Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.

BACKGROUND: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown. OBJECTIVE: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. DESIGN: Nationwide prospective registry-based cohort study. SETTING: Denmark from 1997 to 2016. PARTICIPANTS: All liveborn singletons from mothers without histories of diabetes or essential hypertension. MEASUREMENTS: Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. RESULTS: Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073). LIMITATION: Information on underlying disease status was limited. CONCLUSION: Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation. PRIMARY FUNDING SOURCE: National Institutes of Health.

Nervous system drugs taken by future fathers and birth defects in offspring: a prospective registry-based cohort study.

OBJECTIVES: To evaluate the association of paternal intake of antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, selective serotonin reuptake inhibitors (SSRIs) and (benzo)diazepines during the development of fertilising sperm with birth defects in offspring. DESIGN: Prospective registry-based cohort study. SETTING: Total Danish birth cohort 1997-2016 using Danish national registries. PARTICIPANTS: All 1 201 119 Danish liveborn singletons born 1997-2016 were eligible, 39 803 (3.3%) of whom had at least one major birth defect. EXPOSURE: Offspring were considered exposed if their father had filled at least one prescription in the relevant drug category during development of fertilising sperm (the 3 months prior to conception). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the diagnosis, in the first year of life, of at least one major birth defect as categorised in the EUROCAT guidelines. Secondary outcome was the diagnosis, in the first year of life, of at least one major birth defect in any of the EUROCAT subcategories. Adjusted ORs (AORs) were calculated, along with their 95% CIs, adjusted for year, education, smoking status and age of the mother, and education, disposable income and age of the father. RESULTS: This study found weak or null associations between birth defects and selected drugs. Specifically, antidepressants (17 827 exposed births) gave 3.5% birth defects (AOR 0.97 (0.89 to 1.05)). Diazepines, oxazepines, thiazepines and oxepines (as antipsychotics, 1633 offspring) gave 4.7% birth defects (AOR 1.22 (0.97 to 1.54)), attenuated to 1.13 when excluding by mothers' prescriptions. The study was well powered assuming 100% therapy adherence, while assuming 50% therapy adherence, the study remained well powered for the largest groups (SSRIs and antidepressants overall). CONCLUSIONS: Antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, SSRIs and benzodiazepine-derived anxiolytics, when taken by the father during development of fertilising sperm, are generally safe with regard to birth defects.

Balsalazide Exposure During the Development of Fertilizing Sperm May Be Associated With Offspring Birth Defects.

We report an association between balsalazide exposure during the development of fertilizing sperm and birth defects in offspring. Exposed offspring were approximately 8 times more likely to have a birth defect. There were no pre-existing reasons to suspect such a relationship, which should be confirmed in other data.

The Danaid Theory of Aging.

The classical evolutionary theories of aging suggest that aging evolves due to insufficient selective pressure against it. In these theories, declining selection pressure with age leads to aging through genes or resource allocations, implying that aging could potentially be stalled were genes, resource allocation, or selection pressure somewhat different. While these classical evolutionary theories are undeniably part of a description of the evolution of aging, they do not explain the diversity of aging patterns, and they do not constitute the only possible evolutionary explanation. Without denying selection pressure a role in the evolution of aging, we argue that the origin and diversity of aging should also be sought in the nature and evolution of organisms that are, from their very physiological make up, unmaintainable. Drawing on advances in developmental biology, genetics, biochemistry, and complex systems theory since the classical theories emerged, we propose a fresh evolutionary-mechanistic theory of aging, the Danaid theory. We argue that, in complex forms of life like humans, various restrictions on maintenance and repair may be inherent, and we show how such restrictions are laid out during development. We further argue that there is systematic variation in these constraints across taxa, and that this is a crucial factor determining variation in aging and lifespan across the tree of life. Accordingly, the core challenge for the field going forward is to map and understand the mosaic of constraints, trade-offs, chance events, and selective pressures that shape aging in diverse ways across diverse taxa.

Variability Matters.

Much of science, including public health research, focuses on means (averages). The purpose of the present paper is to reinforce the idea that variability matters just as well. At the hand of four examples, we highlight four classes of situations where the conclusion drawn on the basis of the mean alone is qualitatively altered when variability is also considered. We suggest that some of the more serendipitous results have their origin in variability.

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

Objective: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. Results: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (<300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

Heritability of subfertility among Danish twins.

OBJECTIVE: To investigate the relative contribution of genetic and environmental components to subfertility. DESIGN: Twin design using a quantitative genetic liability threshold model that splits the variation of subfertility into additive genetic effects, common environmental effects, and unique environmental effects. SETTING: Not applicable. PATIENTS: A total of 9053 Danish monozygotic and dizygotic same-sex twins aged 18+ years from nationwide twin surveys (twins born 1931-1976). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Time to pregnancy (TTP) restricted to first pregnancy as a binary outcome, with a cut-off point of 10 months. RESULTS: Based on the Akaike information criterion, a model including additive genetic and unique environmental factors resulted in the best model fit. For females, the relative contribution of additive genetic factors to TTP was 28% (95% confidence interval [CI] 15%, 41%), whereas unique environmental factors explained 72% (95% CI 59%, 85%). For males, additive genetic factors explained 4% (95% CI 0%, 22%) of the variation in TTP, while unique environmental factors accounted for 96% (95% CI 78%, 100%). Results were overall similar for the crude model and consistent across surveys. CONCLUSION: Unique environmental factors explain most of the observed variation in subfertility, when measured as waiting time to pregnancy.

