Fetal loss and long-term maternal morbidity and mortality: A systematic review and meta-analysis.

BACKGROUND: Evidence suggests common pathways between pregnancy losses and subsequent long-term maternal morbidity, rendering pregnancy complications an early chronic disease marker. There is a plethora of studies exploring associations between miscarriage and stillbirth with long-term adverse maternal health; however, these data are inconclusive. METHODS AND FINDINGS: We systematically searched MEDLINE, EMBASE, AMED, BNI, CINAHL, and the Cochrane Library with relevant keywords and MeSH terms from inception to June 2023 (no language restrictions). We included studies exploring associations between stillbirth or miscarriage and incidence of cardiovascular, malignancy, mental health, other morbidities, and all-cause mortality in women without previous pregnancy loss. Studies reporting short-term morbidity (within a year of loss), case reports, letters, and animal studies were excluded. Study selection and data extraction were performed by 2 independent reviewers. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) and publication bias with funnel plots. Subgroup analysis explored the effect of recurrent losses on adverse outcomes. Statistical analysis was performed using an inverse variance random effects model and results are reported as risk ratios (RRs) with 95% confidence intervals (CIs) and prediction intervals (PIs) by combining the most adjusted RR, odds ratios (ORs) and hazard ratios (HRs) under the rare outcome assumption. We included 56 observational studies, including 45 in meta-analysis. There were 1,119,815 women who experienced pregnancy loss of whom 951,258 had a miscarriage and 168,557 stillbirth, compared with 11,965,574 women without previous loss. Women with a history of stillbirth had a greater risk of ischaemic heart disease (IHD) RR 1.56, 95% CI [1.30, 1.88]; p < 0.001, 95% PI [0.49 to 5.15]), cerebrovascular (RR 1.71, 95% CI [1.44, 2.03], p < 0.001, 95% PI [1.92, 2.42]), and any circulatory/cardiovascular disease (RR 1.86, 95% CI [1.01, 3.45], p = 0.05, 95% PI [0.74, 4.10]) compared with women without pregnancy loss. There was no evidence of increased risk of cardiovascular disease (IHD: RR 1.11, 95% CI [0.98, 1.27], 95% PI [0.46, 2.76] or cerebrovascular: RR 1.01, 95% CI [0.85, 1.21]) in women experiencing a miscarriage. Only women with a previous stillbirth were more likely to develop type 2 diabetes mellitus (T2DM) (RR: 1.16, 95% CI [1.07 to 2.26]; p < 0.001, 95% PI [1.05, 1.35]). Women with a stillbirth history had an increased risk of developing renal morbidities (RR 1.97, 95% CI [1.51, 2.57], p < 0.001, 95% [1.06, 4.72]) compared with controls. Women with a history of stillbirth had lower risk of breast cancer (RR: 0.80, 95% CI [0.67, 0.96], p-0.02, 95% PI [0.72, 0.93]). There was no evidence of altered risk of other malignancies in women experiencing pregnancy loss compared to controls. There was no evidence of long-term mental illness risk in women with previous pregnancy losses (stillbirth: RR 1.90, 95% CI [0.93, 3.88], 95% PI [0.34, 9.51], miscarriage: RR 1.78, 95% CI [0.88, 3.63], 95% PI [1.13, 4.16]). The main limitations include the potential for confounding due to use of aggregated data with variable degrees of adjustment. CONCLUSIONS: Our results suggest that women with a history of stillbirth have a greater risk of future cardiovascular disease, T2DM, and renal morbidities. Women experiencing miscarriages, single or multiple, do not seem to have an altered risk.

Gestational diabetes mellitus and adverse maternal and perinatal outcomes in twin and singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). DATA SOURCES: A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May 2023. STUDY ELIGIBILITY CRITERIA: Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. METHODS: This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. RESULTS: Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. CONCLUSION: In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent: a systematic review and meta-analysis of new and published data.

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.

