Multigenerational Effects of Early-Life Health Shocks.

A large literature has documented links between harmful early-life exposures and later-life health and socioeconomic deficits. These studies, however, have typically been unable to examine the possibility that these shocks are transmitted to the next generation. Our study uses representative survey data from the United States to trace the impacts of in utero exposure to the 1918 influenza pandemic on the outcomes of the children and grandchildren of those affected. We find evidence of multigenerational effects on educational, economic, and health outcomes.

Adult body height as a mediator between early-life conditions and socio-economic status: the case of the Dutch Potato Famine, 1846-1847.

Adult body height appears to be a relatively accurate summary variable of early-life exposures' influence on health, and may be a useful indicator of health in populations where more traditional health-related indicators are lacking. In particular, previous studies have shown a strong, positive relationship between environmental conditions in early life (particularly nutritional availability and the disease environment) and adult height. Research has also demonstrated positive associations between height and socioeconomic status. We therefore hypothesize that height mediates the relationship between early-life conditions and later-life socio-economic outcomes. We also hypothesize that the period of exposure in early life matters, and that conditions during pregnancy or the first years of life and/or the years during puberty have the largest effects on height and socio-economic status. To test these relationships, we use a sample of 1817 Dutch military conscripts who were exposed during early life to the Dutch Potato Famine (1846-1847). We conduct mediation analyses using structural equation modelling, and test seven different time periods in early-life. We use potato prices and real wages to proxy early-life environmental conditions, and occupational status (using the HISCAM scale) to proxy socioeconomic status. We find no evidence of mediation, partial or full, in any models. However, there are significant relationships between potato prices in adolescence, height and socio-economic status. To determine causality in these relationships, further research is needed.

Sun Smoke in Sweden: Perinatal Implications of the Laki Volcanic Eruptions, 1783-1784.

BACKGROUND: The Icelandic volcano Laki erupted from June 1783 through January 1784. It produced 122 megatons of sulfur dioxide, particulate matter, and acid rain and contributed to one of the coldest winters on record in Western Europe. Although uncontrollable volcanic eruptions continue, few studies have investigated their perinatal health implications. METHODS: Using the Human Mortality Database, we assessed the association between the Laki event and the secondary sex ratio, infant mortality rates, and the number of births from 1751 to 1800 with time-series models that controlled for temporal trends. RESULTS: The secondary sex ratio decreased 3% below expected levels in 1784 (95% CI = -4%, -1%). Both female and male infant mortality rates exceeded expectation in 1785, by 54% (95% CI = 25%, 83%) and 37% (-1%, 74%), respectively. We observed little change in female live births but a reduction in male live births in 1784. CONCLUSIONS: Our findings are consistent with the hypothesis that the large-scale Laki volcanic eruptions of 1783-1784 resulted in adverse perinatal health outcomes in Sweden.

A Brief History of Awareness of the Link Between Alcohol and Fetal Alcohol Spectrum Disorder.

OBJECTIVE: Fetal alcohol spectrum disorder (FASD) is a medical term used to describe a range of mental and physical disabilities caused by maternal alcohol consumption. The role of alcohol as a teratogen and its effects on the cellular growth of the embryo and the fetus were not determined on scientific grounds until the late 1960s. However, the link between alcohol use during pregnancy and its harms to offspring might have been observed frequently over the many thousands of years during which alcohol has been available and used for social and other reasons. METHODS AND RESULTS: Using sources ranging from the biblical Book of Judges (pre-1700) up until the first public health bulletin (1977), we seek to provide an overview of the academic debate around early historical accounts ostensibly attributed to the awareness of alcohol as a prenatal teratogen as well as to describe the social and political influences that sculpted developments leading to the public recognition of FASD. CONCLUSIONS: Our analysis provides a brief overview of the discourse regarding historical awareness of the detrimental effects of prenatal alcohol exposure on fetal development leading to the formal recognition of FASD as a distinct clinical entity. Further research will be required to fully appreciate the scientific, medical, and societal ills associated with prenatal alcohol exposure.

The long-run effects of pandemic influenza on the development of children from elite backgrounds: Evidence from industrializing Japan.

This study estimates the lingering effects of fetal exposure to the 1918 influenza pandemic on the development of secondary school and girls' high school students in industrializing Japan. In order to refine the verification of the fetal origins hypothesis, we tried not only to focus on children from elite schools but also to construct the continuous influenza mortality measure using monthly variations in the number of births and influenza deaths. By utilizing a nationwide multidimensional physical examination dataset, we found that fetal exposure to influenza in the pandemic years reduced the heights of boys and girls by approximately 0.3 cm and 0.1 cm, respectively. While the strongest negative magnitude was observed in the pandemic period, the lingering relapses in the post-pandemic period still had considerable adverse effects on height. In relation to the lowest decile group which experienced normal influenza mortality in non-pandemic years, the heights of the boys and girls who experienced pandemic influenza in the womb are approximately 0.6 and 0.3 cm lower. The lingering influenza relapse in the post-pandemic period has an adverse effect on the boys' height, accounting for roughly 80% of the maximum pandemic effect.

