Pregnancy, cardiovascular health, and microchimerism.

PURPOSE OF REVIEW: To provide an updated review of scientific literature concerning associations between pregnancy and cardiovascular health among women, and to discuss a possible impact of microchimerism on the association. RECENT FINDINGS: In most studies, pregnancy and childbirth is associated with increased risk of cardiovascular disease in women. Some ascribe the association mainly to lifestyle, whereas others suggest that pregnancy itself negatively affects women's cardiovascular health. Pregnancy is a natural source of microchimerism, which in turn markedly affects female health. The only study published in the area surprisingly shows that among middle-aged women, male-origin microchimerism (MOM) is associated with half the risk of developing ischemic heart disease (IHD). No similar association is found between MOM and ischemic stroke. SUMMARY: The sparse evidence published suggests reduced risk of developing IHD among MOM-positive women. Despite the association being biologically plausible, replication of the findings is warranted to support that this is not a chance finding.

Childcare attendance and risk of childhood acute lymphoblastic leukaemia: A register study based on the Danish childcare database.

Childhood acute lymphoblastic leukaemia (ALL) is suggested to result from a dysregulated immune response to infections in children with a preleukaemic state. Childcare in early life supposedly may protect against childhood ALL by facilitating sufficient exposure to infections to stimulate and ensure normal maturation of the immune system. We assessed the association between childcare attendance before age 2 years and risk of childhood ALL in a register-based cohort study, including all children aged 2 to 14 years born in Denmark during 1991 to 2014 with available childcare information recorded in the Danish Childcare Database (n = 1 116 185). Cox regression was used to estimate hazard ratios (HRs) comparing children enrolled in childcare and children not enrolled before age 2 years. Further, we assessed the association according to age at enrolment, type of childcare facility and specific ALL subtypes. During 10 460 811 person-years of follow-up, 460 children developed ALL at ages 2 to 14 years. Of these, 57 (12.4%) never attended childcare before age 2 years compared with 10.6% in the total cohort. Compared with homecare, childcare attendance before age 2 years was associated with a statistically non-significantly, marginally decreased risk of childhood ALL with adjusted HR = 0.87 (95% confidence interval [CI]: 0.65-1.16). Risk estimates did neither vary statistically significantly by age at enrolment nor by type of childcare facility and also not between childhood ALL subtypes, including frequently prenatally initiated ALL subtypes. Results from this large, nationwide register-based study provided no evidence that childcare attendance in the first years of life protects against childhood ALL.

Impact of Male-Origin Microchimerism on Cardiovascular Disease in Women: A Prospective Cohort Study.

Increasing parity is associated with an increased risk of ischemic heart disease (IHD) and stroke in women. This is probably attributable to biological responses of pregnancy. Male cells of presumed fetal origin are commonly present in women years after pregnancy-a phenomenon termed male-origin microchimerism (MOM). In this study, we investigated whether MOM was associated with risk of IHD and ischemic stroke in women. We evaluated the association between MOM and ischemic events in a cohort of 766 Danish women enrolled in the Diet, Cancer and Health cohort during 1993-1997 when aged 50-64 years. Of these women, 545 (71.2%) tested positive for MOM through targeting of the Y chromosome (DYS14 DNA sequence) in their blood. Multiple Cox regression models were used to calculate hazard ratios with 95% confidence intervals. We found that MOM was associated with a significantly reduced rate of IHD (hazard ratio = 0.44, 95% confidence interval: 0.23, 0.83) but not ischemic stroke (hazard ratio = 0.80, 95% confidence interval: 0.46, 1.41). Our findings show that microchimerism positivity is associated with a lower rate of later IHD development in women. Although the underlying mechanisms are presently unknown, MOM may be relevant in women's cardiovascular health. More studies are needed to confirm these findings.

Maternal use of hormonal contraception and risk of childhood ADHD: a nationwide population-based cohort study.