Prediction of ovarian response using the automated Elecsys anti-Müllerian hormone assay in gonadotrophin-releasing hormone antagonist cycles.

RESEARCH QUESTION: What is the capability of serum anti-Müllerian hormone (AMH) measured using the automated Elecsys® AMH immunoassay to (Roche Diagnostics International Ltd) determine ovarian response after fertility treatment? DESIGN: Single-centre, retrospective, observational, cohort study including women undergoing ovarian stimulation. Serum AMH concentrations were determined using the Elecsys AMH immunoassay based on one blood sample drawn 6 months or less before treatment. Stimulation was conducted in accordance with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Patients were divided into four ovarian response categories based on their oocyte yield: low (0-3), suboptimal (4-9), optimal (10-15) and high (>15). Areas under the curve were calculated for each ovarian response group. RESULTS: Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P < 0.001). Areas under the curve (95% CI) for AMH predicting ovarian response were 0.85 (0.83 to 0.88) for low and 0.89 (0.87 to 0.91) for high response. Optimal serum AMH cut-offs for predicting a low and high response using the Elecsys AMH immunoassay were 6.4 pmol/l (0.89 ng/ml) and 14.2 pmol/l (1.99 ng/ml), respectively. Multivariable regression analysis showed that 47% (R2 = 0.470) of variation in ovarian response could be attributed to AMH alone, increasing to 50.9% (R2 = 0.509) with the addition of age, body weight, and total dose of gonadotrophin. CONCLUSION: Ovarian response and oocyte yield after stimulation in a GnRH antagonist cycle can be predicted with high accuracy using a single determination of serum AMH before ovarian stimulation.

Variation in outcome reporting in studies of fertility-sparing surgery for cervical cancer: A systematic review.

BACKGROUND: Cervical cancer affects 3197 women in the UK, and 604 000 women worldwide annually, with peak incidence seen in women between 30 and 34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies, may undermine future efforts for consistent evidence synthesis. OBJECTIVES: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL from inception to February 2019. SELECTION CRITERIA: Randomised controlled trials, cohort and observational studies, and case studies of more than ten participants from January 1990 to date. DATA COLLECTION AND ANALYSIS: Study characteristics and all reported treatment outcomes. MAIN RESULTS: A total of 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), postoperative complications (74/104), intra-operative complications (72/104) and quality of life (5/104). There was huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. CONCLUSIONS: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians and researchers. This systematic review sets the groundwork for the development of a Core Outcome Set for fertility-sparing surgery in cervical cancer.

Standardising outcome reporting for clinical trials of interventions for heavy menstrual bleeding: Development of a core outcome set.

OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.

The genetic background of female reproductive disorders: a systematic review.

PURPOSE OF REVIEW: Reproductive function is the interplay between environmental factors and the genetic footprint of each individual. The development in genetic analysis has strengthened its role in the investigation of female reproductive disorders, potential treatment options and provision of personalized care. Despite the increasing requirement of genetic testing, the evidence of the gene-disease relationships (GDR) is limited. We performed a systematic review exploring the associations between the most frequent female reproductive endocrine disorders associated with subfertility [including polycystic ovaries syndrome (PCOS), premature ovarian failure (POI) and hypogonadotropic hypogonadism] and their genetic background in order to summarize current knowledge. METHODS: A systematic review of relevant literature in accordance with PRISMA guidelines was conducted until July 2022. Data sources that were used are PubMed and Embase. RECENT FINDINGS: A total of 55 studies were included from the 614 articles identified in the original search. We identified 384 genes associated with one or more of the included female reproductive disorders. The highest number of genes was found to be associated with POI ( N  = 209), followed by hypogonadotropic hypogonadism ( N  = 88) and PCOS ( N  = 87). Four genes, including FSHR , LHß , LEPR and SF1 were associated with multiple reproductive disorders implying common pathways in the development of those diseases. SUMMARY: We provide an up-to-date summary of the currently known genes that are associated with three female reproductive disorders (PCOS, POI and hypogonadotropic hypogonadism). The role of genetic analysis in the field of impaired female reproduction may have a role in the diagnosis of female reproductive disorders and personalized patient care.

