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Plasma adiponectin is inversely associated with the risk of coronary heart disease in healthy people. However, adiponectin and BNP (B-type natriuretic peptide) are both known to be positively associated with a risk of poor outcome, and with each other, in ACS (acute coronary syndrome) patients. Serial changes in plasma adiponectin and BNP following ACS have not been assessed previously, and may clarify these apparently paradoxical associations. In the present study, adiponectin, BNP, classical risk markers and clinical parameters were measured in plasma from 442 consecutive ACS patients in an urban teaching hospital, with repeat measures at 7 weeks (n=338). Patients were followed-up for 10 months. Poor outcome was defined as mortality or readmission for ACS or congestive heart failure (n=90). In unadjusted analysis, the change in adiponectin (but not baseline or 7-week adiponectin) was significantly associated with the risk of an adverse outcome {odds ratio (OR), 5.42 [95% CI (confidence interval), 2.78–10.55]}. This association persisted after adjusting for classical risk factors and clinical markers, but was fully attenuated by adjusting for the 7-week BNP measurement [OR, 1.13 (95% CI, 0.27–4.92)], which itself remained associated with risk [OR, 5.86 (95% CI, 1.04–32.94)]. Adiponectin and BNP positively correlated at baseline and 7 weeks, and the change in both parameters over 7 weeks also correlated (r=0.39, P<0.001). In conclusion, increases in plasma adiponectin (rather than absolute levels) after ACS are related to the risk of an adverse outcome, but this relationship is not independent of BNP levels. The results of the present study allude to a potential direct or indirect relationship between adiponectin and BNP post-ACS which requires further investigation. [ABSTRACT FROM AUTHOR]

Abstract Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART.

Abstract Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n = 7,944; I2 = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n = 989; I2 = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n = 1,925; I2 = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n = 1,202; I2 = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

: BACKGROUND Individualization of controlled ovarian stimulation (COS) for assisted conception is complicated by variable ovarian response to follicle stimulating hormone. We hypothesized that anti-Müllerian hormone (AMH), a predictor of oocyte yield, may facilitate treatment strategies for women undergoing COS, to optimize safety and clinical pregnancy rates. : METHODS Prospective cohort study of 538 patients in two centres with differential COS strategies based on a centralized AMH measurement. : RESULTS AMH was associated with oocyte yield after ovarian stimulation in both centres, and a ‘reduced’ AMH (1 to <5 pmol/l) was associated with a reduced clinical pregnancy rate. Women with a ‘normal’ AMH (5 to <15 pmol/l) treated with a long GnRH-agonist protocol (both centres) showed a low incidence of excess response (0%) and poor response (0%). In women with ‘high’ AMH (>15 pmol/l), the antagonist protocol eliminated the need for complete cryopreservation of embryos due to excess response (P < 0.001) and showed a higher fresh cycle clinical pregnancy rate than agonist cycles [OR 4.40 (95% CI 1.95–9.93), P < 0.001]. : CONCLUSIONS The use of circulating AMH to individualize treatment strategies for COS may result in reduced clinical risk, optimized treatment burden and maintained pregnancy rates, and is worthy of prospective randomized examination. [ABSTRACT FROM AUTHOR]

: BACKGROUND Heparan sulphates play key roles in conception and early pregnancy events. The role of heparin, a structural analogue, and its application to assisted conception, is largely unknown. : METHODS Relevant studies were identified by searching PubMed 1966–November 2007 and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words. : RESULTS The similarities of heparin and heparan, the haemostatic changes induced by ovarian stimulation and the risk of thrombosis, the contribution of thrombophilia to pregnancy and infertility outcomes, early embryo-maternal dialogue and how these various aspects of assisted conception may be modified by heparin are reviewed. : CONCLUSIONS Heparin can alter the haemostatic response to controlled ovarian stimulation and modify the risk of thrombosis. It can also modulate many of the fundamental physiological processes required for blastocyst apposition, adherence and implantation and as well as trophoblast differentiation and invasion due to its similarities with heparan sulphates and has the potential to improve pregnancy rates and outcomes. [ABSTRACT FROM AUTHOR]

