Accelerated biological aging six decades after prenatal famine exposure.

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Infant and child mortality in the Netherlands 1935-47 and changes related to the Dutch famine of 1944-45: A population-based analysis.

Precise estimates of the impact of famine on infant and child mortality are rare due to lack of representative data. Using vital statistics reports on the Netherlands for 1935-47, we examine the impact of the Dutch famine (November 1944 to May 1945) on age-specific mortality risk and cause of death in four age groups (stillbirths, <1 year, 1-4, 5-14) in the three largest famine-affected cities and the remainder of the country. Mortality during the famine is compared with the pre-war period January 1935 to April 1940, the war period May 1940 to October 1944, and the post-war period June 1945 to December 1947. The famine's impact was most visible in infants because of the combined effects of a high absolute death rate and a threefold increase in proportional mortality, mostly from gastrointestinal conditions. These factors make infant mortality the most sensitive indicator of famine severity in this setting and a candidate marker for comparative use in future studies.

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Overweight and obesity at age 19 after pre-natal famine exposure.

BACKGROUND: Weight for height has been used in the past as an indicator of obesity to report that prenatal exposure to the Dutch famine of 1944-1945 determined subsequent obesity. Further evaluation is needed as unresolved questions remain about the possible impact of social class differences in fertility decline during the famine and because being overweight is now defined by a Body Mass Index (BMI: kg/m2) from 25 to <30 and obesity by a BMI of 30 or more. METHODS: We studied heights and weights of 371,100 men in the Netherlands born between 1943 and 1947 and examined for military service at age 19. This group includes men with and without prenatal exposure to the Dutch famine. RESULTS: There was a 1.3-fold increase in the risk of being overweight or obese in young adults at age 19 after prenatal famine exposure in early gestation. The increase was only seen in sons of manual workers born in the large cities of Western Netherlands and not among those born in smaller cities or rural areas in the West. Social class differentials in fertility decline during the famine did not bias study results. CONCLUSIONS: The long-term adverse impact of prenatal famine on later life type 2 diabetes and mortality through age 63 is already showing at age 19 in this population as a significant increase in overweight risk.

Impact of promoting healthy infant feeding practices on energy intake and anthropometric measures of children up to 6 years of age: A randomised controlled trial.

BACKGROUND: The first 2 years of life are the window of opportunity to promote healthy feeding practices. Thus, the present study aimed to assess the impact of a health workers training in infant dietary guidelines on energy intake and anthropometric measurement into childhood. METHODS: Cluster randomised field trial (NCT00635453) was conducted in Porto Alegre, Brazil. Healthcare centres were randomised into intervention (n = 9) and control (n = 11) groups. In intervention sites, health workers were trained to promote healthy feeding practices based on the Brazilian guideline for children's nutrition. Pregnant women who were in the last trimester of pregnancy were registered as potential mothers who would receive dietary counselling from the health workers. Energy and macronutrient intake and anthropometric measurements were obtained from children at ages 6 months, 12 months, 3 years and 6 years from low-income families. RESULTS: At age 3 years, intervention group had lower consumption of energy [-92.5 kcal; 95% confidence interval (CI) = -153.5 to -31.5], carbohydrates (-11.9 g; 95% CI = -19.9 to -2.3), and total fat (-3.9 g; 95% CI = -6.2 to -1.2), compared to the control group. At 6 years of age, children in the intervention group had lower waist circumference (-1.3 cm; 95% CI = -2.7 to -0.0), triceps (-1.3 mm; 95% CI = -2.5 to -0.0) and subscapular skinfolds (-1.3 mm; 16 95% CI = -2.6 to -0.0) thickness measurements compared to those in the control group. CONCLUSIONS: The health workers training to promote infant healthy feeding practices resulted in lower energy, carbohydrates and fat intake at 3 years and lower waist circumference, triceps and subscapular skinfolds measurements at 6 years.

Tea and coffee consumption in relation to DNA methylation in four European cohorts.

Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

Impact of disease screening on awareness and management of hypertension and diabetes between 2011 and 2015: results from the China health and retirement longitudinal study.

BACKGROUND: There has been a limited recognition of hypertension and diabetes in China which has compromised optimal treatment. It is not clear if a screening program implemented by a national health survey has improved awareness and management of these conditions. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) is an ongoing longitudinal health survey conducted since 2011 among Chinese people aged 45 years and older. Participants have been assessed every two years by interviews, physical examinations, and fasting glucose samples were taken in 2011. In 2013 and 2015, participants were asked about awareness and management of selected chronic diseases, and they first became aware of these conditions. RESULTS: Of the 11,000+ participants screened in 2011, 4594 were identified with hypertension and 1703 with diabetes by medical examinations. Over 80% of the middle-aged and elderly Chinese diagnosed with hypertension and/or diabetes in 2011 reported in 2015 that they were unaware of the disease(s). Although some improvement was observed between 2011 and 2015, the main reason for the increase in awareness was a medical examination initiated by the study participant (over 75%), by their work unit or community (12-15%), and rarely (less than 3%) by the CHARLS examination. Participants with a rural household registration status and lower BMI were the most likely to be unaware and to remain unaware of their condition(s). CONCLUSIONS: Disease screening in CHARLS did not lead to significant improvements in awareness of hypertension and diabetes. Improvements should be made by the systematic feedback of screening results to survey participants and the monitoring of disease awareness over time. This will be essential to improve disease recognition and facilitate optimal management.

