Fetal Origins Hypothesis Research Articles

EARLY-LIFE EXPOSURE TO THE CHINESE FAMINE OF 1959–1961 AND LATER-LIFE HEALTH: EARLY LIFE AS A CRITICAL PERIOD

Abstract Barker’s fetal origins hypothesis and the critical period theory suggest that early life events have long-term health effects. However, evidence of the famine exposure in early life and its effects on health in later life is scarce and inconsistent. To explore the effects of early-life exposure to the Chinese famine of 1959-1961 on later-life multimorbidity, we performed Poisson growth curve models using CHARLS Life History 2014 and CHARLS 2011-2018 (42,775 observations from 12,060 respondents). Our analyses revealed two findings. First, there was an overall detrimental effect of the early-life famine exposure on multimorbidity, although there was no effect of severity of famine exposure. Second, there was no overall interaction between famine exposure and life stages, although a more parsimonious model suggested that the detrimental effect of famine exposure was more pronounced in earlier life stages than in later life stages. Findings suggest that early life is a critical period in the life course and provides developmental origins of health and disease in later life.

Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality

BackgroundPrevious studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown.MethodsUsing summary statistics of birthweight and breast cancer, we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer.ResultsWith summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg = 0.123 and P = 0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg = − 0.068, P = 0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis.ConclusionThis study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.

Long-term impacts of the 1970 cyclone in Bangladesh

We use childhood exposures to disasters as natural experiments inducing variations in adulthood outcomes. Following the fetal origin hypothesis, we hypothesize that children from households with greater exposure will have poorer health, schooling, and consumption outcomes. Employing a unique dataset from Bangladesh, we test this hypothesis for the 1970 cyclone that killed over 300,000 people in southern Bangladesh. We find that children surviving the cyclone experience significant health, schooling and consumption adversities, and during their adulthood, have lower probabilities of good health and primary schooling; and lower durations of good health, schooling and consumption. Such adversities are further heightened among the rural and less-educated households. Therefore, public programs benefiting the females and the poor, alongside the development of healthcare and schooling infrastructure, can be useful protective measures against the long-term harms of a disaster.

Season of Birth and Cardiovascular Mortality in Atrial Fibrillation: A Population-Based Cohort Study.

Background: The fetal origins hypothesis have associated early life exposures with the development of adverse health outcomes in adulthood. Season of birth has been shown to be associated with overall and cardiovascular mortality. Methods: We performed a retrospective database study to explore the association between season of birth and mortality in patients with atrial fibrillation. Results: A total of 8962 patients with AF were identified in the database with 1253 deaths recorded. AF patients born in spring and summer had a higher mortality rate when compared to those born in autumn and winter (hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.01–1.26, p = 0.03). This effect was consistent in the male subgroup (HR 1.25, 95% CI 1.03–1.51, p = 0.02 for males born in spring; HR 1.24, 95% CI 1.03–1.51, p = 0.03 for males born in summer when compared to winter as the reference) but not in females (HR 1.02, 95% CI 0.79–1.31, p = 0.88 for females born in spring; HR 1.11, 95% CI 0.87–1.42, p = 0.39 for females born in summer when compared to winter as the reference). Results persisted after adjustment for baseline characteristics and clinical risk profile. A similar pattern was observed with cardiovascular mortality. Conclusion: Birth in spring or summer is associated with a higher risk of cardiovascular mortality in male AF patients, but not in females. This could be related to the underlying differences in rates of major adverse clinical events between genders. Further studies should aim at clarifying the mechanisms behind this association, which may help us understand the higher level of risk in female patients with AF.

