a higher proportion of black/African/Caribbean ethnicities and living in deprived areas, was associated with increased outbreak risk. A higher proportion of employees in the 60-64 age group was associated with reduced outbreak risk. There were significant associations between gender, work commute modes and staff contract type with outbreak risk, but these were highly variable across industries. CONCLUSIONS: This study has used novel national data linkages to identify potential risk factors of workplace COVID-19 outbreaks, including possible protective effects of vaccination and increased physical distance at work. The same methodological approach can be applied to wider occupational and environmental health research.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

BACKGROUND: During a stimulated cycle of in vitro fertilisation or intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. A normal response to stimulation (e.g. retrieval of 5 to 15 oocytes) is considered desirable. Generally, the number of eggs retrieved is associated with the dose of FSH. Both hyper-response and poor response are associated with an increased chance of cycle cancellation. In hyper-response, this is due to increased risk of ovarian hyperstimulation syndrome (OHSS), while poor response cycles are cancelled because the quantity and quality of oocytes is expected to be low. Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response. Traditionally, this meant women's age, but increasingly, clinicians use various ovarian reserve tests (ORTs). These include basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose improves clinical outcomes. This review updates the 2018 version. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, and two trial registers in February 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared (a) 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) or (b) an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. MAIN RESULTS: We included 26 studies, involving 8520 women (6 new studies added to 20 studies included in the previous version). We treated RCTs with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence certainty ranged from very low to low, with the main limitations being imprecision and risk of bias associated with lack of blinding. Direct dose comparisons according to predicted response in women Due to differences in dose comparisons, caution is required when interpreting the RCTs in predicted low responders. All evidence was low or very low certainty. 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 (10 studies, 4 comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units (IU): odds ratio (OR) 0.88, 95% confidence interval (CI) 0.57 to 1.36; I2 = 0%; 2 studies, 522 women) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the OHSS outcome to enable inferences. In predicted high responders, lower doses may or may not affect live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; 1 study, 521 women), severe OHSS, and clinical pregnancy. It is also unclear whether lower doses reduce moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; 1 study, 521 participants). ORT-algorithm studies Eight trials compared an ORT-based algorithm to a non-ORT control group. It is unclear whether live birth/ongoing pregnancy and clinical pregnancy are increased using an ORT-based algorithm (live birth/ongoing pregnancy: OR 1.12, 95% CI 0.98 to 1.29; I2 = 30%; 7 studies, 4400 women; clinical pregnancy: OR 1.04, 95% CI 0.91 to 1.18; I2 = 18%; 7 studies, 4400 women; low-certainty evidence). However, ORT algorithms may reduce moderate or severe OHSS (Peto OR 0.60, 95% CI 0.42 to 0.84; I2 = 0%; 7 studies, 4400 women; low-certainty evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.74, 95% CI 0.42 to 1.28; I2 = 0%; 5 studies, 2724 women; low-certainty evidence). Our findings suggest that if the chance of live birth with a standard starting dose is 25%, the chance with ORT-based dosing would be between 25% and 31%. If the chance of moderate or severe OHSS with a standard starting dose is 5%, the chance with ORT-based dosing would be between 2% and 5%. These results should be treated cautiously due to heterogeneity in the algorithms: some algorithms appear to be more effective than others. AUTHORS' CONCLUSIONS: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT) affected live birth/ongoing pregnancy rates, but we could not rule out differences, due to sample size limitations. Low-certainty evidence suggests that it is unclear if ORT-based individualisation leads to an increase in live birth/ongoing pregnancy rates compared to a policy of giving all women 150 IU. The confidence interval is consistent with an increase of up to around six percentage points with ORT-based dosing (e.g. from 25% to 31%) or a very small decrease (< 1%). A difference of this magnitude could be important to many women. It is unclear if this is driven by improved outcomes in a particular subgroup. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU. However, the size of the effect is also unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates. It is likely that different ORT algorithms differ in their effectiveness. Current evidence does not provide a clear justification for adjusting the dose of 150 IU in poor or normal responders, especially as increased dose is associated with greater total FSH dose and cost. It is unclear whether a decreased dose in predicted high responders reduces OHSS, although this would appear to be the most likely explanation for the results.

Information about fetal movements and stillbirth trends: Analysis of time series data.

