Mortality Risks Associated with Depression in Men with Prostate Cancer.

BACKGROUND: Men diagnosed with prostate cancer (PC) have an increased risk of depression; however, it is unclear to what extent depression affects long-term survival. A better understanding of such effects is needed to improve long-term care and outcomes for men with PC. OBJECTIVE: To determine the associations between major depression and mortality in a national cohort of men with PC. DESIGN, SETTING, AND PARTICIPANTS: A national cohort study was conducted of all 180 189 men diagnosed with PC in Sweden during 1998-2017. Subsequent diagnoses of major depression were ascertained from nationwide outpatient and inpatient records through 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Deaths were identified from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) for all-cause mortality associated with major depression, adjusting for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. PC-specific mortality was examined using competing risks models. RESULTS AND LIMITATIONS: In 1.3 million person-years of follow-up, 16 134 (9%) men with PC were diagnosed with major depression and 65 643 (36%) men died. After adjusting for sociodemographic factors and comorbidities, major depression was associated with significantly higher all-cause mortality in men with high-risk PC (HR, 1.50; 95% confidence interval [CI], 1.44-1.55) or low- or intermediate-risk PC (1.64; 1.56-1.71). These risks were elevated regardless of PC treatment or age at PC diagnosis, except for youngest men (<55 yr) in whom the risks were nonsignificant. Major depression was also associated with increased PC-specific mortality in men with either high-risk PC (HR, 1.35; 95% CI, 1.28-1.43) or low- or intermediate-risk PC (1.42; 1.27-1.59). This study was limited to Sweden and will need replication in other countries when feasible. CONCLUSIONS: In this national cohort of men with PC, major depression was associated with ∼50% higher all-cause mortality. Men with PC need timely detection and treatment of depression to support their long-term outcomes and survival. PATIENT SUMMARY: In this report, we examined the effects of depression on survival in men with prostate cancer. We found that among all men with prostate cancer, those who developed depression had a 50% higher risk of dying than those without depression. Men with prostate cancer need close monitoring for the detection and treatment of depression to improve their long-term health outcomes.

Risks of Depression, Anxiety, and Suicide in Partners of Men with Prostate Cancer: A National Cohort Study.

BACKGROUND: A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown. METHODS: A national cohort study was conducted of 121,530 partners of men diagnosed with PC during 1998-2017 and 1,093,304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors. RESULTS: Partners of men with high-risk PC had increased risks of major depression (adjusted HR, 1.34; 95% CI, 1.30-1.39) and anxiety disorder (1.25; 1.20-1.30), which remained elevated ≥10 years later. Suicide death was increased in partners of men with distant metastases (adjusted HR, 2.38; 95% CI, 1.08-5.22) but not other high-risk PC (1.14; 0.70-1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those aged ≥80 years (adjusted HR, 1.73; 95% CI, 1.53-1.96; and 1.70; 1.47-1.96, respectively), whereas suicide death was highest among those aged <60 years (7.55; 2.20-25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes. CONCLUSIONS: In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for ≥10 years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.

Diabetes risk during pregnancy among second-generation immigrants: A national cohort study in Sweden.

BACKGROUND AND AIMS: Gestational diabetes is more common in many first-generation immigrant women in Europe and other Western countries. Less is known about second-generation immigrant women; such knowledge is needed to understand generational influences on diabetes risk. We aimed to study second-generation immigrant women regarding the presence of all types of diabetes during pregnancy. METHODS AND RESULTS: A cohort study was conducted using the Swedish National Birth Register, the National Patient Register, and the Total Population Register. We used Cox regression analysis to compute hazard ratios (HRs) and 99% confidence intervals (99% CI) for any diabetes during pregnancy and specific subtypes (gestational diabetes, pre-existing diabetes type 1, pre-existing diabetes type 2) in second-generation immigrant women compared with Swedish-born women with two Swedish-born parents while adjusting for sociodemographic factors, family history of diabetes, body mass index, smoking habits, and comorbidities. The study population included a total of 989,986 deliveries and 17,938 diabetes cases. The fully adjusted HR (with 99% CI) for any type of diabetes during pregnancy among second-generation immigrant women was 1.11 (1.05-1.18). Higher risks were found in women with parents from Africa, Asia, or Eastern Europe, as well as Denmark. A lower risk for pre-existing type 1 diabetes was found overall and for women with parents from most geographic regions. CONCLUSION: In this national cohort study, the risk of all types of diabetes during pregnancy was increased in second-generation immigrant women. Diabetes prevention and treatment is especially important in these women both before and during pregnancy.