24.6 EVALUATING THE GENOMIC CONTRIBUTION TO THE FETAL ORIGINS OF MENTAL HEALTH: A TEST USING POLYGENIC RISK SCORES

The fetal origins hypothesis, which emphasizes adaptations to in utero exposures with long-term implications for brain and behavior, has emerged as a leading conceptual model for mental health research. One potentially major factor that has not been given significant attention in existing studies is child genomic risk for mental health disorders, which may confound or modify the association between prenatal exposures and child mental health. We capitalize on recent advances in population genetics, specifically polygenic risk scores, to test if child polygenic risk for major mental health disorders confounds or modifies the relationship between maternal antenatal depression and child psychopathology. The Avon Longitudinal Study of Parents and Children (ALSPAC) provided measures of maternal antenatal mood and child mental health data from 4 to 16 years of age. We used polygenic risk scores to derive measures of child genomic risk for ADHD, schizophrenia, and depression. Child outcomes included internalizing, externalizing, and total emotional/behavioral difficulties from childhood to midadolescence. Our primary analysis focuses on longitudinal symptom data from the ALSPAC cohort (n = 5237) with secondary analyses in an independent cohort of children from the PREDO (Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction) cohort (n = 514). There was a robust prediction of child and adolescent mental health from maternal antenatal depression, or maternal anxiety, independent of child polygenic risk for ADHD, schizophrenia, or depression; there were similar independent effects of maternal depression on child mental health in an independent cohort. These findings provide the most direct test to date of the genomic contribution to the fetal origins of mental health hypothesis and indicate a modest influence of polygenic risk scores on the emergence of symptoms from early childhood through adolescence. Our findings further underscore the potential value of investing in mental health supports in pregnancy for the benefit of both mother and child.

What doesn’t kill her, will make her depressed

In this paper we study the long run effects of the 1959–61 Chinese Famine on mental health outcomes. We focus on cohorts that were born during the famine and examine their mental health as adults, when they are roughly 55 years of age. We find that early-life exposure to this famine leads to a large statistically significant negative impact on women’s mental health, while there is limited effect on men. This gender differential effect is observed because male fetuses experience a stronger natural selection as compared to female fetuses, which implies that in the longer run, surviving females may exhibit larger detrimental effects of early-life famine exposure. Thus, the observed effects are a composite of two well-established factors, the survival of the fittest and the Fetal Origins hypothesis.

Season of birth and cardiovascular mortality in atrial fibrillation: a population-based cohort study

Abstract Funding Acknowledgements Type of funding sources: None. Background. Month and season of birth may be indicators for a variety of prenatal and early postnatal exposures and they have been associated with life expectancy in adulthood. It is suggested that people born in the autumn on the northern hemisphere live longer than those born during the spring or summer, who may have an increase in cardiovascular disease specific mortality. Only few studies have followed populations longitudinally and no study has investigated the relation between season of birth and mortality in patients with established cardiac conditions. Methods. All patients with atrial fibrillation (AF) seen in an academic institution were identified in a database. We examined the clinical course of 8962 consecutive patients with AF seen over a 10-year period. The adverse outcomes were investigated during follow-up and we identified the causes of death. The relation between season of birth (autumn, winter, spring and summer) and mortality risk was assessed using Cox proportional hazard regression models using autumn as the reference. Analyses were also made separately for men and women. Results. In these 8962 patients (age 70 ± 10 years, CHA2DS2VASc score 3.1 ± 1.7), 1253 deaths were recorded during a follow-up of 2.5 ± 3.0 years (median 1.2, interquartile 4.3 years, yearly rate of death 5.5%) and 97% of causes of death were identified. Cardiovascular deaths accounted for 54% and 43% for non-cardiovascular. The three main causes of death were heart failure (29%), infection (18%) and cancer (12%). Season of birth was a significant predictor of cardiovascular mortality (overall p = 0.0006). The lowest mortality was seen for people born in autumn or winter and the highest mortality in those born in spring and summer. This was mainly related to a higher cardiovascular mortality in males (hazard ratio [HR] 1.46, 95%CI 1.10-1.93, p = 0.009 for males born in spring and HR 1.44, 95%CI 1.08-1.91, p = 0.01 for those born in summer when compared to males born in autumn as the reference) while this effect was not seen in women. In a model adjusted for age, CHA2DS2VASc score, HASBLED score, cardiovascular risk factors, other comorbidities, AF pattern, antithrombotic use and other cardiovascular drugs use, a higher cardiovascular mortality was still seen in males born in spring (adjusted HR 1.43, 95%CI 1.05-1.96, p = 0.03) or in summer (adjusted HR 1.46, 95%CI 1.07-1.99, p = 0.02) when compared to those born in autumn while this was not seen in women. Conclusion. Birth in spring or summer is associated with a higher risk of cardiovascular mortality in male AF patients. Further studies should aim at clarifying the mechanisms behind this association, which would support the so-called fetal origins hypothesis.