Strategies to communicate pregnancy complications: a systematic review and practical points for healthcare professionals.

PURPOSE/METHODS: This systematic review aims to provide an overview of strategies available for healthcare professionals (HCPs) to effectively communicate unexpected news in pregnancy, specifically for the most common pregnancy complications. Three medical databases and grey literature were searched until March 2023 using subject headings and keywords. Snowball techniques were also used. The articles were reviewed at each stage of screening independently by two separate authors. Qualitative, quantitative and mixed methods studies were included. RECENT FINDINGS: Forty-three studies were included and grouped according to the gestational age of the pregnancy complication - miscarriage, increased risk screening, foetal conditions, stillbirth. The main key points for communication were outlined at each specific complication and eventually the six common themes that emerged from all the categories were included in the acronym PRICES (Preparation - Referral - Individualized care - Clarity - Empowerment - Sensitivity). SUMMARY: Given the negative impact of failed communications both in pregnancy outcomes and patients' experience, we advocate that communication training for HCP providing pregnancy care should be mandatory, and skills should be updated at regular intervals. Tools like our acronym PRICES can be used during teaching HCPs how to communicate more effectively.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placental Infection Is Associated With Massive Perivillous Fibrin Deposition at the Maternal-Fetal Interface: A Preliminary Study.

We observed an increased frequency of massive perivillous fibrin deposition (MPFD) during the second coronavirus disease 2019 (COVID-19) pandemic wave dominated by the Alpha variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MPFD associated with 100% reverse transcription polymerase chain reaction (RT-PCR) positivity for SARS-CoV-2 and detection by immunohistochemistry. The Alpha variant was identified in all placentas with MPFD that could be sequenced.

Association of birthweight centiles and early childhood development of singleton infants born from 37 weeks of gestation in Scotland: A population-based cohort study.

BACKGROUND: Birthweight centiles beyond the traditional thresholds for small or large babies are associated with adverse perinatal outcomes but there is a paucity of data about the relationship between birthweight centiles and childhood development among children born from 37 weeks of gestation. This study aims to establish the association between birthweight centiles across the whole distribution and early childhood development among children born from 37 weeks of gestation. METHODS AND FINDINGS: This is a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation. The cohort was generated by linking pregnancy and delivery data from the Scottish Morbidity Records (2003 to 2015) and the child developmental assessment at age 2 to 3.5 years. The main outcomes were child's fine motor, gross motor, communication, and social developmental concerns measured with the Ages and Stages Questionnaires-3 (ASQ-3) and Ages and Stages Questionnaire: Social & Emotional-2 (ASQ:SE-2), and for a subset of children with additional specialist tools such as the Modified Checklist for Autism in Toddlers (M-CHAT) if the ASQ3/SE indicate these are necessary. The ASQ score for each domain was categorised as "concern" and "no concern." We used multivariate cubic regression splines to model the associations between birthweight centiles and early childhood developmental concerns. We used multivariate Poisson regression models, with cluster robust errors, to estimate the relative risks (RRs) of developmental concerns below and above the established thresholds. We adjusted for maternal age, early pregnancy body mass index (BMI), parity, year of delivery, gestational age at delivery, smoking history, substance misuse in pregnancy, alcohol intake, ethnicity, residential area deprivation index, maternal clinical conditions in pregnancy (such as diabetes and pre-eclampsia), induction of labour, and child's sex. Babies born from 37 weeks of gestation with birthweight below the 25th centile, compared to those between the 25th and 74th centile, were at higher risk of developmental concerns. Those born between the 10th and 24th centile had an RR of 1.07 (95% CI: 1.03 to 1.12, p < 0.001), between the 3rd and 9th centile had an RR: 1.18 (95% CI: 1.12 to 1.25, p < 0.001), and <3rd centile had an RR of 1.37 (95% CI: 1.24 to 1.50, p < 0.001). There was no substantial increase in the risk of early childhood developmental concerns for larger birthweight categories of 75th to 89th (RR: 1.01; 95% CI: 0.97 to 1.05; p = 0.56), 90th to 96th (RR: 0.99; 95% CI: 0.94 to 1.05; p = 0.86), and ≥97th centiles (RR: 1.04; 95% CI: 0.97 to 1.12; p = 0.27), referent to birthweight between 25th and 74th centile. The percentage of developmental concerns attributable to birthweight between the 10th and 24th centile was more than that of birthweight <3rd centile (p = 0.023) because this group includes more of the population. Approximately 2.50% (95% CI: 1.26 to 3.61) of social skills concerns and 3.00% (95% CI: 1.33 to 4.67) of fine motor developmental concerns were attributable to birthweight between the 10th and 24th centile compared to 0.90% (95% CI: 0.48 to 1.26) and 2.30% (95% CI: 1.73 to 2.67) respectively for birthweight <3rd centile. We acknowledge the limitation of ASQ as a screening tool, the subjective nature of developmental assessments (particularly for speech) among young children, and inability to control for early childhood illness and upbringing factors may have an impact on our findings. CONCLUSIONS: We observed that from 37 weeks of gestation birthweight below the 25th centile was associated with child developmental concerns, with an association apparent at higher centiles above the conventional threshold defining small for gestational age (SGA, 3rd or 10th centile). Mild to moderate SGA is an unrecognised potentially important contributor to the prevalence of developmental concerns. Closer surveillance, appropriate parental counselling, and increased support during childhood may reduce the risks associated with lower birthweight centiles.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK).

