Stamatina Iliodromiti

Can anti-mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data

CONTEXT Existing biochemical tests for polycystic ovary syndrome (PCOS) have poor sensitivity and specificity. Many women with PCOS have high anti-Müllerian hormone (AMH) concentrations; thus, this may be a useful addition to the diagnostic criteria. OBJECTIVE A systematic literature review was performed to assess the true accuracy of AMH in the prediction of PCOS and to determine the optimal diagnostic threshold. DATA SOURCES Published and gray literature were searched for all years until January 2013. STUDY SELECTION Observational studies defining PCOS according to the Rotterdam criteria and assessing the value of AMH in diagnosing PCOS were selected. Ten studies of the initial 314 hits reporting AMH values in the diagnosis of PCOS were included in the meta-analysis and the construction of the summary receiver-operating characteristic curve. Four studies that plotted individual AMH serum levels of women with PCOS and controls on graphs were selected for individual data extraction. DATA EXTRACTION Two researchers independently assessed the abstracts resulted from the initial search against the inclusion criteria, graded the papers for selection and verification biases, and selected the papers that assessed the value of AMH in diagnosing PCOS. Data were extracted from 4 studies with the plotted individual data on graphs with the help of computer software. DATA SYNTHESIS The meta-analysis of the extracted data demonstrated the specificity and sensitivity in diagnosing PCOS in the symptomatic women of 79.4% and 82.8%, respectively, for a cutoff value of AMH of 4.7 ng/mL. The area under the curve was 0.87 (95% confidence interval 0.83-0.92), identical with the area under the curve of 0.87 for the summary receiver-operating characteristic curve involving 10 separate studies. CONCLUSIONS AMH may be a useful initial diagnostic test for PCOS subject to validation in prospective population cohorts.

The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature

BACKGROUND Anti-Müllerian hormone (AMH) is an established marker of ovarian reserve and a good predictor of poor or excessive ovarian response after controlled hyperstimulation. However, it is unclear whether it can predict the ultimate outcome of assisted conception, live birth. We undertook a systematic review and meta-analysis to examine whether AMH is a predictor of live birth in women undergoing assisted conception. METHODS The study was conducted according to the PRISMA guidelines. PubMed, Embase, Medline, Web of Knowledge and the Cochrane trial register and unpublished literature were searched. Studies fulfilling the eligibility criteria were included in the systematic review and those with extractable data were included in the meta-analysis. Quality assessment was performed with the QUADAS 2 checklist. A summary estimate of diagnostic odds ratio (DOR) was derived using the random effects model for binary data. A hierarchical summary receiver operating characteristic model provided pooled estimates before and after adjusting for age and AMH assay as covariates. RESULTS Out of 361 non-duplicate studies, 47 were selected; 17 met the eligibility criteria and 13 had extractable data and thus were included in the meta-analysis. Three out of the 13 studies included only women with expected low ovarian reserve and were analysed individually from the remaining 10 to minimize heterogeneity. The DOR for women with unknown ovarian reserve (n = 5764 women) was 2.39 (95% confidence interval (CI): 1.85-3.08). After adjustment for age the DOR was little changed at 2.48 (95% CI: 1.81-3.22) and the DOR adjusted for AMH assay was almost identical at 2.42 (95% CI: 1.86-3.14). For women with expected low ovarian reserve (n = 542 women) the DOR was 4.63 (95% CI: 2.75-7.81). CONCLUSIONS AMH, independently of age, has some association with predicting live birth after assisted conception and may be helpful when counselling couples before undergoing fertility treatment. However, its predictive accuracy is poor.

