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Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and placental weights, leading to the development of intrauterine growth restriction (IUGR). Electronic cigarettes (eCigs) represent a phenomenon that has recently emerged, and their use is also steadily rising. Even so, the effects of SHS or eCigs during gestation remain limited. In the present study, we wanted to characterize the effects of SHS or eCig exposure at two different important gestational points during mouse pregnancy. C57/Bl6 mice were exposed to SHS or eCigs via a nose-only delivery system for 4 days (from 14.5 to 17.5 gestational days (dGA) or for 6 days (from 12.5 dGA to 17.5 dGA)). At the time of necropsy (18.5 dGA), placental and fetal weights were recorded, maternal blood pressure was determined, and a dipstick test to measure proteinuria was performed. Placental tissues were collected, and inflammatory molecules in the placenta were identified. Treatment with SHS showed the following: (1) a significant decrease in placental and fetal weights following four days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. Treatment with eCigs showed the following: (1) a significant decrease in placental weight and fetal weight following four or six days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. We also observed different inflammatory markers associated with the development of IUGR or PE. We conclude that the detrimental effects of SHS or eCig treatment coincide with the length of maternal exposure. These results could be beneficial in understanding the long-term effects of SHS or eCig exposure in the development of placental diseases.

Introduction: Does an elevation in d-Galactose (D-Gal) levels within the body contribute to abnormal embryonic development and placental dysfunction during pregnancy?, Methods: Mouse embryos were cultivated to the blastocyst stage under varying concentrations of D-Gal. The blastocyst formation rate was measured, and the levels of reactive oxygen species (ROS), sirtuin 1 (SIRT1), and forkhead box O3a (FOXO3a) in blastocysts were assessed. Mice were intraperitoneally injected with either saline or D-Gal with or without SRT1720. On the 14th day of pregnancy, the fetal absorption rate and placental weight were recorded. Placental levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. The expression of senescence-related factors, such as senescence-associated β-galactosidase (SA-β-gal) in the placenta was examined, and the expression of placental SIRT1, FOXO3a and p21 was evaluated by immunohistochemistry and Western blotting., Results: D-Gal adversely affects early embryonic development in vitro, resulting in a decreased blastocyst formation rate. Furthermore, D-Gal downregulates SIRT1 and FOXO3a while increasing ROS levels in blastocysts. Concurrently, D-Gal induces placental dysfunction, characterized by an elevated fetal absorption rate, reduced placental weight, diminished SOD activity, and increased MDA content. The senescence-related factor SA-β-gal was detected in the placenta, along with altered expression of placental SIRT1, FOXO3a, and p21. The SIRT1 agonist SRT1720 mitigated this damage by increasing SIRT1 and FOXO3a expression., Discussion: The inhibition of early embryonic development and placental dysfunction induced by D-Gal may be attributed to the dysregulation of SIRT1. Activating SIRT1 emerges as a potentially effective strategy for alleviating the adverse effects of D-Gal exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000-2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Decidualization is a crucial precedent to embryo implantation, as its impairment is a major contributor to female infertility and pregnancy complications. Unraveling the molecular mechanisms involved in the impairment of decidualization has been a subject of interest in the field of reproductive medicine. Evidence from several experimental settings show that exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the expression of several molecules that are involved in decidualization. Both low and high doses of BPA impair decidualization through the dysregulation of estrogen (ER) and progesterone (PR) receptors. Exposure to low doses of BPA leads to decreased levels and activities of several antioxidant enzymes, increased activity of endothelial nitric oxide synthase (eNOS), and increased production of nitric oxide (NO) via the upregulation of ER and PR. Consequently, oxidative stress is induced and decidualization becomes impaired. On the other hand, exposure to high doses of BPA downregulates ER and PR and impairs decidualization through two distinct pathways. One is through the upregulation of early growth response-1 (EGR1) via increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2; and the other is through a reduced serum glucocorticoid-induced kinase-1 (SGK1)-mediated downregulation of epithelial sodium channel-α and the induction of oxidative stress. Thus, regardless of the dose, BPA can impair decidualization to trigger infertility and pregnancy complications. This warrants the need to adopt lifestyles that will decrease the tendency of getting exposed to BPA., (© 2020 Wiley Periodicals LLC.)