Age-specific cancer rates: a bird's-eye view on progress.

PURPOSE: We aim to shed light on progress in cancer medicine through studying time trends in age-specific rates of cancer incidence and mortality over the last quarter century. METHODS: We analyzed age-specific incidence and mortality rates of all cancer sites combined using the high-quality population-based databases of Denmark, Finland, Norway, Sweden, and the Netherlands for the period 1990-2016. RESULTS: Over these 26 years, cancer incidence rates increased in all investigated countries irrespective of age by about 22%. By contrast, cancer mortality rates decreased across all ages, also by about 22%, except ages 80+ years in Denmark, Norway, and Sweden, where they remained unchanged. This pattern is consistent with earlier diagnoses and more effective treatments of cancer. CONCLUSIONS: This bird's-eye view on cancer reveals substantive progress in cancer medicine.

Progression of the smoking epidemic in high-income regions and its effects on male-female survival differences: a cohort-by-age analysis of 17 countries.

BACKGROUND: Of all lifestyle behaviours, smoking caused the most deaths in the last century. Because of the time lag between the act of smoking and dying from smoking, and because males generally take up smoking before females do, male and female smoking epidemiology often follows a typical double wave pattern dubbed the 'smoking epidemic'. How are male and female deaths from this epidemic differentially progressing in high-income regions on a cohort-by-age basis? How have they affected male-female survival differences? METHODS: We used data for the period 1950-2015 from the WHO Mortality Database and the Human Mortality Database on three geographic regions that have progressed most into the smoking epidemic: high-income North America, high-income Europe and high-income Oceania. We examined changes in smoking-attributable mortality fractions as estimated by the Preston-Glei-Wilmoth method by age (ages 50-85) across birth cohorts 1870-1965. We used these to trace sex differences with and without smoking-attributable mortality in period life expectancy between ages 50 and 85. RESULTS: In all three high-income regions, smoking explained up to 50% of sex differences in period life expectancy between ages 50 and 85 over the study period. These sex differences have declined since at least 1980, driven by smoking-attributable mortality, which tended to decline in males and increase in females overall. Thus, there was a convergence between sexes across recent cohorts. While smoking-attributable mortality was still increasing for older female cohorts, it was declining for females in the more recent cohorts in the US and Europe, as well as for males in all three regions. CONCLUSIONS: The smoking epidemic contributed substantially to the male-female survival gap and to the recent narrowing of that gap in high-income North America, high-income Europe and high-income Oceania. The precipitous decline in smoking-attributable mortality in recent cohorts bodes somewhat hopeful. Yet, smoking-attributable mortality remains high, and therefore cause for concern.

Understanding Differences in Cancer Survival between Populations: A New Approach and Application to Breast Cancer Survival Differentials between Danish Regions.

Large variations in cancer survival have been recorded between populations, e.g., between countries or between regions in a country. To understand the determinants of cancer survival differentials between populations, researchers have often applied regression analysis. We here propose the use of a non-parametric decomposition method to quantify the exact contribution of specific components to the absolute difference in cancer survival between two populations. Survival differences are here decomposed into the contributions of differences in stage at diagnosis, population age structure, and stage-and-age-specific survival. We demonstrate the method with the example of differences in one-year and five-year breast cancer survival between Denmark's five regions. Differences in stage at diagnosis explained 45% and 27%, respectively, of the one- and five-year survival differences between Zealand and Central Denmark for patients diagnosed between 2008 and 2010. We find that the introduced decomposition method provides a powerful complementary analysis and has several advantages compared with regression models: No structural or distributional assumptions are required; aggregated data can be used; and the use of absolute differences allows quantification of the survival that could be gained by improving, for example, stage at diagnosis relative to a reference population, thus feeding directly into health policy evaluation.

Potential gains in life expectancy by reducing inequality of lifespans in Denmark: an international comparison and cause-of-death analysis.

BACKGROUND: Reducing lifespan inequality is increasingly recognized as a health policy objective. Whereas lifespan inequality declined with rising longevity in most developed countries, Danish life expectancy stagnated between 1975 and 1995 for females and progressed slowly for males. It is unknown how Danish lifespan inequality changed, which causes of death drove these developments, and where the opportunities for further improvements lie now. METHODS: We present an analytical strategy based on cause-by-age decompositions to simultaneously analyze changes in Danish life expectancy and lifespan inequality from 1960 to 2014, as well as current Swedish-Danish differences. RESULTS: Stagnation in Danish life expectancy coincided with a shorter period of stagnation in lifespan inequality (1975-1990). The stagnation in life expectancy was mainly driven by increases in cancer and non-infectious respiratory mortality at higher ages (-.63 years) offsetting a reduction in cardiovascular and infant mortality (+ 1.52 years). Lifespan inequality stagnated because most causes of death did not show compression over the time period. Both these observations were consistent with higher smoking-related mortality in Danes born in 1919-1939. After 1995, life expectancy and lifespan equality increased in lockstep, but still lag behind Sweden, mainly due to infant mortality and cancer. CONCLUSIONS: Since 1960, Danish improvements in life expectancy and lifespan equality were halted by smoking-related mortality in those born 1919-1939, while also reductions in old-age cardiovascular mortality held back lifespan equality. The comparison with Sweden suggests that Denmark can reduce inequality in lifespans and increase life expectancy through a consistent policy target: reducing cancer and infant mortality.