Health Disturbances of Negative Nutritional Shocks

The Fetal Origin Hypothesis show that the prenatal development period is a critical period for birth outcomes. Applying a panel data fixed effect model and using the universe of birth records in the US, I find that exposure to the holy month Ramadan, during which Muslim mothers fast for the whole day, during prenatal development has negative birth outcomes. Exposure to a full month of fasting is associated with 96 grams lower birth-weight. These results are robust across specifications and do not appear to be driven by mothers’ selective fertility.

Fetal origins-A life cycle model of health and aging from conception to death.

The fetal origins hypothesis suggests that health and nutrition shocks in utero are causally related to health deficits in old age. It has received considerable empirical support, both within epidemiology and economics but so far it has not been integrated into a life cycle theory of human aging and longevity. The present study shows that the health deficit model, based on the frailty index developed in gerontology, generates shock amplification consistent with the hypothesis. In order to discuss human health over the life cycle from conception to death, we develop a theory of ontogenetic growth and health in utero and during childhood, unify it with the health deficit model of adult aging, and discuss the transmission of early-life shocks to late-life health deficit accumulation.

Spatial Health Inequality and Regional Disparities

Geography and the quality of the environment may have long lasting effects on the living standards of individuals and this, in its turn, may affect even substantially the distribution of income and regional disparities. In this paper I consider malaria as a measure of “bad geography” and propose some evidence showing that it was a major determinant of the health of individuals (as measured by the height of conscripts) and its disparities between individuals and regions in Italy. In particular, to estimate the relationship between malaria exposure and height, I rely on the “fetal origins hypothesis”, that is I hypothesize that exposure to malaria in utero or during childhood has persistent effects on health. Periods under scrutiny in this paper are the last two decades of the XIX century, a period without major public health interventions, and the years around the eradication era in the 1950s. My results support the hypothesis that geographically targeted policies may reduce health inequality between regions and within regions.

Preconceptional and prenatal exposure to air pollution increases incidence of childhood pneumonia: A hypothesis of the (pre-)fetal origin of childhood pneumonia

BackgroundIncreasing evidence has linked childhood pneumonia with early exposure to ambient air pollution. However, the impact of exposure to air pollutants before birth is unclear. ObjectiveTo further clarify whether exposure to a particular pollutant during preconceptional and prenatal periods, may pose a higher risk of developing childhood pneumonia. MethodsThis case-control cohort study consisted of 1510 children aged 0–14 years in Changsha, China between 2017 and 2019. Data of children's history of pneumonia and blood biomarkers were obtained from the XiangYa Hospital records. Each child's exposure to air pollutants, including nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter with an aerodynamic diameter ≤ 10 µm (PM10), was calculated using data from ten air pollution monitoring stations. A multivariate logistic regression model was used to quantify the relationship between childhood pneumonia and exposure to ambient air pollution during the preconceptional and prenatal periods. ResultsChildhood pneumonia was significantly associated with preconceptional and prenatal exposure to the industrial-related air pollutant, SO2, for 1 year before conception, for 3 months before conception and for the entire pregnancy, with ORs(95% CI)= 4.01(3.17–5.07), 4.06(3.29–5.00) and 6.51(4.82–8.79). Also, children who were sick with pneumonia had higher white blood cell and neutrophil counts, and children with low eosinophil count or hemoglobin are likely to get pneumonia. Sensitivity analysis showed that boys, and children in high temperature area were susceptible to the effect of both preconceptional and prenatal exposure to industrial SO2. ConclusionPreconceptional and prenatal exposure to industrial-related air pollution plays a significant role in the incidence and progression of childhood pneumonia, supporting the hypothesis of “(pre-)fetal origin of childhood pneumonia”.

Fetal Origins – A Life Cycle Model of Health and Aging from Conception to Death

The fetal origins hypothesis has received considerable empirical support, both within epidemiology and economics. The present study compares the ability of two rival theoretical frameworks in accounting for the kind of path dependence implied by the fetal origins hypothesis. We argue that while the conventional health capital model is irreconcilable with fetal origins of late-in-life health outcomes, the more recent health deficit model can generate shock amplification consistent with the hypothesis. In order to discuss human health over the life cycle from conception to death, we develop a theory of ontogenetic growth in utero and during childhood, unify it with the theory of adult aging, and discuss the transmission of early-life shocks to late-life health deficit accumulation.