Although maternal use of hormones has been suspected of increasing the risk for childhood attention-deficit/hyperactivity disorder (ADHD), no study has examined hormonal contraception use in this context. We examined the association between maternal hormonal contraception use before or during pregnancy and ADHD risk in children. This nationwide population-based cohort study included 1,056,846 children born in Denmark between 1998 and 2014. Prescriptions for hormonal contraceptives redeemed by the mother was categorized as: no use, previous use (> 3 months before pregnancy), and recent use (≤ 3 months before or during pregnancy). Children were followed for ADHD, from birth until 31 December 2015. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). During 9,819,565 person-years of follow-up (median: 9.2), ADHD was diagnosed or a prescription for ADHD medication redeemed for 23,380 children (2.2%). The adjusted HR for ADHD was higher in children of mothers who had previously (HR 1.23; 95% CI 1.18-1.28) or recently (HR 1.30; 95% CI 1.24-1.37) used hormonal contraception than in those of mothers with no use. The highest estimates were seen for use of non-oral progestin products with HRs of 1.90 (95% CI 1.59-2.26) for previous use, 2.23 (95% CI 1.96-2.54) for recent use, and 3.10 (95% CI 1.62-5.91) for use during pregnancy. Maternal use of hormonal contraception was associated with an increased risk for ADHD in the offspring; more pronounced for non-oral progestin-only than other products.

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.

Maternal diabetes and risk of childhood acute lymphoblastic leukaemia in the offspring.

BACKGROUND: Maternal diabetes may be linked to childhood acute lymphoblastic leukaemia (ALL) in the offspring. METHODS: We assessed the association between maternal pregestational or gestational diabetes and offspring risk of childhood ALL in a register-based study, including all singletons born in Denmark during 1996-2015 (n=1 187 482). RESULTS: Adjusted hazard ratios of childhood ALL were 2.91 (95% confidence interval (CI): 1.30-6.51) for maternal pregestational diabetes and 1.75 (95% CI: 1.02-2.98) for maternal gestational diabetes. Paternal diabetes did not alter offspring ALL risk, and we found no association between offspring ALL and later maternal risk of diabetes. CONCLUSIONS: Regardless that absolute ALL risk among offspring of women with diabetes remains low, our findings suggest that characteristics of the diabetic intrauterine environment promote ALL development. This offers a setting for future research into the biological mechanisms underlying childhood ALL.

Preeclampsia and scleroderma: a prospective nationwide analysis.

INTRODUCTION: In a preliminary case-control study, women with scleroderma more frequently reported having had hypertensive complications during pregnancy compared with healthy women. MATERIAL AND METHODS: To prospectively investigate this possible association, we conducted a nation-wide cohort analysis of a major hypertensive complication during pregnancy, namely preeclampsia, and later scleroderma. Analyses were based on Danish register-based birth and hospital contact data on preeclampsia and scleroderma. We followed 778,758 women from time of giving birth between 1978 and 2010 to end of follow-up, emigration, death, or scleroderma diagnosis, whichever occurred first. The association was evaluated by incidence rate ratios, obtained in Poisson regression models. RESULTS: We report that preeclampsia is associated with a 69% significantly increased risk of later developing scleroderma. CONCLUSIONS: Though these findings do not impact clinical care directly, the association of preeclampsia with scleroderma underscores the significant relation of preeclampsia and other adverse pregnancy outcomes with later disease in women and should be included in patient counseling and education.

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.

Statistical Methods for Unusual Count Data: Examples From Studies of Microchimerism.

Natural acquisition of small amounts of foreign cells or DNA, referred to as microchimerism, occurs primarily through maternal-fetal exchange during pregnancy. Microchimerism can persist long-term and has been associated with both beneficial and adverse human health outcomes. Quantitative microchimerism data present challenges for statistical analysis, including a skewed distribution, excess zero values, and occasional large values. Methods for comparing microchimerism levels across groups while controlling for covariates are not well established. We compared statistical models for quantitative microchimerism values, applied to simulated data sets and 2 observed data sets, to make recommendations for analytic practice. Modeling the level of quantitative microchimerism as a rate via Poisson or negative binomial model with the rate of detection defined as a count of microchimerism genome equivalents per total cell equivalents tested utilizes all available data and facilitates a comparison of rates between groups. We found that both the marginalized zero-inflated Poisson model and the negative binomial model can provide unbiased and consistent estimates of the overall association of exposure or study group with microchimerism detection rates. The negative binomial model remains the more accessible of these 2 approaches; thus, we conclude that the negative binomial model may be most appropriate for analyzing quantitative microchimerism data.