OBJECTIVE: To investigate the implementation of the Count the Kicks campaign in Iowa to increase maternal awareness of fetal movements and its association with stillbirth rates. DESIGN: Time series analysis. SETTING: Iowa, Illinois, Minnesota and Missouri, USA. SAMPLE: Women giving birth between 2005 and 2018. METHODS: Data regarding campaign activity, including uptake of the app and the distribution of information materials, and population-level data on stillbirth rates and potential confounding risk factors were obtained from publicly available data for 2005-2018. Data were plotted over time and examined in relation to key implementation phases. MAIN OUTCOME MEASURE: Stillbirth. RESULTS: App users were largely centred on Iowa, and increased over time, although the numbers were modest relative to the number of births. Only Iowa demonstrated a reduction in stillbirth (OR 0.96, 95% CI 0.96-1.00 per year; interaction between state and time, p < 0.001); there was a decline from 2008 to 2013 (before the launch of the app), an increase from 2014 to 2016 and a decrease from 2017 to 2018, which coincided with increased app use (interaction between period and time, p = 0.06). With the exception of smoking (which fell from approx. 20% in 2005 to approx. 15% in 2018 in Iowa), all risk factors increased in prevalence, so are unlikely to account for a reduction in stillbirth. CONCLUSIONS: There was a reduction in the stillbirth rate in Iowa, where an information campaign about fetal movements was active; this reduction was not present in neighbouring states. Large-scale intervention studies are needed to determine whether the temporal associations between app use and stillbirth rate are causally related.

Occupational differences in the prevalence and severity of long-COVID: analysis of the Coronavirus (COVID-19) Infection Survey.

OBJECTIVES: To establish whether prevalence and severity of long-COVID symptoms vary by industry and occupation. METHODS: We used Office for National Statistics COVID-19 Infection Survey (CIS) data (February 2021-April 2022) of working-age participants (16-65 years). Exposures were industry, occupation and major Standard Occupational Classification (SOC) group. Outcomes were self-reported: (1) long-COVID symptoms and (2) reduced function due to long-COVID. Binary (outcome 1) and ordered (outcome 2) logistic regression were used to estimate odds ratios (OR)and prevalence (marginal means). RESULTS: Public facing industries, including teaching and education, social care, healthcare, civil service, retail and transport industries and occupations, had the highest likelihood of long-COVID. By major SOC group, those in caring, leisure and other services (OR 1.44, 95% CIs 1.38 to 1.52) had substantially elevated odds than average. For almost all exposures, the pattern of ORs for long-COVID symptoms followed SARS-CoV-2 infections, except for professional occupations (eg, some healthcare, education, scientific occupations) (infection: OR<1 ; long-COVID: OR>1). The probability of reporting long-COVID for industry ranged from 7.7% (financial services) to 11.6% (teaching and education); whereas the prevalence of reduced function by 'a lot' ranged from 17.1% (arts, entertainment and recreation) to 22%-23% (teaching and education and armed forces) and to 27% (not working). CONCLUSIONS: The risk and prevalence of long-COVID differs across industries and occupations. Generally, it appears that likelihood of developing long-COVID symptoms follows likelihood of SARS-CoV-2 infection, except for professional occupations. These findings highlight sectors and occupations where further research is needed to understand the occupational factors resulting in long-COVID.

Potential contribution of vaccination uptake to occupational differences in risk of SARS-CoV-2: analysis of the ONS COVID-19 Infection Survey.

OBJECTIVES: To assess variation in vaccination uptake across occupational groups as a potential explanation for variation in risk of SARS-CoV-2 infection. DESIGN: We analysed data from the UK Office of National Statistics COVID-19 Infection Survey linked to vaccination data from the National Immunisation Management System in England from 1 December 2020 to 11 May 2022. We analysed vaccination uptake and SARS-CoV-2 infection risk by occupational group and assessed whether adjustment for vaccination reduced the variation in risk between occupational groups. RESULTS: Estimated rates of triple vaccination were high across all occupational groups (80% or above), but were lowest for food processing (80%), personal care (82%), hospitality (83%), manual occupations (84%) and retail (85%). High rates were observed for individuals working in health (95% for office based, 92% for those in patient-facing roles) and education (91%) and office-based workers not included in other categories (90%). The impact of adjusting for vaccination when estimating relative risks of infection was generally modest (ratio of hazard ratios across all occupational groups reduced from 1.37 to 1.32), but was consistent with the hypothesis that low vaccination rates contribute to elevated risk in some groups. CONCLUSIONS: Variation in vaccination coverage might account for a modest proportion of occupational differences in infection risk. Vaccination rates were uniformly very high in this cohort, which may suggest that the participants are not representative of the general population. Accordingly, these results should be considered tentative pending the accumulation of additional evidence.