BACKGROUND: Risk factors for severe COVID-19 include older age, male sex, obesity, black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. METHODS: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 May 2020 to 5 February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted ORs (aORs) for associations between potential risk factors and odds of COVID-19. RESULTS: We recorded 446 incident cases of COVID-19 in 15 227 participants (2.9%). Increased odds of developing COVID-19 were independently associated with Asian/Asian British versus white ethnicity (aOR 2.28, 95% CI 1.33 to 3.91), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11 to 1.43), any versus no visits to/from other households in previous week (aOR 1.31, 1.06 to 1.62), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.02 to 1.09), frontline occupation excluding health/social care versus no frontline occupation (aOR 1.49, 1.12 to 1.98) and raised body mass index (BMI) (aOR 1.50 (1.19 to 1.89) for BMI 25.0-30.0 kg/m2 and 1.39 (1.06 to 1.84) for BMI >30.0 kg/m2 versus BMI <25.0 kg/m2). Atopic disease was independently associated with decreased odds (aOR 0.75, 0.59 to 0.97). No independent associations were seen for age, sex, other medical conditions, diet or micronutrient supplement use. CONCLUSIONS: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased odds of developing COVID-19, while atopic disease was associated with decreased odds. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04330599).

Management of recurrent miscarriages: an overview of current evidence.

PURPOSE OF REVIEW: Recurrent miscarriage (RM) or recurrent pregnancy loss (RPL) is defined as the consecutive loss of two or more pregnancies before the age of viability. The exact prevalence of RM is unknown, but it has been reported between 1% and 2%. The objective of this review is to provide a critical summary of the latest evidence for the investigation and management of women with RM. RECENT FINDINGS: RMs are associated with multiple factors including increased female age and lifestyle habits, as well as genetic factors, hereditary and acquired thrombophilia and infections. Metabolic and endocrine factors, in addition to anatomical causes such as uterine malformations have also been suggested as a causative factors of RM. SUMMARY: The management of RM would be expected to cause specific, however, in the majority of the cases no cause is identified, and the factors associated with RM may not be causally related with the condition.

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials.

