The prognostic profile of subfertile couples and treatment outcome after expectant management, intrauterine insemination and in vitro fertilisation: a study protocol for the meta-analysis of individual patient data.

OBJECTIVE: The current evidence concerning the best treatment option for couples with unexplained and male subfertility is inconclusive. Most studies that have evaluated the effectiveness of treatment options, such as expectant management (EM), intrauterine insemination (IUI), with or without controlled ovarian stimulation (COS), and in vitro fertilisation (IVF), have not taken the couples' prognosis into account. It is very likely that the individual prognosis of the couple influences the effect of treatment. Individual patient data analyses allow us to take these prognostic factors into account, and to evaluate their effect on treatment outcome. This study aims to use anonymised data from relevant published trials to perform an individual patient data meta-analysis, evaluating the effect of couples' prognosis on the effectiveness of EM, IUI, with or without COS, and IVF. METHODS: Based on earlier systematic reviews and an updated search, randomised controlled trials will be considered for inclusion. Untreated subfertile couples with unexplained or male subfertility included in trials comparing EM, IUI, with or without COS, and IVF are included. Authors of the included studies will be invited to share their original anonymised data. The data will be assessed on validity, quality and completeness. The prognosis of the individual couple will be calculated with existing prognostic models. The effect of the prognosis on treatment outcome will be analysed with marker-by-treatment predictiveness curves, illustrating the effect of prognosis on treatment outcome. This study is registered in PROSPERO (registration number CRD42011001832). CONCLUSION: Ultimately, this study may help to select the appropriate fertility treatment, tailored to the needs of an individual couple.

Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by obesity, hyperandrogenism, and insulin resistance. An adverse lipid profile has also been observed in PCOS-affected women, suggesting that these individuals may be at increased risk for coronary heart disease at a young age. The objective of the present study was to evaluate subclinical atherosclerosis among women with PCOS and age-matched control subjects. A total of 125 white PCOS cases and 142 controls, aged >/=30 years were recruited. Collection of baseline sociodemographic data, reproductive hormone levels, and cardiovascular risk factors was conducted from 1992 to 1994. During follow-up (1996 to 1999), these women underwent B-mode ultrasonography of the carotid arteries for the evaluation of carotid intima-media wall thickness (IMT) and the prevalence of plaque. A significant difference was observed in the distribution of carotid plaque among PCOS cases compared with controls: 7.2% (9 of 125) of PCOS cases had a plaque index of >/=3 compared with 0.7% (1 of 142) of similarly aged controls (P=0.05). Overall and in the group aged 30 to 44 years, no difference was noted in mean carotid IMT between PCOS cases and controls. Among women aged >/=45 years, PCOS cases had significantly greater mean IMT than did control women (0.78+/-0.03 versus 0.70+/-0.01 mm, P:=0. 005). This difference remained significant after adjustment for age and BMI (P:<0.05). These results suggest that (1) lifelong exposure to an adverse cardiovascular risk profile in women with PCOS may lead to premature atherosclerosis, and (2) the PCOS-IMT association is explained in part by weight and fat distribution and associated risk factors. There may be an independent effect of PCOS unexplained by the above variables that is related to the hormonal dysregulation of this condition.

Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation.

