Mortality in Women Treated With Assisted Reproductive Technology-Addressing the Healthy Patient Effect.

In previous studies, investigators have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. Our aim in this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and to explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994-2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until December 31, 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women during the first 2 years after ART treatment (hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequencies of previous medical and psychiatric diagnoses among ART-treated and untreated women were similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make initiation of ART treatment unlikely. The survival advantage among ART-treated women is likely a selection phenomenon rather than a biological phenomenon.

Male and female alcohol consumption and live birth after assisted reproductive technology treatment: a nationwide register-based cohort study.

The objective was to assess the potential association between female and male alcohol consumption and probability of achieving a live birth after assisted reproductive treatment. From a nationwide Danish register-based cohort information on alcohol consumption at assisted reproductive treatment initiation was linked to information on births and abortions. From 1 January 2006 to 30 September 2010, 12,981 women and their partners went through 29,834 treatment cycles. Of these, 22.4% and 20.4% led to a live birth for female abstainers and heavy consumers (>7 drinks/week), respectively. Concerning men, 22.6% and 20.2% of cycles resulted in a live birth for abstainers and heavy consumers (>14 drinks/week), respectively. No statistically significant associations between alcohol consumption and live birth were observed. Adjusted odds ratios from trend analyses were 1.00 (95% confidence interval (CI) 0.99-1.01) and 0.99 (95% CI 0.97-1.01) for every one-unit increase in female and male weekly alcohol consumption at assisted reproductive treatment initiation, respectively. In conclusion, this study did not show significant associations between male or female alcohol consumption and odds of live birth after assisted reproductive treatment.

Male origin microchimerism and brain cancer: a case-cohort study.

BACKGROUND: Despite considerable research effort, causes of brain cancer are largely unknown. Male brain cancer predominance and reduced brain cancer risk with increasing parity among women, however, support a favourable role of pregnancy. We set out to determine whether fetal-origin microchimerism, namely the presence and long-term persistence of fetal cells, likely obtained via natural trafficking across the placenta during pregnancy, associates with reduced risk of brain cancer in women. METHODS: Using a case-cohort design, we sampled 505 middle-aged women randomly at baseline in the Diet, Cancer and Health cohort (controls), and 73 women with incident brain cancer diagnosed during follow-up in the Danish Cancer Registry (cases). Male origin microchimerism was determined by presence of Y chromosome sequences in female blood samples. Data were analysed using weighted proportional Hazards regression, yielding Hazard Ratios with 95% confidence intervals. RESULTS: Compared with male origin microchimerism negative women, positive women had half the risk of developing brain cancer (Hazard Ratio = 0.50 [0.33-0.77]). Sensitivity analyses support that our findings are unlikely due to bias or chance. CONCLUSION: Here, for the first time, we demonstrate half the risk of brain cancer in male origin microchimerism positive compared with negative women. Our findings resemble those of previous studies of male origin microchimerism and other female cancers.

Male-origin microchimerism and endometrial cancer: A prospective case-cohort study.

BACKGROUND: Many women carry male cells of presumed fetal origin-so-called male-origin microchimerism (MOM)-in their circulation and tissues. Studies have found reduced risks of hormone dependent cancers, including breast and ovarian cancer, among MOM-positive women. The aim of this study was to investigate the association between MOM and endometrial cancer. METHODS: We designed a prospective case-cohort study including 76 cases and 505 controls from the Diet, Cancer and Health cohort aged 50-64 years and cancer-free at enrolment in 1993-1997. We analyzed blood samples for the presence of Y-chromosome (DYS14). We examined the association between MOM and endometrial cancer in weighted Cox regression models. As a negative control outcome, we studied the association between MOM and injuries to test for spurious associations. RESULTS: We detected MOM in 65.9% controls and 54.0% cases. While we observed no overall association between MOM and endometrial cancer (HR=0.73, 95% CI: 0.47-1.15), we found a borderline significantly reduced rate of Type 1 endometrial cancer (HR=0.66, 95% CI: 0.39-1.00), but not other types of endometrial cancers (HR=1.00, 95% CI: 0.35-2.90). The reduced rate was not modified by hormonal exposure (P = 0.79). We found no association between MOM and risk of injuries (HR=0.96, 95% CI: 95% CI: 0.78-1.21). CONCLUSIONS: Our study suggests that MOM is inversely associated with Type 1 endometrial cancer, without evidence of an interaction with hormonal exposure. We encourage future research to confirm our findings.

Economic hardship over twenty-two consecutive years of adult life and markers of early ageing: physical capability, cognitive function and inflammation.