Developmental origins of accelerated cardiovascular aging

The Barker hypothesis of fetal origins of disease, derived from observational epidemiological studies, has been modified by the realization that the early influences on cardiovascular development may be recognized in the fetus. Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. Preeclampsia (PE) is the utmost variant of placental insufficiency and is associated with an increase of serum concentrations of inflammation and antiangiogenic agents in mother and fetus. All these factors are specific for the endothelial dysfunction and able to trigger the epigenetic programming of cardiovascular diseases and accelerated aging. The concentrations of cytokines, tumor necrosis factor, C-reactive protein, NO metabolites, endothelin-1 and homocysteine were measured in serum of women with a normal pregnancy (n=27), PE (n=30) and their newborn infants. The concentrations of all these factors were higher in serum of women and newborns of PE group than in serum of women and newborns of the normal group. The significantly positive correlation between factors concentrations in maternal and newborn’s serum was demonstrated in all groups. We suggest the common source of these agents to be the syncytiotrophoblast cells contacting with both maternal and fetal blood and play a significant role in intrauterine programming and epigenetic triggering of accelerated cardiovascular aging.

Comparative study of cord blood lipid profile in preterm and post term neonates

Background: The fetal-origin hypothesis and fetal programming emphasize the profound and sustained impact of factors related to fetal health on the development of chronic disease in adulthood. Several studies suggested that low birth weight and preterm birth linked to abnormalities in cord lipid profile and higher prevalence of atherosclerotic cardiovascular disease. Authors objectives was to estimate and compare cord lipid profile in term, pre-term, and post-term neonates.Methods: In the study group, there were 200 healthy Polish newborns. Newborn characteristics included sex, gestational age at birth, Apgar score, and anthropometric data (weight and length at birth, neonatal ponderal index, head, chest and abdominal circumferences, placental weight, and placental-fetal weight ratio). Cord blood samples were collected for total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG). Information regarding selected maternal factors was collected. Neonates were classified into preterm (<37 weeks) and term (≥37 weeks) based on new Ballard scoring.Results: The preterm had higher Total cholesterol compared to Term and post term and it was Statistically Significant with a p value of < 0.001. The preterm had higher Triglycerides compared to term and post term and it was statistically significant with a p value of <0.01. The preterm had higher HDL compared to Term and post term and it was statistically significant with a p value of <0.001. The preterm had higher LDL compared to Term and post term it was statistically significant with a p value of <0.001. The preterm had higher VLDL compared to Term and post term and it was statistically significant with a p value of <0.01.Conclusions: Abnormal intrauterine milieu created by maternal changes during gestation may bear a profound impact on lipid metabolism in neonates, which may account for their differences in lipid profile and anthropometry at birth.

Hormonal Biomarkers for Evaluating the Impact of Fetal Growth Restriction on the Development of Chronic Adult Disease.

The hypothesis of fetal origins to adult diseases proposes that metabolic chronic disorders, including cardiovascular diseases, diabetes, and hypertension originate in the developmental plasticity due to intrauterine insults. These processes involve an adaptative response by the fetus to changes in the environmental signals, which can promote the reset of hormones and of the metabolism to establish a "thrifty phenotype". Metabolic alterations during intrauterine growth restriction can modify the fetal programming. The present nonsystematic review intended to summarize historical and current references that indicated that developmental origins of health and disease (DOHaD) occur as a consequence of altered maternal and fetal metabolic pathways. The purpose is to highlight the potential implications of growth factors and adipokines in "developmental programming", which could interfere in the development by controlling fetal growth patterns. These changes affect the structure and the functional capacity of various organs, including the brain, the kidneys, and the pancreas. These investigations may improve the approach to optimizing antenatal as well as perinatal care aimed to protect newborns against long-term chronic diseases.