Apgar score and the risk of cause-specific infant mortality: a population-based cohort study

BACKGROUND The Apgar score has been used worldwide as an index of early neonatal condition for more than 60 years. With advances in health-care service provision, neonatal resuscitation, and infant care, its present relevance is unclear. The aim of the study was to establish the strength of the relation between Apgar score at 5 min and the risk of neonatal and infant mortality, subdivided by specific causes. METHODS We linked routine discharge and mortality data for all births in Scotland, UK between 1992 and 2010. We restricted our analyses to singleton livebirths, in women aged over 10 years, with a gestational age at delivery between 22 and 44 weeks, and excluded deaths due to congenital anomalies or isoimmunisation. We calculated the relative risks (RRs) of neonatal and infant death of neonates with low (0-3) and intermediate (4-6) Apgar scores at 5 min referent to neonates with normal Apgar score (7-10) using binomial log-linear modelling with adjustment for confounders. Analyses were stratified by gestational age at birth because it was a significant effect modifier. Missing covariate data were imputed. FINDINGS Complete data were available for 1,029,207 eligible livebirths. Across all gestational strata, low Apgar score at 5 min was associated with an increased risk of neonatal and infant death. However, the strength of the association (adjusted RR, 95% CI referent to Apgar 7-10) was strongest at term (p<0·0001). A low Apgar (0-3) was associated with an adjusted RR of 359·4 (95% CI 277·3-465·9) for early neonatal death, 30·5 (18·0-51·6) for late neonatal death, and 50·2 (42·8-59·0) for infant death. We noted similar associations of a lower magnitude for intermediate Apgar (4-6). The strongest associations were for deaths attributed to anoxia and low Apgar (0-3) for term infants (RR 961·7, 95% CI 681·3-1357·5) and preterm infants (141·7, 90·1-222·8). No association between Apgar score at 5 min and the risk of sudden infant death syndrome was noted at any gestational age (RR 0·6, 95% CI 0·1-4·6 at term; 1·2, 0·3-4·8 at preterm). INTERPRETATION Low Apgar score at 5 min was strongly associated with the risk of neonatal and infant death. Our findings support its continued usefulness in contemporary practice. FUNDING None.

Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study

STUDY QUESTION Are clinical pregnancy rates satisfactory and the incidence of OHSS low after GnRH agonist trigger and modified intensive luteal support in patients with a high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER GnRH agonist trigger combined with 1500 IU hCG at the time of oocyte retrieval and subsequent estradiol and progesterone replacement in OHSS high-risk patients can facilitate fresh embryo transfer with high clinical pregnancy rates and a low risk of severe OHSS. WHAT IS KNOWN ALREADY Conventional luteal support packages are inadequate to facilitate a fresh transfer after a GnRH agonist trigger. A low dose of hCG (1500 IU) after oocyte aspiration can be used to replace the actions of early luteal LH to sustain implantation and the function of the early corpus luteum, although the level of risk of severe OHSS with this strategy is unclear. STUDY DESIGN, SIZE, DURATION This international multicentre retrospective case study, including 275 women at high risk of OHSS, was undertaken during the period January 2011-December 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Women were identified as at high risk of OHSS, based on IVF response, ovarian reserve characteristics and previous history of having had treatment, in three clinical IVF centres in UK, Belgium and Australia. All three centres used a GnRH agonist trigger followed by one bolus of 1500 IU hCG 1h after oocyte retrieval. Moreover, the luteal phase was supported with daily vaginal progesterone and twice daily estradiol valerate. MAIN RESULTS AND THE ROLE OF CHANCE A total of 275 autologous cycles with fresh transfer were undertaken in a cohort of high-risk women as defined by baseline characteristics [median (interquartile range)]: age 31.6 (29-35) years, antral follicle count median 25 (18-34) and anti-Müllerian hormone median 49.1 pmol/l (35.2-69.3). At the end of stimulation, the peak estradiol median of 12 000 pmol/l (9400-15 914) and the mean oocyte yield of 17.8 ± 8.4 confirmed a high response. The overall clinical pregnancy rate was 41.8% per cycle started, with only two cases of severe OHSS reported (0.72%). No significant differences in clinical pregnancy rates between centres were identified. LIMITATIONS, REASONS FOR CAUTION This is a retrospective study and future randomized controlled trials will be able to compare whether these outcomes can be improved upon by either segmentation of the stimulation cycle and embryo transfer or alternative aggressive luteal support strategies. WIDER IMPLICATIONS OF THE FINDINGS In women who are undergoing ovarian stimulation and who develop an excessive ovarian response, the use of a GnRH agonist trigger combined with modified luteal support can provide the opportunity to proceed to fresh embryo transfer with adequate clinical pregnancy rates. However, this procedure will not completely eliminate the risk of OHSS and for women with an extreme ovarian response or with significant comorbidity, where the possibility of severe OHSS is unacceptable, we recommend GnRH agonist trigger followed by a freeze-all policy to completely avoid OHSS.