The Rarity of Survival to Old Age Does Not Drive the Evolution of Senescence.

The evolution of senescence is often explained by arguing that, in nature, few individuals survive to be old and hence it is evolutionarily unimportant what happens to organisms when they are old. A corollary to this idea is that extrinsically imposed mortality, because it reduces the chance of surviving to be old, favors the evolution of senescence. We show that these ideas, although widespread, are incorrect. Selection leading to senescence does not depend directly on survival to old age, but on the shape of the stable age distribution, and we discuss the implications of this important distinction. We show that the selection gradient on mortality declines with age even in the hypothetical case of zero mortality, when survivorship does not decline. Changing the survivorship function by imposing age independent mortality has no affect on the selection gradients. A similar result exists for optimization models: age independent mortality does not change the optimal result. We propose an alternative, brief explanation for the decline of selection gradients, and hence the evolution of senescence.

Size, longevity and cancer: age structure.

There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox refers to the expectation that large, long-lived organisms have a higher lifetime cancer risk, which is not the case: a paradox. This paradox, however, is circular: large, long-lived organisms are large and long-lived because they are cancer robust. Lifetime risk, meanwhile, depends on the age distributions of both cancer and competing risks: if cancer strikes before competing risks, then lifetime risk is high; if not, not. Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer under the multistage model of carcinogenesis. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms.

Intrinsic and extrinsic mortality reunited.

Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment.

Interaction mortality: senescence may have evolved because it increases lifespan.

Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. We describe a model of interaction mortality that does not involve specific functions, making only modest assumptions. Our model distinguishes explicitly between the physiological state of an organism and potential extrinsic, age-independent threats. The resulting mortality may change with age, depending on whether the organism's state changes with age. We find that depending on the physiological constraints, any outcome, be it 'no senescence' or 'high rate of senescence', can be found in any environment; that the highest optimal rate of senescence emerges for an intermediate physiological constraint, i.e. intermediate strength of trade-off; and that the optimal rate of senescence as a function of the environment is driven by the way the environment changes the effect of the organism's state on mortality. We conclude that knowledge about the environment, physiology and their interaction is necessary before reasonable predictions about the evolution of senescence can be made.

The causal pie model: an epidemiological method applied to evolutionary biology and ecology.

A general concept for thinking about causality facilitates swift comprehension of results, and the vocabulary that belongs to the concept is instrumental in cross-disciplinary communication. The causal pie model has fulfilled this role in epidemiology and could be of similar value in evolutionary biology and ecology. In the causal pie model, outcomes result from sufficient causes. Each sufficient cause is made up of a "causal pie" of "component causes". Several different causal pies may exist for the same outcome. If and only if all component causes of a sufficient cause are present, that is, a causal pie is complete, does the outcome occur. The effect of a component cause hence depends on the presence of the other component causes that constitute some causal pie. Because all component causes are equally and fully causative for the outcome, the sum of causes for some outcome exceeds 100%. The causal pie model provides a way of thinking that maps into a number of recurrent themes in evolutionary biology and ecology: It charts when component causes have an effect and are subject to natural selection, and how component causes affect selection on other component causes; which partitions of outcomes with respect to causes are feasible and useful; and how to view the composition of a(n apparently homogeneous) population. The diversity of specific results that is directly understood from the causal pie model is a test for both the validity and the applicability of the model. The causal pie model provides a common language in which results across disciplines can be communicated and serves as a template along which future causal analyses can be made.

No senescence despite declining selection pressure: Hamilton's result in broader perspective.

Theory predicts that senescence should inevitably evolve because selection pressure declines with age. Yet, data show that senescence is not a universal phenomenon. How can these observations peacefully coexist? Evolution of any trait hinges on its impact on fitness. A complete mathematical description of change in fitness, the total fitness differential, involves selection pressure along with a perturbation function that describes how the vital rates, mortality and fecundity, are affected across ages. We propose that the perturbation function can be used to model trade-offs when vital rates are perturbed in different directions and magnitude at different ages. We find that for every trade-off we can identify parameter values for which senescence does evolve and others for which it does not. We argue that this reconciles the apparent contradiction between data and theory. The total fitness differential is also instrumental in deriving mathematical relationships between alternative indicators of selection pressure. We show examples and highlight that any indicator combined with the right perturbation function can be used to parameterize a specific biological change. Biological considerations should motivate what perturbation functions are used. We interpret the relevance of Hamilton's finding that selection pressure declines for the evolution of senescence: declining selection pressure is a necessary but not a sufficient condition.