We have identified 9 pregnant patients who were diagnosed with malignancy and initiated chemotherapy during their second trimester (cervical cancer [n = 3], leukemia [n = 3], breast cancer [n = 2], and Hodgkin's lymphoma [n = 1]). Five of the patients' placentas were small for gestational age (SGA). Pathologic examination revealed inflammatory changes in 4 of the placentas: 2 from the SGA placentas and 2 from non-SGA placentas. Examination revealed 3 placentas with villitis of unknown etiology (VUE) and 1 with intervillositis; all were negative for bacterial and viral cultures and by immunohistochemical (IHC) stains. In the VUE cases, IHC stains showed positivity of CD25+/FOXP3+ with focal positivity and CD3 and CD4 IHC were focally to strongly positive. Literature suggests that the use of chemotherapy during pregnancy can be detrimental to both the mother and the fetus; however, there has been limited focus on the effects of chemotherapy on the placenta. We suggest that the inflammatory process noted in the placentas is due to chemotherapy-induced toxic effects.

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure., Competing Interests: The authors have declared that no competing interests exist.

Placental inflammation increases the risk of adverse pregnancy outcomes and possibly neurodevelopmental disorders in the offspring. Previous research suggests it may be possible to modulate the placental immune response to bacteria to favor an anti-inflammatory phenotype with dietary factors. Sulforaphane (SFN) is a dietary supplement with known anti-inflammatory activities, however, its effects on placental cytokine production are unclear. Therefore, we evaluated the effects of SFN on biomarkers of inflammation and neurodevelopment under basal conditions and a setting of mild infection. Placental explant cultures were established and treated with up to 10 μM SFN in the presence and absence of 10 7 CFU/ml heat-killed E. coli. Concentrations of IL-1β, TNF-α, IL-6, sgp130, HO-1 and BDNF in conditioned medium were quantified by immunoassay. SFN increased antioxidant HO-1 expression in the absence, but not the presence, of infection. SFN inhibited IL-1β and IL-10, but tended to promote, TNF-α production by bacteria-stimulated cultures. IL-6 and BDNF were inhibited by SFN irrespective of co-treatment with E.coli. A negative regulator of IL-6 signaling, sgp130, was increased by SFN under basal conditions, but not in E. coli-stimulated cultures. These results suggest that SFN has mixed effects on the placenta inhibiting both pro-inflammatory (IL-1β) and anti-inflammatory factors (IL-10) but promoting regulators of oxidative stress and inflammation (HO-1 and sgp130) in an infection-dependent manner., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Exposure to air pollution may adversely impact placental function through a variety of mechanisms; however, epidemiologic studies have found mixed results. We examined the association between traffic exposure and placental-related obstetric conditions in a retrospective cohort study on Cape Cod, MA, USA. We assessed exposure to traffic using proximity metrics (distance of residence to major roadways and length of major roadways within a buffer around the residence). The outcomes included self-reported ischemic placental disease (the presence of at least one of the following conditions: preeclampsia, placental abruption, small-for-gestational-age), stillbirth, and vaginal bleeding. We used log-binomial regression models to estimate risk ratios (RR) and 95% confidence intervals (CI), adjusting for potential confounders. We found no substantial association between traffic exposure and ischemic placental disease, small-for-gestational-age, preeclampsia, or vaginal bleeding. We found some evidence of an increased risk of stillbirth and placental abruption among women living the closest to major roadways (RRs comparing living <100 m vs. ≥200 m = 1.75 (95% CI: 0.82-3.76) and 1.71 (95% CI: 0.56-5.23), respectively). This study provides some support for the hypothesis that air pollution exposure adversely affects the risk of placental abruption and stillbirth; however, the results were imprecise due to the small number of cases, and may be impacted by non-differential exposure misclassification and selection bias., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