Evaluating antenatal risk in twin pregnancies-A feasibility study to identify modifiable factors associated with adverse pregnancy outcomes.

INTRODUCTION: Twin pregnancies have significantly higher rates of perinatal morbidity and mortality compared to singleton pregnancies; current attempts to reduce perinatal mortality have been less successful in twin pregnancies. The paucity of information about modifiable risk factors for adverse neonatal outcomes in twin pregnancies, as well as independent effects of chorionicity may have contributed to this outcome. This study aimed to explore the feasibility of an observational study to identify modifiable factors associated with adverse neonatal outcomes in twin pregnancies. MATERIAL AND METHODS: Patients pregnant with twins at six UK hospitals between December 2019-March 2021 completed researcher-administered questionnaires at approximately 20-, 28- and 36-weeks' gestation, recording a wide range of self-reported social, lifestyle and demographic factors, alongside prospectively recorded clinical data from maternity records. Descriptive statistics were used to describe frequencies of exposures; logistic regression was used to determine whether factors were associated with a composite measure of adverse neonatal outcome. RESULTS: Data were collected from 65% (181/277) of eligible participants. A total of 98% (175) of participants had positive views about their participation. Some exposures, including cigarette smoking, supine sleep position and reduced fetal movements were less frequent in twin pregnancies compared to singletons, whereas fertility treatment was more common. Furthermore, different patterns of exposure were seen between monochorionic and dichorionic twins. This pilot study found some associations with adverse neonatal outcomes including: low BMI (OR 8.36, 95% CI: 1.02-68.87), maternal age ≥41 years (OR 9.0 95% CI: 1.07-75.84), maternally perceived high-stress levels (OR 1.96, 95% CI: 1.03-3.75) and inadequate antenatal screening (OR 1.44, 95% CI: 1.01-2.06). Sleep duration ≥9 h and right-sided going to sleep position were more frequent among pregnancies with adverse outcomes. Participants who reported receiving no information on fetal movement and reduced maternal perception of movements were more likely to have an adverse outcome, but sample size prohibited analysis based upon chorionicity. CONCLUSIONS: An observational study of modifiable factors in twin pregnancy is feasible. Differences in the frequencies of exposures between twin and singleton pregnancies highlight the need for twin-specific studies to identify modifiable factors and develop preventative strategies for morbidity and mortality in twin pregnancies.

A Randomized Trial of Endometrial Scratching before In Vitro Fertilization.

BACKGROUND: Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS: We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS: A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .).

Passion, pressure and pragmatism: how fertility clinic medical directors view IVF add-ons.

RESEARCH QUESTION: What are the views of the medical directors of fertility clinics on IVF add-ons? DESIGN: A total of 93 UK clinics were emailed with an invitation for their medical director to participate. Ten IVF clinic medical directors were interviewed to discuss their views on the use of IVF add-ons. Some of the interviewees were medical directors of an IVF clinic with multiple branches across the UK, meaning the total number of clinics accounted for in this study was 35 out of the 93 contacted. Thematic analysis was used to analyse the data. RESULTS: The participants consisted of seven males and three females, with six from solely private clinics and four with NHS and private patients. Four themes were identified: clinical decision-making and the patient-doctor relationship; regulations and the add-on traffic light system; research and evidence; and commercialization and financialization of the IVF sector. CONCLUSIONS: UK IVF medical directors had a wide variety of views and experienced different pressures to offer IVF add-ons. The add-on discussion touches on core aspects of professional identity and the meaning of medical practice. The add-on debate points to broader changes in the organization of the IVF sector, which affect key aspects of practising (reproductive) medicine, including the patient-doctor relationship and responsibility for clinical decision-making, and the relationship between regulator and IVF clinic and between scientific evidence and clinical practice.

A randomized trial of endometrial scratching in women with PCOS undergoing ovulation induction cycles.

