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PP119. The role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in preeclampsia
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 240–339
303
reau: none declared, F. Goffinet: none declared, V. Tsatsaris Grant/Research Support from: Alere.
M. Baumann, M. Marti, L. Durrer, D. Surbek, L. Raio (Obstetrics and Gynecology, University Hospital of Bern, Bern, Switzerland)
doi:10.1016/j.preghy.2012.04.227
Introduction: Preeclampsia contributes to an increased perinatal morbidity and mortality of both the mother and the fetus. The exact pathogenesis of PE is unclear; it is generally believed, however, that the placenta plays a pivotal role in this process. Objectives: The aim of this study was to analyse the effect of the placental mass on the severity of PE. Methods: Following PE placentae were analyzed and their weights were compared with those of normal pregnancies [1]. Moderate and severe PE as well as HELLP syndrome were defined according to international guidelines. To compare placental weights obtained at different gestational ages, a ratio between observed (O) and expected (E) weights were calculated. Chi2-test and Kruskal–Wallis-test were used for statistical analysis and significance was considered when p < 0.05. Results: Two hundred and eight placentae following singleton pregnancies complicated by preeclampsia were enrolled. The mean gestational age at birth was 31.8 ± 3.8 weeks, 130 (62.5%) cases delivered before the 34th week. The group with severe PE delivered earlier than that with moderate PE (mean ± SD, 32 ± 3.9 vs. 34 ± 3 weeks; p < 0.01). Severe PE was found in 176 (84.6%) cases; 85 of this group were associated with a HELLP-syndrome. Isolated HELLP were found in 4 (1.9%) cases. In 144 (69.2%) cases placental weight was below the 10th percentile. The mean of the weights was higher in the group with moderate PE than in those with severe PE, PE with HELLP and isolated HELLP (410 ± 67 g, respectively, 376 ± 79g, 344 ± 86 g, 341 ± 88 g). When normalized using the O/E-ratio (in order to correct for gestational age) these differences were not significant (moderate PE 0.75 ± 0.24; severe PE 0.74 ± 0.22, PE with HELLP 0.73 ± 0.22; isolated HELLP 0.88 ± 0.05; p = NS). Conclusion: Our data show that the placental mass is not associated with the severity of PE. We hypothesize that once the pathogenesis of PE is triggered (by placental factors), the severity of the disease is modulated mainly by the maternal response and not by the placental mass.
PP117. Measurement of sFlt-1 and PlGF for prediction of pregnancy associated diseases J. Stubert 1,*, S. Ullmann 1, M. Bolz 1, M. Bohlmann 2, T. Külz 3, B. Gerber 1, T. Reimer 1 (1 Dept. of Obstetrics and Gynecology, University of Rostock, Rostock, Germany, 2 Dept. of Obstetrics and Gynecology, University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany, 3 Praxiszentrum Frauenheilkunde, Rostock, Germany) Introduction: Severe preeclampsia is associated with characteristic changes of sFlt-1 and PlGF levels in the maternal serum. Objectives: The aim of our study is the determination of the predictive value of sFlt-1 and PlGF for preeclampsia and other pregnancy associated diseases in women with a pathological uterine Doppler measurement during the second trimester of pregnancy. Methods: An updated analysis of an ongoing prospective trial will be presented. Criterion of inclusion was a bilateral pathological uterine Doppler measurement with an increase of the resistance index (RI) >95th percentile and/or a bilateral postsystolic notch during 19 and 24 weeks. Ratio of sFlt-1 and PlGF was repeatedly measured during pregnancy using a full-automated system (ElecsysÒ, Roche). Results: Presently, we recruited 36 patients. Full data are available from 17 patients. Out of these in 23.5% (n = 4) a delivery before 37 weeks was indicated. 41% of all newborns (7/17) showed a birth weight <5th percentile. 23.5% of all patients developed a hypertensive pregnancy disorder but without fulfilling the criterions of preeclampsia. Only two patients had a sFlt-1/PlGF ratio >95th percentile. In both cases we found severe fetal growth retardation. One of them developed a pregnancy related hypertension based on an antiphospholipid syndrome. Conclusion: The additional measurement of the sFlt-1/ PlGF ratio in a high risk group of pregnancies may improve the prediction of severe pregnancy related diseases during the second trimester. But keeping the low incidence of severe preeclampsia in mind, the measurements seem to be only usefulness in a high risk population. Although we reported presently only of a small part of our study population the sFlt-1/PlGF ratio did not revealed a good specificity for prediction of preeclampsia. Pathological values were also found in cases with fetal growth retardation without signs of preeclampsia. Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.228
PP118. Is the placental mass associated with the severity of preeclampsia?