Neighborhood deprivation in relation to lung cancer in individuals with type 2 diabetes-A nationwide cohort study (2005-2018).

BACKGROUND: Neighborhood deprivation has been found associated with both type 2 diabetes and lung cancer. The aim of this study was to examine the potential association between neighborhood deprivation and lung cancer incidence or mortality in individuals diagnosed with type 2 diabetes. The results may identify a new risk or prognostic factor for lung cancer in this important subgroup and help develop a more contextual approach to prevention that includes neighborhood environment. METHODS AND FINDINGS: The study population included adults (n = 613,650) aged ≥ 30 years with type 2 diabetes during 2005 to 2018 in Sweden. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incidence or mortality of lung cancer associated with neighborhood deprivation. All models were conducted in both men and women and adjusted for individual-level characteristics (e.g. age, smoking- and alcohol-related comorbidities, sociodemographic factors). The cumulative incidence and mortality for lung cancer were 1.08% (95% CI, 1.06 to 1.11) and 0.93% (0.90 to 0.95), respectively, in the study population during the study period. Neighborhood deprivation was associated with both incidence and mortality of lung cancer in patients with type 2 diabetes independently of the individual-level characteristics. In the fully adjusted models, comparing high- with low-deprivation neighborhoods, the HRs for lung cancer incidence were 1.21 (1.10 to 1.33) in men and 1.08 (0.95 to 1.21) in women. The corresponding HRs for lung cancer mortality were 1.04 (1.00 to 1.07) in men and 0.97 (0.94 to 1.00) in women. Competing risk analyses including cardiovascular mortality attenuated the results. CONCLUSION: In this large cohort of individuals with type 2 diabetes, we found higher lung cancer incidence and mortality in patients living in areas with high neighborhood deprivation, even after adjusting for individual-level characteristics. These findings may help develop a more contextual approach that includes the neighborhood environment when allocating resources for disease prevention and care in patients with type 2 diabetes. These findings could also help inform clinical care for patients with type 2 diabetes, particularly those living in deprived neighborhoods.

Risks of alcohol and drug use disorders in prostate cancer survivors: a national cohort study.

BACKGROUND: Prostate cancer (PC) survivors may potentially use substances to cope with psychological distress or poorly controlled physical symptoms. Little is known, however, about the long-term risks of alcohol use disorder (AUD) or drug use disorders in men with PC. METHODS: A national cohort study was conducted in Sweden of 180 189 men diagnosed with PC between 1998 and 2017 and 1 801 890 age-matched population-based control men. AUD and drug use disorders were ascertained from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses examined differences by PC treatment from 2005 to 2017. RESULTS: Men with high-risk PC had increased risks of both AUD (adjusted HR = 1.44, 95% confidence interval [CI] = 1.33 to 1.57) and drug use disorders (adjusted HR = 1.93, 95% CI = 1.67 to 2.24). Their AUD risk was highest in the first year and was no longer significantly elevated 5 years after PC diagnosis, whereas their drug use disorders risk remained elevated 10 years after PC diagnosis (adjusted HR = 2.26, 95% CI = 1.45 to 3.52), particularly opioid use disorder (adjusted HR = 3.07, 95% CI = 1.61 to 5.84). Those treated only with androgen-deprivation therapy had the highest risks of AUD (adjusted HR = 1.91, 95% CI = 1.62 to 2.25) and drug use disorders (adjusted HR = 2.23, 95% CI = 1.70 to 2.92). Low- or intermediate-risk PC was associated with modestly increased risks of AUD (adjusted HR = 1.38, 95% CI = 1.30 to 1.46) and drug use disorders (adjusted HR = 1.19, 95% CI = 1.06 to 1.34). CONCLUSIONS: In this large cohort, men with PC had significantly increased risks of both AUD and drug use disorders, especially those with high-risk PC and treated only with androgen-deprivation therapy. PC survivors need long-term psychosocial support and timely detection and treatment of AUD and drug use disorders.