BACKGROUND: The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied. METHODS: After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups. RESULTS: Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%-3.2%) and 2.7% (95% CI 2.0%-3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%-22.6%) and 13.6% (95% CI 11.6%-15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75-3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness. Secondary meta-analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14-7.40) and 2.93 times higher (95% CI 1.41-6.07), respectively, in the active treatment groups compared to placebo. CONCLUSIONS: TMS is a safe and well-tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice.

Do physical activity, commuting mode, cardiorespiratory fitness and sedentary behaviours modify the genetic predisposition to higher BMI? Findings from a UK Biobank study.

OBJECTIVE: To investigate whether the association between a genetic profile risk score for obesity (GPRS-obesity) (based on 93 SNPs) and body mass index (BMI) was modified by physical activity (PA), cardiorespiratory fitness, commuting mode, walking pace and sedentary behaviours. METHODS: For the analyses we used cross-sectional baseline data from 310,652 participants in the UK Biobank study. We investigated interaction effects of GPRS-obesity with objectively measured and self-reported PA, cardiorespiratory fitness, commuting mode, walking pace, TV viewing, playing computer games, PC-screen time and total sedentary behaviour on BMI. Body mass index (BMI) was the main outcome measure. RESULTS: GPRS-obesity was associated with BMI (ß:0.54 kg.m-2 per standard deviation (SD) increase in GPRS, [95% CI: 0.53; 0.56]; P = 2.1 × 10-241). There was a significant interaction between GPRS-obesity and objectively measured PA (P[interaction] = 3.3 × 10-11): among inactive individuals, BMI was higher by 0.58 kg.m-2 per SD increase in GPRS-obesity (p = 1.3 × 10-70) whereas among active individuals the relevant BMI difference was less (ß:0.33 kg.m-2, p = 6.4 × 10-41). We observed similar patterns for fitness (Unfit ß:0.72 versus Fit ß:0.36 kg.m-2, P[interaction] = 1.4 × 10-11), walking pace (Slow ß:0.91 versus Brisk ß:0.38 kg.m-2, P[interaction] = 8.1 × 10-27), discretionary sedentary behaviour (High ß:0.64 versus Low ß:0.48 kg.m-2, P[interaction] = 9.1 × 10-12), TV viewing (High ß:0.62 versus Low ß:0.47 kg.m-2, P[interaction] = 1.7 × 10-11), PC-screen time (High ß:0.82 versus Low ß:0.54 kg.m-2, P[interaction] = 0.0004) and playing computer games (Often ß:0.69 versus Low ß:0.52 kg.m-2, P[interaction] = 8.9 × 10-10). No significant interactions were found for commuting mode (car, public transport, active commuters). CONCLUSIONS: Physical activity, sedentary behaviours and fitness modify the extent to which a set of the most important known adiposity variants affect BMI. This suggests that the adiposity benefits of high PA and low sedentary behaviour may be particularly important in individuals with high genetic risk for obesity.

Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank.

OBJECTIVE: Elevated white blood cell count is associated with a higher risk of cardiovascular disease (CVD). We aimed to investigate whether specific leukocyte subpopulations, which may more closely indicate a specific inflammatory pathway, are specifically associated with CVD. APPROACH AND RESULTS: Participants (478 259) from UK Biobank with data for white blood cell count were included. Death because of CVD (n=1377) and non-CVD causes (n=8987) occurred during median follow-up time of 7.0 years (interquartile range, 6.3-7.6). In Cox models, deciles of leukocyte counts (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) were examined using the fifth decile as the referent group. Models were stratified by sex and adjusted for a range of classical risk factors. A sensitivity analysis excluded participants with baseline comorbidites and the first 2 years of follow-up. Men (hazard ratio [HR], 1.59; 95% confidence interval, 1.22-2.08) and women (HR, 2.15; 95% confidence interval, 1.38-3.35) in the highest decile of neutrophil count were at higher risk of CVD mortality and nonfatal CVD (men HR, 1.28; 95% confidence interval, 1.16-1.42 and women HR, 1.21; 95% confidence interval, 1.06-1.38). In the sensitivity analysis, the power to investigate CVD mortality was limited, but for both sexes combined, the linear HRs for a 1×109/L cell count increase in white blood cell count and neutrophils, respectively, was 1.05 (1.03-1.07) and 1.07 (1.04-1.11). CONCLUSIONS: Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality.