It is increasingly recognized that vitamin D3 (VitD3) has an anti-inflammatory activity. The present study investigated the effects of maternal VitD3 supplementation during pregnancy on LPS-induced placental inflammation and fetal intrauterine growth restriction (IUGR). All pregnant mice except controls were intraperitoneally injected with LPS (100 μg/kg) daily from gestational day (GD)15-17. In VitD3 + LPS group, pregnant mice were orally administered with VitD3 (25 μg/kg) before LPS injection. As expected, maternal LPS exposure caused placental inflammation and fetal IUGR. Interestingly, pretreatment with VitD3 repressed placental inflammation and protected against LPS-induced fetal IUGR. Further analysis showed that pretreatment with VitD3, which activated placental vitamin D receptor (VDR) signaling, specifically suppressed LPS-induced activation of nuclear factor kappa B (NF-κB) and significantly blocked nuclear translocation of NF-κB p65 subunit in trophoblast gaint cells of the labyrinth layer. Conversely, LPS, which activated placental NF-κB signaling, suppressed placental VDR activation and its target gene expression. Moreover, VitD3 reinforced physical interaction between placental VDR and NF-κB p65 subunit. The further study demonstrates that VitD3 inhibits placental NF-κB signaling in VDR-dependent manner. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity. Overall, the present study provides evidence for roles of VDR as a key regulator of placental inflammation.

Background: Prenatal drinking water exposure to tetrachloroethylene (PCE) has been previously related to intrauterine growth restriction and stillbirth. Pathophysiologic and epidemiologic evidence linking these outcomes to certain other pregnancy complications, including placental abruption, preeclampsia, and small-for-gestational-age (SGA) (i.e., ischemic placental diseases), suggests that PCE exposure may also be associated with these events. We examined whether prenatal exposure to PCE-contaminated drinking water was associated with overall or individual ischemic placental diseases., Methods: Using a retrospective cohort design, we compared 1,091 PCE-exposed and 1,019 unexposed pregnancies from 1,766 Cape Cod, Massachusetts women. Exposure between 1969 and 1990 was estimated using water distribution system modeling software. Data on birth weight and gestational age were obtained from birth certificates; mothers self-reported pregnancy complications., Results: Of 2,110 eligible pregnancies, 9% (N = 196) were complicated by ≥1 ischemic placental disease. PCE exposure was not associated with overall ischemic placental disease (for PCE ≥ sample median vs. no exposure, risk ratio (RR): 0.90; 95% confidence interval (CI): 0.65, 1.24), preeclampsia (RR: 0.36; 95% CI: 0.12-1.07), or SGA (RR: 0.98; 95% CI: 0.66-1.45). However, pregnancies with PCE exposure ≥ the sample median had 2.38-times the risk of stillbirth ≥27 weeks gestation (95% CI: 1.01, 5.59), and 1.35-times of the risk of placental abruption (95% CI: 0.68, 2.67) relative to unexposed pregnancies., Conclusions: Prenatal PCE exposure was not associated with overall ischemic placental disease, but may increase risk of stillbirth.

Assisted reproductive technologies (ART) have been associated with several adverse perinatal outcomes involving placentation and fetal growth. It is critical to examine each intervention individually in order to assess its relationship to the described adverse perinatal outcomes. One intervention ubiquitously used in ART is superovulation with gonadotropins. Superovulation results in significant changes in the hormonal milieu, which persist during the peri-implantation and early placentation periods. Epidemiologic evidence suggests that the treatment-induced peri-implantation maternal environment plays a critical role in perinatal outcomes. In this study, using the mouse model, we have isolated the exposure to the peri-implantation period, and we examine the effect of superovulation on placentation and fetal growth. We report that the nonphysiologic peri-implantation maternal hormonal environment resulting from gonadotropin stimulation appears to have a direct effect on fetal growth, trophoblast differentiation, and gene expression. This appears to be mediated, at least in part, through trophoblast expansion and invasion. Although the specific molecular and cellular mechanism(s) leading to these observations remain to be elucidated, identifying this modifiable risk factor will not only allow us to improve perinatal outcomes with ART, but help us understand the pathophysiology contributing to these outcomes.