Evaluating the Relationship Between Birth Weight for Gestational Age and Adult Blood Pressure Using Participants From a Cohort of Same-Sex Siblings, Discordant on Birth Weight Percentile.

Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005-2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex-specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04-mm Hg decrement in adult systolic BP (95% confidence interval (CI): -2.14, 0.06) and a 0.63-mm Hg decrement in diastolic BP (95% CI: -1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to -0.90 mm Hg (95% CI: -1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., -1.22 mm Hg (95% CI: -5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited.

Maternal and Early Childhood Determinants of Women's Body Size in Midlife: Overall Cohort and Sibling Analyses.

Observational evidence suggests that adult body size has its roots earlier in life, yet few life-course studies have data on siblings with which to control for family-level confounding. Using prospective data from the Early Determinants of Mammographic Density Study (n = 1,108; 1959-2008), we examined the association of maternal prepregnancy body mass index (BMI; weight (kg)/height (m)2), gestational weight gain (GWG), birth size, and childhood growth factors with adult BMI in daughters at midlife using quantile, linear, and logistic regression models. We compared overall cohort findings (n = 1,108) with sibling differences (n = 246 sibling sets). Results derived by all 3 regression methods supported positive and independent associations of prepregnancy BMI, GWG, and percentile change in early childhood growth with BMI in daughters at midlife. Sibling analyses demonstrated that higher GWG was independently related to a higher adult BMI in daughters, particularly for the highest 90th quantile of adult BMI (ß = 0.64 (standard error, 0.26) BMI units). Greater increases in weight percentiles between 1 and 4 years of age within siblings were also associated with higher adult BMI in the 75th quantile (ß = 0.06 (standard error, 0.03) kg). Thus, even after consideration of the role of family-level fixed effects, maternal GWG and childhood weight gain are associated with adult body size in midlife.

Early life socioeconomic environment and mammographic breast density.

BACKGROUND: Early life social environment may influence breast cancer through shaping risk factors operating in early life, adolescence and adulthood, or may be associated with breast cancer risk independent of known risk factors. We investigated the associations between early life socioeconomic status (SES) and mammographic density, a strong risk factor for breast cancer, and the extent to which these associations were independent of risk factors across the lifecourse. METHODS: We used data from an adult follow-up study of two U.S. birth cohorts of women (average age = 43 years) with prospectively collected data starting during the pregnancy of the mother and continuing through early childhood of the offspring. We collected data on factors in later life periods through computer-assisted interviews with the offspring as adults, and obtained routine clinical mammograms for measurement of percent density and dense and nondense breast areas using a computer assisted method. We used generalized estimating equation models for multivariable analysis to account for correlated data for sibling sets within the study sample (n = 700 composed of 441 individuals and 127 sibling sets). RESULTS: Highest vs. lowest family income level around the time of birth was associated with smaller dense breast area after adjustment for early life factors (e.g., birthweight, maternal smoking during pregnancy) and risk factors in later life periods, including adult body mass index (BMI) and adult SES (ß = -8.2 cm2, 95% confidence interval [CI]: -13.3, -3.2). Highest vs. lowest parental educational attainment was associated with higher percent density in models that adjusted for age at mammogram and adult BMI (e.g., ß = 4.8, 95% CI = 0.6, 9.1 for maternal education of college or higher degree vs. less than high school), but the association was attenuated and no longer statistically significant after further adjustment for early life factors. There were no associations between early life SES indicators and non-dense area after adjustment for adult BMI. Neither adult education nor adult income was statistically significantly associated with any measure of mammographic density after adjusting for age and adult BMI. CONCLUSIONS: We did not observe consistent associations between different measures of early life SES and mammographic density in adulthood.

Effect of maternal dietary counselling during the 1st year of life on glucose profile and insulin resistance at the age of 8 years: a randomised field trial.

