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Intrapartum factors, IOL and autism risk
Abstracts / Placenta 45 (2016) 63e133
stabilize TNF mRNA, and (3) the PlGF effect was noted only with specific TLR ligands. In kinetic studies we quantified equivalent increases in both spliced and unspliced TNF mRNA and TNF protein, and PlGF prolonged the duration of TNF gene transcription. Additionally, PlGF enhanced TNF production early, and later the production of TNF-independent inflammatory cytokines. PlGF markedly enhanced R848-induced phosphorylation of IkappaB kinase (IKK), and pharmacologic IKK inhibition suppressed the PlGF effect on R848-induced TNF expression. Finally, we observed a positive correlation between increasing plasma levels of PlGF and TNF in women throughout pregnancy. Conclusion: We suggest that PlGF directly contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists. We propose that this aberrant inflammatory environment contributes to maternal and fetal morbidity in the setting of infectious complications during pregnancy.
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P1.53 THE PERIODONTAL BACTERIUM PORPHYROMONAS GINGIVALIS IMPAIRS SPIRAL ARTERY REMODELLING AND INDUCES ACUTE ATHEROSIS IN A RAT MODEL OF PERIODONTITIS Mary Brown 1, Priscilla Phillips 3, Ann Progulske-Fox 2, Leticia Reyes 2, 4. 1 University of Florida, Department of Infectious Disease and Pathology, Gainesville, FL, USA; 2 University of Florida, Department of Oral Biology, Gainesville, FL, USA; 3 A.T. Still University of Health Sciences, Department of Microbiology & Immunology, Kirksville, MO, USA; 4 University of Wisconsin e Madison, Department of Pathobiological Sciences, Madison, WI, USA
Porphyromonas gingivalis (Pg) is a periodontopathogenic bacterium that has been linked to early onset preeclampsia (PE). Since impaired physiologic remodelling of the uterine spiral arteries is a significant component in the pathogenesis of early onset PE, we proposed Pg infection disrupts this process leading to placental abnormalities and fetal distress. Using a standard periodontitis model, virgin female rats received repeated oral inoculations of sterile vehicle (control), Pg strain W83, A7A1-28, 381, or A7436 for three months prior to breeding. Uteroplacental tissues and fetuses were collected for analysis at gestation day 18. Remodelling of spiral arteries in the metrial triangle were quantified by morphometry of endothelial cell (anti-CD31), smooth muscle cell (a-actin) staining of the vessel wall and infiltration of the uterus by extravillous trophoblasts (cytokeratin 7), measured as % area. Spiral artery remodelling was significantly reduced in animals infected with Pg A7A1-28 or A7436 as indicated by increased CD31and a-actin, and reduced cytokeratin staining within the metrial triangle (P <0.001). Pg A7A1-28 and A7436 infected animals also exhibited acute atherosis (AA) characterized by fibrinoid necrosis of the uterine artery with infiltration of CD68+/TNF-a+ macrophages within the vessel wall (P < 0.01). Pg A7A1-28 antigens were detected in the uterine stroma, chorionic plate mesenchyme and umbilical artery. Placentas from Pg A7A128 infected dams had a greater density of proliferating mesenchymal cells (PCNA +) in the chorionic plate and umbilical cord than control dams (P < 0.05). Fetuses from dams with reduced spiral artery remodelling and AA were larger than control dams and Pg infected dams without these lesions (P < 0.01); litter sizes were equivalent among groups. Our results demonstrate that certain wildtype Pg strains can disrupt normal placentation by impairing the physiologic remodelling of the uterine arteries during pregnancy, which may have consequences on maternal and fetal health.
