705: Ex vivo placental transfer of pioglitazone and sitagliptin

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www.AJOG.org SMFM Abstracts

02 PREECLAMPSIA IS ASSOCIATED WITH MODULATION OF ANGIOGENIC FACTORS BUTNOT WITH THE EXPRESSION OF HUMAN PLACENTAL CATECHOL-O-METHYLTRANSFERASE (COMT) AND ITS HORMONAL METABOLITES ADANNAAMANZE1, SUZY DAVIES1, ANNA HOLMES1, LAURA LAIDLER1, SUNANDA SADANANDAN1,ALICE ROBINSON1, ELIZA BERKLEY1, RONALD SCHRADER2, SANG-JOON LEE3, KIMBERLYLESLIE1, 1University of New Mexico, Obstetrics and Gynecology, Abuquerque, NewMexico, 2University of New Mexico, General Clinical Research Center, Albuquer-que, New Mexico, 3University of New Mexico, Dept. of Internal Medicine, CRTC,Albuquerque, New Mexico

OBJECTIVE: Catechol-O-Methyltransferase (COMT) is a ubiquitous cytosolicenzyme expressed in many tissues responsible for the biotransformation of catecholcompounds. 2-methoxyestradiol (2-ME2) is a metabolite of subsequent enzymatico-methylation of 2-hydroxyestradiol via COMT. Its dose-dependent regulatoryeffects include inhibition of tubulin polymerization, migration, and proliferation inendothelial cells. Recent studies in engineered mice and human trophoblast cellssuggest that perturbations in the COMT pathway along with subsequent decreasedconcentrations of 2-ME2 may be the link between preeclampsia and hypoxia. Ourobjective was to confirm these findings in women with preeclampsia.

STUDY DESIGN: Serum and plasma samples were collected from 15 preeclamp-tic patients and 15 gestational age matched controls. Pro-angiogenic and anti-angiogenic markers were measured by ELISA and HPLC. Protein lysates preparedfrom placental tissue were analyzed and quantitated by Western blotting (densi-tometry) and immunohistochemistry (the product of intensity of staining and thepercent 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�0.01and p�0.0001, respectively). Placental growth factor (PlGF) concentrations weresignificantly decreased in preeclamptic samples (p�0.0001). However, no differ-ences were observed in circulating 2-ME2 and 2-ME1 in patients with preeclampsiaversus controls (p�0.28 and p�0.43, respectively). In addition, robust and equalCOMT expression was identified in placental villi from controls as well as frompatients with preeclampsia.

CONCLUSION: Our results reconfirm an increase in anti-angiogenic (sFlt-1 andsEng) and a decrease in pro-angiogenic (PlGF) factors in women with preeclamp-sia. However, COMT expression and its metabolites were unchanged. Therefore,we found no direct evidence linking a diminution in COMT expression or activityin women with preeclampsia.

0002-9378/$ - see front matterdoi:10.1016/j.ajog.2008.09.733

03 MATERNAL SERUM BIOMARKERS OF PLACENTAL INSUFFICIENCY IN PRE-ECLAMPSIA JUHA RASANEN1, ANNA GIRSEN2, ARCHANA THOMAS3, MELISSASTANDLEY3, THOMAS JACOB3, JOHN MICHAELS3, ASHOK REDDY3, XINFANG LU3, JODILAPIDUS3, MICHAEL GRAVETT4, SRINIVASA NAGALLA3, 1Oregon Health & Science Uni-versity, Obstetrics & Gynecology, Portland, Oregon, 2University of Oulu, Obstet-rics and Gynecology, Oulu, Finland, Finland, 3ProteoGenix, Inc., Beaverton, Ore-gon, 4University of Washington, Obstetrics and Gynecology, Seattle, Washington

OBJECTIVE: Preeclampsia (PE) and fetal growth restriction are associated withplacental insufficiency. The early prediction of placental insufficiency associatedwith PE may lead to novel, early interventions to prevent fetal growth restriction.We sought to characterize maternal serum biomarkers of placental insufficiencyassociated with PE by proteomic analysis.

STUDY DESIGN: This was a secondary analysis of 57 women who developed PEfrom whom maternal sera was obtained between 21 and 37 weeks gestation as partof a large cohort study. None had PE at the time of sera collection. PE was definedas mild or severe following ACOG classification. Placental insufficiency was deter-mined by umblical artery Doppler criteria. Maternal serum proteome analysis wasperformed using multidimensional liquid chromatography tandem mass spec-trometry (2D LC-MS/MS) and label-free quantification (spectral counting). Im-munoassays were used for accurate quantification and evaluated using the ReceiverOperating Characteristic (ROC) curves and logistic regression analysis.