Objective: Termination of pregnancy (TOP) for medical reasons is regularly performed using misoprostol. Presence of placental remnants followed by curettage, frequently complicate the procedure. Aim of this analysis is to audit our current policy for medical termination in late first and second trimester, looking at the management of third stage., Methods: A retrospective analysis of patient data was performed. Included were patients that underwent medical TOP in late first or second trimester. Patients were reviewed 6 weeks postdelivery. Characteristics of procedure, patient and pregnancy were analysed to determine factors associated with an increased risk of retained placenta/placental remnants., Results: We included 175 patients. Eighty-five patients (48%) underwent curettage immediately after delivery because of retained placenta or because placental remnants were suspected. Nineteen patients (11%) underwent curettage at later stage. All tissue was examined microscopically for confirmation of placental tissue. Analysis of characteristics of procedure, patients and pregnancies did not identify factors associated with an increased risk of retained placenta or placental remnants., Conclusion: A large number of immediate and late curettages was seen after medical TOP. Misoprostol-dose might play a role and the role of ultrasonographic assessment of the uterine cavity immediately post-placenta-delivery needs to be studied.

We have previously described diminished uterine progesterone response and increased uterine sensitivity to inflammation in adult female mice with a history of developmental exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). Since parturition in mammals is an inflammatory process mediated in part by a decline in progesterone action, toxicant-mediated disruption of progesterone receptor (PR) expression at the maternal-fetal interface would likely impact the timing of birth. Therefore, in the current study, we examined pregnancy outcomes in adult female mice with a similar in utero exposure to TCDD. We also examined the impact of in utero TCDD exposure of male mice on pregnancy outcomes in unexposed females since the placenta, a largely paternally derived organ, plays a major role in the timing of normal parturition via inflammatory signaling. Our studies indicate that developmental exposure of either parent to TCDD is associated with preterm birth in a subsequent adult pregnancy due to altered PR expression and placental inflammation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

During placentation, the concentration of fibrinous deposits on the surfaces of maternal vasculature plays a role in villous development and has been strongly implicated in the pathophysiology of human fetal growth restriction (FGR). Fibrinous deposits are conspicuous sites of platelet aggregation where there is local activation of the hemostatic cascade. During activation of the hemostatic cascade, a number of pro- and antiangiogenic agents may be generated at the cell surface, and an imbalance in these factors may contribute to the placental pathology characteristic of FGR. We tested the hypothesis that angiostatin(4.5) (AS(4.5)), a cleavage fragment of plasminogen liberated at the cell surface, is capable of causing FGR in mice. Increased maternal levels of AS(4.5) in vivo result in reproducible placental pathology, including an altered vascular compartment (both in decidual and labyrinthine layers) and increased apoptosis throughout the placenta. In addition, there is significant skeletal growth delay and conspicuous edema in fetuses from mothers that received AS(4.5). Maternally generated AS(4.5), therefore, can access maternal placental vasculature and have a severe effect on placental architecture and inhibit fetal development in vivo. These findings strongly support the hypothesis that maternal AS(4.5) levels can influence placental development, possibly by directly influencing trophoblast turnover in the placenta, and contribute to fetal growth delay in mice.