Long-term impact of preeclampsia on maternal endometrial cancer risk.

BACKGROUND: Endometrial cancer is mainly dependent on oestrogen exposure. Preeclampsia has shown to reduce oestrogen levels hence preeclampsia may affect later endometrial cancer risk. METHODS: We conducted a case-control study of 523 Danish women with endometrial cancer and 52 299controls during 1978-2010. The association between preeclampsia and later endometrial cancer was evaluated overall and according to preeclampsia onset and type of endometrial cancer in conditional logistic regression models. RESULTS: We observed no overall association between preeclampsia and endometrial cancer risk (OR=1.11 (95% CI 0.68-1.81)). This was true for all endometrial cancer subtypes. In an analysis of preeclampsia onset, however, we report a markedly increased risk of endometrial cancer following early-onset preeclampsia (OR=2.64 (95% CI 1.29-5.38)). CONCLUSIONS: Although we report no obvious association between preeclampsia and endometrial cancer, studying the subset of early-onset preeclampsia may prove fruitful in further understanding the aetiology of endometrial cancer.

Cervical cancer screening in Greenland, 1997-2011: Screening coverage and trends in the incidence of high-grade cervical lesions.

OBJECTIVE: In spite of the high incidence of cervical cancer in Greenland, no assessment has been made of the impact of organized cervical screening, introduced in 1998, in relation to occurrence of high-grade cervical lesions. The objectives of the present study were to estimate coverage of the screening program and to examine possible changes in cervical intraepithelial neoplasia (CIN3) incidence in Greenland during 1997-2011 according to calendar period and age. METHODS: Using nationwide registries, we calculated age-standardized incidence rates for all women born and living in Greenland. To investigate whether possible variation in the incidence of CIN3 were related to differences in screening coverage, we further estimated relative risks of CIN3 within two years of screening among women who participated in the screening program using log-linear binomial regression. RESULTS: Coverage of the screening program was low during 1997-2011 with the highest level of 54% observed in 2011. Peaks in CIN3 incidence of around 300 per 100,000 person-years were observed in 1999 and between 2009 and 2011, while the incidence was lower of approximately 100 per 100,000 person-years between 2000 and 2008. During 2009-2011, the highest incidence was found among women aged 25-34 years. Similar patterns of CIN3 risk according to calendar period and age groups were observed among screened women. CONCLUSIONS: The great variations in CIN3 incidence and low screening coverage observed during 1997-2011 suggest that improvements in the Greenlandic screening program are warranted.

Blood donation and blood donor mortality after adjustment for a healthy donor effect.

BACKGROUND: Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also reflect the selection of healthy persons into the donor population. To overcome this bias, we investigated the relation between blood donation frequency and mortality within a large cohort of blood donors. In addition, our analyses also took into consideration the effects of presumed health differences linked to donation behavior. STUDY DESIGN AND METHODS: Using the Scandinavian Donation and Transfusion database (SCANDAT), we assessed the association between annual number of donations in 5-year windows and donor mortality by means of Poisson regression analysis. The analyses included adjustment for demographic characteristics and for an internal healthy donor effect, estimated among elderly donors exempted from continued donation because of age criteria. RESULTS: Statistical analyses included 1,182,495 donors of whom 15,401 died during 9,526,627 person-years of follow-up. Analyses adjusted only for demographic characteristics showed a 18.6% reduction in mortality per additional annual donation (95% confidence interval [CI], 16.8%-20.4%). After additional adjustment for the internal healthy donor effect, each additional annual donation was associated with a 7.5% decreased mortality risk 7.5% (95% CI, 5.7%-9.4%). CONCLUSION: We observed an inverse relationship between donation frequency and mortality. The magnitude of the association was reduced after adjustment for an estimate of self-selection in the donor population. Our observations indicate that repeated blood donation is not associated with premature death, but cannot be interpreted as conclusive evidence of a beneficial health effect.

Pregnancy and birth cohort resources in europe: a large opportunity for aetiological child health research.