Reference range for the antimüllerian hormone Generation II assay: a population study of 10,984 women, with comparison to the established Diagnostics Systems Laboratory nomogram

OBJECTIVE To develop an optimal model and age-specific centiles for the decline in antimüllerian hormone (AMH) as measured by the new Beckman Coulter AMH Generation II (Gen II) assay and compare this to the previous nomogram derived for the Diagnostics Systems Laboratory (DSL) assay. DESIGN Multicenter retrospective population study, with validation of linear, biphasic linear, differential, power, and quadratic equations. SETTING Two clinical pathology laboratories. PATIENT(S) A new cohort of 10,984 women aged 25 to 45 years old attending infertility clinics, randomly divided into a training cohort of 5,492 women and a validation cohort of 5,492 women, and an existing cohort of 9,601 women, who had contributed to the development and validation of a nomogram for AMH measured by the DSL assay. INTERVENTION(S) Serum measurement of AMH as determined by the Beckman Coulter AMH Generation II assay in 10,984 women. MAIN OUTCOME MEASURE(S) Optimal model for the decline in AMH as measured by the AMH Gen II assay with age, with age-specific 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. RESULT(S) A quadratic model defined as (2.431 + 0.089 * Age + -0.003 * Age(2)) fitted the decline in AMH with age. The anticipated 40% increase in age-specific population values relative to the previously validated DSL assay nomogram was not observed. CONCLUSION(S) Age-specific reference ranges for the AMH gen II assay suggest a systematic shift in assay calibration since initial evaluation and commercial release of the AMH Gen II assay.

The association between physical activity and risk of mortality is modulated by grip strength and cardiorespiratory fitness: evidence from 498 135 UK-Biobank participants

Aims It is unclear whether the potential benefits of physical activity differ according to level of cardiorespiratory fitness (CRF) or strength. The aim of this study was to determine whether the association between physical activity and mortality is moderated by CRF and grip strength sufficiently to inform health promotion strategies. Methods and results 498 135 participants (54.7% women) from the UK Biobank were included (CRF data available in 67 702 participants). Exposure variables were grip strength, CRF, and physical activity. All-cause mortality and cardiovascular disease (CVD) events were the outcomes. 8591 died over median 4.9 years [IQR 4.3–5.5] follow-up. There was a significant interaction between total physical activity and grip strength (P < 0.0001) whereby the higher hazard of mortality associated with lower physical activity was greatest among participants in the lowest tertile for grip strength (hazard ratio, HR:1.11 [95% CI 1.09–1.14]) and lowest among those in the highest grip strength tertile (HR:1.04 [1.01–1.08]). The interaction with CRF did not reach statistical significance but the pattern was similar. The association between physical activity and mortality was larger among those in the lowest tertile of CRF (HR:1.13 [1.02–1.26]) than those in the highest (HR:1.03 [0.91–1.16]). The pattern for CVD events was similar. Conclusions These data provide novel evidence that strength, and possibly CRF, moderate the association between physical activity and mortality. The association between physical activity and mortality is strongest in those with the lowest strength (which is easily measured), and the lowest CRF, suggesting that these sub-groups could benefit most from interventions to increase physical activity.

