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.

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.

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.

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.

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.

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

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

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

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

Cardiovascular mortality in relation to birth weight of children and grandchildren in 500,000 Norwegian families.

AIMS: Cardiovascular diseases (CVDs) have been related to low birth weight, suggesting the foetal environment may program future risk. Alternatively, common genetic factors for both low birth weight and CVD could explain such associations. We investigated associations between offspring birth weight and paternal and maternal cardiovascular mortality and offspring birth weight and cardiovascular mortality among all four grandparents, and further assessed the mediating role of maternal smoking during pregnancy. METHODS AND RESULTS: All births from 1967 to 2008 that could be linked to parents and grandparents comprised the population (n = 1,004,255). The mortality follow-up among parents was from 1970 to 2008 and among grandparents from 1960 to 2008. The association of grandparental mortality with maternal smoking during pregnancy was analysed in a subpopulation of those born after 1997 (n = 345,624). Per quintile higher in birth weight was related to 0.82 (0.75-0.89) hazard ratio from coronary heart disease in mothers and 0.94 (0.92-0.97) in fathers. For stroke, these were 0.85 (0.78-0.92) and 0.94 (0.89-1.00), respectively. In grandparents for cardiovascular causes, the effects were 0.95 (0.93-0.96) (maternal grandmother), 0.97 (0.96-0.98) (maternal grandfather), 0.96 (0.94-0.98) (paternal grandmother), and 0.98 (0.98-1.00) (paternal grandfather). Adjusting for maternal smoking in pregnancy in the subpopulation accounted for much of the effect on grandparental cardiovascular mortality in all categories of birth weight. For grandparental diabetes mortality, U-shaped associations were seen with grandchild birth weight for the maternal grandmother and inverse associations for all other grandparents. CONCLUSION: Associations between CVD mortality in all four grandparents and grandchild birth weight exist, and while genetic and environmental factors may contribute to these, it appears that there is an important role for maternal smoking during pregnancy (and associated paternal smoking) in generating these associations. For diabetes, however, it appears that intrauterine environmental influences and genetic factors contribute to the transgenerational associations.

Mortality rate in children born to mothers and fathers with celiac disease: a nationwide cohort study.

Celiac disease (CD) is associated with increased mortality rate and adverse pregnancy outcome, but little is known about offspring mortality rate. In this nationwide retrospective cohort study, we identified persons whose biopsy-verified CD was diagnosed in Sweden in 1969-2008. We compared mortality rates in children born to mothers with and without CD (n = 16,121 vs. n = 61,782) and children born to fathers with and without CD (n = 9,289 vs. n = 32,984). Median age of offspring at end of follow-up was 28.7 (range, 16.7-39.7) years. We also examined mortality rates in children born to mothers with undiagnosed CD (later CD diagnosis; n = 12,919) and diagnosed CD (n = 3,202) to determine if intrauterine exposures associated with CD could affect offspring mortality rate. We estimated hazard ratios for death by using Cox regression. Death rates were independent of maternal CD (60 deaths per 100,000 person-years in children of mothers with CD, vs. 54 in controls) and paternal CD (53 deaths per 100,000 person-years in children of fathers with CD, vs. 53 in controls). Corresponding adjusted hazard ratios were 1.09 (95% confidence interval: 0.95, 1.26) for maternal CD and 1.02 (95% confidence interval: 0.85, 1.23) for paternal CD. Death rates were similar in children born to mothers with undiagnosed CD and in children whose mothers had diagnosed CD during pregnancy. Parental CD does not seem to influence mortality rate in offspring, which suggests that neither genetic influences of CD nor intrauterine conditions have adverse effects on offspring mortality rate.

Effect of heavy metals in the meconium on preterm mortality: preliminary study.

BACKGROUND: There have been many studies that have investigated the risk factors of mortality in preterm infants, but none has shown an association between preterm mortality and exposure to heavy metals or trace elements. The aim of this study was therefore to measure the levels of toxic metals (lead, cadmium) and trace elements (zinc, iron, copper) in meconium samples and elucidate their association with preterm mortality. METHODS: Metals and trace elements were measured in the meconium of 304 preterm infants using a flame atomic absorption spectrophotometer. RESULTS: The level of heavy metals and trace elements in non-surviving infants was significantly higher than in surviving infants. Moreover, the level of heavy metals and trace elements in non-surviving infants whose gestational age was <30 weeks (n = 11) was significantly higher than in surviving infants (n = 12). Receiver operating characteristic curve analysis showed that gestational age and meconium lead level predicted early mortality in premature newborns. Furthermore, this curve analysis showed that, when comparing meconium lead level and gestational age, meconium lead level had a similar effect on mortality as gestational age. CONCLUSION: Meconium lead level and gestational age are associated with increased mortality risk in preterm neonates.