Long-term Risks of Depression and Suicide Among Men with Prostate Cancer: A National Cohort Study.

BACKGROUND: A diagnosis of prostate cancer (PC) may cause psychosocial distress that worsens quality of life; however, long-term mental health outcomes are unclear. OBJECTIVE: To determine the long-term risks of major depression and death by suicide in a large population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: This was a national cohort study of 180 189 men diagnosed with PC during 1998-2017 and 1 801 890 age-matched, population-based, control men in Sweden. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Major depression and death by suicide were ascertained from nationwide outpatient, inpatient, and death records up to 2018. Cox regression was used to compute hazard ratios (HRs) adjusted for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. RESULTS AND LIMITATIONS: Men diagnosed with high-risk PC had higher relative rates of major depression (adjusted HR [aHR] 1.82, 95% confidence interval [CI] 1.75-1.89) and death by suicide (aHR 2.43, 95% CI 2.01-2.95). These associations persisted for ≥10 yr after PC diagnosis. The relative increase in major depression was lower among those treated with radiation (aHR 1.44, 95% CI 1.31-1.57) or surgery (aHR 1.60, 95% CI 1.31-1.95) in comparison to androgen deprivation therapy (ADT) alone (aHR 2.02, 95% CI 1.89-2.16), whereas the relative rate of suicide death was higher only among those treated solely with ADT (aHR 2.83, 95% CI 1.80-4.43). By contrast, men with low- or intermediate-risk PC had a modestly higher relative rate of major depression (aHR 1.19, 95% CI 1.16-1.23) and higher relative rate of suicide death at 3-12 mo after PC diagnosis (aHR 1.88, 95% CI 1.11-3.18) but not across the entire follow-up period (aHR 1.02, 95% CI 0.84-1.25). This study was limited to Sweden and will need replication in other populations. CONCLUSIONS: In this large cohort, high-risk PC was associated with substantially higher relative rates of major depression and death by suicide, which persisted for ≥10 yr after PC diagnosis. PC survivors need close follow-up for timely detection and treatment of psychosocial distress. PATIENT SUMMARY: In a large Swedish population, men with aggressive prostate cancer had higher long-term relative rates of depression and suicide.

Drug use disorder and risk of incident and fatal prostate cancer among Swedish men: a nationwide epidemiological study.

PURPOSE: Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden. METHODS: We performed a follow-up study based on Swedish national register data for the period January 1997-December 2016. The study was based on 1,361,532 men aged 50-75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD. RESULTS: DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00-1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40-1.82, p < 0.001), adjusted for age, socioeconomic factors, and comorbidities related to tobacco smoking and alcohol use disorder. No association was found between DUD and prostate cancer stage at diagnosis. CONCLUSIONS: Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.

Preterm delivery and long term mortality in women: national cohort and co-sibling study.

OBJECTIVES: To examine the long term mortality associated with preterm delivery in a large population based cohort of women, and to assess for potential confounding by shared familial factors. DESIGN: National cohort study. SETTING: Sweden. PARTICIPANTS: All 2 189 477 women with a singleton delivery in 1973-2015. MAIN OUTCOME MEASURES: All cause and cause specific mortality up to 2016, identified from nationwide death records. Cox regression was used to calculate hazard ratios while adjusting for confounders, and co-sibling analyses assessed the potential influence of unmeasured shared familial (genetic and environmental) factors. RESULTS: In 50.7 million person years of follow-up, 76 535 (3.5%) women died (median age at death was 57.6). In the 10 years after delivery, the adjusted hazard ratio for all cause mortality associated with preterm delivery (<37 weeks) was 1.73 (95% confidence interval 1.61 to 1.87), and when further stratified was 2.20 (1.63 to 2.96) for extremely preterm delivery (22-27 weeks), 2.28 (2.01 to 2.58) for very preterm delivery (28-33 weeks), 1.52 (1.39 to 1.67) for late preterm delivery (34-36 weeks), and 1.19 (1.12 to 1.27) for early term delivery (37-38 weeks) compared with full term delivery (39-41 weeks). These risks declined but remained significantly raised after longer follow-up times: for preterm versusfull term births, 10-19 years after delivery, the adjusted hazard ratio was 1.45 (95% confidence interval 1.37 to 1.53); 20-44 years after delivery, the adjusted hazard ratio was 1.37 (1.33 to 1.41). These findings did not seem to be attributable to shared genetic or environmental factors within families. Several causes were identified, including cardiovascular and respiratory disorders, diabetes, and cancer. CONCLUSIONS: In this large national cohort of women, the findings suggested that preterm and early term delivery were independent risk factors for premature mortality from several major causes. These associations declined over time but remained raised up to 40 years later.