Education interventions that stimulate complementary feeding practices can improve the nutritional status of children and may protect against future chronic diseases. We assessed the long-term effectiveness of dietary intervention during the 1st year of life on insulin resistance levels, and investigated the relationship between insulin resistance and weight changes over time. A randomised field trial was conducted among 500 mothers who gave birth to full-term infants between October 2001 and June 2002 in a low-income area in São Leopoldo, Brazil. Mother-child pairs were randomly assigned to intervention (n 200) and control groups (n 300), and the mothers in the intervention group received dietary counselling on breast-feeding and complementary feeding of their children during the 1st year of life. Fieldworkers blinded to assignment assessed socio-demographic, dietary and anthropometric data during follow-up at ages 1, 4 and 8 years. Blood tests were performed in 305 children aged 8 years to measure fasting serum glucose and insulin concentrations and the homoeostasis model assessment index of insulin resistance (HOMA-IR). At the age of 8 years, the intervention group showed no changes in glucose and insulin concentrations or HOMA-IR values (change 0·07; 95 % CI -0·06, 0·21 for girls; and change -0·07; 95 % CI -0·19, 0·04 for boys) compared with study controls. Insulin resistance was highly correlated, however, with increases in BMI between birth and 8 years of age. Although this dietary intervention had no impact on glucose profile at age 8 years, our findings suggest that BMI changes in early childhood can serve as an effective marker of insulin resistance.

War-related excess mortality in The Netherlands, 1944-45: New estimates of famine- and non-famine-related deaths from national death records.

Despite there being several estimates for famine-related deaths in the west of The Netherlands during the last stage of World War II, no such information exists for war-related excess mortality among the civilian population from other areas of the country. Previously unavailable data files from Statistics Netherlands allow researchers to estimate the number of war-related excess deaths during the last stage of the war in the whole country. This study uses a seasonal-adjusted mortality model combined with a difference-in-difference approach to estimate the number of excess deaths in the period between January 1944 and July 1945 at a total of close to 91,000 (75%) excess deaths. Almost half of all war-related excess mortality during the last year of the war occurred outside the west.

Can resource dilution explain differences in height by birth order and family size? A study of 389,287 male recruits in twentieth-century Netherlands.

'Resource dilution' has been invoked as a possible mechanism to explain the inverse relation between sibship size and sibling heights in European populations (Öberg, 2015). Alternative explanations include confounding of the relation by other measured or unmeasured family characteristics including socio-economic position or birth order. It is difficult to quantify the contribution of any factor in isolation. To examine the question, we accessed data from the national birth cohort of 389,287 Dutch conscripts born in 1944-1947 and examined for military service at age 18. The records include all men of Dutch nationality born between January 1, 1944 and December 31, 1947 examined for military service in the Netherlands. The birth cohorts provide a well-defined study population to reliably assess the impact of family size and birth order on adult height, accounting for potential confounders. The cohorts include a large number of high-parity families, provide reliable information on both family size and birth order, and differentiate between all birth orders. The military examinations provide reliable information on height for all study subjects and uniform measurements at age 18. We show that recruits from larger families are shorter than recruits from smaller families; that birth order effects are small in relation to family size effects; and that birth order and family size effects are comparable in recruits from higher to lower socio-economic backgrounds. Recruits from higher backgrounds are significantly taller however. Our findings are compatible with a 'resource dilution' hypothesis, but our data provide no information on any specific differences in the childhood environment in terms of nutrition, education, or other family behaviours could explain the observed height differences at age 18. Additional studies will be needed to identify what differences in specific family behaviours could lead to changes in height development.

Maternal weight gain in excess of pregnancy guidelines is related to daughters being overweight 40 years later.

BACKGROUND: Exceeding the Institute of Medicine guidelines for pregnancy weight gain increases childhood and adolescent obesity. However, it is unknown if these effects extend to midlife. OBJECTIVE: We sought to determine if exceeding the Institute of Medicine guidelines for pregnancy weight gain increases risk of overweight/obesity in daughters 40 years later. STUDY DESIGN: This cohort study is based on adult offspring in the Child Health and Development Studies and the Collaborative Perinatal Project pregnancy cohorts originally enrolled in the 1960s. In 2005 through 2008, 1035 daughters in their 40s were recruited to the Early Determinants of Mammographic Density study. We classified maternal pregnancy weight gain as greater than vs less than or equal to the 2009 clinical guidelines. We used logistic regression to compare the odds ratios of daughters being overweight/obese (body mass index [BMI] ≥25) at a mean age of 44 years between mothers who did not gain or gained more than pregnancy weight gain guidelines, accounting for maternal prepregnant BMI, and daughter body size at birth and childhood. We also examined potential family related confounding through a comparison of sisters using generalized estimating equations, clustered on sibling units and adjusted for maternal age and race. RESULTS: Mothers who exceeded guidelines for weight gain in pregnancy were more likely to have daughters who were overweight/obese in their 40s (odds ratio [OR], 3.4; 95% confidence interval {CI}, 2.0-5.7). This magnitude of association translates to a relative risk (RR) increase of 50% (RR = 1.5; 95% CI, 1.3-1.6). The association was of the same magnitude when examining only the siblings whose mother exceeded guidelines in 1 pregnancy and did not exceed the guidelines in the other pregnancy. The association was stronger with increasing maternal prepregnancy BMI (P trend < .001). Compared to mothers with BMI <25 who did not exceed guidelines, the relative risks (RR) for having an overweight/obese adult daughter were 1.3 (95% CI, 1.1-1.7), 1.7 (95% CI, 1.4-2.1) and 1.8 (95% CI, 1.5-2.1), respectively, if mothers exceeded guidelines and their prepregnancy BMI was <25, overweight (BMI 25-<30), or obese (BMI >30). This pattern held irrespective of daughters' weight status at birth, at age 4 years, or at age 20 years. CONCLUSION: Our findings support that obesity prevention before pregnancy and strategies to maintain weight gain during pregnancy within the IOM guidelines might reduce the risk of being overweight in midlife for the offspring.

