with PE may lead to novel, early interventions to prevent fetal growth restriction. We sought to characterize maternal serum biomarkers of placental insufficiency.
SMFM Abstracts
www.AJOG.org 702
PREECLAMPSIA IS ASSOCIATED WITH MODULATION OF ANGIOGENIC FACTORS BUT NOT WITH THE EXPRESSION OF HUMAN PLACENTAL CATECHOL-OMETHYLTRANSFERASE (COMT) AND ITS HORMONAL METABOLITES ADANNA AMANZE1, SUZY DAVIES1, ANNA HOLMES1, LAURA LAIDLER1, SUNANDA SADANANDAN1, ALICE ROBINSON1, ELIZA BERKLEY1, RONALD SCHRADER2, SANG-JOON LEE3, KIMBERLY LESLIE1, 1University of New Mexico, Obstetrics and Gynecology, Abuquerque, New Mexico, 2University of New Mexico, General Clinical Research Center, Albuquerque, New Mexico, 3University of New Mexico, Dept. of Internal Medicine, CRTC, Albuquerque, New Mexico OBJECTIVE: Catechol-O-Methyltransferase (COMT) is a ubiquitous cytosolic enzyme expressed in many tissues responsible for the biotransformation of catechol compounds. 2-methoxyestradiol (2-ME2) is a metabolite of subsequent enzymatic o-methylation of 2-hydroxyestradiol via COMT. Its dose-dependent regulatory effects include inhibition of tubulin polymerization, migration, and proliferation in endothelial cells. Recent studies in engineered mice and human trophoblast cells suggest that perturbations in the COMT pathway along with subsequent decreased concentrations of 2-ME2 may be the link between preeclampsia and hypoxia. Our objective was to confirm these findings in women with preeclampsia. STUDY DESIGN: Serum and plasma samples were collected from 15 preeclamptic patients and 15 gestational age matched controls. Pro-angiogenic and antiangiogenic markers were measured by ELISA and HPLC. Protein lysates prepared from placental tissue were analyzed and quantitated by Western blotting (densitometry) and immunohistochemistry (the product of intensity of staining and the percent of positive cells) for COMT expression. RESULTS: Soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng) concentrations were significantly elevated in preeclamptic serum samples (p⫽0.01 and p⬍0.0001, respectively). Placental growth factor (PlGF) concentrations were significantly decreased in preeclamptic samples (p⬍0.0001). However, no differences were observed in circulating 2-ME2 and 2-ME1 in patients with preeclampsia versus controls (p⫽0.28 and p⫽0.43, respectively). In addition, robust and equal COMT expression was identified in placental villi from controls as well as from patients with preeclampsia. CONCLUSION: Our results reconfirm an increase in anti-angiogenic (sFlt-1 and sEng) and a decrease in pro-angiogenic (PlGF) factors in women with preeclampsia. However, COMT expression and its metabolites were unchanged. Therefore, we found no direct evidence linking a diminution in COMT expression or activity in women with preeclampsia.
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INPATIENT, CONTINUOUS FETAL MONITORING VERSUS OUTPATIENT, ANTENATAL TESTS IN MONOAMNIOTIC TWINS: A COST-EFFECTIVENESS ANALYSIS JIN CHANG1, AARON CAUGHEY2, 1University of California, San Francisco, Obstetrics and Gynencology, San Francisco, California, 2University of California, San Francisco, San Francisco, California OBJECTIVE: To determine the cost-effectiveness of inpatient, continuous fetal monitoring versus outpatient management of monoamniotic twin gestations. STUDY DESIGN: A decision analytic model was designed comparing inpatient continuous fetal monitoring versus outpatient once daily nonstress tests. The two arms were broken down based on gestational age with the earliest admission assumed to be at 28 weeks. Baseline costs for hospitalization of the trio (mom and mo/mo set) were derived from the literature and adjusted appropriately using CPI. We considered cost effectiveness as less than $50,000 per life year (LY). RESULTS: Compared to outpatient management, overall cost was $77,870 more in the inpatient continuous fetal monitoring arm ($89,218 versus $167,089). In order to prevent death of one mo/mo set, the extra cost was calculated to be $526,153. With sensitivity analysis varying the cost of hospitalization, even at four times our estimated costs, costi, we found hospitalization to be cost effective at $36,233/LY (figure). When we varied the risk of IUFD, hospitalization remained cost effective up to an IUFD risk of 0.12 at $39,921/LY.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.733