BACKGROUND: During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. METHODS: European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. RESULTS: In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. CONCLUSION: This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.

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.

Risk and trajectory of premature ischaemic cardiovascular disease in women with a history of pre-eclampsia: a nationwide register-based study.

AIMS: Pre-eclampsia increases women's lifetime risk of cardiovascular disease (CVD). Little is known about the trajectory of CVD after pre-eclampsia, limiting the usefulness of this knowledge for informing screening, prevention, and interventions. We investigated when the risk of CVD increases after pre-eclampsia and how the risk changes over time since pregnancy. METHODS AND RESULTS: This register-based study included 1 157 666 women with >1 pregnancy between 1978 and 2017. Cumulative incidences of acute myocardial infarction (AMI) and ischaemic stroke were estimated, as well as hazard ratios (HRs) by attained age and time since delivery. Up to 2% [95% confidence interval (CI): 1.46-2.82%] of women with pre-eclampsia in their first pregnancy had an AMI or stroke within two decades of delivery, compared with up to 1.2% (95% CI: 1.08-1.30%) of pre-eclampsia-free women; differences in cumulative incidences were evident 7 years after delivery. Ten years after delivery, women with pre-eclampsia had four- and three-fold higher rates of AMI (HR = 4.16, 95% CI: 3.16-5.49) and stroke (HR = 2.59, 95% CI 2.04-3.28) than women without pre-eclampsia; rates remained doubled >20 years later. Women with pre-eclampsia aged 30-39 years had five-fold and three-fold higher rates of AMI (HR = 4.88, 95% CI 3.55-6.71) and stroke (HR = 2.56, 95% CI 1.95-3.36) than women of similar age without pre-eclampsia. CONCLUSIONS: Women with a history of pre-eclampsia have high rates of AMI and stroke at early ages and within a decade after delivery. The findings suggest that pre-eclampsia history could be useful in identifying women at increased risk of CVD and that targeted interventions should be initiated soon after delivery.

Women with a history of pre-eclampsia constitute a high-risk subgroup of women who would benefit from additional clinical monitoring while still comparatively young. Up to twice as many women with a first pregnancy complicated by pre-eclampsia develop acute myocardial infarction or ischaemic stroke within 20 years of delivery compared with women without pre-eclampsia in their first pregnancy (2 vs. 1.2%).Relative risks of acute myocardial infarction and ischaemic stroke were greatest in women aged 30­39 years and within a decade of pre-eclampsia but remained substantial even <20 years later and in older women.

Childcare attendance and risk of infections in childhood and adolescence.

BACKGROUND: It has been suggested that the transiently increased infection risk following childcare enrolment is compensated by decreased infection risk later in childhood and adolescence. We investigated how childcare enrolment affected rates of antimicrobial-treated infections during childhood and adolescence. METHODS: In a register-based cohort study of all children born in Denmark 1997-2014 with available exposure information (n = 1 007 448), we assessed the association between childcare enrolment before age 6 years and infection risks up to age 20 years, using antimicrobial exposure as proxy for infections. Nationwide childcare and prescription data were used. We estimated infection rates and the cumulative number of infections using adjusted Poisson regression models. RESULTS: We observed 4 599 993 independent episodes of infection (antimicrobial exposure) during follow-up. Childcare enrolment transiently increased infection rates; the younger the child, the greater the increase. The resulting increased cumulative number of infections associated with earlier age at childcare enrolment was not compensated by lower infection risk later in childhood or adolescence. Accordingly, children enrolled in childcare before age 12 months had experienced 0.5-0.7 more infections at age 6 years (in total 4.5-5.1 infections) than peers enrolled at age 3 years, differences that persisted throughout adolescence. The type of childcare had little impact on infection risks. CONCLUSIONS: Early age at childcare enrolment is associated with a modest increase in the cumulative number of antimicrobial-treated infections at all ages through adolescence. Emphasis should be given to disrupting infectious disease transmission in childcare facilities through prevention strategies with particular focus on the youngest children.

Migrant tuberculosis: the extent of transmission in a low burden country.