The biology of placental and fetal development suggests that alcohol may play a significant role in increasing the risk of feto-infant morbidity and mortality, but study results are inconsistent and the mechanism remains poorly defined. Previous studies have not examined the risk of placenta-associated syndromes (PASs: defined as the occurrence of either placental abruption, placenta previa, preeclampsia, small for gestational age, preterm, or stillbirth) as a unique entity. Therefore, we sought to examine the relationship between prenatal alcohol use and the risk of PAS among singleton births in the Missouri maternally linked data files covering the period 1989-2005. Logistic regression with adjustment for intracluster correlation was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Compared with nondrinkers, drinkers were more likely to be smokers, 35 years of age or older, black, and multiparous. Drinkers had an increased risk of PAS (OR=1.26, 95% CI=1.22,1.31) when compared with their nondrinking counterparts. The risk of PAS was progressively amplified with increasing prenatal alcohol consumption (P for trend <.01). Women who reported consuming five or more alcoholic drinks per week had more than twofold increased risk of PASs, whereas women in the lowest drinking category (one to two drinks per week) had only a slight increased risk of PAS (OR=1.09, 95% CI=1.05, 1.14). Enhanced understanding of the mechanism by which prenatal alcohol consumption leads to PAS may aid in the development of more targeted interventions designed to prevent adverse pregnancy outcomes. Screening women for alcohol use may assist providers in protecting developing fetuses from the potential dangers of prenatal alcohol use., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The aim of this study was to elucidate whether a novel mitochondrial antioxidant protein, SP-22, is localized in placenta and whether its expression is induced in placenta of lipopolysaccharide (LPS)-exposed mouse. Western blot analysis of normal human placenta indicated that the SP-22 protein was located in the mitochondrial fraction. Immunohistochemical analysis of SP-22 in normal placenta showed that immunoreactive SP-22 was distributed mostly in cytotrophoblastic cells but with almost no signal in syncytiotrophoblasts. The positive signals were also detected in the decidual cells and stromal cells in stem villi of normal placenta. We also examined LPS-mediated inflammatory placenta on day 13 of pregnancy at various time points after LPS injection (50 microg/kg, intraperitoneally). Western blot analysis indicated that LPS approximately quadrupled the expression of SP-22 in placenta of LPS-exposed mouse. When the SP-22 protein was localized immunohistochemically, the decidua and the diploid trophoblasts in the basal zone were intensively stained in placenta of LPS-exposed mouse compared to the control. The localization and inducible expression of SP-22 protein in placenta suggest a possible role in antioxidant system in mitochondria of normal and inflammatory placentae., (Copyright 2000 Harcourt Publishers Ltd.)

The use of antenatal dexamethasone to mature the fetal lung in pregnancies likely to deliver before 34 weeks is almost universal. It reduces the incidence of respiratory distress syndrome in the newborn and results in an overall improvement in neonatal morbidity and mortality. Although considered to be generally safe, there are concerns about adverse maternal and fetal effects. In a series of studies, we have found that antenatal dexamethasone administration is associated with reduced placental hormone production and maternal bone formation, impaired glucose tolerance and altered function of the hypothalamic-pituitary-adrenal axis. In this article, we have compared our data with other reports in the human and reviewed the relevant animal data. We conclude that further studies on the long-term effects of antenatal dexamethasone therapy in the human are warranted with particular emphasis on the long-term effects on the fetus.

This study evaluated the effects of chronic exposure to cocaine during pregnancy on the morphology and function of the placenta. Pregnant rats received either 45 or 60 mg/kg of cocaine hydrochloride by i.p. injection as a divided daily dose on days 8 to 18 of gestation. The maternal weight gain decreased by 20% to 24% (P < .05) in the two cocaine treatment groups, whereas the placental weight was not significantly altered. Fetal growth showed a dose-related decrease in the 45- and 60-mg/kg cocaine treatment groups; fetal body weights and length were significantly decreased by 5% to 10%. The plasma levels of cocaine were 0.79 and 1.09 micrograms/ml in the 45- and 60-mg treatment dose groups, respectively; the level in the fetal plasma was 3-fold higher in the latter group. Placental tissue explants were cultured in the presence of [35S]-methionine to investigate whether cocaine exposure altered placental protein synthesis. Secreted proteins were analyzed by polyacrylamide gel electrophoresis followed by fluorography or by western blotting and immunostaining with antibodies to placental prolactin-like proteins-B and -C and growth hormone-related protein-1. The data showed that there were no quantitative or qualitative changes in placental peptide hormone secretion as a result of the cocaine treatment. These data indicate that chronic cocaine exposure in the pregnant rat is associated with fetal growth retardation in the absence of alterations in placental morphology or secretory protein synthesis.

