Infant Mortality Associated With Prenatal Opioid Exposure.

Importance: Knowledge of health outcomes among opioid-exposed infants is limited, particularly for those not diagnosed with neonatal opioid withdrawal syndrome (NOWS). Objectives: To describe infant mortality among opioid-exposed infants and identify how mortality risk differs in opioid-exposed infants with and without a diagnosis of NOWS compared with infants without opioid exposure. Design, Setting, and Participants: A retrospective cohort study of maternal-infant dyads was conducted, linking health care claims with vital records for births from January 1, 2010, to December 31, 2014, with follow-up of infants until age 1 year (through 2015). Maternal-infant dyads were included if the infant was born in Texas at 22 to 43 weeks' gestational age to a woman aged 15 to 44 years insured by Texas Medicaid. Data analysis was performed from May 2019 to October 2020. Exposure: The primary exposure was prenatal opioid exposure, with infants stratified by the presence or absence of a diagnosis of NOWS during the birth hospitalization. Main Outcomes and Measures: Risk of infant mortality (death at age <365 days) was examined using Kaplan-Meier and log-rank tests. A series of logistic regression models was estimated to determine associations between prenatal opioid exposure and mortality, adjusting for maternal and neonatal characteristics and clustering infants at the maternal level to account for statistical dependence owing to multiple births during the study period. Results: Among 1 129 032 maternal-infant dyads, 7207 had prenatal opioid exposure, including 4238 diagnosed with NOWS (mean [SD] birth weight, 2851 [624] g) and 2969 not diagnosed with NOWS (mean [SD] birth weight, 2971 [639] g). Infant mortality was 20 per 1000 live births for opioid-exposed infants not diagnosed with NOWS, 11 per 1000 live births for infants with NOWS, and 6 per 1000 live births in the reference group (P < .001). After adjusting for maternal and neonatal characteristics, mortality in infants with a NOWS diagnosis was not significantly different from the reference population (odds ratio, 0.82; 95% CI, 0.58-1.14). In contrast, the odds of mortality in opioid-exposed infants not diagnosed with NOWS was 72% greater than the reference population (odds ratio, 1.72; 95% CI, 1.25-2.37). Conclusions and Relevance: In this study, opioid-exposed infants appeared to be at increased risk of mortality, and the treatments and supports provided to those diagnosed with NOWS may be protective. Interventions to support opioid-exposed maternal-infant dyads are warranted, regardless of the perceived severity of neonatal opioid withdrawal.

Maternal celiac disease and the risk for long-term infectious morbidity of the offspring.

PROBLEM: Celiac disease is an autoimmune disease, patients with celiac have increased risk for infections, and offspring of celiac mothers have increased morbidity. The aim of the study was to assess long-term infectious morbidity among offspring of pregnant women with celiac disease. METHOD OF STUDY: A population-based cohort study was conducted, including all singleton deliveries between the years 1991-2014 at a tertiary medical center. The offsprings were subdivided into two groups: offsprings of mothers with and without celiac disease. Data on demographics, maternal, perinatal, and long-term hospitalizations for infectious morbidity were compared between the two groups. RESULTS: During the study period there were 210 (0.09%) deliveries of mothers with celiac, and they were compared to 242170 (99.91%) deliveries of non-celiac mothers. Cumulative infectious morbidity was significantly higher in offspring of mothers with celiac compared to offspring of mothers without celiac (Kaplan-Meier, log-rank p = .004). Specifically, among the offspring of mothers with celiac significantly higher rates of bacteremia was noted (1.0% vs. 0.1%; p = .001), and infections of the central nervous system (1% vs. 0.2%; p = .028). In the Cox multivariable model which accounted for confounding variables, being born to mothers with celiac disease was associated with significantly increased risk for long-term infectious morbidity of the offspring (adjusted HR = 1.6, 95% CI 1.165-2.357, p = .005). CONCLUSIONS: Maternal celiac disease is an independent risk factor for long-term infectious morbidity for the offspring.

Gestational exposure to excessive levels of dexamethasone impairs maternal care and impacts on the offspring's survival in rats.

