Predicting pregnancy chances leading to term live birth in oligo/anovulatory women diagnosed with PCOS.

RESEARCH QUESTION: Which patient features predict the time to pregnancy (TTP) leading to term live birth in infertile women diagnosed with polycystic ovary syndrome (PCOS)? DESIGN: Prospective cohort follow-up study was completed, in which initial standardized phenotyping was conducted at two Dutch university medical centres from January 2004 to January 2014. Data were linked to the Netherlands Perinatal Registry to obtain pregnancy outcomes for each participant. All women underwent treatment according to a standardized protocol, starting with ovulation induction as first-line treatment. Predictors of pregnancies (leading to term live births) during the first year after PCOS diagnosis were evaluated. RESULTS: A total of 1779 consecutive women diagnosed with PCOS between January 2004 and January 2014 were included. In the first year following screening, 659 (37%) women with PCOS attained a pregnancy leading to term birth (≥37 weeks of gestational age). A higher chance of pregnancy was associated with race, smoking, body mass index (BMI), insulin, total testosterone and sex hormone-binding globulin (SHBG) concentrations (c-statistic = 0.59). CONCLUSIONS: Predictors of an increased chance of a live birth include White race, no current smoking, lower BMI, insulin and total testosterone concentrations, and higher SHBG concentrations. This study presents a nomogram to predict the chances of achieving a pregnancy (leading to a term live birth) within 1 year of treatment.

The cardiovascular risk profile of middle age women previously diagnosed with premature ovarian insufficiency: A case-control study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 µm (500-615) versus 684 µm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02616510.

The cardiovascular risk profile of middle-aged women with polycystic ovary syndrome.

OBJECTIVES: Contradictory results have been reported regarding the association between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD). We assessed the cardiometabolic phenotype and prevalence of CVD in middle-aged women with PCOS, compared with age-matched controls from the general population, and estimated 10-year CVD risk and cardiovascular health score. DESIGN: A cross-sectional study. PARTICIPANTS: 200 women aged >45 with PCOS, and 200 age-matched controls. MEASUREMENTS: Anthropometrics, insulin, lipid levels, prevalence of metabolic syndrome and type II diabetes. Ten-year Framingham risk score and the cardiovascular health score were calculated, and carotid intima-media thickness (cIMT) was measured. RESULTS: Mean age was 50.5 years (SD = 5.5) in women with PCOS and 51.0 years (SD = 5.2) in controls. Increased waist circumference, body mass index and hypertension were more often observed in women with PCOS (P < .001). In women with PCOS, the prevalence of type II diabetes and metabolic syndrome was not significantly increased and lipid levels were not different from controls. cIMT was lower in women with PCOS (P < .001). Calculated cardiovascular health and 10-year CVD risk were similar in women with PCOS and controls. CONCLUSIONS: Middle-aged women with PCOS exhibit only a moderately unfavourable cardiometabolic profile compared to age-matched controls, even though they present with an increased BMI and waist circumference. Furthermore, we found no evidence for increased (10-year) CVD risk or more severe atherosclerosis compared with controls from the general population. Long-term follow-up of women with PCOS is necessary to provide a definitive answer concerning long-term risk for CVD.

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis.

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (ß) as outcome. OUTCOMES: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (ß = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (ß = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (ß = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (ß = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (ß = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (ßf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((ßm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (ßf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (ßm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (ßf = -0.31(95%CI: -0.57 to 0.06), ßm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (ßf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (ßm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: ßf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: ßm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONS: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.

Coronary artery calcification in middle-aged women with premature ovarian insufficiency.

OBJECTIVE: Women with premature ovarian insufficiency (POI) enter menopause before age 40. Early menopause was associated with increased risk for coronary artery disease (CAD), death from cardiovascular disease and all-cause mortality. We compared the prevalence of CAD between middle-aged women on average 10 years following the initial POI diagnosis, with a population-based cohort. DESIGN: Cross-sectional case-control study. PARTICIPANTS: Women from two Dutch University Medical Centers above 45 years of age previously diagnosed with POI (n = 98) were selected and compared with age- and race-matched controls from the Multi-Ethnic Study of Atherosclerosis (MESA). MEASUREMENTS: The primary outcome was detectable coronary artery calcium (CAC) determined by coronary computed tomography (CCT). RESULTS: Women with POI had significantly higher blood pressure, cholesterol and glucose, despite lower BMI compared to controls. Similar proportions of detectable CAC (CAC score >0 Agatston Units) were observed in women with POI and controls (POI n = 16 (16%), controls n = 52 (18%), P = 0.40 and Padj  = 0.93). In women with POI separately, we were not able to identify associations between CVD risk factors and CAC. The following CVD risk factors in controls were positively associated with CAC: age, diabetes mellitus, hypertension and LDL cholesterol. HRT use was negatively associated with CAC in controls. CONCLUSIONS: The presence of CAC did not differ significantly in women with POI around 50 years of age, compared to an age- and race-matched control group. We observe no increased calcified coronary disease in POI patients, despite the presence of unfavourable cardiovascular risk factors in these women.

Pre-Conception Characteristics Predict Obstetrical and Neonatal Outcomes in Women With Polycystic Ovary Syndrome.

