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.

Prenatal Exposure to Tobacco and Childhood Cognition and Behavior: Effect Modification by Maternal Folate Intake and Breastfeeding Duration.

In this exploratory analysis, we assessed whether nutrition modified the association between prenatal exposure to tobacco and childhood cognition/behavior among 366 Colorado-based mothers and their offspring (born ≥ 37 weeks with birthweights ≥ 2500 g). Interaction by folate ( 5 months, but not for shorter durations. Our findings support the need for smoking cessation campaigns throughout pregnancy and throughout the postpartum period breastfeeding to reduce neurobehavioral risks in the offspring.

Association of In Utero Exposures With Risk of Early Natural Menopause.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

Utility of preclinical models of altered maternal nutrition to support the developmental origins of health and disease hypothesis.

A clear link has been established between alterations in the early life environment and the risk for developing a range of cardiometabolic diseases in later life, a process preferentially termed developmental programming. In particular, alterations in the maternal nutritional environment have been associated with a range of adverse health outcomes in offspring across the lifecourse; effects that can be passed on to future generations. Following from the early epidemiological observations that provided the basis for the developmental origins of health and disease (DOHaD) hypothesis, a range of animal models were developed to examine the impact of early life programming and provide empirical data to support the emerging framework. These models became key tools to aid in our understanding of developmental programming as allowed investigation of potential mechanisms, strategies for intervention and transgenerational effects. The study published by Langley and Evans (Clin. Sci. 1994;86(2):217-222; DOI:10.1042/CS0860217), using a rat model of maternal low protein exposure, was one of the first to highlight the impact of an altered maternal nutritional environment on programming of elevated blood pressure in offspring. This work became a hallmark study in the DOHaD field by demonstrating key proof of principle to support the early epidemiological associations and characterizing a key preclinical model that has contributed greatly to our understanding of mechanisms underpinning developmental programming-particularly in the area of cardiovascular and renal function.

Impact of maternal diabetes exposure on soluble adhesion molecules in the offspring.

BACKGROUND AND AIMS: Soluble adhesion molecules are associated with cardiovascular disease and increased in individuals with diabetes. This study assesses the impact of diabetes exposure in utero on the abundance of circulating adhesion molecules in cord serum and soluble adhesion molecules released from human umbilical vein endothelial cells (HUVEC) exposed to high glucose concentrations. METHODS AND RESULTS: Women with and without diabetes were recruited. DM was diagnosed based on the American Diabetes Association criteria. Primary cultures of HUVEC were cultured in 5 mM and 25 mM glucose with 25 mM mannitol osmotic control. The soluble adhesion molecules, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and E-selectin were measured by ELISA in the cord blood serum and conditioned HUVEC media. The mothers with DM were older with higher BMI (p = 0.027 and 0.008, respectively). In a fully adjusted model, VCAM was significantly increased in the cord serum of infants born to mothers with diabetes (p = 0.046), but ICAM and E-selectin were not different. ICAM was also significantly correlated with maternal HbA1c (r2 = 0.16, p = 0.004) and cord serum non-esterified fatty acids (r2 = 0.08, p = 0.013). From the HUVEC media, the abundance of adhesion molecules was not different based on DM or high glucose exposure; however, VCAM abundance in the HUVEC supernatant was significantly correlated with ICAM (r2 = 0.27, p = 0.010) and cord serum c-peptide (R2 = 0.19, p = 0.043). CONCLUSIONS: Alterations in soluble adhesion molecule abundance in infants exposed to the diabetic milieu of pregnancy may reflect early alterations in vascular function predicting future cardiovascular disease.

Profiling of exosomal microRNAs expression in umbilical cord blood from normal and preeclampsia patients.