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MATERNAL SERUM BIOMARKERS OF PLACENTAL INSUFFICIENCY IN PREECLAMPSIA JUHA RASANEN1, ANNA GIRSEN2, ARCHANA THOMAS3, MELISSA STANDLEY3, THOMAS JACOB3, JOHN MICHAELS3, ASHOK REDDY3, XINFANG LU3, JODI LAPIDUS3, MICHAEL GRAVETT4, SRINIVASA NAGALLA3, 1Oregon Health & Science University, Obstetrics & Gynecology, Portland, Oregon, 2University of Oulu, Obstetrics and Gynecology, Oulu, Finland, Finland, 3ProteoGenix, Inc., Beaverton, Oregon, 4University of Washington, Obstetrics and Gynecology, Seattle, Washington OBJECTIVE: Preeclampsia (PE) and fetal growth restriction are associated with placental insufficiency. The early prediction of placental insufficiency associated with PE may lead to novel, early interventions to prevent fetal growth restriction. We sought to characterize maternal serum biomarkers of placental insufficiency associated with PE by proteomic analysis. STUDY DESIGN: This was a secondary analysis of 57 women who developed PE from whom maternal sera was obtained between 21 and 37 weeks gestation as part of a large cohort study. None had PE at the time of sera collection. PE was defined as mild or severe following ACOG classification. Placental insufficiency was determined by umblical artery Doppler criteria. Maternal serum proteome analysis was performed using multidimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) and label-free quantification (spectral counting). Immunoassays were used for accurate quantification and evaluated using the Receiver Operating Characteristic (ROC) curves and logistic regression analysis. RESULTS: 30 patients developed mild PE and 27 developed severe PE. 13 women (12 subjects with severe PE and 1 subject with mild PE) had placental insufficiency. Analysis of 17 differentially expressed protein biomarkers for PE by specific immunoassay revealed only 2 with discriminant capability between those with and without placental insufficiency. PE subjects with placental insufficiency had decreased levels of chorionic somatomamotrophin1 (p⫽0.007) and pregnancy specific glycoprotein 1(p⫽0.03) compared to women without placental insufficiency. Other biomarkers of PE did not correlate with placental insufficiency. CONCLUSION: Placental insufficiency in PE does not correlate with biomarkers associated with the pathophysiology of active PE disease. Reliable diagnosis of placental insufficiency using novel maternal serum biomarkers in early gestation could facilitate new intervention strategies. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.734
CONCLUSION: We found that hospitalization of 7 patients would prevent the death of one mo/mo pair. When compared to outpatient management with once daily nonstress tests, inpatient, continuous fetal monitoring is cost effective. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.735
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EX VIVO PLACENTAL TRANSFER OF PIOGLITAZONE AND SITAGLIPTIN SCOTT ROBERTS1, ROGER BAWDON2, 1University of Texas Southwestern Medical Center at Dallas, Obstetrics & Gynecology, Dallas, Texas, 2University of Texas Southwestern Medical Center at Dallas, Texas OBJECTIVE: The purpose of this study was to determine the maternal-fetal transplacental passage of pioglitazone (a thiazolidinedione) and sitagliptin ( a dipeptidyl peptidase 4 inhibitor) in the ex vivo human placental model. STUDY DESIGN: In this study we used 6 placentas for the pioglitazone (Actos) study and 5 for sitagliptin (Januvia). Working solutions for the drugs were prepared and ex vivo perfusion studies were performed using therapeutic drug concentrations. Placentas were collected at the time of delivery and a suitable non traumatized cotyledon was identified. Both the maternal and fetal veins were canulated with umbilical vessel catheters. The medium used in this study was Earles Minimum Essential Medium with 3% bovine serum albumin and 0.8 U heparin. The circulation was open for 1 hour and then closed for one hour (to measure fetal accumulation) with samples collected every 10 minutes. Samples of both the maternal and fetal perfusates were frozen at ⫺80 C until assayed by validated High Pressure Liquid Chromatography (HPLC). RESULTS: The mean clearance index (CI) of pioglitazone was 0.23 ⫾ 0.05. Fetal accumulation was present in 6 of 6 placentas ranging from 114 ng/ml to 409 ng/ml of drug transferred. Mean accumulation was 212 ng/ml (13.8%). The mean CI of sitagliptin was 0.35 ⫾ 0.09. Fetal accumulation after 2 hours was present in only 2 of 5 placentas with a mean of 74 ng/ml (3.1%). CONCLUSION: Management of glycemic control in pregnancy is critically important. The offspring of these women with type I or II diabetes as well as those with gestational diabetes have a number of risks: macrosomia, perinatal complications and postpartum hypoglycemia. From these data it is noted that there is a difference in the CI of these 2 drugs, and also a difference in accumulation. Because of the extended half-lives of pioglitazone and sitagliptin (3-7 hours, 8-14 hours respectively) and clearance indexes, as well as the significant fetal accumulation of pioglitazone, these oral hypoglycemics are unacceptable for the treatment of diabetes in pregnancy. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.736
Supplement to DECEMBER 2008 American Journal of Obstetrics & Gynecology
S201