RESEARCH QUESTION: Does endometrial scratching improve the chance of a live birth in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction and trying to conceive? DESIGN: An international, multicentre, randomized, sham-controlled trial across six fertility clinics in three countries (New Zealand, UK and Brazil). Women with a diagnosis of PCOS who were planning to commence ovulation induction cycles (at least three cycles) in order to conceive were randomly assigned to receive the pipelle (scratch) procedure or a sham (placebo) procedure in the first cycle of ovulation induction. Women kept a diary of ovulation induction and sexual intercourse timing over three consecutive cycles and pregnancies were followed up to live birth. Primary outcome was live birth and secondary outcomes were clinical pregnancy, ongoing pregnancy, multiple pregnancy, adverse pregnancy outcomes, neonatal outcomes, bleeding following procedure and pain score following procedure. RESULTS: A total of 117 women were randomized; 58 to the scratch group and 59 to the sham group. Live birth occurred in 11 (19%) women in the scratch group and 14 (24%) in the sham group (odds ratio 0.76, 95% confidence interval [CI] 0.30-1.92). Secondary outcomes were similar in each group. Significantly higher pain scores were reported in the scratch group (adjusted mean difference 3.2, 95% CI 2.5-3.9) when measured on a visual analogue scale. CONCLUSION: No difference was detected in live birth rate for women with PCOS who received an endometrial scratch when trying to conceive using ovulation induction; however, uncertainty remains due to the small sample size in this study.

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

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

Does PGT-A improve assisted reproduction treatment success rates: what can the UK Register data tell us?

PURPOSE: To show how naïve analyses of aggregated UK ART Register data held by the Human Fertilisation and Embryology Authority to estimate the effects of PGT-A can be severely misleading and to indicate how it may be possible to do a more credible analysis. Given the limitations of the Register, we consider the extent to which such an analysis has the potential to answer questions about the real-world effectiveness of PGT-A. METHODS: We utilise the publicly available Register datasets and construct logistic regression models for live birth events (LBE) which adjust for confounding. We compare all PGT-A cycles to control groups of cycles that could have had PGT-A, excluding cycles that did not progress to having embryos for biopsy. RESULTS: The primary model gives an odds ratio for LBE of 0.82 (95% CI 0.68-1.00) suggesting PGT-A may be detrimental rather than beneficial. However, due to limitations in the availability of important variables in the public dataset, this cannot be considered a definitive estimate. We outline the steps required to enable a credible analysis of the Register data. CONCLUSION: If we compare like with like groups, we obtain estimates of the effect of PGT-A that suggest an overall modest reduction in treatment success rates. These are in direct contrast to an invalid comparison of crude success rates. A detailed analysis of a fuller dataset is warranted, but it remains to be demonstrated whether the UK Register data can provide useful estimates of the impact of PGT-A when used as a treatment add-on.

Choice of statistical model in observational studies of ART.

Analyzing data on ART presents unique and sometimes complicated challenges related to choosing the unit(s) of analysis and the statistical model. In this commentary, we provide examples of how these challenges arise and guidance for overcoming them. We discuss the implications of different ways to count treatment cycles, considering the perspectives of research questions, data management and analysis and patient counseling. We present the advantages and disadvantages of different statistical models, and finally, we discuss the definition and calculation of the cumulative incidence of live birth, which is a key outcome of research on ART.

State-of-the-art technologies provide new insights linking skin and blood vessel abnormalities in SSc-related disorders.

OBJECTIVE: A key unanswered question in systemic sclerosis (SSc) is how microvascular abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive imaging methods to gain new insights into pathophysiology, comparing patients with different subtypes of SSc, including early dcSSc, not only to healthy controls but also to patients with causes of Raynaud's phenomenon not progressing to fibrosis. METHODS: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress, and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud's phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 'early') and 60 healthy controls. RESULTS: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion units [standard deviation 157], late-dcSSc 90 [145], early-dcSSc 68 [137] vs. controls 211 [146]; p = 0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc 12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p = 0.0049). Oxidative stress was increased at the hand-dorsum in SSc groups (p = 0.0007). Perfusion positively correlated with oxygenation (r = 0.23, p < 0.001), and capillary density negatively with skin thickness (r = -0.26, p < 0.001). CONCLUSION: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc, (but not in PRP or UCTD), reduced perfusion (together with structural microvascular abnormality) associates with reduced oxygenation, with oxidative stress and with skin thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible tissue injury. Findings in skin may mirror alterations in internal organs.

The prevalence, promotion and pricing of three IVF add-ons on fertility clinic websites.