BACKGROUND: Epidemiological and experimental studies suggest that preeclampsia has a negative impact on maternity and offspring health. Previous studies report that dysregulation in utero-environment increases risk for elderly disease such as cardiovascular disease. However, the underlying mechanisms remain elusive. Specific microRNAs (miRNAs) are packaged in exosomes may regulate microvascular dysfunction in offspring of mothers with preeclampsia. The present study aimed to identify the differential expression profiles of microRNAs in the serum exosomes between patients with preeclampsia and normal pregnancies. METHODS: A comprehensive miRNA sequence-based approach was performed to compare exosomes carry miRNAs (Exo-miRNAs) expression levels in umbilical serum between normal and preeclampsia patients. Exosomes were isolated using the ExoQuick precipitation kit. Serum exosomes were then viewed under electron microscopy, and their characteristics determined by western blotting and nanoparticle-tracking analysis. Illumina platform was used to perform sequencing. Bioinformatics analysis was used to explore differentially expressed Exo-miRNAs in umbilical serum. RESULTS: Based on sequence similarity, 1733 known miRNAs were retrieved. Furthermore, 157 mature miRNAs in serum exosomes were significantly differential expressed between PE and those control groups (P<0.05, log2|FC| > 1). Out, of the 157 miRNAs, 96 were upregulated miRNAs whereas 61 miRNAs were downregulated. The 157 differentially expressed miRNAs targeted 51,424 differentially expressed genes. Functional analysis through KEGG pathway and Gene Ontology results uncovered that target genes of miRNAs with differential expression were significantly linked to several pathways and biological processes. CONCLUSION: The findings of this study showed differential expression of umbilical serum Exo-miRNAs in normal compared with PE patients, implying that these Exo-miRNAs may associate with microvascular dysfunction in offspring of mothers with preeclampsia.

iTRAQ-based quantitative proteomic analysis of thoracic aortas from adult rats born to preeclamptic dams.

BACKGROUND: Preeclampsia and gestational hypertension can cause vascular function impairment in offspring. In our previous work, we described the protein expression profiles of umbilical artery tissues from patients with preeclampsia. METHODS: To gain insights into the mechanisms of vascular dysfunction in adult rats born to preeclamptic dams, we analyzed thoracic aorta tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS. RESULTS: By using the iTRAQ method, we analyzed 1825 proteins, of which 106 showed significantly different expression in the thoracic aortic. Ingenuity pathway analysis (IPA) showed that the majority of differentially expressed proteins (DEPs) were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, had the strongest effect on cardiovascular function. The expression of G6PD was upregulated in thoracic aorta tissues, as confirmed by Western blotting. The expression of two other vascular function-related proteins, cysteine- and glycine-rich protein 2 (CSRP2) and tubulin alpha-4 A (TUBA4A), was upregulated, as demonstrated by mass spectrometry (MS). CONCLUSIONS: Although the results require further functional validation, these data provide novel findings related to vascular function impairment in the adult offspring of preeclamptic mothers.

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.

Developmental origins and transgenerational inheritance of polycystic ovary syndrome.

BACKGROUND: There has been increasing awareness that polycystic ovary syndrome (PCOS) phenotypes may represent a mismatch between ancient genetically programmed metabolic and reproductive survival mechanisms and modern lifestyle practices. In-utero developmental programming of metabolic and endocrine pathways may play an important role in activating gene variants that predispose the offspring to develop PCOS when exposed to specific postnatal conditions. Postnatal exposure to lifestyle factors such as poor-quality diet and endocrine disrupting chemicals may modulate epigenetically programmed pathways that result in the observed pathophysiological changes and clinical features seen in women with PCOS. AIM: To review the developmental origins and transgenerational transmission of PCOS and the impact of lifestyle, androgens and endocrine disrupting chemicals on fetal epigenetic programming. MATERIALS AND METHODS: The literature was reviewed using Google, Google Scholar, Medline and PubMed databases. The results are presented as a narrative review. RESULTS: Human observational and animal experimental data support the hypothesis that PCOS is an inherited condition that arises as a result of developmental programming of normal gene variants. It is likely that these genes can be amplified by in-utero androgen exposure and activated by a range of postnatal lifestyle and environmental factors. Endocrine disrupting chemicals have the potential to influence developmental programming of PCOS susceptibility genes. CONCLUSIONS: The current evidence suggests that developmental epigenetic programming following exposure to an adverse maternal metabolic and endocrine environment contributes to the pathogenesis of PCOS. Lifestyle interventions, as recommended by the International Guidelines, have the potential to reduce both symptoms and transgenerational transmission of PCOS.

Relationship between season of birth, temperature exposure, and later life wellbeing.

We study how exposure to extreme temperatures in early periods of child development is related to adult economic outcomes measured 30 y later. Our analysis uses administrative earnings records for over 12 million individuals born in the United States between 1969 and 1977, linked to fine-scale, daily weather data and location and date of birth. We calculate the length of time each individual is exposed to different temperatures in utero and in early childhood, and we estimate flexible regression models that allow for nonlinearities in the relationship between temperature and long-run outcomes. We find that an extra day with mean temperatures above 32 °C in utero and in the first year after birth is associated with a 0.1% reduction in adult annual earnings at age 30. Temperature sensitivity is evident in multiple periods of early development, ranging from the first trimester of gestation to age 6-12 mo. We observe that household air-conditioning adoption, which increased dramatically over the time period studied, mitigates nearly all of the estimated temperature sensitivity.