Dose-response associations of cardiorespiratory fitness with all-cause mortality and incidence and mortality of cancer and cardiovascular and respiratory diseases: the UK Biobank cohort study.

OBJECTIVE: To investigate the association of cardiorespiratory fitness with all-cause mortality, and cardiovascular disease (CVD), respiratory disease, chronic obstructive pulmonary disease (COPD) and cancer mortality and incidence. DESIGN: Prospective population-based study. SETTING: UK Biobank. PARTICIPANTS: Of the 5 02 628 (5.5% response rate) participants recruited by UK Biobank, we included 73 259 (14.6%) participants with available data in this analysis. Of these, 1374 participants died and 4210 developed circulatory diseases, 1293 respiratory diseases and 4281 cancer, over a median of 5.0 years (IQR 4.3-5.7) follow-up. MAIN OUTCOME MEASURES: All-cause mortality and circulatory disease, respiratory disease, COPD and cancer (such as colorectal, lung, breast and prostate) mortality/incidence. Fitness was estimated using a submaximal cycle ergometer test. RESULTS: The HR for all-cause mortality for each metabolic equivalent of task (MET) higher fitness was 0.96 (95% CI 0.93 to 0.98). Similar results were observed for incident circulatory disease (HR 0.96 [0.95 to 0.97]), respiratory disease (HR 0.96 [0.94 to 0.98]), COPD (HR 0.90 [0.86 to 0.95) and colorectal cancer (HR 0.96 [0.92 to 1.00]). Nonlinear analysis revealed that a high level of fitness (>10METs) was associated with a greater incidence of atrial fibrillation (HR 1.24 [1.07 to 1.44]) and prostate cancer (HR 1.16 [1.02 to 1.32]) compared with average fitness. All results were adjusted for sociodemographic, lifestyle and dietary factors, body composition, and morbidity at baseline and excluded events in the first 2 years of follow-up. CONCLUSIONS: Higher cardiorespiratory fitness was associated with lower risk of premature mortality and incidence of CVD, respiratory disease and colorectal cancer.

The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent.

Aims: The data regarding the associations of body mass index (BMI) with cardiovascular (CVD) risk, especially for those at the low categories of BMI, are conflicting. The aim of our study was to examine the associations of body composition (assessed by five different measures) with incident CVD outcomes in healthy individuals. Methods and results: A total of 296 535 participants (57.8% women) of white European descent without CVD at baseline from the UK biobank were included. Exposures were five different measures of adiposity. Fatal and non-fatal CVD events were the primary outcome. Low BMI (≤18.5 kg m-2) was associated with higher incidence of CVD and the lowest CVD risk was exhibited at BMI of 22-23 kg m-2 beyond, which the risk of CVD increased. This J-shaped association attenuated substantially in subgroup analyses, when we excluded participants with comorbidities. In contrast, the associations for the remaining adiposity measures were more linear; 1 SD increase in waist circumference was associated with a hazard ratio of 1.16 [95% confidence interval (CI) 1.13-1.19] for women and 1.10 (95% CI 1.08-1.13) for men with similar magnitude of associations for 1 SD increase in waist-to-hip ratio, waist-to-height ratio, and percentage body fat mass. Conclusion: Increasing adiposity has a detrimental association with CVD health in middle-aged men and women. The association of BMI with CVD appears more susceptible to confounding due to pre-existing comorbidities when compared with other adiposity measures. Any public misconception of a potential 'protective' effect of fat on CVD risk should be challenged. Take home figureThe obesity paradox is mainly due to the effect of confounding on BMI and disappears on other adiposity measures.