Perinatal supplementation with thymoquinone improves diabetic complications and T cell immune responses in rat offspring.

BACKGROUND: Epidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications later in life compared to offspring born to nondiabetic mothers. AIM OF THE STUDY: We investigated whether supplementation with a natural antioxidant (thymoquinone; TQ) in female rats with streptozotocin (STZ)-induced gestational diabetes (GD) improved diabetic complications and T cell immune responses in their offspring. METHODS: Three groups of female rats were tested: nondiabetics, diabetics treated with TQ during pregnancy and lactation periods and diabetics that were not treated with TQ (n=10 female rats in each group). RESULTS: Our data demonstrated a significant decrease in the numbers of neonates born to diabetic rats compared with those born to control rats. GD led to macrosomic pups with several postpartum complications, such as a significant increase in plasma levels of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α (but not of IL-10); a marked decrease in the plasma level of IL-2; a marked reduction in the proliferative capacity of superantigen (SEB)-stimulated T-lymphocytes; and an obvious reduction in the number of circulating and thymus homing T cells. TQ supplementation of diabetic mothers during pregnancy and lactation periods had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the IL-2 level and T cell proliferation and subsequently rescued both circulating and thymus homing T cells in the offspring. CONCLUSIONS: Our data suggest that nutritional supplementation of GD mothers with the natural antioxidant TQ during pregnancy and lactation periods improves diabetic complications and maintains an efficient T cell immune response in their offspring, providing a protective effect in later life.

Maternal birth characteristics and perinatal mortality in twin offspring. An intergenerational population-based study in Norway, 1967-2008.

OBJECTIVE: To investigate the relationship between maternal preterm birth and fetal growth in one generation and perinatal mortality of twin offspring in the next generation. DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway from 1967 to 2008. POPULATION: Linked generational data with 9426 mother-twin pair units. METHODS: Twin offspring were linked to their mothers by means of the unique national identification numbers. MAIN OUTCOME MEASURES: Perinatal mortality in twin offspring. RESULTS: The twin prevalence was not dependent on the mother's gestational age at birth, but increased with increasing birthweight in term mothers. Maternal gestational age was strongly and inversely associated with a risk of perinatal death in one or both of her twin offspring. Compared with term mothers, preterm mothers born at 27-31 and 32-34 weeks had relative risks (RRs) for perinatal loss of 3.83 [95% confidence interval (CI), 1.56-9.36] and 2.41 (95% CI, 1.29-4.50), respectively. This effect was even stronger after the use of assisted reproductive technologies (ART), with a significant interaction between maternal gestational age and ART (P = 0.03). Further, term mothers with birthweight-by-gestational age Z-scores of -2 or less had more than twice the risk of a perinatal loss in their twin offspring relative to mothers with the most favourable birthweight Z-scores (1-1.99) [RR, 2.42 (95% CI, 1.37-4.29)]. CONCLUSIONS: Women born preterm had an increased risk of perinatal mortality in their twin offspring, particularly after ART treatment. The same was true for women who were growth restricted at term. A twin pregnancy is a high-risk pregnancy in general, but even more so if the mother herself was born preterm or was growth restricted at birth.

Sex differences in the consequences of early-life exposure to epidemiological stress--a life-history approach.

OBJECTIVES: Exposure to infectious disease in early life has been suggested to have a negative effect on later-life survival,possibly through the induction of inflammatory responses. Although a life-course perspective emphasizes the importance of both survival and reproduction for individual fitness, to date, no studies have investigated whether early-life exposure to infectious disease has an impact on reproduction as it has been suggested for later survival. METHODS: To address this question, I have used family reconstitution data from a historical (18th and 19th century) human population in the Krummhörn (Germany) comparing survival and reproduction between an exposed and a non-exposed group. The exposed group comprised those exposed to a high-infectious disease load during prenatal and early postnatal development. RESULTS: The results show a marked sex difference in the impact of early-life exposure to infectious disease. Exposed females show no effect on their life expectancy but significantly reduced fertility (number of children). For exposed males, however, the effect on survival is opponent over time: mortality is increased during childhood but decreased in late adulthood. Above that, exposed males reproduce earlier and have a smaller proportion of surviving children. CONCLUSIONS: This study does not support former studies indicating a negative association between early-life disease load and later survival. I argue that due to differences in male and female life strategies, males in general are more vulnerable especially early in life. Hence, adverse environmental conditions may have a stronger effect on male survivability and reproductive performance.