Administration of dexamethasone (DEX) during late gestation is a model to study growth restriction in rodents, but the pup's mortality index can be high, depending on DEX dosage, and little is known about the effects of DEX on maternal care (MC). Considering that an inadequate MC can also contribute to pup's mortality in this model, we evaluated the effects of DEX on dams' behavior and its consequences on offspring survival. We also investigated whether the cross-fostering of pups from dams treated or not with DEX could improve pup's survival. Wistar rats were treated with DEX (14th to 19th day of gestation -0.2 mg/kg, B.W, in the drinking water). Nest building, MC and responses in the elevated plus-maze, forced swimming and object recognition tests were evaluated. DEX reduced gestational weight gain and impaired neonatal development, reducing pup's survival to 0% by the 3rd postnatal day. DEX-treated dams reduced the expression of typical MC and increased anxiety-like behaviors. After cross-fostering, DEX-treated mothers behaved similarly to controls, indicating that a healthy offspring is crucial to induce adequate MC. Cross-fostering increased the survival index from zero to 25% in the DEX offspring. Postnatal development of the DEX offspring was comparable to controls after cross-fostering. We concluded that exposure to DEX during late gestation causes behavioral changes that compromise the maternal emotional state, disrupting the expression of MC. Although it does not seem to be the main cause of pup's mortality, our data indicate that an adequate MC improves pup's survival in this model.

Hospitalizations and mortality among patients with fetal alcohol spectrum disorders: a prospective study.

With nearly 10% of women consuming alcohol during pregnancy, fetal alcohol spectrum disorders (FASDs) are becoming an increasing concern for clinicians and policymakers interested in the field of healthcare. Known as the range of mental and/or physical disabilities that occur among individuals with prenatal alcohol exposure, FASDs can result in dysmorphic features, problems with physical growth, neurobehavioral and cognitive problems that not only increase risk of various diseases, but also premature mortality. We investigated whether the diagnosis of FASDs result in increased risk of hospitalizations and mortality, with respect to FASD domains and relative diseases, when age effects are controlled for. The data for this study was taken from the National Health Insurance Service - National Sample Cohort (NHIS-NSC) between 2003 and 2013. The population attributable risk (PAR) statistic was used to estimate the percentage of hospitalizations and mortality attributable to FASDs and other factors. A time-dependent Cox proportional hazards model with age of diagnosis as the time-scale was employed to calculate adjusted hazard ratios and 95% CIs for hospitalizations and mortality among FASD populations compared to their general population peers. Among the 3,103 FASD cases, 27.5% experienced hospitalizations and 12.5% died. Overall, FASDs accounted for 853 FASD-attributable hospitalizations (51.0% of all hospitalizations in the study population) and 387 mortality events (34.5% of all deaths in the study population). 20.52% of hospitalizations and 21.35% of mortalities were attributable to FASDs in this population. Compared to the control group, FASD patients had a 1.25-fold (HR: 1.25, 95% CI: 1.05-1.49, p = 0.0114) increased risk of hospitalizations and a 1.33-fold (HR: 1.33, 95% CI: 1.07-1.67, p = 0.0118) increased risk of all-cause mortality. The most common cause for hospitalization was diseases of the nervous system, which accounted for 450 FASD-attributable hospitalizations (96.2% of all nervous system hospitalizations in the study population). In fact, FASD patients were 52 times more likely to be hospitalized for nervous system diseases than their peers (HR: 51.78, 95% CI: 29.09-92.17, p < .0001). The most common cause for mortality was neoplasms, which accounted for 94 FASD-attributable deaths (28.7% of all neoplasm deaths in the study population). However, FASD patients did not have increased risk of neoplasm mortality than the general population (HR: 0.88, 95% CI: 0.59-1.32, p < .0001). Overall, this study found that individuals diagnosed with FASDs have increased risk of both hospitalizations and mortality, compared to their general population peers. This is particularly so for diseases of the nervous system, which showed a 52-fold increase in hospitalizations and four-fold increase in mortality for FASD patients in our study. Likewise, while the association between FASDs and neoplasm mortality was not significant in our investigation, more attention by neurologists and related healthcare providers regarding the link between these two factors is necessary.Trial Registration: Institutional Review Board of Yonsei University's Health System: Y-2019-0174.

Implications of early life stress on fetal metabolic programming of schizophrenia: A focus on epiphenomena underlying morbidity and early mortality.

