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Objective: To examine the socioeconomic patterns and time trends in fetal growth in Denmark, Finland, Norway, and Sweden from 1981 to 2000. Design and settings: Data on all live-born singleton births was drawn from national population registries in each of the four countries (Denmark n = 1 077 584; Finland n = 400 442; Norway n = 929 458; Sweden n = 1 761 562). Main outcome measure: Slope index of inequality (SII) and mean differences in birthweight for gestational age, SII and risk differences in small-for-gestational-age (SGA) and large-for-gestational-age (LGA) infants. Results: In all countries, gradients in fetal growth by parental education existed. Low parental education was associated with lower birthweight, increased risk of SGA and decreased risk of LGA. Mother's education exerted the strongest influence on outcomes, whereas father's education had a weaker effect. The educational gradients as measured by the SII were generally steepest in Denmark, followed by Norway, Sweden, and Finland. From 1981 to 2000, the educational gradients in birthweight decreased in all countries, except Denmark where it increased. All countries experienced small decreases in the educational gradient in SGA over time. Conclusion: The economic recession in Denmark in the 1980s was concurrent with an increase in disparities in fetal growth, whereas the economic recession in Finland and Sweden in the early 1990s did not substantially increase the socioeconomic inequality in fetal growth. The economic growth in the later part of the 1990s may have diminished the socioeconomic inequality in fetal growth in Finland, Norway, and Sweden. [ABSTRACT FROM AUTHOR]

People are having children later in life. The consequences for offspring adult survival have been little studied due to the need for long follow-up linked to parental data and most research has considered offspring survival only in early life. We used Swedish registry data to examine all-cause and cause-specific adult mortality (293,470 deaths among 5,204,433 people, followed up to a maximum of 80 years old) in relation to parental age. For most common causes of death adult survival was improved in the offspring of older parents (HR for all-cause survival was 0.96 (95% CI: 0.96, 0.97) and 0.98 (0.97, 0.98) per five years of maternal and paternal age, respectively). The childhood environment provided by older parents may more than compensate for any physiological disadvantages. Within-family analyses suggested stronger benefits of advanced parental age. This emphasises the importance of secular trends; a parent's later children were born into a wealthier, healthier world. Sibling-comparison analyses can best assess individual family planning choices, but our results suggested a vulnerability to selection bias when there is extensive censoring. We consider the numerous causal and non-causal mechanisms which can link parental age and offspring survival, and the difficulty of separating them with currently available data.

Background: High body mass index (BMI) is associated with mortality, but the pervasive problem of confounding and reverse causality in observational studies limits inference about the direction and magnitude of causal effects. We aimed to obtain estimates of the causal association of BMI with all-cause and cause-specific mortality., Methods and Findings: In a record-linked, intergenerational prospective study from the general population of Sweden, we used two-sample instrumental variable (IV) analysis with data from 996,898 fathers (282,407 deaths) and 1,013,083 mothers (153,043 deaths) and their sons followed up from January 1, 1961, until December 31, 2004. Sons' BMI was used as the instrument for parents' BMI to compute hazard ratios (HRs) for risk of mortality per standard deviation (SD) higher parents' BMI. Using offspring exposure as an instrument for parents' exposure is unlikely to be affected by reverse causality (an important source of bias in this context) and reduces confounding. IV analyses supported causal associations between higher BMI and greater risk of all-cause mortality (HR [95% confidence interval (CI)] per SD higher fathers' BMI: 1.29 [1.26-1.31] and mothers' BMI: 1.39 [1.35-1.42]) and overall cancer mortality (HR per SD higher fathers' BMI: 1.20 [1.16-1.24] and mothers' BMI: 1.29 [1.24-1.34]), including 9 site-specific cancers in men (bladder, colorectum, gallbladder, kidney, liver, lung, lymphatic system, pancreas, and stomach) and 11 site-specific cancers in women (gallbladder, kidney, liver, lung, lymphatic system, ovaries, pancreas, stomach, uterus, cervix, and endometrium). There was evidence supporting causal associations between higher BMI in mothers and greater risk of mortality from kidney disease (HR: 2.17 [1.68-2.81]) and lower risk of mortality from suicide (HR: 0.77 [0.65-0.90]). In both sexes, there was evidence supporting causal associations between higher BMI and mortality from cardiovascular diseases (CVDs), stroke, diabetes, and respiratory diseases. We were unable to test the association between sons' and mothers' BMIs (as mothers' data were unavailable) or whether the instrument was independent of unmeasured or residual confounding; however, the associations between parents' mortality and sons' BMI were negligibly influenced by adjustment for available confounders., Conclusions: Consistent with previous large-scale meta-analyses and reviews, results supported the causal role of higher BMI in increasing the risk of several common causes of death, including cancers with increasing global incidence. We also found positive effects of BMI on mortality from respiratory disease, prostate cancer, and lung cancer, which has been inconsistently reported in the literature, suggesting that the causal role of higher BMI in mortality from these diseases may be underestimated. Furthermore, we expect different patterns of bias in the current observational and IV analyses; therefore, the similarities between our findings from both methods increases confidence in the results. These findings support efforts to understand the mechanisms underpinning these effects to inform targeted interventions and develop population-based strategies to reduce rising obesity levels for disease prevention., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: GDS is a member of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.