Early-Life Cardiorespiratory Fitness and Long-term Risk of Prostate Cancer.

BACKGROUND: Adolescence is a period of rapid prostatic growth, yet is understudied for susceptibility for future risk of prostate cancer. We examined cardiorespiratory fitness (CRF) in late adolescence in relation to long-term prostate cancer risk. METHODS: A population-based cohort study was conducted of all 699,125 Swedish military conscripts during 1972-1985 (97%-98% of 18-year-old men) in relation to risk of prostate cancer overall, aggressive prostate cancer, and prostate cancer mortality during 1998-2017 (ages 50-65 years). CRF was measured by maximal aerobic workload, and prostate cancer was ascertained using the National Prostate Cancer Register. Muscle strength was examined as a secondary predictor. RESULTS: In 38.8 million person-years of follow-up, 10,782 (1.5%) men were diagnosed with prostate cancer. Adjusting for sociodemographic factors, height, weight, and family history of prostate cancer, high CRF was associated with a slightly increased risk of any prostate cancer [highest vs. lowest quintile: incidence rate ratio (IRR), 1.10; 95% CI, 1.03-1.19; P = 0.008], but was neither significantly associated with aggressive prostate cancer (1.01; 0.85-1.21; P = 0.90) nor prostate cancer mortality (1.24; 0.73-2.13; P = 0.42). High muscle strength also was associated with a modestly increased risk of any prostate cancer (highest vs. lowest quintile: IRR, 1.14; 95% CI, 1.07-1.23; P < 0.001), but neither with aggressive prostate cancer (0.88; 0.74-1.04; P = 0.14) nor prostate cancer mortality (0.81; 0.48-1.37; P = 0.43). CONCLUSIONS: High CRF or muscle strength in late adolescence was associated with slightly increased future risk of prostate cancer, possibly related to increased screening, but neither with risk of aggressive prostate cancer nor prostate cancer mortality. IMPACT: These findings illustrate the importance of distinguishing aggressive from indolent prostate cancer and assessing for potential detection bias.

Accounting for Multiple Comparisons in Statistical Analysis of the Extensive Bioassay Data on Glyphosate.

Glyphosate is a widely used herbicide worldwide. In 2015, the International Agency for Research on Cancer (IARC) reviewed glyphosate cancer bioassays and human studies and declared that the evidence for carcinogenicity of glyphosate is sufficient in experimental animals. We analyzed 10 glyphosate rodent bioassays, including those in which IARC found evidence of carcinogenicity, using a multiresponse permutation procedure that adjusts for the large number of tumors eligible for statistical testing and provides valid false-positive probabilities. The test statistics for these permutation tests are functions of p values from a standard test for dose-response trend applied to each specific type of tumor. We evaluated 3 permutation tests, using as test statistics the smallest p value from a standard statistical test for dose-response trend and the number of such tests for which the p value is less than or equal to .05 or .01. The false-positive probabilities obtained from 2 implementations of these 3 permutation tests are: smallest p value: .26, .17; p values ≤ .05: .08, .12; and p values ≤ .01: .06, .08. In addition, we found more evidence for negative dose-response trends than positive. Thus, we found no strong evidence that glyphosate is an animal carcinogen. The main cause for the discrepancy between IARC's finding and ours appears to be that IARC did not account for the large number of tumor responses analyzed and the increased likelihood that several of these would show statistical significance simply by chance. This work provides a more comprehensive analysis of the animal carcinogenicity data for this important herbicide than previously available.

Risk of being born preterm in offspring of survivors with childhood or adolescent central nervous system tumor in Sweden.