89
P1.54 INTRAPARTUM FACTORS, IOL AND AUTISM RISK Carolyn Salafia 1, 2, Jennifer Straughen 3, Gabriela Perez-Avilan 2, Victoria Onbreyt 1, Beata Dygulska 1, Sandford Lederman 1, Pramod Narula 1. 1 New York Methodist Hospital, Brooklyn, NY, USA; 2 Placental Analytics, LLC, New Rochelle, NY, USA; 3 Henry Ford Hospital, Detroit, MI, USA Objectives: Is oxytocin during IOL and/or labor augmentation associated with increased ASD risk independent of reason for IOL and other medications used during IOL. Methods: Our case-control sample was drawn from a population based sample at a large urban community based hospital (New York Methodist Hospital) from 2007 to 2014, during which time there was universal placental examination of births. We study a unique population based cohort with a total of 51 cases (39 males, 12 females) and 183 controls (138 males, 45 females), matched for gestational age, gender, and maternal age. Conditional odds ratios (COR) and 95% confidence intervals (CI) were calculated. Results: Labor Factors:
More ASD cases has IOL (COR¼3.7 (95% CI¼1.9, 7.5). The association did not change after adjustment for maternal conditions. More ASD cases were exposed to oxytocin (31% v. 16.5%, COR ¼2.61; 95% CI 1.34,5.08). Since >80% of IOL received oxytocin, the two factors could not be separated in this analysis due to sample size. Total oxytocin dose was not associated with ASD. After adjustment for oxytocin, prostaglandins (Cervidil) and Misoprostol (Cytotec) had no association with ASD. Labor augmentation was not associated with ASD (p¼0.71). Mode of delivery was not associated with ASD (p¼0.055). Conclusions: Based on our preliminary data, IOL and oxytocin exposure both showed a statistically significant association with ASD. Augmentation of labor had no association with ASD. We suspect that it is the indications for IOL, rather than induction that are related to ASD, although a combination variable or “any maternal”, or “any fetal” indications did not alter the OR of the association. P1.55 MECHANISTIC STUDY OF HUMAN PLACENTAL INFECTION BY LISTERIA MONOCYTOGENES Joanna Marshall 1, John Robinson 1, William Ackerman 1, Catalin Buhimschi 1, Yoel Sadovsky 2, Stephanie Seveau 1. 1 The Ohio State University, Columbus, OH, USA; 2 Magee-Womens Research Institute, Pittsburgh, PA, USA A key function of the placenta is to protect the developing fetus against pathogens. The barrier function of the syncytiotrophoblast at the interface with maternal blood is crucial for this protection. This protection is so efficient that only a few pathogens can circumvent it. Little is known about the innate defense mechanisms used by the syncytiotrophoblast to prevent most infections. Also, there is a lack of understanding of the mechanisms by which pathogens overcome the placental innate defense. (Objective) To solve these gaps in our knowledge, we study the interplay between human placental cells and Listeria monocytogenes, the etiologic agent of the life-threatening foodborne illness listeriosis. Previous studies convincingly argued that L. monocytogenes enters the placenta by invading extravillous cytotrophoblasts and/or the syncytiotrophoblast. However, the fate of L. monocytogenes within and beyond those cells remains unsolved. (Methods) We used the BeWo cell line and isolated primary cytotrophoblasts and fibroblasts from term human placenta. The percentage of cell fusion, cell integrity, and production bHCG were measured by fluorescence microscopy, LDH assay, and ELISA, respectively. Purity of isolated primary cells was established by flow cytometry
stabilize TNF mRNA, and (3) the PlGF effect was noted only with specific TLR ligands. In kinetic studies we quantified equivalent increases in both spliced and unspliced TNF mRNA and TNF protein, and PlGF prolonged the duration of TNF gene transcription. Additionally, PlGF enhanced TNF production early, and later the production of TNF-independent inflammatory cytokines. PlGF markedly enhanced R848-induced phosphorylation of IkappaB kinase (IKK), and pharmacologic IKK inhibition suppressed the PlGF effect on R848-induced TNF expression. Finally, we observed a positive correlation between increasing plasma levels of PlGF and TNF in women throughout pregnancy. Conclusion: We suggest that PlGF directly contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists. We propose that this aberrant inflammatory environment contributes to maternal and fetal morbidity in the setting of infectious complications during pregnancy.
Ă
P1.53 THE PERIODONTAL BACTERIUM PORPHYROMONAS GINGIVALIS IMPAIRS SPIRAL ARTERY REMODELLING AND INDUCES ACUTE ATHEROSIS IN A RAT MODEL OF PERIODONTITIS Mary Brown 1, Priscilla Phillips 3, Ann Progulske-Fox 2, Leticia Reyes 2, 4. 1 University of Florida, Department of Infectious Disease and Pathology, Gainesville, FL, USA; 2 University of Florida, Department of Oral Biology, Gainesville, FL, USA; 3 A.T. Still University of Health Sciences, Department of Microbiology & Immunology, Kirksville, MO, USA; 4 University of Wisconsin e Madison, Department of Pathobiological Sciences, Madison, WI, USA
Porphyromonas gingivalis (Pg) is a periodontopathogenic bacterium that has been linked to early onset preeclampsia (PE). Since impaired physiologic remodelling of the uterine spiral arteries is a significant component in the pathogenesis of early onset PE, we proposed Pg infection disrupts this process leading to placental abnormalities and fetal distress. Using a standard periodontitis model, virgin female rats received repeated oral inoculations of sterile vehicle (control), Pg strain W83, A7A1-28, 381, or A7436 for three months prior to breeding. Uteroplacental tissues and fetuses were collected for analysis at gestation day 18. Remodelling of spiral arteries in the metrial triangle were quantified by morphometry of endothelial cell (anti-CD31), smooth muscle cell (a-actin) staining of the vessel wall and infiltration of the uterus by extravillous trophoblasts (cytokeratin 7), measured as % area. Spiral artery remodelling was significantly reduced in animals infected with Pg A7A1-28 or A7436 as indicated by increased CD31and a-actin, and reduced cytokeratin staining within the metrial triangle (P <0.001). Pg A7A1-28 and A7436 infected animals also exhibited acute atherosis (AA) characterized by fibrinoid necrosis of the uterine artery with infiltration of CD68+/TNF-a+ macrophages within the vessel wall (P < 0.01). Pg A7A1-28 antigens were detected in the uterine stroma, chorionic plate mesenchyme and umbilical artery. Placentas from Pg A7A128 infected dams had a greater density of proliferating mesenchymal cells (PCNA +) in the chorionic plate and umbilical cord than control dams (P < 0.05). Fetuses from dams with reduced spiral artery remodelling and AA were larger than control dams and Pg infected dams without these lesions (P < 0.01); litter sizes were equivalent among groups. Our results demonstrate that certain wildtype Pg strains can disrupt normal placentation by impairing the physiologic remodelling of the uterine arteries during pregnancy, which may have consequences on maternal and fetal health.