Relationship between early-life nutrition and ages at menarche and first pregnancy, and childbirth rates of young adults: Evidence from APCAPS in India.

India's Integrated Child Development Services (ICDS) provides daily supplementary nutrition and other public health services to women and children. We estimated associations between exposure to early-childhood ICDS nutrition and adult reproductive outcomes. During 1987-1990, a balanced protein-calorie supplement called "upma"-made from locally available corn-soya ingredients-was rolled out by subdistricts near Hyderabad and offered to pregnant women and children under age 6 years. In a controlled trial, 15 villages received the supplement and 14 did not. We used data from a 2010-2012 resurvey of adults born during the trial (n = 715 in intervention and n = 645 in control arms). We used propensity score matching methods to estimate the associations between birth in an intervention village and menarcheal age, age at first pregnancy, and fertility of adults. We found that women born in the intervention group during the trial, as compared with the control group, had menarche 0.45 (95% confidence interval [CI: 0.22, 0.68]; p < .001) years later and first pregnancy 0.53 (95% CI [0.04, 1.02]; p < .05) years later. Married women from the intervention group had menarche 0.36 (95% CI [0.09, 0.64]; p < .01) years later, first cohabitation with partner 0.8 (95% CI [0.27, 1.33]; p < .01) years later, and first pregnancy 0.53 (95% CI [0.04, 1.02]; p < .05) years later than married women in the control group. There was no significant difference between intervention and control group women regarding whether they had at least one childbirth or the total number of children born. The findings were similar when we employed inverse propensity score weighted regression models.

The Long-Lasting Influenza: The Impact of Fetal Stress During the 1918 Influenza Pandemic on Socioeconomic Attainment and Health in Sweden, 1968-2012.

The 1918 influenza pandemic had not only a massive instant death toll but also lasting effects on its survivors. Several studies have shown that children born in 1919, and thus exposed to the H1N1 virus in utero, experienced worse health and socioeconomic outcomes in older ages than surrounding birth cohorts. This study combines several sources of contemporary statistics with full-population individual-level data for Sweden during 1968-2012 to examine the influence of fetal exposure to the Spanish flu on health, adulthood income, and occupational attainment. For both men and women, fetal exposure resulted in higher morbidity in ages 54-87, as measured by hospitalization. For males, exposure during the second trimester also affected mortality in cancer and heart disease. Overall, the effects on all-cause mortality were modest, with about three months shorter remaining life expectancy for the cohorts exposed during the second trimester. For socioeconomic outcomes, results fail to provide consistent evidence supporting any long-term consequences of fetal exposure. We conclude that although the immediate health effects of exposure to the 1918 pandemic were huge, the long-term effects were modest in size.

Predictors of Steroid Hormone Concentrations in Early Pregnancy: Results from a Multi-Center Cohort.

Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy. Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography-tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics. Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1-2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1-2% lower estrogen (E1, E2, E3) levels, but 1-2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4-18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1-2% higher (no difference in estrogens). Androgen concentrations were 18-30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations. Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring.

In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring.

BACKGROUND/AIMS: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor (D1R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D1R dysfunction is involved in PM2.5-induced hypertension in the offspring. METHODS: Pregnant Sprague-Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. RESULTS: As compared with saline-treated dams, offspring of PM2.5-treated dams had increased blood pressure, impaired sodium excretion, and reduced D1R-mediated natriuresis and diuresis, accompanied by decreased renal D1R expression and GRK4 expression. The impaired renal D1R function and increased GRK4 expression could be caused by increased reactive oxidative stress (ROS) induced by PM2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM2.5-treated dam normalized the decreased renal D1R expression and increased renal D1R phosphorylation and GRK4 expression. Furthermore, tempol normalized the increased renal expression of c-Myc, a transcription factor that regulates GRK4 expression. CONCLUSIONS: In utero exposure to PM2.5 increases ROS and GRK4 expression, impairs D1R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D1R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM2.5 during pregnancy.

Early-Life Nutrition Is Associated Positively with Schooling and Labor Market Outcomes and Negatively with Marriage Rates at Age 20-25 Years: Evidence from the Andhra Pradesh Children and Parents Study (APCAPS) in India.