Induction of aryl hydrocarbon hydroxylase (AHH) activity in the placenta has been well documented. This enzyme may be induced by a variety of Polycyclic Aromatic Hydrocarbons (PAHs) and the AHH inducibility is associated with harmful effects of environmental chemicals. Toxic effects of PAHs in tissues such as placenta have been demonstrated to be due to their metabolites, epoxides, which interact with DNA. Thus, environmental PAHs may be related to its alterations in fetal development. Founded on these findings the PAH metabolites could interfere with the normal course of the pregnancy and may be an aborticide, a teratogen or a carcinogen. We hypothesize that low increased activity of placental Aryl Hydrocarbon Hydroxylase (AHH) may be an important determinant of human fetotoxicity. The present investigation was designed to examine the possible implications of PAH exposure at environmental exposure levels on the normal course of the pregnancy using AHH induction as an indicator of PAH exposure. Threatened Preterm Delivery (TPD) was used as an index of problems in the normal course of pregnancy. A group of forty pregnancies at term with TPD was compared with eighty controls for placental AHH induction. Macroscopic placental examination was also performed. A significant increase in prevalence of placental AHH induction with TPD was shown (Odds-Ratio = 2.8; 95% confidence bounds [1.3-6.2]; chi 2 = 6.7 p < 0.01). No such increases were found associated with placental pathology. When taking into account the group of placenta without basal plate calcifications, the significant increase in prevalence of placental AHH induction with TPD above mentioned was greatly increased (Odds-Ratio = 8.9; 95% confidence bounds [2.4-32.9]; chi 2 = 11.1 p < 0.001) controlling for gestational age. The increase in prevalence of placental AHH induction with TPD disappeared when taking into account the subgroup with basal plate or parenchyma calcifications. It is hypothesized that the high estrogen and progesterone at term may explain these associations.

The effect of mercury (HgCl2) on placental amino acid and glucose transfer as determined by the use of their nonmetabolizable radioactive analogues, aminoisobutyric acid (AIB) and 3-o-methyl glucose (3MG), respectively, was studied in an in vitro perfusion model of a term human placenta. Hg2+ was found to decrease the transfer and accumulation of AIB without affecting 3MG transfer. It was also found to decrease the placental oxygen consumption rate. Placental circulation and tissue morphology remained intact, as demonstrated by the antipyrine transfer rate, and by electron microscopy, respectively. The mechanism by which Hg2+ may interfere with placental amino acid transfer and accumulation is discussed. Although much higher concentrations than those found in the ordinary polluted environment were used, this is the first report showing that Hg2+ interferes with an essential human placental function in a system employing a whole human placental cotyledon. This finding may indicate the possible involvement of Hg2+ in impaired organogenesis in early pregnancy or deranged fetal growth during the last trimester.

The pathogenesis of the FAS, particularly the characteristic IUGR, may be due in part to ethanol-related placental injury. Ethanol and/ or acetaldehyde may impair placental transfer of nutrients essential for growth, e.g., amino acids. Such restriction could occur regardless of maternal nutritional status: selective fetal malnutrition. Impairment of placental nutrient transport at critical phases of fetal organogenesis could compound any direct fetotoxic effects of ethanol or acetaldehyde. The effect of ethanol upon human placental hormone synthesis and transport of vitamins, minerals, glucose, and nucleic acid precursors awaits further investigation. Similarly, potential interactions between ethanol and other xenobiotics commonly abused by alcoholics require clarification.