Disclosure of interest: None declared. Reference [1] Pinar H, Sung CJ, Oyer CE, Singer DB. Reference values for singleton and twin placental weights. Pediatr Pathol Lab Med 1996;16(6):901–7. doi:10.1016/j.preghy.2012.04.229
PP119. The role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in preeclampsia N. Kweider 1,*, A. Fragoulis 1, C. Rosen 1, U. Pecks 2, W. Rath 2, M. Kadyrov 1, T. Pufe 1, C.J. Wruck 1 (1 Department of Anatomy and Cell Biology, RWTH Aachen University, Germany, 2 Department of Obstetrics and Gynaecology, University Hospital RWTH, Aachen, Germany)
304
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 240–339
Introduction: Preeclampsia is a multi-organ syndrome characterized by maternal endothelial damage, is an independent long-term risk factor for hypertension and cardiovascular disease. Objectives: In animal models the administration of the Vascular Endothelial Growth Factor (VEGF) could reverse the hypertensive signs accompanying this disease. In addition VEGF is implicated in placental oxidative stress during preeclampsia. One of the major cellular defence mechanisms against oxidative stress is the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2). Therefore, the activation of Nrf2 up regulates the HO-1/CO system. The principal aim of this work is to investigate whether the activation of Nrf2 raises VEGF levels by up regulation of CO release. Methods: This study took place in vitro, the choriocarcinoma cell line BeWo cells and the primary human umbilical vein endothelial cells (HUVECs) were used to study the relationship between VEGF and an Nrf2 inducer Sulforaphane, a naturally occurring compound derived from broccoli. ELISA, Western blot assay and the Dual Luciferase Assay were both mainly applied for protein and VEGF activity analysis. Results: It was found that activation of HO-1 expression via Nrf2/ARE pathway augmented the production of CO, which in turn up-regulated the gene expression of VEGF, and down regulated the production of the antiangiogenic protein, the VEGF antagonist sFlt-1. Conclusion: Nrf2 driven HO-1 expression elevates the levels of VEGF via CO production. In particular, activating of Nrf2 via sulforaphane, may have therapeutic potential in preeclampsia. Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.230
PP120. Hydatidiform mole as a cause of eclampsia in the first trimester: A case report S. Ottanelli 1, S. Simeone 1, C. Serena 1, M.P. Rambaldi 1,*, A. Villanucci 2, K. Tavella 2, G. Amunni 2, F. Mecacci 1, G. Mello 1 (1 Centro di Riferimento regionale per la gravidanza ad alto rischio, Italy, 2 SOD Oncologia Medica Ginecologica, AOU Careggi, Florence, Italy) Introduction: The occurrence of preeclampsia before the 20th week of gestation is rare and it has been associated with hydatidiform molar pregnancy. Objectives: We describe a case of first trimester eclampsia which occurred in a patient with hydatidiform mole. Methods: Case report. Results: A 16-year-old woman came to emergency service for abdominal pain and vaginal bleeding. She had been suffering of vomiting after meals and complaining for abdominal mass for 2 months, without consulting her physician. The last reported period was 1 month before; the patient told her periods were regular and the only disease she reported was chronic HBV hepatitis. Vital parameters were all normal. Urine pregnancy test resulted always negative. The gynecological exam reported an increased uterus and
a little bleeding, so serum bhCG was performed because of the exam findings and resulted 110,5317 UI/L. The transvaginal ultrasound showed images consistent with gestational trophoblastic disease. Computed tomography (CT) scan revealed the presence of an uterine mass and three lung nodules, reported as possibly metastatic. A few days later, the patient underwent dilation and curettage (D&C). Second grade hydatiform mole was diagnosed by histology. After D&C, the serum bhCG was 202,511 UI/L. The day after, the patient presented bilateral acute blindness, followed by incoming general seizures, concurrent hypertension and tachycardia. Intravenous diazepam, levetiracetam and mannitol controlled the seizures, but the conscious state of the patient remained critical. Temperature reached 40 °C, with concurrent leukocytosis. Then, a lumbar puncture was performed but it resulted negative for inflammatory/infective processes. A head CT was performed the same day and showed a posterior reversible encephalopathy syndrome (PRES). Intravenous methylprednisolone was started. Long term therapy with methylprednisolone and levetiracetam was effective and the patient’s status improved and stabilized. A subsequent chemotherapy with EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine) was performed for six cycles, until serum bhCG resulted negative and the abdomen/pelvis ultrasound, head NMR and chest X-ray resulted normal. Conclusion: Preeclampsia and eclampsia are regarded as common causes of PRES, which is considered to be the result of vasogenic brain edema. Clinical and imaging findings are usually reversible. Early diagnosis and elimination of possible causes are important in order to avoid permanent visual or brain injury. Imaging (especially MRI) should be carried out in eclamptic patients with visual disturbance in order to exclude other causes of blindness. Molar pregnancy is a rare but important cause of eclampsia, and it has always to be considered in case of early manifestations.
Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.231
PP121. Expression of PlGF, sFlt, MTF-1, HO-1 and HIF-1 alpha mRNAs in preeclampsia placenta and effect of preeclampsia sera on their expression of choriocarcinoma cells A. Maebayashi *, T. Yamamoto, H. Azuma, E. Kato, S. Kuno, T. Murase, F. Chishima (Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan) Introduction: Placenta growth factor (PlGF) is a growth factor originated from placenta. The sFlt-1 is soluble receptor for PlGF and suppresses PlGF function. It has been reported that in preeclampsia, serum level of PlGF decreased and sFlt-1 level increased and that preeclampsia placenta is in hypoxic condition. Metal-responsive transcription factor (MTF)-1, Hemoxigenase 1 (HO-1) and Hypoxia responsive factor -1 (HIF-1) may be induced in hypoxic condition. Objectives: In order to investigate pathophysiology in preeclampsia, we studied the expression of PlGF, sFlt-1, MTF-1,
303
reau: none declared, F. Goffinet: none declared, V. Tsatsaris Grant/Research Support from: Alere.
M. Baumann, M. Marti, L. Durrer, D. Surbek, L. Raio (Obstetrics and Gynecology, University Hospital of Bern, Bern, Switzerland)
doi:10.1016/j.preghy.2012.04.227
Introduction: Preeclampsia contributes to an increased perinatal morbidity and mortality of both the mother and the fetus. The exact pathogenesis of PE is unclear; it is generally believed, however, that the placenta plays a pivotal role in this process. Objectives: The aim of this study was to analyse the effect of the placental mass on the severity of PE. Methods: Following PE placentae were analyzed and their weights were compared with those of normal pregnancies [1]. Moderate and severe PE as well as HELLP syndrome were defined according to international guidelines. To compare placental weights obtained at different gestational ages, a ratio between observed (O) and expected (E) weights were calculated. Chi2-test and Kruskal–Wallis-test were used for statistical analysis and significance was considered when p < 0.05. Results: Two hundred and eight placentae following singleton pregnancies complicated by preeclampsia were enrolled. The mean gestational age at birth was 31.8 ± 3.8 weeks, 130 (62.5%) cases delivered before the 34th week. The group with severe PE delivered earlier than that with moderate PE (mean ± SD, 32 ± 3.9 vs. 34 ± 3 weeks; p < 0.01). Severe PE was found in 176 (84.6%) cases; 85 of this group were associated with a HELLP-syndrome. Isolated HELLP were found in 4 (1.9%) cases. In 144 (69.2%) cases placental weight was below the 10th percentile. The mean of the weights was higher in the group with moderate PE than in those with severe PE, PE with HELLP and isolated HELLP (410 ± 67 g, respectively, 376 ± 79g, 344 ± 86 g, 341 ± 88 g). When normalized using the O/E-ratio (in order to correct for gestational age) these differences were not significant (moderate PE 0.75 ± 0.24; severe PE 0.74 ± 0.22, PE with HELLP 0.73 ± 0.22; isolated HELLP 0.88 ± 0.05; p = NS). Conclusion: Our data show that the placental mass is not associated with the severity of PE. We hypothesize that once the pathogenesis of PE is triggered (by placental factors), the severity of the disease is modulated mainly by the maternal response and not by the placental mass.