The effects of in utero exposure to the 1918 influenza pandemic on family formation.

A growing literature ties in utero conditions to life course outcomes, including education, earnings, and adult health and mortality. A smaller literature has begun to examine the intergenerational impacts of in utero conditions. A link between these two literatures-the impacts of in utero conditions on family formation-has had few examinations but offers a potential set of mechanisms for the intergenerational reach of early conditions. This paper draws from the 1960 US Decennial Census to examine whether individuals exposed in utero to the 1918/19 influenza pandemic had different family formation patterns than adjacent unexposed cohorts. The findings suggest small overall effects on marriage rates, number of children, and several measures of "type" of spouse for men, but moderate effects for women. For example, women with in utero exposure during their first trimester marry men with 0.2 fewer years of schooling than those not exposed. The findings show that exposed individuals have spouses with lower schooling than unexposed counterparts, this effect is particularly large for women, and it increases the likelihood of marrying spouses with very low levels of schooling.

Scurvy at the agricultural transition in the Atacama desert (ca 3600-3200 BP): nutritional stress at the maternal-foetal interface?

Studies of contemporary populations have demonstrated an association between decreased dietary diversity due to resource scarcity or underutilization and an increase in diseases related to poor micronutrient intake. With a reduction of dietary diversity, it is often the women and children in a population who are the first to suffer the effects of poor micronutrient status. Scurvy, a disease of prolonged vitamin C deficiency, is a micronutrient malnutrition disorder associated with resource scarcity, low dietary diversity, and/or dependence on high carbohydrate staple-foods. The aim of this paper is to assess the potential impact of nutritional transition on the prevalence of diseases of nutritional insufficiency in an archaeological sample. Here, we report palaeopathological findings from an Early Formative Period transitional site located in coastal Northern Chile (Quiani-7). The subadult cohort from this site is composed of four perinates who exhibit a number of non-specific skeletal changes suggestive of a systemic pathological condition. One of these is associated with an adult female exhibiting diagnostic skeletal lesions of scurvy. We argue that the lesions exhibited by these perinates may represent maternal transmission of vitamin C deficiency but acknowledge that there are difficulties in applying current diagnostic criteria for scurvy to individuals this young.

Neurological disease or intellectual disability among sons of female Swedish dental personnel.

OBJECTIVE: Prenatal exposure to elemental mercury may be a potential hazard for the offspring of female dental personnel working with dental amalgam. The aim of this study was to investigate whether potential in utero exposure to mercury might have affected the development of nervous system of the sons of Swedish female dental personnel leading to an increased risk of neurological disease or intellectual disability. MATERIAL AND METHODS: We used national Swedish registers to investigate risks for diseases potentially related to adverse effects on neurodevelopment. Sons of female dentists (n=1690) and dental nurses (n=10,420) were compared with cohorts consisting of sons of other female healthcare personnel. Due to changes in mercury exposure in dentistry during the study period, analyses were stratified by decade of birth. Hazard ratios (HRs) were calculated using Cox proportional hazard models. RESULTS: We found no elevated risk for neurological disease, epilepsy or intellectual disability among the sons of dental personnel during any of the decades studied. HRs for neurological disease among the dental nurse cohort were even below 1.00 during the 1970s and 1980s. A low number of events resulted in uncertainty regarding results in the dentist cohort. CONCLUSIONS: We did not find any support for the hypothesis that mercury exposure in Swedish dentistry during the 1960s, 1970s or 1980s had any effect on the incidence of neurological disease or intellectual disability among the sons of female dental personnel. Our results imply that current use of dental amalgam should not represent an elevated risk for neurological disease or intellectual disability among the offspring of dental personnel.

The history of Distilbène® (Diethylstilbestrol) told to grandchildren--the transgenerational effect.

The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications.

Does in utero exposure to Illness matter? The 1918 influenza epidemic in Taiwan as a natural experiment.

This paper tests whether in utero conditions affect long-run developmental outcomes using the 1918 influenza pandemic in Taiwan as a natural experiment. Combining several historical and current datasets, we find that cohorts in utero during the pandemic are shorter as children/adolescents and less educated compared to other birth cohorts. We also find that they are more likely to have serious health problems including kidney disease, circulatory and respiratory problems, and diabetes in old age. Despite possible positive selection on health outcomes due to high infant mortality rates during this period (18%), our paper finds a strong negative impact of in utero exposure to influenza.

Mortality among sons of female dental personnel--a national cohort study.

AIMS: Dental personnel are exposed to mercury when using dental amalgam. This exposure constitutes a potential hazard to offspring of women working in dentistry. The present study examined increased mortality risk in offspring of mothers working in dentistry. METHODS: Mortality was compared between sons of dental personnel and sons of nondental health-care personnel. Hazard ratios were calculated for three decades (1960s-1980s), when the magnitude of mercury exposure in dentistry was likely to have varied. RESULTS: During the 1960s, there was a statistically significant increase in the risk of neonatal mortality for sons of dental nurses when compared with sons of assistant nurses: hazard ratio (HR) 1.82 (95% confidence interval, CI: 1.04-3.22). There was no increased risk in the subsequent decades, but a trend test demonstrated a consistent decrease in the risk over the three decades: HR for trend 0.63 (95% CI: 0.44-0.90). The raised mortality risk was limited to neonatal mortality. The comparison between dentists and physicians had insufficient statistical power. CONCLUSIONS: There is no increased mortality risk among sons of female dentists after the 1960s. Although the results should be interpreted with caution, they suggest a modestly raised risk of neonatal mortality, during the 1960s, when exposure to mercury was thought to be highest.