The fetal origin of adult disease hypothesis postulates that a stressful in utero environment can have deleterious consequences on fetal programming, potentially leading to chronic disease in later life. Factors known to impact fetal programming include the timing, intensity, duration and nature of the external stressor during pregnancy. As such, dynamic modulation of fetal programming is heavily involved in shaping health throughout the life course, possibly by influencing metabolic parameters including insulin action, hypothalamic-pituitary-adrenal activity and immune function. The ability of prenatal insults to program adult disease is likely to occur as a result of reduced functional capacity in key organs-a "thrifty" phenotype-where more resources are re-allocated to preserve critical organs such as the brain. Notably, it has been postulated that the manifestation of neuropsychiatric disorders in individuals priorly exposed to prenatal stress may arise from the interaction between hereditary factors and the intrauterine environment, which together precipitate disease onset by disrupting the trajectory of normal brain development. In this review we discuss the evidence linking prenatal programming to neuropsychiatric disorders, mainly schizophrenia, via a "Thrifty psychiatric phenotype" concept. We start by outlining the conception of the thrifty psychiatric phenotype. Next, we discuss the convergence of potential mechanistic pathways through which prenatal insults may trigger epigenetic changes that contribute to the increased morbidity and early mortality observed in neuropsychiatric disorders. Finally, we touch on the public health importance of fetal programming for these disorders. We conclude by providing a brief outlook on the future of this evolving field of research.

SAM targeting methylation by the methyl donor, a novel therapeutic strategy for antagonize PFOS transgenerational fertilitty toxicity.

DNA methylation have been suggested as possible mediators of long-term health effects of environmental stressors. This study aimed to evaluate the potential therapy of methylation of S-adenosyl-l-methionine (SAM) on PFOS induced trangeneral reproductive toxicity. In this study, postnatal 5d Sprague Dawley rats were randomly divided into four groups: control, PFOS, PFOS + SAM, and PFOS + Decitabine (DAC). The F0 rats were exposed to 5 mg/kg PFOS and SAM or DAC until PND60. The development of the offsprings were monitored without PFOS exposure. The fertility in F0, F1 rats, and change in F1 testes were observed. The results were as follows. The significant increase in F0 pregnancy rate, and survival rate in F1 offspring in PFOS + SAM relative to PFOS group were observed. Changes of birth weights and physical development in F1 offspring with SAM were approached as a corresponding variation of the control after the deparation period. No pregnant in F1 maternal rats in the PFOS and DAC groups were found, but pregnant in the SAM group. Significantly decrease in the percentage of abnormal seminiferous tubules and increase in expression of promyelocytic leukemia zinc finger (PLZF+) spermatogonial stem cells in F1 testis compared with the PFOS group. Taken together, Methyl donor SAM improve PLZF + spermatogonia stem cell proliferation, attenuate damage in testicular tissue structure, which subsequently improve the transgenerational growth retard and infertility induced by PFOS chronic stress.

Advancing metabolism research to overcome low litter survival in metabolically stressed mice.

Elucidating the mechanism underlying the transmission of metabolic disease to subsequent generations requires robust preclinical mouse breeding strategies. Western diets rich in fat and carbohydrates are contributing factors in the rise of diabetes and obesity rates worldwide. Therefore, determining the impact of Western diets consumed by parents on offspring and future generations is critical for understanding the perpetuation of these diseases. Specifically, epigenetic regulation and transgenerational inheritance of metabolic disease is an emerging field of study requiring robust murine models. However, a major challenge to transgenerational studies is offspring mortality, exacerbated by maternal stress during pregnancy. Here, we describe a challenge experienced in our metabolic research in Western diet-fed female mice leading to the loss of litters via pup mortality and cannibalism by the mother. Furthermore, our study evaluates various breeding schemes with pregnancy efficiency and refined husbandry techniques to overcome pup mortality and infanticide, to characterize dams' and pups' metabolic characteristics, and to determine the impact on physiology of dams under detailed breeding schemes.

Childhood cancer research in Oxford I: the Oxford Survey of Childhood Cancers.

BACKGROUND: Significant research on the epidemiology and natural history of childhood cancer took place in the Universities of Oxford and Birmingham over sixty years. This is the first of three papers recording this work and describes the Oxford Survey of Childhood Cancers (OSCC), the largest case-control survey of childhood cancer ever undertaken. METHODS: The OSCC studied deaths in Britain from 1953 to 1981. Parents were interviewed and medical records from ante-natal clinics and treatment centres were followed up and abstracted. The survey left Oxford in 1975 and was run subsequently from Birmingham. The data are now being documented and archived to make them available for future study. RESULTS: Many papers have resulted from this survey, most notably those relating to the association first reported therein between childhood cancer and ante-natal X-raying. This paper is a historical review of the OSCC. CONCLUSIONS: In spite of many analyses of the study, this historic data set has continuing value because of the large number of examples of some very rare tumours and the detailed clinical and family history data that are available; and also because of the possibility of carrying out new analyses to investigate emerging research issues.

Ramadan Exposure In Utero and Child Mortality in Burkina Faso: Analysis of a Population-Based Cohort Including 41,025 Children.