Whether differences in foetoplacental weight and post-implantation mortality in rodents are secondary to heterosis and inbreeding depression or antigenic differences between mother and foetus has been a continuing controversy. To determine whether non-specific depression or stimulation of the maternal immune system affects the success of the foetoplacental allograft, groups of virgin Fischer (Ag-B1) females of similar age and weight mated with DA (Ag-B4) males were treated with daily intraperitoneal injections of: (a) saline, (b) methylprednisolone (MP), 1-0 mg/kg, (c) cyclophosphamide (CY), 3.0 mg/kg, or (d) azathioprine (AZ), 3.0 mg/kg; or they were injected intraperitoneally on the fifth day of gestation with: (a) B. pertussis, 1.0 ml, (b) C. parvum, 0.2 ml, or (c) BCG, 0.1 ml. None of the immunostimulating agents were detrimental to the progeny, but the immunosupprissive drugs caused an increased percentage of foetal deaths and foetoplacental growth retardation. The reduced foetal and placental size induced by CY or AZ could be partially blocked by simultaneous maternal treatment with BCG. Analysis of mean maternal weight gain, spleen weight assays, changes in the lymph nodes draining the uterus and comparison of data from non-pregnant animals and syngeneic pregnancies treated with these agents suggest that immunosuppressive drugs reduce foetal survival rates and produce foetoplacental growth retardation via a combination of immunological and cytotoxic mechanisms.

Methylmercury (MeHg: 5 mg Hg/kg maternal body weight) in 0.13 M NaCl, 0.01 M NaH2PO4-Na2HPO4, pH 7.4 (PBS) administered to gravid CFW mice on day 12, hour 6 (12(6)) of gestation induced a high incidence of cleft palate in fetuses examined on days 15(6) (72%), 16(6) (62%) and 17(6) (40%). Palate closure (100%) in PBS control animals occurred by 14(10). One day post MeHg administration, total fetal protein was decreased 22% while DNA content was unaltered. Protein was maximally decreased (28%) on 14(6) and, thereafter, returned toward control levels. Alterations in DNA content followed a similar pattern; but the maximal decrease (32%) occurred on 15(6). The rate of fetal protein synthesis was depressed 5% at 12(9) and between 20% to 26% from this time to 13(6) (end of observation). The agreement between the calculated decrease in protein synthesis (19%) and the measured decrease in protein content (22%) suggests that a reduction in protein synthesis is responsible for the decreased fetal protein content. Placental blood flow and fetal water space, measured with 3H--H2O at 12(18), were not affected by MeHg treatment. However, fetal free amino acid concentrations at 12(18) were generally decreased (alanine, 23.0%; valine, 9.7%; methionine, 22.6%; isoleucine, 12.0%; leucine, 18.2%) while uptake of the non-metabolizable amino acid, 14C-cycloleucine, was decreased 23%. From this, it is concluded that the growth inhibitory effects of MeHg are related, at least in part, to impaired placental/fetal transfer of amino acids.

Placentas of different gestational age from women with oral contraception in the early phase of gravidity were studied morphometrically. An elevated risk for a placental insufficiency could not be found.

An acute dose (10 mg/100 g body weight) of biotin at the post-implantation stage (day 14 and 15) inhibited the fetal and placental growth, and in few rats it also caused resorption of fetuses and placentae. The maintenance of pregnancy with normal fetal and placental growth was effected with estrogen therapy, but progesterone failed to correct the biotin-induced effect. The uterine and placental glycogen, RNA and protein levels, as well as, glucose-6-phosphate dehydrogenase activity in the ovary, liver and uterus showed a reduction following biotin treatment. Estrogen therapy under such conditions corrected these adverse effects of biotin overdose, while progesterone had no significant effects. The study suggests that the acute dose of biotin at an advance stage of pregnancy may cause adverse effects on the physiological regulation of gestation, possibly by creating deficiency of estrogen and gestagen. The possible role of estrogen in the fetal and placental growth and regulation of gestagen secretion is discussed.

Under the influence of atmospheric pollutions certain structural-functional changes take place in placenta: terminal villi per stipulated square unite, villi with desquamated epithelium, with dilated vessels, with deposition of fibrinoid masses, with plasmodial buds increase in number; section area occupied by epithelial layer decreases; RNA concentration and histoenzymatic activity change in the latter.