Women with hyperandrogenic anovulation (HAA) have increased circulating levels of LH relative to those of FSH. The cause of this disturbance in gonadotropin secretion is uncertain. Previous investigations have sought to determine if increased GnRH drive is responsible for the excessive LH concentrations. Because previous results have conflicted, we addressed this question by comparing the 24-h secretory patterns of alpha-subunit and LH in women with HAA (n = 9) to those in eumenorrheic women in the midfollicular phase (n = 9). The mean (+/- SEM) pulse frequency was increased in women with HAA compared to that in eumenorrheic women of comparable age and percent ideal body weight for both LH (23.0 +/- 0.7 pulses/24 h vs. 3 17.1 +/- 1.7; P = 0.002) and alpha-subunit (23.0 +/- 0.8 vs. 19.1 +/- 1.2; P = 0.02). LH and alpha-subunit, but not FSH, responses to a submaximal dose of exogenous GnRH were increased in HAA, as were basal LH and alpha-subunit levels (P < 0.01). The present observations provide evidence for increased GnRH drive, including pulse frequency, in HAA. Although the results confirm the presence of a disturbance in gonadotropin secretion and suggest that its proximate cause may be of hypothalamic origin, they do not exclude the possibility that other factors, perhaps of ovarian origin, play a role in the establishment and/or maintenance of the altered gonadotropin secretory patterns and the chronic anovulation characteristic of HAA.

Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) exhibit an adverse cardiovascular risk profile, characteristic of the metabolic cardiovascular syndrome (MCS). The aim of this study was to determine the prevalence of coronary artery (CAC) and aortic (AC) calcification among middle-aged PCOS cases and controls and to explore the relationship among calcification, MCS, and other cardiovascular risk factors assessed 9 yr earlier. This was a prospective study of 61 PCOS cases and 85 similarly aged controls screened in 1993-1994 for risk factors and reevaluated in 2001-2002. The main outcome measures were CAC and AC, measured by electron beam tomography. Women with PCOS had a higher prevalence of CAC (45.9% vs. 30.6%) and AC (68.9% vs. 55.3%) than controls. After adjustment for age and body mass index, PCOS was a significant predictor of CAC (odds ratio = 2.31; P = 0.049). PCOS subjects were also 4.4 times more likely to meet the criteria for MCS than controls. High-density lipoprotein cholesterol and insulin appeared to mediate the PCOS influence on CAC. Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034). We conclude that women with PCOS are at increased risk of MCS and demonstrate increased CAC and AC compared with controls. Components of MCS mediate the association between PCOS and CAC, independently of obesity.

The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with premature carotid atherosclerosis. C-Reactive protein (CRP) has been implicated as a vascular disease risk factor. The objective of this study was to determine whether elevated CRP is associated with increased carotid intima-media wall thickness (IMT) in PCOS women. Forty-seven PCOS patients and 59 similarly aged controls were screened for cardiovascular risk factors and concurrently underwent carotid ultrasonography (1996-1999). The main outcome measure was carotid IMT. CRP was significantly higher in PCOS patients than in controls (3.4 vs. 2.1 mg/dl; P = 0.002). In regression modeling, PCOS associated with IMT independently of CRP and age (P = 0.019). Body mass index reduced the association of PCOS and CRP with IMT and was also associated with IMT (P = 0.029). The CRP-IMT relationship was attenuated when either insulin or visceral fat was included in the PCOS-age-CRP model (P = 0.197 and P = 0.550, respectively). PCOS remained associated with IMT independent of insulin (P = 0.033) or visceral fat (P = 0.040). CRP does not appreciably mediate the effect of PCOS on IMT. Obesity partially explained the influence of PCOS and CRP on IMT. The effect of body mass index on the PCOS-IMT relationship was not completely determined by hyperinsulinemia or visceral fat, and might be mediated by other aspects of PCOS-related adiposity.

Age-adjusted threshold values for reduced REM latency in unipolar depression using ROC analysis.

To determine an age-adjusted, clinically meaningful depressive diathesis, we have implemented Receiver Operator Characteristic (ROC) analysis for mean rapid eye movement (REM) latency in patients with unipolar depression. Depressed patients were compared with age-matched normal control subjects. Sensitivity and specificity estimates were calculated for selected threshold values on the ROC curves as well as for the Research Diagnostic Criteria endogenous/nonendogenous subtype. The mean REM latency value of 65.0-66.0 min was most sensitive and specific for depressed patients aged 35-72. The threshold value of 70.0 min appeared optimally sensitive and specific for depressed patients aged 20-34. There was no effect of age on REM latency in the normal control sample. Among depressed patients there was an effect of age but this was clearly observable only in nonendogenous depressed patients.