Prenatal famine exposure and adult mortality from cancer, cardiovascular disease, and other causes through age 63 years.

Nutritional conditions in early life may affect adult health, but prior studies of mortality have been limited to small samples. We evaluated the relationship between pre-/perinatal famine exposure during the Dutch Hunger Winter of 1944-1945 and mortality through age 63 years among 41,096 men born in 1944-1947 and examined at age 18 years for universal military service in the Netherlands. Of these men, 22,952 had been born around the time of the Dutch famine in 6 affected cities; the remainder served as unexposed controls. Cox proportional hazards models were used to estimate hazard ratios for death from cancer, heart disease, other natural causes, and external causes. After 1,853,023 person-years of follow-up, we recorded 1,938 deaths from cancer, 1,040 from heart disease, 1,418 from other natural causes, and 523 from external causes. We found no increase in mortality from cancer or cardiovascular disease after prenatal famine exposure. However, there were increases in mortality from other natural causes (hazard ratio = 1.24, 95% confidence interval: 1.03, 1.49) and external causes (hazard ratio = 1.46, 95% confidence interval: 1.09, 1.97) after famine exposure in the first trimester of gestation. Further follow-up of the cohort is needed to provide more accurate risk estimates of mortality from specific causes of death after nutritional disturbances during gestation and very early life.

Severe prenatal shocks and adolescent health: Evidence from the Dutch Hunger Winter.

This paper investigates health impacts at the end of adolescence of prenatal exposure to multiple shocks, by exploiting the unique natural experiment of the Dutch Hunger Winter. At the end of World War II, a famine occurred abruptly in the Western Netherlands (November 1944-May 1945), pushing the previously and subsequently well-nourished Dutch population to the brink of starvation. We link high-quality military recruits data with objective health measurements for the cohorts born in the years surrounding WWII with newly digitised historical records on calories and nutrient composition of the war rations, daily temperature, and warfare deaths. Using difference-in-differences and triple differences research designs, we first show that the cohorts exposed to the Dutch Hunger Winter since early gestation have a higher Body Mass Index and an increased probability of being obese at age 18. We then find that this effect is partly moderated by warfare exposure and a reduction in energy-adjusted protein intake. Lastly, we account for selective mortality using a copula-based approach and newly-digitised data on survival rates, and find evidence of both selection and scarring effects. These results emphasise the complexity of the mechanisms at play in studying the consequences of early conditions.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

Background: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type-2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to provide a deeper insight into the metabolic changes associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and explore their link to disease. Methods: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. Results: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3x10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type-2 diabetes (r = 0.77, p = 3x10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1x10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2x10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. Conclusions: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study.

STUDY QUESTION: Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? SUMMARY ANSWER: No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. WHAT IS KNOWN ALREADY: Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. STUDY DESIGN, SIZE, DURATION: This cohort study included men and women born around the time of the Dutch famine of 1944-1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. MAIN RESULTS AND THE ROLE OF CHANCE: Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the NHLBI/NIH (R01 HL-067914). TRIAL REGISTRATION NUMBER: Not applicable.

A re-analysis of the long-term effects on life expectancy of the Great Finnish Famine of 1866-68.

The results of studies exploring the long-term consequences of famine during foetal or infant development are inconsistent. We tested the hypothesis that selection forces occurring during a famine change the distribution of frailty in the affected cohorts, possibly hiding negative long-term effects. Using mortality data for Finland, gathered from the Human Mortality Database, we explored the effect of being born during the Great Finnish Famine of 1866-68 by comparing mortality at age 60 and over for the 1850-89 births, taking into account unobserved cohort heterogeneity. Contemporaneous Swedish cohorts, unexposed to the famine, were used as an additional control group. When cohort heterogeneity is accounted for, a lower life expectancy at age 60 for male cohorts in Finland born during the famine is observed. The results for females are less conclusive. No substantial changes are seen in the Swedish cohorts. In order to provide consistent estimates of the long-run effects of famines, selection forces need to be considered.