Plasma polyps can be found at the end of a normal pregnancy. Following NaF and MJA-intoxication, there is an extreme increase of plasma polyps. This accelerated formation can be prevented by the injection of Na-pyruvate and often the number of polyps can be reduced below the norm. 2,4-Dinitrophenol intoxication and breathing of hypoxic gas mixture (2,5% O2, 5% CO2, 92,5% N2) do not lead to increased plasma polyp formation. This proves, that it is not hypoxia, not an energy deficit secondary to separation of oxydative phosphorylation and not cardiac insufficiency leading to secondary ischemia which are responsible for the extreme increase in the number of plasma polyps following the injection of MJA and NaF.

The effect of maternal envenomation with N. nigricollis venom on the placental tissues was studied in mice. The venom seemed to exert a direct toxic effect on the constituent parts of the placenta. Glycogen appeared to advantage in the cells of the trophospongeal part of the placenta. Giant cells and basophilic cells were encountered around such glycogen cells. However, some giant cells showed vacuolation of the cytoplasm and pyknosis of the nuclei. The labyrinthine part of the placenta showed large and multiple small thrombi and congestion of the blood spaces. Again glycogen appeared to advantage in the syncytial cells. Non cellular exudate was also met with in such cases. The possible mechanisms of these changes were discussed.

Forty-eight hours after oral administration of a single dose (3.0 mg/kg BW) of T-2 toxin to mice on days 7, 8, 10, 11 and 12 of pregnancy, 17% maternal mortality following vaginal hemorrhage was encountered. Necropsy examination of the dead females revealed that massive hemorrhages originating from the placental regions had occurred into the reproductive tract. This observation supports the studies in which hemorrhagic disease has been described as characteristic for intoxications with T-2 toxin. The results suggest that fatal hemorrhage during pregnancy can occur in hemochorial and hemoendotheliochorial placental mammals as a result of T-2 toxin administration.

Ampicillin administration during pregnancy exerted no toxic effect on the developing fetus. However, it decreased the body weight of the progeny and the weight of the placenta. Oxacillin had an adverse effect on the pregnancy, labor, fetus and newborn. It is inferred that ampicillin can be used for treatment purposes at any time of the pregnancy whilst oxacillin administration might involve a high risk for the mother, fetus and newborn.

Ergocalciferol (320,000 or 480,000 IU/kg) plus cholesterol (60 mg/kg) in olive oil solution was administered daily on 1, 2, or 4 consecutive days to pregnant rats from 9,10, 14, or 18 of gestation. The control animals received only olive oil. Disseminated lesions of metastic calcinosis were found in various tissues, in the coronary arteries and myocardium, in the media of the abnormal aorta, in the lung and pleura, in the gastoinstestinal tract, and in the kidney. This is in contrast to the atherosclerosis described in nonpregnant rats fed a similiar diet. A significant decline in maternal weight as well as a high rate of morbidity and mortality was observed. In mothers killed on day 22 of pregnancy, fetal and placental growths appeared significantly retarded suggesting a direct effect of the steroid or its more active metabolite, 1,25-dihydroxycholecalciferol, on the fetus or the trophoblastic tissue. Fetal bone lesionsassociated with a generalized retardation of ossification, placental edema, or calcification accompanied by a loss of the normal structure of the placenta and degenerative manifestation at this level were observed. Moreover, we noted a striking alteration of the fetal face in 33-39% of experimental fetuses, called by us carnival fetuses.

Acute maternal hypervitaminosis A established on Day 9 of gestation in Sprague-Dawley-derived rats caused a dose-related increase in the resorption of implants. The median embryolethal dose was 189,000 i.u./kg. In addition to suppression of the allantois leading to placental agenesis, damaged embryos showed retarded somatic development and hydraemia, all apparent 24 h after treatment. At about Day 11 the hydraemia involved the visceral wall of the yolk sac causing death of the embryo soon after. The fluid in the vitelline vessels continued to collect until Day 13 when it absorbed following necrosis of the wall of the yolk sac. Two mechanisms are suggested for the embryonal hydraemia: either the excess fluid resulted from a permeability disorder induced by the vitamin A; or it was retained metabolic water or water specifically absorbed to inflate the allantois and, being unused for this purpose, it pooled in the blood vessels of the embryo. The yolk sac hydraemia is more likely to have followed injury to the proximal endoderm.