Ramadan exposure in utero can be regarded as a natural experiment with which to study how nutritional conditions in utero influence susceptibility to disease later in life. We analyzed data from rural Burkina Faso on 41,025 children born between 1993 and 2012, of whom 25,093 were born to Muslim mothers. Ramadan exposure was assigned on the basis of overlap between Ramadan dates and gestation, creating 7 exclusive categories. We used proportional hazards regression with difference-in-differences analysis to estimate the association between Ramadan exposure at different gestational ages and mortality among children under 5 years of age. Under-5 mortality was 32 deaths per 1,000 child-years. Under-5 mortality among Muslims was 15% higher than that among non-Muslims (P < 0.001). In the difference-in-differences analysis, the occurrence of Ramadan during conception or the first or second trimester was associated with higher under-5 mortality rates among Muslims only. The mortality rates of children born to Muslim mothers were 33%, 29%, and 22% higher when Ramadan occurred during conception, the first trimester, and the second trimester, respectively, compared with children of non-Muslim mothers born at the same time (P = 0.01, P < 0.001, and P = 0.007). Having a Muslim mother was not associated with mortality when the child was not exposed to Ramadan, born during Ramadan, or exposed during the third trimester. Observance of Ramadan during early pregnancy can have detrimental consequences for the future health of the unborn child.

Offspring birth weight and cardiovascular mortality among parents: the role of cardiovascular risk factors.

An inverse association between offspring birth weight (BW) and higher risk of parental cardiovascular disease (CVD) mortality and morbidity has been reported. Shared environmental, genetic and intrauterine factors may be responsible for explaining these associations. We studied the role of parental CVD risk factors in the association between offspring BW and CVD mortality among mothers and fathers. All births registered in Medical Birth Registry Norway (1967-2012) were linked to three health surveys, National Educational Registry and Cause of Death Registry. Number of births with information of parental CVD risk factors available for the analyses was 1,006,557 (520,670 for mothers and 485,887 for fathers). Cox proportional hazards regression models were used, following CVD deaths in parents from 1974 to 2012. An inverse association between offspring BW and CVD mortality was observed among both parents: hazard ratio 1.60 (1.44-1.75) for mothers and 1.16 (1.10-1.23) for fathers. Among mothers, adjustment for smoking, triglycerides and diabetes reduced the risk to 1.36 (1.25-1.52), 1.57 (1.43-1.73) and 1.58 (1.43-1.79), respectively. Adjustment for diastolic blood pressure (DBP) and systolic blood pressure (SBP) both reduced the risk to 1.53 (1.37-1.66). Among fathers, adjustments for smoking, DBP, SBP reduced the risk to 1.08 (1.02-1.15), 1.13 (1.06-1.19) and 1.14 (1.08-1.22), respectively. Triglycerides and diabetes both reduced the risk to 1.15 (1.09-1.12). Our results indicate that shared environmental factors might be important in the association. A stronger association in mothers suggest that intrauterine factors also are at play.

Excess mortality in children born to opioid-addicted parents: A national register study in Taiwan.

BACKGROUND: Young offspring of individuals with opioid use disorders have great exposure to a wide array of social disadvantages and stressors. This study aimed to investigate excess mortality before the age of six and predictors of premature death in children born to opioid-involved parents. METHODS: A total of 3210 children born between 2004 and 2009 to parents with opioid use disorders (roughly a quarter of whom were born after parental methadone treatment enrollment) were identified in Taiwan. Information concerning sociodemographic characteristics, history of medical condition, and survival status was obtained through data linkage with the National Health Insurance Database and death registration. The age-, birth year-, and sex-adjusted standardized mortality ratios (SMRs) and survival analyses were used to assess risk estimates and evaluate predictors. RESULTS: The overall SMR for children with opioid-involved parents was 2.31 (95% confidence interval [CI] = 1.68-3.10), with the estimate reaching 4.23 (95% CI = 2.37-6.97) when the causes of death were unnatural (e.g., injury and accident). The most salient predictors of premature death were low birth weight and paternal opioid problem severity, which increased risk of premature death 2.5--5.2-fold (all P < 0.05). Being born after parents enrolled in methadone treatment was slightly associated with a reduced risk of death in those mothered by opioid users (adjusted hazard ratio = 0.30). CONCLUSION: The elevated risk of premature death in the offspring of opioid-addicted parents suggests the need to prioritize resource allocation to safeguard this marginalized and vulnerable segment of the pediatric population.

Cancer Incidence after In Utero Exposure to Ionizing Radiation in Techa River Residents.