High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son's SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents' cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.

Previous reports suggest that offspring of mothers who smoke during pregnancy have greater risk of developing depression. However, it is unclear whether this is due to intrauterine effects. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) from the UK (N = 2,869), the Nord-Trøndelag health study (HUNT) from Norway (N = 15,493), the Pelotas 1982 Birth Cohort Study from Brazil (N = 2,626), and the Swedish Sibling Health Cohort (N = 258 sibling pairs), we compared associations of maternal smoking during pregnancy and mother's partner's smoking during pregnancy with offspring depression and performed a discordant sibling analysis. In meta-analysis, maternal smoking during pregnancy was associated with higher odds of offspring depression (OR 1.20, 95% CI:1.08,1.34), but mother's partner's smoking during pregnancy was not (OR 1.05, 95% CI:0.94,1.17). However, there was only weak statistical evidence that the odds ratios for maternal and mother's partner's smoking differed from each other (p = 0.08). There was no clear evidence for an association between maternal smoking during pregnancy and offspring depression in the sibling analysis. Findings do not provide strong support for a causal role of maternal smoking during pregnancy in offspring depression, rather observed associations may reflect residual confounding relating to characteristics of parents who smoke.

Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,(1) or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents' height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: To obtain valid estimates of the association between body mass index (BMI) and mortality by using offspring BMI as an instrumental variable for own BMI., Design: Cohort study based on record linkage, with 50 years of follow-up for mortality. Associations of offspring BMI with all cause and cause specific maternal and paternal mortality were estimated as hazard ratios per standard deviation of offspring BMI., Setting: A large intergenerational prospective population based database covering the general population of Sweden., Participants: More than one million Swedish parent-son pairs., Results: The final dataset analysed contained information on 1 018 012 mother-son pairs (122 677 maternal deaths) and 1 004 617 father-son pairs (242 126 paternal deaths). For some causes of death, the patterns of associations between offspring BMI and mortality were similar to those seen for own BMI and mortality in previous studies. Parental mortality from diabetes, coronary heart disease, and kidney cancer had the strongest positive associations with offspring BMI (for example, hazard ratio (HR) for coronary heart disease per standard deviation increase in offspring BMI for mothers 1.15, 95% CI 1.14 to 1.17 and for fathers 1.10, 1.09 to 1.11). However, in contrast to the inverse association of own BMI with lung cancer and respiratory disease mortality seen in other studies, there was a positive association between offspring BMI and lung cancer mortality in mothers (1.12, 1.09 to 1.15) and fathers (1.03, 1.02 to 1.05) and between offspring BMI and respiratory mortality in mothers (1.05, 1.02 to 1.08) and fathers (1.02, 1.00 to 1.04). Associations of own BMI and offspring BMI with all cause, cardiovascular disease related, and non-cardiovascular disease related mortality were compared in a subset of father-son pairs (n=72 815). When offspring BMI was used as an instrumental variable for paternal BMI, the causal association between BMI and paternal cardiovascular disease mortality (HR per standard deviation of BMI 1.82, 95% CI 1.17 to 2.83) was stronger than that indicated by the directly observed association between own BMI and cardiovascular disease mortality (1.45, 1.31 to 1.61)., Conclusions: Use of offspring BMI as a predictor of own BMI, a technique that avoids problems of reverse causality, suggests that positive associations of BMI with all cause and cardiovascular mortality may be underestimated in conventional observational studies. Use of offspring BMI instead of own BMI in analyses of respiratory disease and lung cancer mortality, for which previous studies have reported consistent and strong inverse associations with own BMI, suggests that such studies have overstated the apparent adverse consequences of lower BMI with respect to these outcomes.