An increasing number of patients with central nervous system (CNS) tumor could survive to reproductive age. However, it is largely unknown whether the history of CNS tumor might affect pregnancy outcome. We aimed to explore the risk of being born preterm among children of CNS tumor survivors. By linking several nationwide registers in Sweden, we identified 1,369 children whose parents were childhood or adolescent CNS tumor survivors. Children whose parents did not have CNS tumor were matched randomly with a 5:1 ratio to generate the reference group. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The prevalence of preterm birth (PTB) was 6.9% among children of survivors with CNS tumor and 5.2% among the matched controls. Children of survivors had an increased risk of PTB (adjusted OR = 1.29, 95%CI 1.01-1.65) compared to the matched controls. This risk was increased specifically among offspring of those diagnosed in childhood (adjusted OR = 1.53, 95%CI 1.14-2.06) but not adolescence (adjusted OR = 0.89, 95%CI 0.56-1.41). For families with more than one child, the risk was slightly lower among the second child as compared to the first child. The risk was negatively associated with time interval between parental diagnosis and childbirth. Parental medulloblastoma and ependymoma were most strongly associated with a higher risk of PTB. Children of survivors with CNS tumor experienced an elevated risk of PTB. However, the risk diminishes gradually after parental diagnosis of CNS tumor. Offspring of childhood CNS tumor survivors and medulloblastoma or ependymoma survivors may have the highest risk of PTB.

Gestational age at birth and mortality from infancy into mid-adulthood: a national cohort study.

BACKGROUND: Breakthroughs in the treatment of preterm birth approximately 40 years ago have enabled a generation of preterm survivors to now reach mid-adulthood. Understanding their health sequelae is essential for guiding their long-term care. We did a study to examine preterm birth in relation to mortality into mid-adulthood. METHODS: A national cohort study was done of all 4 296 814 singleton livebirths in Sweden between 1973 and 2015, who were followed up for mortality through Dec 31, 2017 (maximum age 45 years). Cox regression was used to examine gestational age at birth in relation to all-cause and cause-specific mortality, and cosibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. FINDINGS: In 103·5 million person-years of follow-up, 43 916 (1·0%) deaths were reported. Gestational age at birth was inversely associated with mortality from infancy to mid-adulthood. Relative to full-term birth (39-41 weeks), the adjusted hazard ratios for mortality associated with gestational age at birth were: 66·14 (95% CI 63·09-69·34) for extremely preterm (22-27 weeks), 8·67 (8·32-9·03) for very preterm (28-33 weeks), 2·61 (2·52-2·71) for late preterm (34-36 weeks), and 1·34 (1·30-1·37) for early term (37-38 weeks), from birth to age 45 years; and 2·04 (0·92-4·55) for extremely preterm, 1·48 (1·17-1·87) for very preterm, 1·22 (1·07-1·39) for late preterm, and 1·16 (1·08-1·25) for early term, at ages 30-45 years. Preterm birth accounted for more deaths among males than females (additive interaction p<0·001). Multiple underlying causes were identified, including congenital anomalies; respiratory, endocrine, cardiovascular, and neurological diseases; cancer; and external causes. Cosibling analyses suggested that the observed associations were not due to shared genetic or environmental factors in families. INTERPRETATION: Preterm and early term birth should be recognised as chronic conditions that require long-term follow-up for adverse health sequelae in adulthood. FUNDING: National Heart, Lung, and Blood Institute at the National Institutes of Health.

Fetal growth and subsequent maternal risk of thyroid cancer.

Thyroid cancer has peak incidence among women of reproductive age, and growth factors, which have procarcinogenic properties, may play an important etiologic role. However, the association between fetal growth rate during a woman's pregnancy and her subsequent risk of thyroid cancer has not been previously examined. We conducted a national cohort study of 1,837,634 mothers who had a total of 3,588,497 live-births in Sweden in 1973-2008, followed up for thyroid cancer incidence through 2009. There were 2,202 mothers subsequently diagnosed with thyroid cancer in 36.8 million person-years of follow-up. After adjusting for maternal age, height, weight, smoking, and sociodemographic factors, high fetal growth (birth weight standardized for gestational age and sex) was associated with a subsequent increased risk of thyroid cancer in the mother (incidence rate ratio [IRR] per additional 1 standard deviation, 1.05; 95% CI, 1.01-1.09; p = 0.02). Each 1,000 g increase in the infant's birth weight was associated with a 13% increase in the mother's subsequent risk of thyroid cancer (IRR, 1.13; 95% CI, 1.05-1.22; p = 0.001). These findings appeared to involve both papillary and follicular subtypes, and did not vary significantly by the mother's height, weight or smoking status. In this large national cohort study, high fetal growth during a woman's pregnancy was independently associated with a subsequent increased risk of her developing thyroid cancer. If confirmed, these findings suggest an important role of maternal growth factors in the development of thyroid cancer, and potentially may help facilitate the identification of high-risk subgroups of women.