Health effects of in utero exposure to ionizing radiation, especially among adults, are still unclear. The aim of this study was to analyze cancer risk in a cohort of subjects exposed in utero due to releases of nuclear waste into the Techa River in the Southern Urals, taking into account additional postnatal exposure. Analysis for solid cancer was based on 242 cases among 10,482 cohort members, accumulating 381,948 person-years at risk, with follow-up from 1956-2009, while analysis for hematological malignancies was based on 26 cases among 11,070 persons, with 423,502 person-years at risk, with follow-up from 1953-2009. Mean doses accumulated in soft tissues and in red bone marrow during the prenatal period were 4 mGy and 30 mGy, respectively. Additional respective mean postnatal doses received by cohort members were 11 and 84 mGy. Poisson regression analysis was used to estimate the excess relative risk (ERR) of cancer incidence related to in utero and postnatal doses. No association was observed for in utero exposure with solid cancer risk [ERR per 10 mGy: -0.007; 95% confidence interval (CI): <-0.107; 0.148] or with hematological malignancy risk (ERR/10 mGy: -0.011; 95% CI: <-0.015; 0.099). However, ERR of solid cancer increased significantly with increasing postnatal dose (ERR/10 mGy: 0.11; 95% CI: 0.04; 0.22). The very wide confidence intervals in these ERR results are similar to those of studies performed on the LSS cohort and the offspring of the Mayak Female Worker Cohort, as well as case-control studies of effects after in utero medical exposure. There were limitations of this study, with decreased statistical power, due to the low prenatal doses received by most of the cohort members, the small number of cancer cases and the absence of cohort members over the age of 59 years (living cohort members had reached 49-59 years of age). Further aging of the cohort and extension of the follow-up period will enhance the statistical power of this study in the future. There is a shortage of cohort studies reporting on the effects of prenatal radiation exposure, as well as information on chronic exposure during the prenatal period. Therefore, further research of this unique cohort will be a useful addition to the published literature on this subject, and a valuable means of elucidating the long-term effects of low-dose radiation exposure in the fetus.

Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation.

STUDY QUESTION: Do paternal exposures to folic acid deficient (FD), and/or folic acid supplemented (FS) diets, throughout germ cell development adversely affect male germ cells and consequently offspring health outcomes? SUMMARY ANSWER: Male mice exposed over their lifetimes to both FD and FS diets showed decreased sperm counts and altered imprinted gene methylation with evidence of transmission of adverse effects to the offspring, including increased postnatal-preweaning mortality and variability in imprinted gene methylation. WHAT IS KNOWN ALREADY: There is increasing evidence that disruptions in male germ cell epigenetic reprogramming are associated with offspring abnormalities and intergenerational disease. The fetal period is the critical time of DNA methylation pattern acquisition for developing male germ cells and an adequate supply of methyl donors is required. In addition, DNA methylation patterns continue to be remodeled during postnatal spermatogenesis. Previous studies have shown that lifetime (prenatal and postnatal) folic acid deficiency can alter the sperm epigenome and increase the incidence of fetal morphological abnormalities. STUDY DESIGN, SIZE, DURATION: Female BALB/c mice (F0) were placed on one of four amino-acid defined diets for 4 weeks before pregnancy and throughout pregnancy and lactation: folic acid control (Ctrl; 2 mg/kg), 7-fold folic acid deficient (7FD; 0.3 mg/kg), 10-fold high FS (10FS, 20 mg/kg) or 20-fold high FS (20FS, 40 mg/kg) diets. F1 males were weaned to their respective prenatal diets to allow for diet exposure during all windows of germline epigenetic reprogramming: the erasure, re-establishment and maintenance phases. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: F0 females were mated with chow-fed males to produce F1 litters whose germ cells were exposed to the diets throughout embryonic development. F1 males were subsequently mated with chow-fed female mice. Two F2 litters, unexposed to the experimental diets, were generated from each F1 male; one litter was collected at embryonic day (E)18.5 and one delivered and followed postnatally. DNA methylation at a global level and at the differentially methylated regions of imprinted genes (H19, Imprinted Maternally Expressed Transcript (Non-Protein Coding)-H19, Small Nuclear Ribonucleoprotein Polypeptide N-Snrpn, KCNQ1 Opposite Strand/Antisense Transcript 1 (Non-Protein Coding)-Kcnq1ot1, Paternally Expressed Gene 1-Peg1 and Paternally Expressed Gene 3-Peg3) was assessed by luminometric methylation analysis and bisulfite pyrosequencing, respectively, in F1 sperm, F2 E18.5 placenta and F2 E18.5 brain cortex. MAIN RESULTS AND THE ROLE OF CHANCE: F1 males exhibited lower sperm counts following lifetime exposure to both folic acid deficiency and the highest dose of folic acid supplementation (20FS), (both P < 0.05). Post-implantation losses were increased amongst F2 E18.5 day litters from 20FS exposed F1 males (P < 0.05). F2 litters derived from both 7FD and 20FS exposed F1 males had significantly higher postnatal-preweaning pup death (both P < 0.05). Sperm from 10FS exposed males had increased variance in methylation across imprinted gene H19, P < 0.05; increased variance at a few sites within H19 was also found for the 7FD and 20FS groups (P < 0.05). While the 20FS diet resulted in inter-individual alterations in methylation across the imprinted genes Snrpn and Peg3 in F2 E18.5 placenta, ≥50% of individual sites tested in Peg1 and/or Peg3 were affected in the 7FD and 10FS groups. Inter-individual alterations in Peg1 methylation were found in F2 E18.5 day 10FS group brain cortex (P < 0.05). LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: The cause of the increase in postnatal-preweaning mortality was not investigated post-mortem. Further studies are required to understand the mechanisms underlying the adverse effects of folic acid deficiency and supplementation on developing male germ cells. Genome-wide DNA and histone methylome studies as well as gene expression studies are required to better understand the links between folic acid exposures, an altered germ cell epigenome and offspring outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study provide further support for paternally transmitted environmental effects. The results indicate that both folic acid deficiency and high dose supplementation can be detrimental to germ cell development and reproductive fitness, in part by altering DNA methylation in sperm. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR #89944). The authors declare they have no conflicts of interest.