Background: India's Integrated Child Development Services (ICDS) is among the world's largest public nutritional programs, providing daily nutritional supplements and other public health and educational services to pregnant and nursing women, children aged <6 y, and adolescent girls. Objective: We estimated the long-term association between early-childhood ICDS nutrition and adult outcomes. Methods: We used follow-up data from a controlled nutritional trial conducted during 1987-1990 in 29 villages near the city of Hyderabad. In 15 intervention villages, a balanced protein-calorie supplement-made from locally available corn-soya ingredients and called upma-was offered to pregnant women and to children <6 y old. No supplement was offered in the 14 control villages. During 2010-2012, adults born during the trial were re-surveyed (n = 715 in the intervention arm and n = 645 in the control arm). We used probit regression and propensity score-matching methods to estimate the association between birth in an intervention village and rates of secondary and graduate education completion, marriage, and employment or enrollment in higher education of these adults. Results: Adults born in the intervention group during the trial, compared with the control group, were 9% (95% CI: 0.04, 0.14; P < 0.01) more likely to complete secondary school and 11% (95% CI: 0.06, 0.15; P < 0.01) more likely to complete graduate education, were 6% (95% CI: -0.11, -0.01; P < 0.05) less likely to be ever-married at age 20-25 y, and were 5% (95% CI: 0, 0.11; P < 0.05) more likely to be employed or enrolled in higher education. The estimated associations for graduate education completion and employment-study rates were greater for men, whereas the associations for secondary education and ever-married rates were greater for women. Conclusion: Exposure to nutritional supplement in utero or during the first 3 y of life was associated with improved adult educational and employment outcomes and lower marriage rates in India.

Better Diet Quality during Pregnancy Is Associated with a Reduced Likelihood of an Infant Born Small for Gestational Age: An Analysis of the Prospective New Hampshire Birth Cohort Study.

Background: Birth weight has a U-shaped relation with chronic disease. Diet quality during pregnancy may impact fetal growth and infant birth weight, yet findings are inconclusive. Objective: We examined the relation between maternal diet quality during pregnancy and infant birth size among women enrolled in a prospective birth cohort. Methods: Women 18-45 y old with a singleton pregnancy were recruited at 24-28 wk of gestation from prenatal clinics in New Hampshire. Women completed a validated food frequency questionnaire at enrollment. Diet quality was computed as adherence to the Alternative Healthy Eating Index. Infant birth outcomes (sex, head circumference, weight, and length) were extracted from medical records. Weight-for-length z scores, low birth weight, macrosomia, and size for gestational age [small for gestational age (SGA) or large for gestational age (LGA)] were computed. Multivariable regression models fit each outcome on quartiles of diet quality, adjusted for covariates. Models were computed overall and stratified by smoking status. Results: Analyses included 862 women and infants with complete data. Lower diet quality was associated with lower maternal education, being a smoker, prepregnancy obesity status, and lack of exercise during pregnancy. Overall, 3.4% of infants were born with a low birth weight, 12.1% with macrosomia, 4.6% were SGA, and 8.7% were LGA. In an adjusted model, increased diet quality appeared linearly associated with a reduced likelihood of SGA (P-trend = 0.03), although each quartile comparison did not reach statistical significance. Specifically, ORs for SGA were 0.89 (95% CI: 0.37, 2.15), 0.73 (95% CI: 0.28, 1.89), and 0.35 (95% CI: 0.11, 1.08) for each increasing quartile of diet quality compared to the lowest quartile. Similar trends for SGA were observed among non-smokers (n = 756; P-trend = 0.07). Also among non-smokers, increased diet quality was associated with lower infant birth weight (P-trend = 0.03) and a suggested reduction in macrosomia (P-trend = 0.07). Conclusions: Increased diet quality during pregnancy was related to a reduced risk of SGA in this cohort of pregnant women from New Hampshire. Additional studies are needed to elucidate the relation between maternal diet quality and macrosomia.

Long-term impacts of early-life exposure to malaria: Evidence from Taiwan's Eradication Campaign in the 1950s.

This paper utilizes the eradication campaign in Taiwan in the 1950s to estimate the long-term impacts of early-life (in utero and postnatal) exposure to malaria. Matching adults in the 1992-2012 Taiwan Social Change Survey to the malaria intensity in their individual place and year of birth, difference-in-difference estimation shows strong evidence that the eradication increased men's own educational attainment as well as their family income in adulthood. We also use the 1980 census data to show there was a sharp education increase after the eradication. Furthermore, the eradication increased the educational attainment of married men's spouses. Finally, quantile regressions show that the effect concentrated on the lower percentile of the income distribution. Overall, our results suggest negative effects of early-life exposure to malaria.