Context: Women with polycystic ovary syndrome (PCOS) are at increased risk for obstetric and perinatal complications. At present, it is unknown how characteristics of PCOS relate to the likelihood of these complications. Objective: To evaluate which preconception features are associated with obstetric and perinatal disease among infertile women with PCOS. Design: Data from two prospective cohort studies completed from January 2004 until January 2014 were linked to Dutch Perinatal national registry outcomes. Setting: Two Dutch university medical centers. Participants: 2768 women diagnosed with PCOS were included. Participants underwent an extensive standardized preconception screening. Exclusion criteria included: age <18 years or >45 years, language barrier, or failure to meet PCOS criteria. Interventions: None. Main Outcome Measures: Outcome measures were obtained from the Dutch Perinatal national registry and included: preeclampsia, preterm delivery, small for gestational age (SGA), low Apgar score, and any adverse outcome. Results: 1715 (62% of participants) women with PCOS were identified as undergoing a pregnancy with live birth after screening. In fully adjusted models, prepregnancy free androgen index was associated with subsequent preeclampsia [OR (95% CI), 1.1 (1.0 to 1.1)]. Fasting glucose [1.4 (1.2 to 1.7)] and testosterone [1.5 (1.2 to 1.7)] predicted preterm delivery. Fasting insulin [1.003 (1.001 to 1.005)], and testosterone [1.2 (1.1 to 1.4)] predicted any adverse outcome. SGA was only predicted by features nonspecific to PCOS. Conclusions: Primary disease characteristics of PCOS, chiefly hyperandrogenism and impaired glucose tolerance, predict suboptimal obstetric and neonatal outcomes. Increased surveillance during pregnancy should focus on women with PCOS and these features to help mitigate disease risk.

Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency.

OBJECTIVE: To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). DESIGN: Cross-sectional study conducted between 1996 and 2016. SETTING: Tertiary referral centers. PATIENT(S): A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. RESULT(S): Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (ß 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (-0.15 [-0.24, -0.05]; -0.16 [-0.29, -0.03], respectively), as well as low density lipoprotein cholesterol (-0.03 [-0.06, 0.00]) and non-high density lipoprotein cholesterol (-0.04 [-0.07, 0.00]). CONCLUSION(S): Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. CLINICAL TRIAL REGISTRATION NUMBER: NCT0230904.

Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (ß = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (ß = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (ß = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (ß = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (ß = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Influence of Ossicular Chain Damage on Hearing After Chronic Otitis Media and Cholesteatoma Surgery: A Systematic Review and Meta-analysis.

IMPORTANCE: Physicians should ideally be able to provide patients with chronic otitis media and/or cholesteatoma specific information about postoperative hearing outcome, based on their level of preoperative ossicular chain damage (OCD). OBJECTIVE: To identify the influence of preoperative OCD on hearing outcomes in patients after chronic otitis media and/or cholesteatoma surgery. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library databases were systematically searched for available evidence, without any constraints, on December 13, 2014, for articles published between January 1, 1975, and December 13, 2014. STUDY SELECTION: We reviewed the literature for articles assessing the prognostic value of OCD on postoperative hearing outcome (air-bone gap [ABG] in decibels), using Austin-Kartush criteria or independent OCD classification systems. We assessed relevance and validity using a self-designed critical appraisal tool based on the Cochrane Collaboration's risk of bias tool. DATA EXTRACTION: Characteristics of study populations and postoperative ABGs in decibels were extracted from all included studies by 4 authors (E.F.B., M.N.G., N.J.K., A.S.H.J.L.). RESULTS: The tested hypothesis was formulated before data collection. Primary study outcome was defined as postoperative adult hearing outcomes after COM and/or cholesteatoma surgery defined as mean postoperative ABG. Our search yielded 5661 articles. Nine articles with high relevance were included. Pooled results of studies using the Austin-Kartush criteria showed a significant (P < .001) difference in mean ABG in favor of group B, when comparing group B (patients with malleus present, stapes absent; 11.1 [95% CI, 10.3-11.8] dB) to group C (patients with malleus absent, stapes present; 15.7 [95% CI, 14.6-16.7] dB) and group B to group D (patients with malleus absent, stapes absent; 16.5 [95% CI, 15.2-17.9] dB). Three studies using independent OCD classification criteria found no influence of stapes structure (intact stapes suprastructure, 13.5 [95% CI, 10.3-16.7], 15.1 [95% CI, 11.8-18.3], and 21.9 [95% CI, 15.0-28.8] dB vs absent stapes structure, 12.8 [95% CI, 9.5-16.1], 19.5 [95% CI, 14.9-24.1], and 30.2 [95% CI, 24.7-35.8] dB) on postoperative ABG. One study reported a significant (P = .04) difference in mean ABG between patients with present (18.9 [95% CI, 15.7-22.1] dB) and absent (24.4 [95% CI, 20.2-28.6] dB) malleus. CONCLUSIONS AND RELEVANCE: Pooled results of Austin-Kartush studies showed that in patients with COM, with or without cholesteatoma, the malleus status is a significant predictor of postoperative hearing outcome, independent of the stapes condition. Studies reporting on individual ossicle status supported this finding by showing that only malleus condition influenced postoperative hearing outcome. These findings are based on level IV evidence, which indicates the need for future high-level evidence studies.