Accuracy of circulating adiponectin for predicting gestational diabetes: a systematic review and meta-analysis

Aims/hypothesisUniversal screening for gestational diabetes mellitus (GDM) has not been implemented, and this has had substantial clinical implications. Biomarker-directed targeted screening might be feasible. We sought to determine the accuracy of circulating adiponectin for early prediction of GDM.MethodsA systematic review and meta-analysis of the literature to May 2015 identified studies in which circulating adiponectin was measured prior to a diagnosis of GDM. Data on diagnostic accuracy were synthesised by bivariate mixed effects and hierarchical summary receiver operating characteristic (HSROC) models.ResultsThirteen studies met the eligibility criteria, 11 of which (2,865 women; 794 diagnosed with GDM) had extractable data. Circulating adiponectin had a pooled diagnostic odds ratio (DOR) of 6.4 (95% CI 4.1, 9.9), a summary sensitivity of 64.7% (95% CI 51.0%, 76.4%) and a specificity of 77.8% (95% CI 66.4%, 86.1%) for predicting future GDM. The AUC of the HSROC was 0.78 (95% CI 0.74, 0.81). First trimester adiponectin had a pooled sensitivity of 60.3% (95% CI 46.0%, 73.1%), a specificity of 81.3% (95% CI 71.6%, 88.3%) and a DOR of 6.6 (95% CI 3.6, 12.1). The AUC was 0.79 (95% CI 0.75, 0.82). Pooled estimates were similar after adjustment for age, BMI or specific GDM diagnostic threshold.Conclusions/interpretationPre-pregnancy and early pregnancy measurement of circulating adiponectin may improve the detection of women at high risk of developing GDM. Prospective evaluation of the combination of adiponectin and maternal characteristics for early identification of those who do and do not require OGTT is warranted.

Mediators of chronic inflammation in polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is an endocrine disorder affecting 5–10% of reproductive-age women. Hyperandrogenemia, which characterizes the syndrome, stimulates the maturation of adipocytes and favors central obesity. The linking hub between obesity and other metabolic manifestations of the syndrome seems to be chronic low-grade inflammation. We discuss the most reliable current data regarding the role of inflammatory mediators in PCOS, with particular focus on the genetic mechanisms implicated. C-reactive protein levels are 96% higher in PCOS patients than in healthy controls. Patients with the -308A polymorphism of the tumor necrosis factor-α gene have elevated androgens in comparison with carriers of the -308G. Interleukin 18 (IL-18) is elevated in lean patients, with a further rise in the presence of obesity and insulin resistance. Polymorphisms of the IL-1a, IL-1b and IL-6 genes have also been associated with PCOS. Plasminogen activator inhibitor-1 levels are positively associated with the syndrome, and carriers of the 4G allele of the 4G/5G polymorphism are at risk of developing PCOS. Other mediators discussed include adhesion molecules, osteoprotegerin, asymmetric dimethylarginine, homocysteine and advanced glycation end-products. The elucidation of the pathogenetic mechanisms implicated in PCOS and their connection with low-grade inflammation may in the future offer the opportunity for the formulation of novel therapeutic strategies and individualized therapy for these patients.

Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study

Importance Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016. Main Outcomes and Measures Prevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach. Results Of the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10−19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10−17), as well as systolic blood pressure (&bgr; = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10−04) and diastolic blood pressure (&bgr;  = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10−08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history. Conclusions and Relevance The results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels.

Ovarian response biomarkers: physiology and performance

Purpose of review This review summarizes recent technological developments in the measurement of anti-Müllerian hormone (AMH) and presents an update of the relative performance characteristics of both AMH and antral follicle count (AFC) in predicting the ovarian response to controlled stimulation. Recent findings The introduction of two automated AMH immunoassays appears to have resolved the majority of preanalytical and analytical limitations of the manual assays thereby facilitating the delivery of consistent and accurate results. However, as they exhibit different calibration from preexisting assays, derivation of new reference ranges and clinical thresholds for prediction of ovarian response categories will be required. Randomized controlled trials have highlighted the superiority of AMH to AFC in ovarian response prediction and provide a sound basis for its ongoing assessment for stratification and personalization of treatment. Summary Trial evidence combined with full automation of AMH assay measurement suggests that the future for ovarian response prediction will be AMH focused. Sonography will continue to be invaluable for the identification of tubal, ovarian and endometrial pathologies, but the days of counting follicles are numbered.