BACKGROUND: Human migration caused by political unrest, wars and poverty is a major topic in international health. Infectious diseases like tuberculosis follow their host, with potential impact on both the migrants and the population in the recipient countries. In this study, we evaluate Mycobacterium tuberculosis transmission between the national population and migrants in Denmark. METHODS: Register study based on IS6110-RFLP results from nationwide genotyping of tuberculosis cases during 1992 through 2004. Cases with 100% identical genotypes were defined as clustered and part of a transmission chain. Origin of clusters involving both Danes and migrants was defined as Danish/migrant/uncertain. Subsequently, the proportion of cases likely infected by the "opposite" ethnic group was estimated. RESULTS: 4,631 cases were included, representing 99% of culture confirmed cases during 1992 through 2004. Migrants contributed 61.6% of cases. Up to 7.9% (95% CI 7.0-8.9) of migrants were infected by Danes. The corresponding figure was 5.8% (95% CI 4.8-7.0) for Danes. Thus, transmission from Danes to migrants occurred up to 2.5 (95% CI 1.8-3.5) times more frequent than vice versa (OR = 1). A dominant strain, Cluster-2, was almost exclusively found in Danes, particular younger-middle-aged males. CONCLUSIONS: Transmission between Danes and migrants is limited, and risk of being infected by the "opposite" ethnic group is highest for migrants. TB-control efforts should focus on continues micro-epidemics, e.g. with Cluster-2 in Danes, prevention of reactivation TB in high-risk migrants, and outbreaks in socially marginalized migrants, such as Somalis and Greenlanders. Fears that TB in migrants poses a threat for resident Danes seem exaggerated and unjustified. We believe this to be true for other low incidence countries as well.

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.

Childcare and health: a review of using linked national registers.

INTRODUCTION: To present the work previously and presently being carried out based on the nationwide Childcare Database. RESEARCH TOPICS: The Childcare Database comprises individually linked Danish register-based data on childcare attendance, childcare facility characteristics, child and family characteristics, and infectious disease hospitalisations. The database includes about 1 million children aged 0-5 years and has, since the creation, been linked with separate disease registers on atopic disease, pneumococcal disease, and childhood cancers. The present paper is a review of epidemiological studies based on the Childcare Database. Studies of childhood infections confirmed that childcare attendance dramatically increases the risk, but emphasised that the increased risk is often transient and confined to subsets of children. Studies of childhood cancers showed that early childhood infections are likely to reduce the risk of childhood leukaemia and that this risk reduction applies to all children. CONCLUSION: The Childcare Database is a unique data source for studying the association between childcare attendance and health outcomes. Further linkage with Danish registers is possible on an individual level. The studies based on the Childcare Database confirm and extend previous findings of an increased risk of infection associated with childcare attendance, as well as point towards a possible protective role of early infections in childhood cancer.

Male origin microchimerism and ovarian cancer.

BACKGROUND: Reduced risk of ovarian cancer is commonly ascribed to reduced exposure to endogenous hormones during pregnancy, using oral contraceptives or not using hormone replacement therapy. However, exposure to hormones alone account for less than half of all cases. Many women carry small amounts of male cells-known as male origin microchimerism-in their circulation and remarkable impacts of these cells on women's health are being published. Here, we pursue the possibility that male origin microchimerism has a role in reducing ovarian cancer risk. METHODS: We conducted a prospective case-cohort study using blood samples and questionnaire data from 700 women participating in the Danish Diet, Cancer, and Health cohort. Blood samples were analysed for Y chromosome presence as a marker of male microchimerism. We evaluated the association between male microchimerism and ovarian cancer, using weighted Cox regression models reporting hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). RESULTS: Male microchimerism was detected in 46% of cases and 65.9% of controls. Women testing positive for male microchimerism had a reduced hazard rate of ovarian cancer compared with women testing negative (HR = 0.44, 95% CI: 0.29-0.68). We found no evidence of interaction with measures of hormonal exposures (P = 0.50). CONCLUSIONS: For the first time we report that women who test positive for male microchimerism in their circulation have reduced rates of ovarian cancer compared with women who test negative. Although the underlying mechanisms are presently unknown, we believe male microchimerism is potent in preventing ovarian cancer.