Prenatal exposure to ambient temperature variation increases the risk of common cold in children.

BACKGROUND: Common cold is a frequent upper respiratory tract infection, but the role of ambient temperature in the infection is unclear. OBJECTIVE: We investigated the role of prenatal exposure to diurnal temperature variation (DTV), the difference between the daily maximal and minimal temperatures, in the risk of common cold in children. METHODS: We conducted a cohort study of 2598 preschool children in Changsha, China. Occurrence of common cold during the past year was surveyed using questionnaire. We then estimated each child's prenatal exposure to DTV during pregnancy. Multivariate logistic regression model was used to examine the association between occurrence of common cold and prenatal exposure to DTV in terms of odds ratios (OR) and 95% confidence interval (CI). RESULTS: About 45% children have common cold (≥3 times) during the past year. We found that common cold in children was associated with maternal DTV exposure during pregnancy, particularly during the first trimester with adjusted OR (95% CI) = 1.27 (1.10-1.46). Male and atopic children were more susceptible to the effect of DTV during pregnancy. The risk of common cold due to DTV is higher in children living in the suburban areas and the bigger houses and in those exposed to environmental tobacco smoke, mold/dampness, new furniture and redecoration. We observed that the risk of common cold in children has been increased in recent years due to increasing DTV. CONCLUSIONS: Common cold in children was associated with maternal exposure to temperature variation during pregnancy, suggesting that the risk of common cold may originate in pregnancy.

An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related effects.

VACTERL, the prototype for associated congenital anomalies, also has connections with functional issues such as pregnancy losses, prematurity, growth delays, perinatal difficulties, and parental subfertility. This segues into a broader association with similar connections even in the absence of malformations. DNA methylation disturbances in the ovum are a likely cause, with epigenetic links to individual components and to folate effects before conception, explaining diverse fetal and placental findings and providing a link to fetal origin hypothesis-related effects. The association encompasses the following: (1) Pre- and periconceptual effects, with frequent fertility issues and occasional imprinting disorders. (2) Early malformations. (3) Adverse pregnancy outcomes (APOs), as above. (4) Developmental destabilization that resolves soon after birth. This potentiates other causes of association findings, introducing multiple confounders. (5) Long-term fetal origins hypothesis-related risks. The other findings are exceptional when the same malformations have Mendelian origins, supporting a distinct pathogenesis. Expressions are facilitated by one-carbon metabolic issues, maternal and fetal stress, and decreased embryo size. This may be one of the commonest causes of adverse reproductive outcomes, but multifactorial findings, variable onsets and phenotypes, and interactions with multiple confounders make recognition difficult. This association supports VACTERL as a continuum that includes isolated malformations, extends the fetal origins hypothesis, explains adverse effects linked to maternal obesity, and suggests possible interventions.

Prenatal exposure to diurnal temperature variation and early childhood pneumonia.

BACKGROUND: Childhood pneumonia is one of the leading single causes of mortality and morbidity in children worldwide, but its etiology still remains unclear. OBJECTIVE: We investigate the association between childhood pneumonia and exposure to diurnal temperature variation (DTV) in different timing windows. METHODS: We conducted a prospective cohort study of 2,598 children aged 3-6 years in Changsha, China. The lifetime prevalence of pneumonia was assessed by a questionnaire administered by the parents. Individual exposure to DTV during both prenatal and postnatal periods was estimated. Logic regression models was used to examine the association between childhood pneumonia and DTV exposure in terms of odds ratios (OR) and 95% confidence interval (CI). RESULTS: Lifetime prevalence of childhood pneumonia in preschool children in Changsha was high up to 38.6%. We found that childhood pneumonia was significantly associated with prenatal DTV exposure, with adjusted OR (95%CI) =1.19 (1.02-1.38), particularly during the second trimester. However, childhood pneumonia not associated with postnatal DTV exposure. Sensitivity analysis indicated that boys are more susceptible to the pneumonia risk of diurnal temperature variation than girls. We further observed that the prevalence of childhood pneumonia was decreased in recent years as DTV shrinked. CONCLUSIONS: Early childhood pneumonia was associated with prenatal exposure to the diurnal temperature variation (DTV) during pregnancy, particularly in the second trimester, which suggests fetal origin of childhood pneumonia.