Prenatal maternal bereavement and mortality in the first decades of life: a nationwide cohort study from Denmark and Sweden.

BACKGROUND: The loss of a close relative is one of the most stressful life events. In pregnancy, this experience has been associated with a higher risk of fetal death and under-five mortality, but little is known about potential effects on long-term mortality in offspring. We examined the association between prenatal maternal bereavement and mortality in a cohort of 5.3 million children followed until up to 37 years of age. METHOD: The population-based cohort study included 5 253 508 live singleton births in Denmark (1973-2004) and Sweden (1973-2006). Children born to mothers who lost a child, spouse, sibling, or parent during or 1 year before pregnancy were categorized as exposed. RESULTS: Prenatal maternal bereavement was associated with a 10% increased all-cause mortality risk in offspring [mortality rate ratio (MRR) 1.10, 95% confidence interval (CI) 1.03-1.18]. The association was the most pronounced for children of mothers who lost a child/spouse (MRR 1.28, 95% CI 1.14-1.44) and was stronger during the first 10 years of life. Prenatal maternal bereavement may have stronger effects on natural causes of death in offspring, including infectious/parasitic disease (MRR 1.86, 95% CI 1.07-3.23), endocrine/nutritional/metabolic diseases (MRR 3.23, 95% CI 2.02-5.17), diseases of nervous system (MRR 3.36, 95% CI 2.47-4.58), and congenital malformations (MRR 1.39, 95% CI 1.08-1.80). No excess mortality risk in offspring was observed for unnatural causes of death. CONCLUSION: Prenatal maternal bereavement was associated with an increased long-term mortality risk in offspring, particularly for selected natural causes of diseases and medical conditions. Our results support the fetal programming hypothesis that prenatal stress may contribute to ill health from physical diseases later in life.

Do adverse perinatal events predict mortality in schizophrenia during midlife?

BACKGROUND: We examined mortality in schizophrenia spectrum disorder (SSD) and non-schizophrenic psychosis (NSSD) compared to individuals without psychosis, and whether perinatal factors predict mortality. METHODS: Within Northern Finland Birth Cohort 1966 (n=10 933; 203 with SSD, 178 with NSSD), mortality was followed until end of 2011 by national register. Wantedness of pregnancy, mother's antenatal depression, smoking and age, parity, paternal socio-economic status (SES) and family type at birth were examined as predictors of mortality. RESULTS: Mortality was higher in SSD (hazard ratio (HR) 3.60; 95% confidence interval (CI) 2.38-5.45) and NSSD (4.05; 2.65-6.17) compared to persons without psychoses after adjustment for gender. HR for natural death was 2.01 (0.82-4.91) in SSD and 4.63 (2.43-8.80) in NSSD after adjustment for gender. Corresponding figures for unnatural deaths were 4.71 (2.94-7.54) and 2.94 (1.56-5.55), respectively. Among non-psychotic persons, mother's depression, smoking and low SES predicted mortality after adjustment for gender and parental psychoses (and SES), whereas among psychosis those whose father was a farmer had lower risk of mortality compared to those with high SES. CONCLUSIONS: Individuals with SSD had a higher risk of unnatural death and individuals with NSSD of natural and unnatural deaths. Perinatal factors seem to be more important predictors of mortality in individuals without psychoses than with psychoses. According to population-based long follow-up data, it is important to pay attention to somatic morbidity behind natural causes of death in psychoses and to prevent suicides in order to prevent excess mortality.