Identifying the intergenerational effects of the 1959-1961 Chinese Great Leap Forward Famine on infant mortality.

Using the 1959-1961 Chinese Great Leap Forward Famine as a natural experiment, this study examines the relationship between mothers' prenatal exposure to acute malnutrition and their children's infant mortality risk. According to the results, the effect of mothers' prenatal famine exposure status on children's infant mortality risk depends on the level of famine severity. In regions of low famine severity, mothers' prenatal famine exposure significantly reduces children's infant mortality, whereas in regions of high famine severity, such prenatal exposure increases children's infant mortality although the effect is not statistically significant. Such a curvilinear relationship between mothers' prenatal malnutrition status and their children's infant mortality risk is more complicated than the linear relationship predicted by the original fetal origins hypothesis but is consistent with the more recent developmental origins of health and disease theory.

Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine.

OBJECTIVE: We previously showed that maternal under-nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren. DESIGN: Historical cohort study. SETTING: Web-based questionnaire. POPULATION: The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944-45 Dutch famine. METHODS: We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire. MAIN OUTCOME MEASURES: Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure. RESULTS: Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m(2), P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups. CONCLUSIONS: Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under-nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future.

Hungry in the womb: what are the consequences? Lessons from the Dutch famine.

An increasing body of evidence suggests that poor nutrition at the very beginning of life - even before birth - leads to large and long term negative consequences for both mental and physical health. This paper reviews the evidence from studies on the Dutch famine, which investigated the effects of prenatal undernutrition on later health. The effects of famine appeared to depend on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable period. People who were conceived during the famine were at increased risk of schizophrenia and depression, they had a more atherogenic plasma lipid profile, were more responsive to stress and had a doubled rate of coronary heart disease. Also, they performed worse on cognitive tasks which may be a sign of accelerated ageing. People exposed during any period of gestation had more type 2 diabetes. Future investigation will expand on the finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms. Recent evidence suggests that similar effects of prenatal undernutrition are found in Africa, where many are undernourished. Hunger is a major problem worldwide with one in seven inhabitants of this planet suffering from lack of food. Adequately feeding women before and during pregnancy may be a promising strategy in preventing chronic diseases worldwide.

The 2D:4D digit ratio is not a useful marker for prenatal famine exposure: Evidence from the Dutch hunger winter families study.

OBJECTIVES: Digit lengths, and in particular the ratio of the 2nd (2D) to 4th (4D) digit (2D:4D), are stable in adulthood and have been linked to characteristics thought to have developmental origins, but little research has focused on early life determinants of these measures. We examined whether exposure to acute famine during specific periods of gestation was associated with 2D, 4D or the 2D:4D ratio. METHODS: We studied men and women (1) born in one of three hospitals in western Netherlands whose mothers were exposed to a limited period of famine immediately prior to or during the pregnancy (n = 337); (2) born in the same hospitals to mothers not exposed to famine during the pregnancy (n = 271) or same-sex siblings of individuals in Groups 1 and 2 (n = 295). We measured 2D and 4D on both hands using calipers and computed the 2D:4D ratio. RESULTS: Mean 2D and 4D lengths were 73.5 (SD 5.1) and 75.0 (5.4) mm, respectively. The 2D:4D ratio was 0.981 (SD 0.030). Both 2D and 4D were associated with male gender and height (all P < 0.001), and weakly with BMI. The 2D:4D ratio was 0.0070 (95% confidence interval 0.0017, 0.0123) lower among males as compared with females, and was not significantly associated with height (0.0002 per cm; 95% -0.0001, 0.0005). The 2D:4D ratio was not significantly associated with exposure to famine, overall (-0.0010, 95% CI 0.0030, 0.0050) or within any period of gestation. CONCLUSIONS: The 2D:4D ratio is not significantly affected by prenatal exposure to famine and therefore is not a useful marker for generalized prenatal undernutrition.

Testing the Fetal Origins Hypothesis in a developing country: evidence from the 1918 Influenza Pandemic.

The 1918 Influenza Pandemic is used as a natural experiment to test the Fetal Origins Hypothesis. This hypothesis states that individual health as well as socioeconomic outcomes, such as educational attainment, employment status, and wages, are affected by the health of that individual while in utero. Repeated cross sections from the Pesquisa Mensal de Emprego (PME), a labor market survey from Brazil, are used to test this hypothesis. I find evidence to support the Fetal Origins Hypothesis. In particular, compared to individuals born in the few years surrounding the Influenza Pandemic, those who were in utero during the pandemic are less likely to be college educated, be employed, have formal employment, or know how to read and have fewer years of schooling and a lower hourly wage. These results underscore the importance of fetal health especially in developing countries.