Developmental Origins of Health Inequality

Building on early animal studies, 20th-century researchers increasingly explored the fact that early events – ranging from conception to childhood – affect a child’s health trajectory in the long-term. By the 21st century, a wide body of research had emerged, incorporating the original ‘Fetal Origins Hypothesis’ into the ‘Developmental Origins of Health and Disease’. Evidence from OECD countries suggests that health inequalities are strongly correlated with many dimensions of socio-economic status, such as educational attainment; and that they tend to increase with age and carry stark intergenerational implications. Different economic theories have been developed to rationalize this evidence, with an overarching comprehensive framework still lacking. Existing models widely rely on human capital theory, which has given rise to separate dynamic models of adult and child health capital, within a production function framework. A large body of empirical evidence has also found support for the developmental origins of inequalities in health. On the one hand, studies exploiting quasi-random exposure to adverse events have shown long-term physical and mental health impacts of exposure to early shocks, including pandemics or maternal illness, famine, malnutrition, stress, vitamin deficiencies, maltreatment, pollution and economic recessions. On the other hand, studies from the 20th century have shown that early interventions of various content and delivery format improve life course health. Further, given that the most socioeconomically disadvantaged groups show the greatest gains, such measures can potentially reduce health inequalities. However, studies of long-term impacts, as well as the mechanisms via which shocks or policies affect health, and the dynamic interaction amongst them, are still lacking. Mapping the complexities of those early event dynamics is an important avenue for future research.

Accounting for Fetal Origins: Health Capital vs. Health Deficits

The fetal origins hypothesis has received considerable empirical support, both within epidemiology and economics. The present study compares the ability of two rival theoretical frameworks in accounting for the kind of path dependence implied by the fetal origins hypothesis. We argue that while the conventional health capital model is irreconcilable with fetal origins of late-in-life health outcomes, the more recent health deficit model can generate shock amplification consistent with the hypothesis. We also develop a theory of ontogenetic growth in utero and during childhood, unify it with the theory of adult aging, and discuss the transmission of early-life shocks to late-life health deficit accumulation.

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.

Transgenerational impaired spermatogenesis with sperm H19 and Gtl2 hypomethylation induced by the endocrine disruptor p,p’-DDE

The hypothesis of fetal origins unraveled that environmental exposures in early life could alter epigenetic modifications in the male germ-line, increasing the susceptibility to adult-onset diseases for generations. In our previous study, p,p’-dichlorodiphenoxydichloroethylene (p,p’-DDE), a representative endocrine disruptor, was found to induce transgenerational impaired male fertility with sperm Igf2 hypomethylation. However, whether other imprinted genes involved remains uncovered. In the present study, we administered p,p’-DDE (100 mg/kg body weight) to pregnant Sprague-Dawley rats from gestational day (GD) 8 to GD15. Male F1 offspring were mated with the females from the same group to obtain F2 progeny. F3 progeny was obtained by inter-crossing the control and exposed F2 generation. Gestational exposure to p,p’-DDE impaired the testis histology and decreased the sperm fertility with H19 and Gtl2 hypomethylation in F1 offspring. Interestingly, this impaired spermatogenesis and DNA hypomethylation were maintained through F2 and F3 generations. DNA methyltransferase DNMT1 and 3a were significantly decreased in the embryonic testis of p,p’-DDE-treated F1 and F2 generation and returned to control levels by the F3 generation. p,p’-DDE induced a transgenerational impaired spermatogenesis with altered epigenetic modification, posing significant implications for disease etiology.

Is maternal microbial metabolism an early-life determinant of health?

Mounting evidence suggests that environmental stress experienced in utero (for example, maternal nutritional deficits) establishes a predisposition in the newborn to the development of chronic diseases later in life. This concept is often referred to as the "fetal origins hypothesis" or "developmental origins of health and disease". Since its first proposal, epigenetics has emerged as an underlying mechanism explaining how environmental cues become gestationally "encoded". Many of the enzymes that impart and maintain epigenetic modifications are highly sensitive to nutrient availability, which can be influenced by the metabolic activities of the intestinal microbiota. Therefore, the maternal microbiome has the potential to influence epigenetics in utero and modulate offspring's long-term health trajectories. Here we summarize the current understanding of the interactions that occur between the maternal gut microbiome and the essential nutrient choline, that is not only required for fetal development and epigenetic regulation but is also a growth substrate for some microbes. Bacteria able to metabolize choline benefit from the presence of this nutrient and compete with the host for its access, which under extreme conditions may elicit signatures of choline deficiency. Another consequence of bacterial choline metabolism is the accumulation of the pro-inflammatory, pro-thrombotic metabolite trimethylamine-N-oxide (TMAO). Finally, we discuss how these different facets of microbial choline metabolism may influence infant development and health trajectories via epigenetic mechanisms and more broadly place a call to action to better understand how maternal microbial metabolism can shape their offspring's propensity to chronic disease development later in life.