This study assesses the associations between annual measures of economic hardship (EH) across 22 years of adulthood and objective measures of early ageing in a Danish late-middle-aged population (N = 5575). EH (years < 60% of the National median equivalized household disposable income) was experienced by 18% during 1987-2008. Four or more years in EH (reference = null years in EH) was related to poorer physical capability (chair rise: - 1.49 counts/30 s [95% confidence interval (CI) - 2.36, - 0.61], hand grip strength: - 1.22 kg [95% CI - 2.38, - 0.07], jump height: - 1.67 cm [95% CI - 2.44, - 0.91] and balance: 18% [95% CI 9, 28]), poorer cognitive function (Intelligenz-Struktur-Test: - 1.50 points [95% CI - 2.89, - 0.12]) and higher inflammatory levels (C-reactive protein: 22% [95% CI 4, 44], and Interleukin-6: 23% [95% CI 10, 39]). Comparing four EH trajectories, people with a high versus low probability of EH over time had poorer physical capability (chair rise: - 1.70 counts/30 s [95% CI - 3.38, - 0.01], grip: - 4.33 kg [95% CI - 6.50, - 2.16], jump: - 1.68 cm [95% CI - 3.12, - 0.25] and balance: 31% [95% CI 12, 52]). No associations were observed with tumour necrosis factor-α. Results were adjusted for sex, age, long-term parental unemployment/financial problems, education, baseline income and cohort. This study suggested EH for four or more years to be associated with poorer physical capability, cognitive function and increased inflammatory levels in midlife. High probability of EH across adulthood was similarly related to poorer physical capability and CRP, but not cognitive function and the remaining inflammatory markers. In conclusion, preventive initiatives focusing on reducing the burden of sustained economic hardship may lead to increased healthy ageing.

Maternal infections during pregnancy and offspring midlife inflammation.

BACKGROUND: Microbial exposures early in life have been found to be associated with lower levels of inflammation in adulthood; however, the role of prenatal exposure to infection on offspring inflammatory profiles is unexplored. The aim was to study if maternal infections during pregnancy are associated with inflammation among offspring in later life and to determine if there are sensitive periods of exposure. METHODS: The study was comprised of 1719 participants in the Copenhagen Aging and Midlife Biobank (CAMB) who were also members of the Copenhagen Perinatal Cohort (CPC). When the CPC was established, information on maternal infections during pregnancy was prospectively collected by a trained medical doctor. The inflammatory measures collected in late midlife included, C-reactive protein (CRP), Interleukin-6 (IL-6), TNF-alpha (TNF-α) and Interleukin-10 (IL-10). Multivariable ordinary least squared regression models were implemented to explore associations between maternal infection and inflammatory measures in offspring, controlling for maternal smoking, pre-pregnancy body mass index, age, marital status and parity. RESULTS: Maternal infection was associated with a 7% lower CRP level (95% CI, - 17,5%) among offspring compared with offspring born to women without an infection and similarly an 8% lower level of IL-6 (95% CI -15,1%), and a 9% lower level of IL-10 (95% CI, - 23,20%). However, differences did not reach significance. The effects of infection during the first trimester did not differ from infections later in the pregnancy. CONCLUSIONS: Our results suggested that prenatal exposure to infection may be associated with lower levels of inflammatory markers among adult offspring. Additional prospective studies are needed to further explore this finding.

Childhood socioeconomic position and physical capability in late-middle age in two birth cohorts from the Copenhagen aging and midlife biobank.

This study examines the association between childhood socioeconomic position and objective physical capability including new functional measures of potential relevance to a population in late-middle age. The study population covers two Danish birth cohorts followed-up in the Copenhagen Aging and Midlife Biobank (age 48-58 years, 2009-2011, N = 4,204). Results from linear regression models revealed that being born in higher socioeconomic position was associated with higher jump height: Paternal occupational class four = 0.19 cm (95% confidence interval (CI): -0.44, 0.82), three = 0.59 cm (95% CI: -0.02, 1.19), two = 1.29 cm (95% CI: 0.64, 1.94), and one = 1.29 cm (95% CI: 0.45, 2.13) (reference = five); medium parental social class = 0.88 cm (95% CI: 0.03, 1.72) and high = 1.79 cm (95% CI: 0.94, 2.63) (reference = low). Higher childhood socioeconomic position was also associated with better chair rise performance and hand grip strength, while among women it was related to reduced flexibility: Medium parental social class = -1.31 cm (95% CI: -3.05, 0.42) and high = -2.20 cm (95% CI: -3.94, -0.47) (reference = low); unwed mother = 1.75 cm (95% CI: 0.36, 3.14) (reference = married). Overall, the findings suggest that higher childhood socioeconomic position is primarily related to moderately better scores in the most strenuous physical capability measures and hand grip strength among healthy adults in late-middle age.

Correction: Childhood socioeconomic position and physical capability in late-middle age in two birth cohorts from the Copenhagen aging and midlife biobank.

[This corrects the article DOI: 10.1371/journal.pone.0205019.].

Prenatal and early postnatal stress and later life inflammation.