89
P1.54 INTRAPARTUM FACTORS, IOL AND AUTISM RISK Carolyn Salafia 1, 2, Jennifer Straughen 3, Gabriela Perez-Avilan 2, Victoria Onbreyt 1, Beata Dygulska 1, Sandford Lederman 1, Pramod Narula 1. 1 New York Methodist Hospital, Brooklyn, NY, USA; 2 Placental Analytics, LLC, New Rochelle, NY, USA; 3 Henry Ford Hospital, Detroit, MI, USA Objectives: Is oxytocin during IOL and/or labor augmentation associated with increased ASD risk independent of reason for IOL and other medications used during IOL. Methods: Our case-control sample was drawn from a population based sample at a large urban community based hospital (New York Methodist Hospital) from 2007 to 2014, during which time there was universal placental examination of births. We study a unique population based cohort with a total of 51 cases (39 males, 12 females) and 183 controls (138 males, 45 females), matched for gestational age, gender, and maternal age. Conditional odds ratios (COR) and 95% confidence intervals (CI) were calculated. Results: Labor Factors:
More ASD cases has IOL (COR¼3.7 (95% CI¼1.9, 7.5). The association did not change after adjustment for maternal conditions. More ASD cases were exposed to oxytocin (31% v. 16.5%, COR ¼2.61; 95% CI 1.34,5.08). Since >80% of IOL received oxytocin, the two factors could not be separated in this analysis due to sample size. Total oxytocin dose was not associated with ASD. After adjustment for oxytocin, prostaglandins (Cervidil) and Misoprostol (Cytotec) had no association with ASD. Labor augmentation was not associated with ASD (p¼0.71). Mode of delivery was not associated with ASD (p¼0.055). Conclusions: Based on our preliminary data, IOL and oxytocin exposure both showed a statistically significant association with ASD. Augmentation of labor had no association with ASD. We suspect that it is the indications for IOL, rather than induction that are related to ASD, although a combination variable or “any maternal”, or “any fetal” indications did not alter the OR of the association. P1.55 MECHANISTIC STUDY OF HUMAN PLACENTAL INFECTION BY LISTERIA MONOCYTOGENES Joanna Marshall 1, John Robinson 1, William Ackerman 1, Catalin Buhimschi 1, Yoel Sadovsky 2, Stephanie Seveau 1. 1 The Ohio State University, Columbus, OH, USA; 2 Magee-Womens Research Institute, Pittsburgh, PA, USA A key function of the placenta is to protect the developing fetus against pathogens. The barrier function of the syncytiotrophoblast at the interface with maternal blood is crucial for this protection. This protection is so efficient that only a few pathogens can circumvent it. Little is known about the innate defense mechanisms used by the syncytiotrophoblast to prevent most infections. Also, there is a lack of understanding of the mechanisms by which pathogens overcome the placental innate defense. (Objective) To solve these gaps in our knowledge, we study the interplay between human placental cells and Listeria monocytogenes, the etiologic agent of the life-threatening foodborne illness listeriosis. Previous studies convincingly argued that L. monocytogenes enters the placenta by invading extravillous cytotrophoblasts and/or the syncytiotrophoblast. However, the fate of L. monocytogenes within and beyond those cells remains unsolved. (Methods) We used the BeWo cell line and isolated primary cytotrophoblasts and fibroblasts from term human placenta. The percentage of cell fusion, cell integrity, and production bHCG were measured by fluorescence microscopy, LDH assay, and ELISA, respectively. Purity of isolated primary cells was established by flow cytometry