RESULTS: 30 patients developed mild PE and 27 developed severe PE. 13women (12 subjects with severe PE and 1 subject with mild PE) had placentalinsufficiency. Analysis of 17 differentially expressed protein biomarkers for PE byspecific immunoassay revealed only 2 with discriminant capability between thosewith and without placental insufficiency. PE subjects with placental insufficiencyhad decreased levels of chorionic somatomamotrophin1 (p�0.007) and pregnancyspecific glycoprotein 1(p�0.03) compared to women without placental insuffi-ciency. Other biomarkers of PE did not correlate with placental insufficiency.

CONCLUSION: Placental insufficiency in PE does not correlate with biomarkersassociated with the pathophysiology of active PE disease. Reliable diagnosis of pla-cental insufficiency using novel maternal serum biomarkers in early gestation couldfacilitate new intervention strategies.

0002-9378/$ - see front matterdoi:10.1016/j.ajog.2008.09.734

Supplemen

04 INPATIENT, CONTINUOUS FETAL MONITORING VERSUS OUTPATIENT, ANTENATALTESTS IN MONOAMNIOTIC TWINS: A COST-EFFECTIVENESS ANALYSIS JIN CHANG1,AARON CAUGHEY2, 1University of California, San Francisco, Obstetrics and Gynen-cology, San Francisco, California, 2University of California, San Francisco, SanFrancisco, California

OBJECTIVE: To determine the cost-effectiveness of inpatient, continuous fetalmonitoring versus outpatient management of monoamniotic twin gestations.

STUDY DESIGN: A decision analytic model was designed comparing inpatientcontinuous fetal monitoring versus outpatient once daily nonstress tests. The twoarms were broken down based on gestational age with the earliest admission as-sumed to be at 28 weeks. Baseline costs for hospitalization of the trio (mom andmo/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 $77,870more 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 fourtimes our estimated costs, costi, we found hospitalization to be cost effective at$36,233/LY (figure). When we varied the risk of IUFD, hospitalization remainedcost effective up to an IUFD risk of 0.12 at $39,921/LY.

CONCLUSION: We found that hospitalization of 7 patients would prevent thedeath of one mo/mo pair. When compared to outpatient management with oncedaily nonstress tests, inpatient, continuous fetal monitoring is cost effective.

0002-9378/$ - see front matterdoi:10.1016/j.ajog.2008.09.735

05 EX VIVO PLACENTAL TRANSFER OF PIOGLITAZONE AND SITAGLIPTIN SCOTTROBERTS1, ROGER BAWDON2, 1University of Texas Southwestern Medical Center atDallas, Obstetrics & Gynecology, Dallas, Texas, 2University of Texas SouthwesternMedical Center at Dallas, Texas

OBJECTIVE: The purpose of this study was to determine the maternal-fetaltransplacental passage of pioglitazone (a thiazolidinedione) and sitagliptin ( adipeptidyl 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 preparedand ex vivo perfusion studies were performed using therapeutic drug concentra-tions. Placentas were collected at the time of delivery and a suitable non traumatizedcotyledon was identified. Both the maternal and fetal veins were canulated withumbilical vessel catheters. The medium used in this study was Earles MinimumEssential Medium with 3% bovine serum albumin and 0.8 U heparin. The circula-tion was open for 1 hour and then closed for one hour (to measure fetal accumu-lation) with samples collected every 10 minutes. Samples of both the maternal andfetal perfusates were frozen at �80 C until assayed by validated High PressureLiquid Chromatography (HPLC).

RESULTS: The mean clearance index (CI) of pioglitazone was 0.23 � 0.05. Fetalaccumulation was present in 6 of 6 placentas ranging from 114 ng/ml to 409 ng/mlof drug transferred. Mean accumulation was 212 ng/ml (13.8%). The mean CI ofsitagliptin was 0.35 � 0.09. Fetal accumulation after 2 hours was present in only 2of 5 placentas with a mean of 74 ng/ml (3.1%).

CONCLUSION: Management of glycemic control in pregnancy is critically im-portant. The offspring of these women with type I or II diabetes as well as those withgestational diabetes have a number of risks: macrosomia, perinatal complicationsand postpartum hypoglycemia. From these data it is noted that there is a differencein the CI of these 2 drugs, and also a difference in accumulation. Because of theextended half-lives of pioglitazone and sitagliptin (3-7 hours, 8-14 hours respec-tively) and clearance indexes, as well as the significant fetal accumulation of piogli-tazone, these oral hypoglycemics are unacceptable for the treatment of diabetes inpregnancy.

0002-9378/$ - see front matterdoi:10.1016/j.ajog.2008.09.736

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