Incidence and Mortality of Solid Cancers in People Exposed In Utero to Ionizing Radiation: Pooled Analyses of Two Cohorts from the Southern Urals, Russia.

BACKGROUND: Previous studies have shown that acute external in utero exposure to ionizing radiation can increase cancer risk. It is not known whether chronic exposure at low dose rates, including due to radionuclide intake, influences the lifetime risk of solid cancers in the offspring. The objective of this study was to investigate solid cancer risk after in utero irradiation. METHODS: Cancer incidence and mortality over a 60-year period (from January 1950 to December 2009) were analyzed in the Urals Prenatally Exposed Cohort (UPEC). The cohort comprised in utero exposed offspring of Mayak Production Association female workers and of female residents of Techa River villages. Some of the offspring also received postnatal exposure, either due to becoming radiation workers themselves or due to continuing to live in the contaminated areas of the Techa River. The mortality analyses comprised 16,821 subjects (601,372 person-years), and the incidence analyses comprised 15,813 subjects (554,411 person-years). Poisson regression was used to quantify the relative risk as a function of the in utero soft tissue dose (with cumulative doses up to 944.9 mGy, mean dose of 14.1 mGy in the pooled cohort) and the postnatal stomach dose for solid cancer incidence and mortality. RESULTS: When a log-linear model was used, relative risk of cancer per 10 mGy of in utero dose was 0.99 (95% confidence interval (CI) = 0.96 to 1.01) based on incidence data and 0.98 (CI = 0.94 to 1.01) based on mortality data. Postnatal exposure to ionizing radiation was positively associated with the solid cancer risk in members of the UPEC, with a relative risk of 1.02 per 10mGy CI = 1.00 to 1.04). CONCLUSIONS: No strong evidence was found that chronic low-dose-rate exposure of the embryo and fetus increased the risk of solid cancers in childhood or in adulthood. For both incidence and mortality, a tendency towards a decreased relative risk was noted with increasing doses to soft tissues of the fetus. Further follow-up will provide more precise radiation risk estimates of solid cancer as cohort members are approaching their 60s and cancer becomes more common.

Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung.

RATIONALE: Infants born to diabetic or obese mothers are at risk of respiratory distress and persistent pulmonary hypertension of the newborn (PPHN), conceivably through fuel-mediated pathogenic mechanisms. Prior research and preventative measures focus on controlling maternal hyperglycemia, but growing evidence suggests a role for additional circulating fuels including lipids. Little is known about the individual or additive effects of a maternal high-fat diet on fetal lung development. OBJECTIVE: The objective of this study was to determine the effects of a maternal high-fat diet, alone and alongside late-gestation diabetes, on lung alveologenesis and vasculogenesis, as well as to ascertain if consequences persist beyond the perinatal period. METHODS: A rat model was used to study lung development in offspring from control, diabetes-exposed, high-fat diet-exposed and combination-exposed pregnancies via morphometric, histologic (alveolarization and vasculogenesis) and physiologic (echocardiography, pulmonary function) analyses at birth and 3 weeks of age. Outcomes were interrogated for diet, diabetes and interaction effect using ANOVA with significance set at p≤0.05. Findings prompted additional mechanistic inquiry of key molecular pathways. RESULTS: Offspring exposed to maternal diabetes or high-fat diet, alone and in combination, had smaller lungs and larger hearts at birth. High-fat diet-exposed, but not diabetes-exposed offspring, had a higher perinatal death rate and echocardiographic evidence of PPHN at birth. Alveolar mean linear intercept, septal thickness, and airspace area (D2) were not significantly different between the groups; however, markers of lung maturity were. Both diabetes-exposed and diet-exposed offspring expressed more T1α protein, a marker of type I cells. Diet-exposed newborn pups expressed less surfactant protein B and had fewer pulmonary vessels enumerated. Mechanistic inquiry revealed alterations in AKT activation, higher endothelin-1 expression, and an impaired Txnip/VEGF pathway that are important for vessel growth and migration. After 3 weeks, mortality remained highest and static lung compliance and hysteresis were lowest in combination-exposed offspring. CONCLUSION: This study emphasizes the effects of a maternal high-fat diet, especially alongside late-gestation diabetes, on pulmonary vasculogenesis, demonstrates adverse consequences beyond the perinatal period and directs attention to mechanistic pathways of interest. Findings provide a foundation for additional investigation of preventative and therapeutic strategies aimed at decreasing pulmonary morbidity in at-risk infants.