PP117. Measurement of sFlt-1 and PlGF for prediction of pregnancy associated diseases J. Stubert 1,*, S. Ullmann 1, M. Bolz 1, M. Bohlmann 2, T. Külz 3, B. Gerber 1, T. Reimer 1 (1 Dept. of Obstetrics and Gynecology, University of Rostock, Rostock, Germany, 2 Dept. of Obstetrics and Gynecology, University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany, 3 Praxiszentrum Frauenheilkunde, Rostock, Germany) Introduction: Severe preeclampsia is associated with characteristic changes of sFlt-1 and PlGF levels in the maternal serum. Objectives: The aim of our study is the determination of the predictive value of sFlt-1 and PlGF for preeclampsia and other pregnancy associated diseases in women with a pathological uterine Doppler measurement during the second trimester of pregnancy. Methods: An updated analysis of an ongoing prospective trial will be presented. Criterion of inclusion was a bilateral pathological uterine Doppler measurement with an increase of the resistance index (RI) >95th percentile and/or a bilateral postsystolic notch during 19 and 24 weeks. Ratio of sFlt-1 and PlGF was repeatedly measured during pregnancy using a full-automated system (ElecsysÒ, Roche). Results: Presently, we recruited 36 patients. Full data are available from 17 patients. Out of these in 23.5% (n = 4) a delivery before 37 weeks was indicated. 41% of all newborns (7/17) showed a birth weight <5th percentile. 23.5% of all patients developed a hypertensive pregnancy disorder but without fulfilling the criterions of preeclampsia. Only two patients had a sFlt-1/PlGF ratio >95th percentile. In both cases we found severe fetal growth retardation. One of them developed a pregnancy related hypertension based on an antiphospholipid syndrome. Conclusion: The additional measurement of the sFlt-1/ PlGF ratio in a high risk group of pregnancies may improve the prediction of severe pregnancy related diseases during the second trimester. But keeping the low incidence of severe preeclampsia in mind, the measurements seem to be only usefulness in a high risk population. Although we reported presently only of a small part of our study population the sFlt-1/PlGF ratio did not revealed a good specificity for prediction of preeclampsia. Pathological values were also found in cases with fetal growth retardation without signs of preeclampsia. Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.228
PP118. Is the placental mass associated with the severity of preeclampsia?
Disclosure of interest: None declared. Reference [1] Pinar H, Sung CJ, Oyer CE, Singer DB. Reference values for singleton and twin placental weights. Pediatr Pathol Lab Med 1996;16(6):901–7. doi:10.1016/j.preghy.2012.04.229
PP119. The role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in preeclampsia N. Kweider 1,*, A. Fragoulis 1, C. Rosen 1, U. Pecks 2, W. Rath 2, M. Kadyrov 1, T. Pufe 1, C.J. Wruck 1 (1 Department of Anatomy and Cell Biology, RWTH Aachen University, Germany, 2 Department of Obstetrics and Gynaecology, University Hospital RWTH, Aachen, Germany)
304
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 240–339
Introduction: Preeclampsia is a multi-organ syndrome characterized by maternal endothelial damage, is an independent long-term risk factor for hypertension and cardiovascular disease. Objectives: In animal models the administration of the Vascular Endothelial Growth Factor (VEGF) could reverse the hypertensive signs accompanying this disease. In addition VEGF is implicated in placental oxidative stress during preeclampsia. One of the major cellular defence mechanisms against oxidative stress is the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2). Therefore, the activation of Nrf2 up regulates the HO-1/CO system. The principal aim of this work is to investigate whether the activation of Nrf2 raises VEGF levels by up regulation of CO release. Methods: This study took place in vitro, the choriocarcinoma cell line BeWo cells and the primary human umbilical vein endothelial cells (HUVECs) were used to study the relationship between VEGF and an Nrf2 inducer Sulforaphane, a naturally occurring compound derived from broccoli. ELISA, Western blot assay and the Dual Luciferase Assay were both mainly applied for protein and VEGF activity analysis. Results: It was found that activation of HO-1 expression via Nrf2/ARE pathway augmented the production of CO, which in turn up-regulated the gene expression of VEGF, and down regulated the production of the antiangiogenic protein, the VEGF antagonist sFlt-1. Conclusion: Nrf2 driven HO-1 expression elevates the levels of VEGF via CO production. In particular, activating of Nrf2 via sulforaphane, may have therapeutic potential in preeclampsia. Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.230