RESEARCH QUESTION: How are IVF clinic websites advertising three common IVF add-ons: assisted hatching, time-lapse embryo imaging and preimplantation genetic testing for aneuploidies (PGT-A)? DESIGN: The Human Fertilisation and Embryology Authority 'Choose a fertility clinic' website service was used to identify IVF clinics and their websites. Assisted hatching, time-lapse embryo imaging and PGT-A were examined to determine which websites advertised them, what price they charged and what claims they made in relation to the add-ons. RESULTS: Eighty-seven eligible clinics were identified, with 72 unique websites; 37 (43%) clinics were part of one of nine groups of IVF clinics, of sizes ranging from two to eight clinics in the UK. Time-lapse imaging (TLI) was the most frequently advertised of the three add-ons (67% of clinics), followed by PGT-A (47%) and assisted hatching (28%). Very few websites stated that the effectiveness of the add-on was in doubt or unclear (four, two and one websites for TLI, PGT-A and assisted hatching, respectively), and none raised the possibility that an add-on might have negative effects. Claims of efficacy were often based on upstream outcomes (e.g. implantation, pregnancy). Some claims that PGT-A and TLI improved live birth rates were found. There was substantial variation in pricing. CONCLUSIONS: IVF clinic websites provide valuable information for patients seeking fertility treatment so it is key that the information is accurate and complete. There is a need for transparent information on interventions, including uncertainties and risks, to be made available by IVF clinics to support well-informed treatment decisions. The selected add-ons are widely advertised, and there is wide variation in pricing.

Hysterectomy with opportunistic salpingectomy versus hysterectomy alone.

BACKGROUND: Ovarian cancer has the highest mortality rate of all gynaecological malignancies with an overall five-year survival rate of 30% to 40%. In the past two decades it has become apparent and more commonly accepted that a majority of ovarian cancers originate in the fallopian tube epithelium and not from the ovary itself. This paradigm shift introduced new possibilities for ovarian cancer prevention. Salpingectomy during a hysterectomy for benign gynaecological indications (also known as opportunistic salpingectomy) might reduce the overall incidence of ovarian cancer. Aside from efficacy, safety is of utmost importance, especially due to the preventive nature of opportunistic salpingectomy. Most important are safety in the form of surgical adverse events and postoperative hormonal status. Therefore, we compared the benefits and risks of hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy. OBJECTIVES: To assess the effect and safety of hysterectomy with opportunistic salpingectomy versus hysterectomy without salpingectomy for ovarian cancer prevention in women undergoing hysterectomy for benign gynaecological indications; outcomes of interest include the incidence of epithelial ovarian cancer, surgery-related adverse events and postoperative ovarian reserve. SEARCH METHODS: The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two clinical trial registers were searched in January 2019 together with reference checking and contact with study authors. SELECTION CRITERIA: We intended to include both randomised controlled trials (RCTs) and non-RCTs that compared ovarian cancer incidence after hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. For assessment of surgical and hormonal safety, we included RCTs that compared hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were ovarian cancer incidence, intraoperative and short-term postoperative complication rate and postoperative hormonal status. Secondary outcomes were total surgical time, estimated blood loss, conversion rate to open surgery (applicable only to laparoscopic and vaginal approaches), duration of hospital admission, menopause-related symptoms and quality of life. MAIN RESULTS: We included seven RCTs (350 women analysed). The evidence was of very low to low quality: the main limitations being a low number of included women and surgery-related adverse events, substantial loss to follow-up and a large variety in outcome measures and timing of measurements.No studies reported ovarian cancer incidence after hysterectomy with opportunistic salpingectomy compared to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. For surgery-related adverse events, there were insufficient data to assess whether there was any difference in both intraoperative (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.11 to 3.94; 5 studies, 286 participants; very low-quality evidence) and short-term postoperative (OR 0.13, 95% CI 0.01 to 2.14; 3 studies, 152 participants; very low-quality evidence) complication rates between hysterectomy with opportunistic salpingectomy and hysterectomy without opportunistic salpingectomy because the number of surgery-related adverse events was very low. For postoperative hormonal status, the results were compatible with no difference, or with a reduction in anti-Müllerian hormone (AMH) that would not be clinically relevant (mean difference (MD) -0.94, 95% CI -1.89 to 0.01; I2 = 0%; 5 studies, 283 participants; low-quality evidence). A reduction in AMH would be unfavourable, but due to wide CIs, the postoperative change in AMH can still vary from a substantial decrease to even a slight increase. AUTHORS' CONCLUSIONS: There were no eligible studies reporting on one of our primary outcomes - the incidence of ovarian cancer specifically after hysterectomy with or without opportunistic salpingectomy. However, outside the scope of this review there is a growing body of evidence for the effectiveness of opportunistic salpingectomy itself during other interventions or as a sterilisation technique, strongly suggesting a protective effect. In our meta-analyses, we found insufficient data to assess whether there was any difference in surgical adverse events, with a very low number of events in women undergoing hysterectomy with and without opportunistic salpingectomy. For postoperative hormonal status we found no evidence of a difference between the groups. The maximum difference in time to menopause, calculated from the lower limit of the 95% CI and the natural average AMH decline, would be approximately 20 months, which we consider to be not clinically relevant. However, the results should be interpreted with caution and even more so in very young women for whom a difference in postoperative hormonal status is potentially more clinically relevant. Therefore, there is a need for research on the long-term effects of opportunistic salpingectomy during hysterectomy, particularly in younger women, as results are currently limited to six months postoperatively. This limit is especially important as AMH, the most frequently used marker for ovarian reserve, recovers over the course of several months following an initial sharp decline after surgery. In light of the available evidence, addition of opportunistic salpingectomy should be discussed with each woman undergoing a hysterectomy for benign indication, with provision of a clear overview of benefits and risks.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