Babies of the War: The Effect of War Exposure Early in Life on Mortality Throughout Life.

There is increasing evidence that circumstances very early in our lives, and particularly during pregnancy, can affect our health for the remainder of life. Studies that have looked at this relationship have often used extreme situations, such as famines that occurred during wartime. Here we investigate whether less extreme situations during World War II also affected later-life mortality for cohorts born in Belgium, France, The Netherlands, and Norway. We argue that these occupied countries experienced a considerable deterioration in daily life situations and show that this resulted in strongly increased mortality rates and lower probabilities of survival until age 55 among civilian populations who had been prenatally exposed to wartime circumstances. However, this mortality effect among the prenatally exposed is entirely concentrated in the first years of life, particularly infanthood. Once we condition on having survived the first years of life, those who had been prenatally exposed do not have higher mortality rates. This suggests that "culling" is important and that effects found in earlier studies may have been biased downward substantially.

Maternal hypomagnesemia causes placental abnormalities and fetal and postnatal mortality.

INTRODUCTION: Magnesium (Mg(2+)) is essential for cellular growth and the maintenance of normal cellular processes. However, little is known about how maternal hypomagnesemia during pregnancy affects fetal growth and development. This study investigated the effects of maternal hypomagnesemia on the late gestation placenta and fetus, and postnatal outcomes until weaning. METHODS: Female CD1 mice consumed a control (0.2% w/w Mg(2+)), moderately Mg(2+) deficient (MMD; 0.02% w/w Mg(2+)) or severely Mg(2+) deficient (SMD; 0.005% w/w Mg(2+)) diet for 4 weeks prior to mating and throughout pregnancy. Dams were killed at E18.5 for embryonic studies or allowed to litter naturally and the offspring studied up to postnatal day 21. RESULTS: At E18.5, both Mg(2+) deficient diets decreased maternal plasma and bone Mg(2+) but only the SMD diet decreased fetal plasma Mg(2+). Maternal hypomagnesemia led to fetal loss and fetal growth restriction. Maternal Mg(2+) deficiency increased placental glycogen cell area and decreased spongiotrophoblast cell area while upregulating mRNA expression of the MagT1 Mg(2+) transporter in spongiotrophoblast cells. The SMD animals also displayed instances of gross placental abnormalities. After birth, pups in the SMD group had increased early postnatal mortality and failed to thrive. Pups in the MMD group underwent catch-up growth but remained shorter than controls at PN21 and were hypomagnesemic and hypoglycemic. CONCLUSIONS: These changes suggest that maternal Mg(2+) deficiency during pregnancy impairs placental development and fetal growth, which may have long-term health consequences for offspring. Collectively, these results have important implications for women who are Mg(2+) deficient during pregnancy.

Multisystem Morbidity and Mortality in Offspring of Women With Type 1 Diabetes (the EPICOM Study): A Register-Based Prospective Cohort Study.

OBJECTIVE: This study examined the long-term consequences for offspring born to mothers with pregestational type 1 diabetes regarding mortality, hospital admissions, and medication. We also examined the association between HbA1c levels during pregnancy and mortality and incidence of hospital admissions. RESEARCH DESIGN AND METHODS: We performed a prospective combined clinical and register-based cohort study comparing mortality, hospital admissions, and use of medication in offspring (n = 1,326) of women with pregestational type 1 diabetes (index children) with matched control subjects (n = 131,884). We also examined the association between HbA1c levels during pregnancy and mortality and the incidence of hospital admissions. Participants were monitored from birth to the age of 13-21 years. RESULTS: Overall mortality was significantly increased for index children (hazard ratio 2.10, 95% CI 1.33-3.30, P = 0.001). The incidence of hospital admissions for index children was significantly increased (incidence rate ratio [IRR] 1.45, 95% CI 1.38-1.53, P < 0.001), and this was the case for all age groups until the age of 15 years. The incidence of hospital admissions among index children was positively associated with maternal HbA1c before pregnancy and in the first trimester. In addition, the overall use of medication was increased in index children (IRR 1.13, 95% CI 1.07-1.19, P < 0.001). CONCLUSIONS: Type 1 diabetes during pregnancy has long-term implications on the health of offspring, with increased mortality, incidence of hospital admissions, and use of medication. Among mothers with type 1 diabetes, glycemic regulation is positively associated with incidence of hospital admissions in offspring.