Perinatal risk factors for acute myeloid leukemia.

Infectious etiologies have been hypothesized for acute leukemias because of their high incidence in early childhood, but have seldom been examined for acute myeloid leukemia (AML). We conducted the first large cohort study to examine perinatal factors including season of birth, a proxy for perinatal infectious exposures, and risk of AML in childhood through young adulthood. A national cohort of 3,569,333 persons without Down syndrome who were born in Sweden in 1973-2008 were followed up for AML incidence through 2010 (maximum age 38 years). There were 315 AML cases in 69.7 million person-years of follow-up. We found a sinusoidal pattern in AML risk by season of birth (P < 0.001), with peak risk among persons born in winter. Relative to persons born in summer (June-August), incidence rate ratios for AML were 1.72 (95 % CI 1.25-2.38; P = 0.001) for winter (December-February), 1.37 (95 % CI 0.99-1.90; P = 0.06) for spring (March-May), and 1.27 (95 % CI 0.90-1.80; P = 0.17) for fall (September-November). Other risk factors for AML included high fetal growth, high gestational age at birth, and low maternal education level. These findings did not vary by sex or age at diagnosis. Sex, birth order, parental age, and parental country of birth were not associated with AML. In this large cohort study, birth in winter was associated with increased risk of AML in childhood through young adulthood, possibly related to immunologic effects of early infectious exposures compared with summer birth. These findings warrant further investigation of the role of seasonally varying perinatal exposures in the etiology of AML.

Fetal growth and subsequent maternal risk of colorectal cancer.

BACKGROUND: High birth weight has been associated with subsequent increased risk of breast cancer in the infant's mother, possibly related to maternal estrogen and growth factor pathways. However, its association with maternal risk of colorectal cancer, the third most common cancer among women, is unknown. METHODS: We conducted a national cohort study of 1,838,509 mothers who delivered 3,590,523 babies in Sweden in 1973-2008, followed up for colorectal cancer incidence through 2009. RESULTS: There were 7,318 mothers diagnosed with colorectal cancer in 36.8 million person-years of follow-up. After adjusting for maternal age, body mass index, diabetes, and other potential confounders, high fetal growth was associated with a subsequent increased risk of colorectal cancer in the mother [incidence rate ratio (IRR) per additional 1 SD relative to mean birth weight for gestational age and sex, 1.05; 95% confidence intervals (CI), 1.03-1.07; P < 0.0001]. Each 1,000 g increase in the infant's birth weight was associated with a 12% increase in the mother's subsequent risk of colorectal cancer (IRR, 1.12; 95% CI, 1.07-1.17; P < 0.0001). Multiple gestation was also independently associated with increased maternal risk of colorectal cancer (IRR for twin or higher order vs. singleton, 1.22; 95% CI, 1.04-1.44; P = 0.02). CONCLUSION: In this large cohort study, high fetal growth and multiple gestation were independently associated with subsequent higher maternal risk of colorectal cancer. These findings warrant further investigation of maternal growth factor and estrogen pathways in the etiology of colorectal cancer. IMPACT: If confirmed, our findings may help identify subgroups of women at high risk of colorectal cancer.

Perinatal and familial risk factors for acute lymphoblastic leukemia in a Swedish national cohort.