BACKGROUND: Evidence suggests that maternal psychological and social stress during the prenatal period and in childhood represent an important condition that may adversely impact the anatomy and physiology of the developing child with implications for a number of health-related conditions and disorders. In a large prospective study, we aim to address if social stressors in the prenatal and early postnatal periods, as individual exposures as well as their accumulation, are associated with a range of inflammatory markers in late middle-aged offspring. METHODS: The study sample includes Danish men and women born between 1959 and 1961 (n = 1206) who were members of the Copenhagen Perinatal Cohort and participated in the Copenhagen Aging and Midlife Biobank in 2009-2011 (age 49-52). Information on social stressors was collected through an interview with the mothers at the first antenatal visit and postnatal stressor data was collected at year one follow-up. A series of ordinary least square regression models were performed with the stress measures as the exposures and C-reactive protein (CRP), Interleukin-6 (IL-6), Interleukin-10 (IL-10), and Tumor necrosis factor α (TNF-α) separately as the outcomes. RESULTS: The individual prenatal maternal stressors (being unmarried and having an unwanted pregnancy) and the prenatal index were associated with higher levels of CRP and IL-6 among offspring but not with IL-10 or TNF-α. Low social status, but not living away from parents or having an unmarried mother in the first year of life, was associated with higher levels of CRP and IL-6. The accumulation of social stressors in the early postnatal period was associated with higher levels of CRP and IL-6 but not IL-10 and TNF-α. The accumulation of stressors in the prenatal and postnatal periods combined was associated with higher levels of CRP and IL-6, but not with IL-10 or TNF-α. CONCLUSIONS: The findings suggest that exposure to the accumulation of prenatal and early life stressors, is associated with higher levels of CRP and IL-6 in later life. This may indicate that the effects of early stressors on later inflammation operate through pathways with clear links to cardiovascular disease.

Cardiorespiratory fitness and the metabolic syndrome: Roles of inflammation and abdominal obesity.

OBJECTIVE: Individuals with metabolic syndrome have increased risk of type 2 diabetes and cardiovascular disease. We aimed to test the hypothesis that a high level of cardiorespiratory fitness (CR-fitness), counteracts accumulation of visceral fat, decreases inflammation and lowers risk factors of the metabolic syndrome. METHOD: The study sample included 1,293 Danes (age 49-52 years) who from 2009 to 2011 participated in the Copenhagen Aging and Midlife Biobank, including a questionnaire, physical tests, and blood samples. Multiple linear regression models were performed with CR-fitness as exposure and plasma levels of cytokines and high sensitive C-reactive protein as outcomes and measures of abdominal obesity were added to test if they explained the potential association. Similarly, multiple linear regression models were performed with CR-fitness as exposure and factors of the metabolic syndrome as outcomes and the potential explanation by inflammatory biomarkers were tested. All models were adjusted for the effect of age, sex, smoking, alcohol consumption, socio-economic status, and acute inflammatory events within the preceding two weeks. RESULTS: CR-fitness was inversely associated with high sensitive C-reactive protein, Interleukin (IL)-6, and IL-18, and directly associated with the anti-inflammatory cytokine IL-10, but not associated with tumor necrosis factor alpha, interferon gamma or IL-1ß. Abdominal obesity could partly explain the significant associations. Moreover, CR-fitness was inversely associated with an overall metabolic syndrome score, as well as triglycerides, glycated haemoglobin A1c, systolic blood pressure, diastolic blood pressure and directly associated with high-density lipoprotein. Single inflammatory biomarkers and a combined inflammatory score partly explained these associations. CONCLUSION: Data suggest that CR-fitness has anti-inflammatory effects that are partly explained by a reduction in abdominal obesity and a decrease in the metabolic syndrome risk profile. The overall inflammatory load was mainly driven by high sensitive C-reactive protein and IL-6.

The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.

OBJECTIVE: To investigate the independent and combined associations between female and male body mass index (BMI) on the probability of achieving a live birth after treatments with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) under adjustment for relevant covariates. DESIGN: Population-based cohort study. SETTING: Danish national registers. PATIENT(S): Patients with permanent residence in Denmark receiving IVF or ICSI treatment with use of autologous oocytes from January 1, 2006, to September 30, 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth. Analyses were adjusted for age and smoking at treatment initiation and results stratified by BMI groups and presented by IVF/ICSI treatment. RESULT(S): In total, 12,566 women and their partners went through 25,191 IVF/ICSI cycles with 23.7% ending in a live birth. Overweight and obese women with regular ovulation had reduced odds of live birth (adjusted OR 0.88, 95% CI 0.79-0.99 and adjusted OR 0.75, 95% CI 0.63-0.90, respectively) compared with normal-weight women. IVF-treated couples with both partners having BMI ≥25 kg/m(2) had the lowest odds of live birth (adjusted OR 0.73, 95% CI 0.48-1.11) compared with couples with BMI <25 kg/m(2). BMI showed no significant effect on chance of live birth after ICSI. CONCLUSION(S): Increased female and male BMI, both independently and combined, negatively influenced live birth after IVF treatments. With ICSI, the association with BMI was less clear.