Background: While several studies have reported an inverse relation between IQ and total mortality rates, little is known about the association, if any, between IQ and disease-specific outcomes, particularly cancer., Methods: A cohort of 959,540 Swedish men who underwent IQ testing at military conscription at around 19 years of age, and who were followed for incident cancer. Hazards ratios for the relation between IQ and 20 cancer outcomes were computed using Cox regression., Results: During an average of 19.5 years of follow-up, there were 10 273 new cancer cases. IQ showed few associations with the cancer end points studied. There was a suggestion that IQ was positively associated with lung cancer, and inversely related to stomach, oesophageal and liver malignancies, although effects were modest. The only robust gradient was found for IQ in relation to skin cancer (HRper one standard deviation advantage in IQ; 95% confidence interval 1.18; 1.13, 1.24; P value for trend across categories: <0.01), which was attenuated but retained statistical significance after adjustment for indices of socioeconomic position across the life course., Conclusions: In this large cohort of Swedish men followed into middle age, IQ was related to very few of the cancer outcomes under investigation. This indicates that the recent observation that low IQ is related to increased mortality rates may not be generated by an IQ-cancer gradient. Given that the present analyses are among the first to examine these associations, replication is required.

Previous studies have lacked sufficient power to assess associations between early-life socioeconomic position and adult cause-specific mortality. The authors examined associations of parental social class at age 0-16 years with mortality among 1,824,064 Swedes born in 1944-1960. Females and males from manual compared with nonmanual childhood social classes were more likely to die from smoking-related cancers, stomach cancer, respiratory disease, cardiovascular disease, and diabetes. Males from manual compared with nonmanual social classes were more likely to die from unintentional injury, homicide, and alcoholic cirrhosis. The association with stomach cancer was little affected by adjustment for parental later-life and own adult social class or education. For other outcomes, educational attainment resulted in greater attenuation of associations than did adjustment for adult social class. Early-life social class was not related to suicide or to melanoma, colon, breast, brain, or lymphatic cancers or to leukemia. With the exception of stomach cancer, caused by Helicobacter pylori infection acquired in childhood, poorer social class in early life was associated with diseases largely caused by behavioral risk factors such as smoking, physical inactivity, and an unhealthy diet. Educational attainment may be important in reducing the health inequalities associated with early-life disadvantage.

Objective: Previous studies have found associations between poor fetal and infant growth and the risk of suicide. The authors' goal was to investigate the association between height--a measure of childhood growth--and suicide risk., Method: The authors conducted a record linkage study of the birth, conscription, mortality, family, and census register data of 1,299,177 Swedish men followed from age 18 to a maximum of age 49., Results: There were 3,075 suicides over an average follow-up period of 15 years. There was a strong inverse association between height and suicide risk. In fully adjusted models, a 5-cm increase in height was associated with a 9% decrease in suicide risk., Conclusions: The strong inverse association between height and suicide may signify the importance of childhood exposure in the etiology of adult mental disorder or reflect stigmatization or discrimination encountered by short men in their adult lives.

Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.