Obesity is a major health problem across the world. Recent editorials suggest that obese patients should be denied treatment of any kind aimed to improve ovulation rates and achieve pregnancy until they have reduced their BMI. We propose that this approach is not a resolution of the problem, but indeed may amplify the maternal and perinatal complications attributed to fertility centres. Obesity independent of polycystic ovary syndrome (PCOS) is associated with anovulation, and minimal weight loss alone is an effective therapy for induction of ovulation in both obese women and obese PCOS women. Consequently, lifestyle programmes encouraging weight loss should be considered to be an ovulation induction therapy and due consideration for a potential pregnancy in an obese woman given. We propose that women with a BMI in excess of 35 kg m2 should lose weight prior to conception—not prior to receiving infertility treatment. Therefore, clinicians undertaking the management of infertility in obese women should adopt measures to reduce their body mass prior to exposing them to the risks of pregnancy. We advocate that this approach should be aggressively managed including pharmacological strategies; intrinsic in this programme is the use of contraception and high-dose folic acid during that period of preconceptual weight reduction. [ABSTRACT FROM AUTHOR]

Abstract Background Women experience adverse changes in cardiovascular health in mid-life; whether the menopausal transition influences these remains strongly debated. The aim of this study was to examine associations of reproductive age (time since final menstrual period (FMP)) with change in carotid intima media thickness (CIMT) and cardiovascular risk factors and determine the role of chronological and reproductive age. Methods We used data from 1702 women from a pregnancy-based UK cohort who had up to four repeat cardiovascular health measures between mean age 51 (SD = 4.0) and 56 (SD = 3.6) years and experienced a natural menopause. Multilevel models were used to assess the relationship between cardiovascular measures and time since FMP (reproductive age), whilst adjusting for the underlying effects of chronological age and confounders (socioeconomic factors, body mass index, smoking, alcohol, parity, age at menarche). In addition, we looked at the relationship between cardiovascular measures by chronological age according to menopausal stages (pre-menopause, peri-menopause and post-menopause) using information from women who had and had not experienced menopause (N = 3892). Results There was no strong evidence that reproductive age was associated with CIMT (difference in mean 0.8 μm/year, 95% CI − 0.4, 2.1), whereas there was a strong positive association of chronological age (7.6 μm/year, 95% CI 6.3, 8.9). Consistent with this, we found weaker linear associations of reproductive compared with chronological age for atherosclerotic risk factors, such as with systolic blood pressure (− 0.1 mmHg/year, 95% CI − 0.3, 0.1, and 0.4 mmHg/year, 95% CI 0.2, 0.5, respectively) and non-HDL-cholesterol (0.02 mmol/l/year, 95% CI 0.005, 0.03, and 0.06, 95% CI 0.04, 0.07, respectively). In contrast, associations with fat mass (0.06 kg/m2/year, 95% CI 0.03, 0.10, and 0 kg/m2/year, 95% CI − 0.04, 0.04, respectively) and C-reactive protein (0.01, 95% CI 0.001, 0.02, and 0.01, 95% CI − 0.001, 0.02 natural logged mg/l/year, respectively) were stronger for reproductive compared with chronological age. Both reproductive and chronological age were (weakly) positively associated with glucose (0.002, 95% CI 0.0001, 0.003, and 0.002, 95% CI 0.0001, 0.003 natural logged mmol/l/year, respectively). Conclusions Our results suggest that going through the menopausal transition does not further increase women’s risk of atherosclerosis (measured by CIMT) beyond effects of ageing. Menopausal transition may, in additional to ageing, modestly increase adiposity and glucose levels and therefore a possible associated diabetes risk.

Abstract Background There may be changes in cognitive function in women going through the menopause. The current evidence remains unclear, however, whether these changes occur over and above those of general ageing. We aimed to evaluate the potential impact of the menopause (assessed by reproductive age and hormone levels) on cognitive function in women in mid-life accounting for the underlying effects of ageing. Methods The study was based on the follow up of women originally enrolled in pregnancy in a birth cohort when resident in the South West of England, UK between 1991 and 1992. Using up to three repeated measurements in 2411 women (mean age 51 at first assessment), we modelled changes in six cognitive function domains: immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence and verbal fluency. The exposures of interest were reproductive age measured as years relative to the final menstrual period (FMP), chronological age and reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)). Results Processing speed (− 0.21 (95% CI − 0.36 to − 0.06) standard deviation (SD) difference per 10 years since FMP), immediate verbal episodic memory (− 0.15 (95% CI − 0.35 to 0.06)) and delayed verbal episodic memory (− 0.17 (95% CI − 0.37 to 0.03)) declined with reproductive age. Reproductive hormones were not robustly associated with processing speed, but FSH and LH were both negatively associated with immediate (− 0.08 (95% CI − 0.13 to − 0.02) SD difference per SD difference in hormone level) and delayed verbal episodic memory (− 0.08 (95% CI − 0.13 to − 0.03)). There was little consistent evidence of cognitive function declining with menopause in other cognitive domains. Conclusions Of the cognitive domains tested only verbal episodic memory declined both in relation to age since the menopause and in conjunction with the reproductive hormones that reflect the menopause. This decline was independent of normal ageing and suggests that the menopause is associated with a mild impact on this specific domain of cognitive function.