BACKGROUND: During 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. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We 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 CRITERIA: We 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 ANALYSIS: We 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 RESULTS: We 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' CONCLUSIONS: We 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.

No common denominator: a review of outcome measures in IVF RCTs.

STUDY QUESTION: Which outcome measures are reported in RCTs for IVF? SUMMARY ANSWER: Many combinations of numerator and denominator are in use, and are often employed in a manner that compromises the validity of the study. WHAT IS KNOWN ALREADY: The choice of numerator and denominator governs the meaning, relevance and statistical integrity of a study's results. RCTs only provide reliable evidence when outcomes are assessed in the cohort of randomised participants, rather than in the subgroup of patients who completed treatment. STUDY DESIGN, SIZE, DURATION: Review of outcome measures reported in 142 IVF RCTs published in 2013 or 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Trials were identified by searching the Cochrane Gynaecology and Fertility Specialised Register. English-language publications of RCTs reporting clinical or preclinical outcomes in peer-reviewed journals in the period 1 January 2013 to 31 December 2014 were eligible. Reported numerators and denominators were extracted. Where they were reported, we checked to see if live birth rates were calculated correctly using the entire randomised cohort or a later denominator. MAIN RESULTS AND THE ROLE OF CHANCE: Over 800 combinations of numerator and denominator were identified (613 in no more than one study). No single outcome measure appeared in the majority of trials. Only 22 (43%) studies reporting live birth presented a calculation including all randomised participants or only excluding protocol violators. A variety of definitions were used for key clinical numerators: for example, a consensus regarding what should constitute an ongoing pregnancy does not appear to exist at present. LIMITATIONS, REASONS FOR CAUTION: Several of the included articles may have been secondary publications. Our categorisation scheme was essentially arbitrary, so the frequencies we present should be interpreted with this in mind. The analysis of live birth denominators was post hoc. WIDER IMPLICATIONS OF THE FINDINGS: There is massive diversity in numerator and denominator selection in IVF trials due to its multistage nature, and this causes methodological frailty in the evidence base. The twin spectres of outcome reporting bias and analysis of non-randomised comparisons do not appear to be widely recognised. Initiatives to standardise outcome reporting, such as requiring all effectiveness studies to report live birth or cumulative live birth, are welcome. However, there is a need to recognise that early outcomes of treatment, such as stimulation response or embryo quality, may be appropriate choices of primary outcome for early phase studies. STUDY FUNDING/COMPETING INTERESTS: J.W. is funded by a Doctoral Research Fellowship from the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. J.W. also declares that publishing research is beneficial to his career. J.W. and A.V. are statistical editors, and M.S. is Information Specialist, for the Cochrane Gynaecology and Fertility Group, although the views expressed here are not necessarily those of the group. D.R.B. is funded by the NHS as Scientific Director of a clinical IVF service. The authors declare no other conflicts of interest.