PP120. Hydatidiform mole as a cause of eclampsia in the first trimester: A case report S. Ottanelli 1, S. Simeone 1, C. Serena 1, M.P. Rambaldi 1,*, A. Villanucci 2, K. Tavella 2, G. Amunni 2, F. Mecacci 1, G. Mello 1 (1 Centro di Riferimento regionale per la gravidanza ad alto rischio, Italy, 2 SOD Oncologia Medica Ginecologica, AOU Careggi, Florence, Italy) Introduction: The occurrence of preeclampsia before the 20th week of gestation is rare and it has been associated with hydatidiform molar pregnancy. Objectives: We describe a case of first trimester eclampsia which occurred in a patient with hydatidiform mole. Methods: Case report. Results: A 16-year-old woman came to emergency service for abdominal pain and vaginal bleeding. She had been suffering of vomiting after meals and complaining for abdominal mass for 2 months, without consulting her physician. The last reported period was 1 month before; the patient told her periods were regular and the only disease she reported was chronic HBV hepatitis. Vital parameters were all normal. Urine pregnancy test resulted always negative. The gynecological exam reported an increased uterus and
a little bleeding, so serum bhCG was performed because of the exam findings and resulted 110,5317 UI/L. The transvaginal ultrasound showed images consistent with gestational trophoblastic disease. Computed tomography (CT) scan revealed the presence of an uterine mass and three lung nodules, reported as possibly metastatic. A few days later, the patient underwent dilation and curettage (D&C). Second grade hydatiform mole was diagnosed by histology. After D&C, the serum bhCG was 202,511 UI/L. The day after, the patient presented bilateral acute blindness, followed by incoming general seizures, concurrent hypertension and tachycardia. Intravenous diazepam, levetiracetam and mannitol controlled the seizures, but the conscious state of the patient remained critical. Temperature reached 40 °C, with concurrent leukocytosis. Then, a lumbar puncture was performed but it resulted negative for inflammatory/infective processes. A head CT was performed the same day and showed a posterior reversible encephalopathy syndrome (PRES). Intravenous methylprednisolone was started. Long term therapy with methylprednisolone and levetiracetam was effective and the patient’s status improved and stabilized. A subsequent chemotherapy with EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine) was performed for six cycles, until serum bhCG resulted negative and the abdomen/pelvis ultrasound, head NMR and chest X-ray resulted normal. Conclusion: Preeclampsia and eclampsia are regarded as common causes of PRES, which is considered to be the result of vasogenic brain edema. Clinical and imaging findings are usually reversible. Early diagnosis and elimination of possible causes are important in order to avoid permanent visual or brain injury. Imaging (especially MRI) should be carried out in eclamptic patients with visual disturbance in order to exclude other causes of blindness. Molar pregnancy is a rare but important cause of eclampsia, and it has always to be considered in case of early manifestations.
Disclosure of interest: None declared. doi:10.1016/j.preghy.2012.04.231
PP121. Expression of PlGF, sFlt, MTF-1, HO-1 and HIF-1 alpha mRNAs in preeclampsia placenta and effect of preeclampsia sera on their expression of choriocarcinoma cells A. Maebayashi *, T. Yamamoto, H. Azuma, E. Kato, S. Kuno, T. Murase, F. Chishima (Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan) Introduction: Placenta growth factor (PlGF) is a growth factor originated from placenta. The sFlt-1 is soluble receptor for PlGF and suppresses PlGF function. It has been reported that in preeclampsia, serum level of PlGF decreased and sFlt-1 level increased and that preeclampsia placenta is in hypoxic condition. Metal-responsive transcription factor (MTF)-1, Hemoxigenase 1 (HO-1) and Hypoxia responsive factor -1 (HIF-1) may be induced in hypoxic condition. Objectives: In order to investigate pathophysiology in preeclampsia, we studied the expression of PlGF, sFlt-1, MTF-1,