BACKGROUND: Perinatal factors including high birth weight have been found to be associated with acute lymphoblastic leukemia (ALL) in case-control studies. However, to the best of our knowledge, these findings have seldom been examined in large population-based cohort studies, and the specific contributions of gestational age and fetal growth remain unknown. METHODS: The authors conducted a national cohort study of 3,569,333 individuals without Down syndrome who were born in Sweden between 1973 and 2008 and followed for the incidence of ALL through 2010 (maximum age, 38 years) to examine perinatal and familial risk factors. RESULTS: There were 1960 ALL cases with 69.7 million person-years of follow-up. After adjusting for potential confounders, risk factors for ALL included high fetal growth (incidence rate ratio [IRR] per additional 1 standard deviation, 1.07; 95% confidence interval [95% CI], 1.02-1.11 [P =.002]; and IRR for large vs appropriate for gestational age, 1.22; 95% CI, 1.06-1.40 [P =.005]), first-degree family history of ALL (IRR, 7.41; 95% CI, 4.60-11.95 [P<.001]), male sex (IRR, 1.20; 95% CI, 1.10-1.31 [P<.001]), and parental country of birth (IRR for both parents born in Sweden vs other countries, 1.13; 95% CI, 1.00-1.27 [P =.045]). These risk factors did not appear to vary by patient age at the time of diagnosis of ALL. Gestational age at birth, season of birth, birth order, multiple birth, parental age, and parental education level were not found to be associated with ALL. CONCLUSIONS: In this large cohort study, high fetal growth was found to be associated with an increased risk of ALL in childhood through young adulthood, independent of gestational age at birth, suggesting that growth factor pathways may play an important long-term role in the etiology of ALL.

Perinatal and familial risk factors for brain tumors in childhood through young adulthood.

Perinatal factors, including high birth weight, have been associated with childhood brain tumors in case-control studies. However, the specific contributions of gestational age and fetal growth remain unknown, and these issues have never been examined in large cohort studies with follow-up into adulthood. We conducted a national cohort study of 3,571,574 persons born in Sweden in 1973-2008, followed up for brain tumor incidence through 2010 (maximum age 38 years) to examine perinatal and familial risk factors. There were 2,809 brain tumors in 69.7 million person-years of follow-up. After adjusting for potential confounders, significant risk factors for brain tumors included high fetal growth [incidence rate ratio (IRR) per additional 1 SD, 1.04; 95% confidence interval (CI), 1.01-1.08, P = 0.02], first-degree family history of a brain tumor (IRR, 2.43; 95% CI, 1.86-3.18, P < 0.001), parental country of birth (IRR for both parents born in Sweden vs. other countries, 1.21; 95% CI, 1.09-1.35, P < 0.001), and high maternal education level (Ptrend = 0.01). These risk factors did not vary by age at diagnosis. The association with high fetal growth appeared to involve pilocytic astrocytomas, but not other astrocytomas, medulloblastomas, or ependymomas. Gestational age at birth, birth order, multiple birth, and parental age were not associated with brain tumors. In this large cohort study, high fetal growth was associated with an increased risk of brain tumors (particularly pilocytic astrocytomas) independently of gestational age, not only in childhood but also into young adulthood, suggesting that growth factor pathways may play an important long-term role in the etiology of certain brain tumor subtypes.

Season of birth and risk of Hodgkin and non-Hodgkin lymphoma.

Infectious etiologies have been hypothesized for Hodgkin and non-Hodgkin lymphoma (HL and NHL) in early life, but findings to date for specific lymphomas and periods of susceptibility are conflicting. We conducted the first national cohort study to examine whether season of birth, a proxy for infectious exposures in the first few months of life, is associated with HL or NHL in childhood through young adulthood. A total of 3,571,574 persons born in Sweden in 1973-2008 were followed up through 2009 to examine the association between season of birth and incidence of HL (943 cases) or NHL (936 cases). We found a sinusoidal pattern in NHL risk by season of birth (p = 0.04), with peak risk occurring among birthdates in April. Relative to persons born in fall (September-November), odds ratios for NHL by season of birth were 1.25 [95% confidence interval (CI), 1.04-1.50; p = 0.02] for spring (March-May), 1.22 (95% CI, 1.01-1.48; p = 0.04) for summer (June-August) and 1.11 (95% CI, 0.91-1.35; p = 0.29) for winter (December-February). These findings did not vary by sex, age at diagnosis or major subtypes. In contrast, there was no seasonal association between birthdate and risk of HL (p = 0.78). In this large cohort study, birth in spring or summer was associated with increased risk of NHL (but not HL) in childhood through young adulthood, possibly related to immunologic effects of delayed infectious exposures compared with fall or winter birth. These findings suggest that immunologic responses in early infancy may play an important role in the development of NHL.