Abstract Background It is not known whether segmentation of an in vitro fertilisation (IVF) cycle, with freezing of all embryos prior to transfer, increases the chance of a live birth after all embryos are transferred. Methods In a prospective study of UK Human Fertilisation and Embryology Authority data, we investigated the impact of segmentation, compared with initial fresh embryo followed by frozen embryo transfers, on live birth rate and perinatal outcomes. We used generalised linear models to assess the effect of segmentation in the whole cohort, with additional analyses within women who had experienced both segmentation and non-segmentation. We compared rates of live birth, low birthweight (LBW 4 kg), small for gestational age (SGA 90th centile) for a given ovarian stimulation cycle accounting for all embryo transfers. Results We assessed 202,968 women undergoing 337,148 ovarian stimulation cycles and 399,896 embryo transfer procedures. Live birth rates were similar in unadjusted analyses for segmented and non-segmented cycles (rate ratio 1.05, 95% CI 1.02–1.08) but lower in segmented cycles when adjusted for age, cycle number, cause of infertility, and ovarian response (rate ratio 0.80, 95% CI 0.78–0.83). Segmented cycles were associated with increased risk of macrosomia (adjusted risk ratio 1.72, 95% CI 1.55–1.92) and LGA (1.51, 1.38–1.66) but lower risk of LBW (0.71, 0.65–0.78) and SGA (0.64, 0.56–0.72). With adjustment for blastocyst/cleavage-stage embryo transfer in those with data on this (329,621 cycles), results were not notably changed. Similar results were observed comparing segmented to non-segmented within 3261 women who had both and when analyses were repeated excluding multiple embryo cycles and multiple pregnancies. When analyses were restricted to women with a single embryo transfer, the transfer of a frozen-thawed embryo in a segmented cycles was no longer associated with a lower risk of LBW (0.97, 0.71–1.33) or SGA (0.84, 0.61–1.15), but the risk of macrosomia (1.74, 1.39–2.20) and LGA (1.49, 1.20–1.86) persisted. When the analyses for perinatal outcomes were further restricted to solely frozen embryo transfers, there was no strong statistical evidence for associations. Conclusions Widespread application of segmentation and freezing of all embryos to unselected patient populations may be associated with lower cumulative live birth rates and should be restricted to those with a clinical indication.

Abstract Background Women who experience menopause are at higher cardiometabolic risk and often display adverse changes in metabolic biomarkers compared with pre-menopausal women. It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging. Well-conducted longitudinal studies are required to determine this. The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status, defined according to the 2012 Stages of Reproductive Aging Workshop criteria, with 74 metabolic biomarkers, and establish whether any associations are independent of age-related changes. Methods We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women. In a subgroup of 1,492 women who had repeat assessments after 2.5 years, we assessed how the change in reproductive status was associated with the changes in metabolic biomarkers. Metabolic profiles were measured by high-throughput quantitative nuclear magnetic resonance metabolomics. In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive-status category change to that of the reference of being pre-menopausal at both time points. As all women aged by a similar amount during follow-up, these analyses contribute to distinguishing age-related changes from those related to change in reproductive status. Results Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting the transition to menopause induces multiple metabolic changes independent of chronological aging. The metabolic changes included increased concentrations of very small very low-density lipoproteins, intermediate-density lipoproteins, low-density lipoproteins (LDLs), remnant, and LDL cholesterol, and reduced LDL particle size, all toward an atherogenic lipoprotein profile. Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein. Also, levels of glutamine and albumin increased during the transition. Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years. Conclusions The transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory. The adverse changes in multiple apolipoprotein-B-containing lipoprotein subclasses and increased inflammation may underlie women’s increased cardiometabolic risk in their post-menopausal years.