Associations of Dietary Protein Intake With Fat-Free Mass and Grip Strength: A Cross-Sectional Study in 146,816 UK Biobank Participants.

Adequate dietary protein intake is important for the maintenance of fat-free mass (FFM) and muscle strength, but optimal requirements remain unknown. Our aim in the current study was to explore the associations of protein intake with FFM and grip strength. We used baseline data from the UK Biobank (a study of 146,816 participants aged 40-69 years with data collected across the United Kingdom in 2007-2010) to examine the associations of protein intake with FFM and grip strength. Protein intake was positively associated with FFM (men: 5.1% (95% confidence interval (CI): 5.0, 5.2); women: 7.7% (95% CI: 7.7, 7.8)) and grip strength (men: 0.076 kg/kg (95% CI: 0.074, 0.078); women: 0.074 kg/kg (95% CI: 0.073, 0.076)) per 0.5-g/kg/day (grams per kg of body mass per day) increment in protein intake. FFM and grip strength were higher with higher intakes across the full range of intakes (i.e., highest in persons who reported consuming ≥2.00 g/kg/day) independently of sociodemographic factors, other dietary measures, physical activity, and comorbidity. FFM and grip strength were lower with age, but this association did not differ by category of protein intake (P > 0.05). The current recommendation for all adults (ages 40-69 years) to maintain a protein intake of 0.8 g/kg/day may need to be increased to optimize FFM and grip strength.

Associations of discretionary screen time with mortality, cardiovascular disease and cancer are attenuated by strength, fitness and physical activity: findings from the UK Biobank study.

BACKGROUND: Discretionary screen time (time spent viewing a television or computer screen during leisure time) is an important contributor to total sedentary behaviour, which is associated with increased risk of mortality and cardiovascular disease (CVD). The aim of this study was to determine whether the associations of screen time with cardiovascular disease and all-cause mortality were modified by levels of cardiorespiratory fitness, grip strength or physical activity. METHODS: In total, 390,089 participants (54% women) from the UK Biobank were included in this study. All-cause mortality, CVD and cancer incidence and mortality were the main outcomes. Discretionary television (TV) viewing, personal computer (PC) screen time and overall screen time (TV + PC time) were the exposure variables. Grip strength, fitness and physical activity were treated as potential effect modifiers. RESULTS: Altogether, 7420 participants died, and there were 22,210 CVD events, over a median of 5.0 years follow-up (interquartile range 4.3 to 5.7; after exclusion of the first 2 years from baseline in the landmark analysis). All discretionary screen-time exposures were significantly associated with all health outcomes. The associations of overall discretionary screen time with all-cause mortality and incidence of CVD and cancer were strongest amongst participants in the lowest tertile for grip strength (all-cause mortality hazard ratio per 2-h increase in screen time (1.31 [95% confidence interval: 1.22-1.43], p < 0.0001; CVD 1.21 [1.13-1.30], p = 0.0001; cancer incidence 1.14 [1.10-1.19], p < 0.0001) and weakest amongst those in the highest grip-strength tertile (all-cause mortality 1.04 [0.95-1.14], p = 0.198; CVD 1.05 [0.99-1.11], p = 0.070; cancer 0.98 [0.93-1.05], p = 0.771). Similar trends were found for fitness (lowest fitness tertile: all-cause mortality 1.23 [1.13-1.34], p = 0.002 and CVD 1.10 [1.02-1.22], p = 0.010; highest fitness tertile: all-cause mortality 1.12 [0.96-1.28], p = 0.848 and CVD 1.01 [0.96-1.07], p = 0.570). Similar findings were found for physical activity for all-cause mortality and cancer incidence. CONCLUSIONS: The associations between discretionary screen time and adverse health outcomes were strongest in those with low grip strength, fitness and physical activity and markedly attenuated in those with the highest levels of grip strength, fitness and physical activity. Thus, if these associations are causal, the greatest benefits from health promotion interventions to reduce discretionary screen time may be seen in those with low levels of strength, fitness and physical activity.