Early healthcare utilization and welfare interventions among children of mothers with alcohol and substance abuse: a retrospective cohort study.

AIM: Early childhood healthcare utilization, mortality and welfare interventions were studied among children of mothers with identified gestational alcohol and/or substance abuse. METHODS: Register-based retrospective cohort study. The exposed cohort consisted of 638 children born to 524 women followed up antenatally 1992-2001 at special outpatient clinics in the capital area of Finland. Nonexposed children (n = 1914) born to control women were matched for maternal age, parity, number of foetuses, month of birth and delivery hospital of the index child. Postnatal data of both cohorts were collected from national registers until 2007. RESULTS: The exposed cohort displayed twice the amount of in- and outpatient hospital care episodes compared with nonexposed children. Differences attributable to exposure were found in categories of conditions originating in the perinatal period, mental and behavioural disorders, and nonspecific factors influencing health status and contact with health services. This was reflected in amounts of reimbursements for drugs of the central nervous system, as well as special care allowances and rehabilitation for mental and behavioural disorders. The highest degree of healthcare utilization was observed among exposed children placed in out-of-home care. One-third of these children received outpatient care and one-tenth required inpatient care for a mental and behavioural disorder. No significant differences were found in early mortality. CONCLUSION: The exposed children displayed significant neonatal and early mental and behavioural healthcare utilization, and need for significant psychosocial support during their first decade of life.

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.

Changes in biologic and/or immunologic parameters induced by intratracheal instillation of pregnant mice with benzo(a)pyrene are potentially confounded by anesthesia.

Benzo(alpha)pyrene (B(alpha)P) is a potent multiorgan carcinogen released into the atmosphere from commercial, domestic, and industrial sources. Studies using animal models have shown that giving B(alpha)P parenterally to pregnant animals (i.e., dams) led to increased tumor frequency and sensitivity to tumorigenesis in their progeny. The authors' studies also showed that the progeny of the B(alpha)P-exposed dams displayed increased deficiencies in cell-mediated and humoral immune functions, changes among T-cell subsets in developing lymphoid tissues, and significant expression of B(alpha)P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts in thymic, splenic, and (fetal) liver tissues. The authors evaluated whether similar biologic/immunologic effects of B(alpha)P seen earlier in parenterally exposed mouse dams (and offspring) occurred if dams were exposed to B(alpha)P via the lungs. Pregnant dams were subjected to intratracheal instillation of B(alpha)P (at 1 mg/ml corn oil, 0.1 ml/instillate) beginning on day 11 of pregnancy (GD 11) and again on GDs 12 and 14. In each case, the dams were anesthetized with metofane. Other dams were left untreated (controls), anesthetized only, or anesthetized and then instilled with vehicle. Effects of the B(alpha)P exposures included lower dam body weights during gestation, decreased postbirth pup survival, increased pup tumor frequency, and decreased mixed-lymphocyte responses by pup lymphocytes. These studies also revealed that metofane imparted effects on the dams and progeny. These effects equaled the B(alpha)P treatments alone; in other instances, the metofane had no impact, and thus questions the observed biologic/immunologic effects of B(alpha)P induced in pregnant mice (and their progeny), which might have been confounded by use of this (or potentially other) anesthesia.

Effect of astragaloside IV on the general and peripartum reproductive toxicity in Sprague-Dawley rats.

Fertility and early embryonic developmental toxicity in rats were evaluated by intravenously administering astragaloside IV (AS-IV) daily at 0.25, 0.5, and 1.0 mg/kg for 4 weeks before mating, throughout the mating period, and continuing to day 6 of gestation period in females. Perinatal toxicity in rats was evaluated on gestational days (GD) 15 to 21 and lactational days LD (LD) 1 to 21. Astragaloside IV had no maternal toxicity at 0.25 to 1.0 mg/kg in rats. Although it has an inhibitory effect on female fertility in F0/F1 rats, AS-IV was devoid of early embryonic developmental toxicity in F0/F1 rats and in the survival parameters of F1 postnatal rats. Maternal AS-IV exposure at the dose of 1.0 mg/kg per d resulted in a significant delay in time for fur development, eye opening, and cliff parry reflex of pups compared to control group (P < .05), whereas it did not affect the memory and learning of F1 pups.