Clinical predictors of recurrence in depression.

In a longitudinal study of 30 successfully treated unipolar depressed patients, the authors evaluated number of depressive episodes, early onset of depression, and lifetime prevalence of affective disorders other than major depression as risk factors for recurrence. Early onset of depression (before age 20) and a history of affective disorders other than major depression were each significantly associated with recurrence. Number of episodes was not as powerful in predicting recurrence as either early onset or lifetime prevalence of other affective disorders.

Prenatal care evaluation and cohort analyses.

The value of prenatal care has been obscured by multiple factors, including the limitations of birth certificate data, large socioeconomic disparities between women who seek prenatal care and those who do not, and the "preterm delivery bias", ie, the reduced pregnancy duration and opportunity for prenatal care among women who give birth prematurely. Perinatal mortality and morbidity (neonatal intensive care unit admission; ventilator therapy) were carefully assessed in an indigent population (28,838 deliveries at Parkland Memorial Hospital). To avoid the preterm delivery bias, a cohort of all women whose pregnancy reached a specific week of gestation was identified and their prenatal care status (zero vs one or more visits) by that week was related to pregnancy outcome. Separate cohorts were defined at 26, 30, 34, 38, and 42 weeks. Prenatal care was associated with improved pregnancy outcomes in only the 34-, 38-, and 42-week cohorts (P less than .01). Findings suggest substantial benefit from prenatal care after 30 weeks' gestation but not from early prenatal care. Unfortunately, it may not be possible to assess prenatal care accurately in observational studies even if cohort analyses are used. Clinical trials are needed to assess the effects of strategies for increasing or improving prenatal care, especially in early pregnancy.

Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study.

Polycystic ovary syndrome (PCOS), a disorder of hyperandrogenism and chronic anovulation affects 5%-10% of all women. Women with PCOS often have elevated cardiovascular risk factors. A total of 244 PCOS cases were identified through the Division of Reproductive Endocrinology at Magee-Womens Hospital and were age-matched to 244 neighborhood controls. The average age of cases and controls was 35.3 +/- 7.4 and 36.7 +/- 7.7. Women with PCOS compared to controls had substantially higher LDL-C and total cholesterol levels at each age group under 45 years after adjustment for body mass index, hormone use, and insulin levels. In the over 40-year age group, little difference was noted between cases and controls. Among cases and controls (<40), PCOS predicted LDL-C, total cholesterol and triglycerides, but did not have a significant effect on lipid levels in older cases and controls after controlling for the other variables. The primarily pre- to perimenopausal PCOS cases > or =40 years of age have similar LDL-C and total cholesterol levels as their age-matched controls, probably reflecting the LDL-C increase with age among controls.

The association of chorioamnionitis with preterm delivery.

To ascertain what proportion of preterm deliveries are attributable to the association with chorioamnionitis, the authors examined prospectively the placentas from all 2774 women who delivered at the Johns Hopkins Hospital during 1980. The incidence of preterm delivery was 5.4% (110 of 2027) when neither chorioamnionitis nor premature rupture of membranes (PROM) was present, 11.9% (29 of 243) when chorioamnionitis was present without PROM, and 56.7% (51 of 90) when both chorioamnionitis and PROM were present (P less than .05). Only 27 of 333 cases of histopathologic chorioamnionitis or 8.1% had maternal antepartum fever, and only 11 of 333 or 3.3% had neonatal sepsis. Using logistic regression analysis to control for confounding variables, approximately 25% of the preterm deliveries were statistically attributable to histopathologic chorioamnionitis, occurring either alone or in association with PROM. In light of the infrequency with which histopathologic chorioamnionitis is clinically evident, the strong relationship between histopathologic chorioamnionitis and preterm delivery suggests that occult antepartum infection of the genital tract is an important cause of preterm delivery.