654: Endocan (ESM-1): a novel soluble endothelial cell injury marker in preeclampsia (PE) and intrauterine growth restriction (IUGR)

Poster Session IV

Academic Issues, Antepartum Fetal, Clinical Ob, Fetus, Genetics, Hypertension, Med-Surg-Diseases, Operative Ob, U/S

women with hypertensive disorder (19 with pure preeclampsia, 23 with chronic hypertension and 20 with superimposed preeclampsia) and 66 healthy pregnant women underwent 3DUS examination once during the pregnancy. Case and controls were a match according to maternal age, gestational age at ultrasound examination and parity. Placental vascularity was calculated using the 3D-power Doppler histogram using pre-established power Doppler settings. Comparison among groups and subgroups were analyzed using t-student and ANOVA tests. RESULTS: The population demographics and characteristics were similar in both groups. Mean gestational age at evaluation was 32.6⫾3.4 weeks. The placental vascularity index was significantly reduced in cases with hypertension (11.1⫾0.8%) in comparison with healthy pregnancies (15.2⫾1.1%; p⬍0.01); but with similar reduction in those with pure preeclampsia (10.7⫾1.1%), chronic hypertension (11.5⫾1.3%) and superimposed preeclampsia (11.2⫾1.2%; p⫽0.89). CONCLUSION: Pregnancies complicated with hypertensive disorders have reduced placental vascularity than healthy pregnancies, independently of the classification of the disorder.

653 Evidence for excessive feto-placental activation of the polyol pathway: implications for hyperuricemia of preeclampsia (PE) Sami Makaroun1, Catalin Buhimschi1, Guomao Zhao1, Megan McCarthy1, John Hardy1, Antonette Dulay1, Christine Laky1, Irina Buhimschi1 1

Yale University, Ob/Gyn & Reprod. Sci., New Haven, CT

OBJECTIVE: Uric acid (UA) can result from fructose (FRU) metabo-

lism. Aside from ingestion, FRU is endogenously produced from glucose (GLU) via the polyol pathway: aldose reductase (ARD) converts GLU to sorbitol (SOR) and SOR-dehydrogenase (SORD) converts SOR to FRU. We hypothesized that overactivation of an existing polyol pathway in the feto-placental unit contributes to hyperuricemia of PE. STUDY DESIGN: FRU, SOR, GLU, and UA were assayed in serum and urine of 65 pregnant healthy controls (CRL: GA: ⬍20w, n⫽4; GA: 20-34w, n⫽15; GA: ⬎37w, n⫽46) and 29 women with severe PE (sPE, GA: 29⫾2w). Same analytes were assayed in cord blood (CB) of fetuses delivered in the setting of sPE (n⫽23, GA: 30⫾1), idiopathic preterm birth (iPTB, n⫽23, GA: 31⫾1), and normal healthy term gestation (n⫽22). Placental and amniochorion ARD & SORD expression was studied in sPE, iPTB and term gestation (n⫽4/group) by RT-PCR and IHC. Placenta and membrane explants were employed to test their ability to generate SOR in vitro. RESULTS: In normal gestation, serum UA increased with GA (P⬍.001) in relationship with SOR (r⫽.67, P⬍.001) and FRU (r⫽.32, P⫽.03) but not GLU (P⬎.05). Fractional excretion (FE) of FRU and UA decreased with GA (P⬍.001). sPE increased serum UA (P⬍.001) and SOR (P⬍0.001) but not FRU & GLU (P⬎0.05). FE of UA, FRU and SOR but not of GLU were decreased in sPE (P⬍.001). In sPE, UA level was predicted by the combination of SOR and serum creatinine (P⬍.001 for both), accounting for 53% of variability. SOR & UA in CB of healthy term newborns exceed maternal levels. sPE further increased CB SOR and UA vs iPTB group (P⬍.05). PCR and IHC demonstrated preferential expression of ARD in trophoblasts and of SORD in decidual cells. Fetal membranes release 3-fold SOR compared to placenta in vitro. CONCLUSION: An active polyol pathway is present and functional in the feto-placental unit. Decidual dysfunction and accumulation of SOR at this site could be an alternative explanation for the increased UA in PE.

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654 Endocan (ESM-1): a novel soluble endothelial cell injury marker in preeclampsia (PE) and intrauterine growth restriction (IUGR) Sarah Cross1, Irina Buhimschi1, Christina Duzyj1, Lydia Shook1, Megan McCarthy1, John Hardy1, Guomao Zhao1, Catalin Buhimschi1 1

Yale University, Ob/Gyn & Reprod. Sci., New Haven, CT

OBJECTIVE: ESM-1 is a newly discovered soluble endothelial cell pro-

teoglycan, released by damaged vascular endothelium in response to inflammatory cytokines and angiogenic stimuli. Recent data show ESM-1 regulates angiogenesis and its bioactivity is mediated via interaction with hepatocyte growth factor (HGF). Vascular endothelial dysfunction and injury plays a key role in the pathogenesis of PE and IUGR. We hypothesized that soluble ESM-1 is upregulated in women with severe PE (sPE), and its circulatory levels relate to the timing and clinical manifestation of the disease. STUDY DESIGN: We analyzed 211 serum samples from: normotensive healthy pregnant controls (CRL, GA ⬍20w, n⫽29; GA 20-34w, n⫽31; GA ⬎37w, n⫽18), early-onset sPE (GA 20-34w, n⫽28), early onset sPE⫹IUGR (GA ⬍37w, n⫽16), late-onset sPE (GA ⬎37w, n⫽39), chronic hypertension (crHTN, GA ⬍37w, n⫽39) and idiopathic IUGR (GA ⬍37w, n⫽18). ESM-1 and HGF were measured by ELISA and validated by Western blotting. Placental ESM-1 mRNA expression and localization were studied by RT-PCR, IHC and image analysis. RESULTS: Maternal serum levels of ESM-1 were GA-regulated with a significant decrease toward term (R⫽⫺.43, P⬍.001). Compared to GA-matched CRLs, women with early-onset sPE had higher ESM-1 serum concentrations (P⫽.003) that varied independent of maternal circulatory levels of HGF. Late-onset sPE, crHTN and idiopathic IUGR did not significantly impact circulating ESM-1 levels (P⬎.05). ESM-1 mRNA was detected in villous trophoblast and had high immunostaining in endothelial, cytotrophoblast and decidual cells. There was an increase in the expression of ESM-1 in the peri-infarct areas of IUGR placentas (P⫽.016), independent of sPE. CONCLUSION: Women with preterm sPE have elevated serum ESM-1 levels, likely reflecting advanced degree of endothelial activation and injury at earlier GA. Enhanced expression at sites of major placental damage suggests ESM-1 may play a role in the pathophysiology of trophoblast injury in IUGR.

655 Relationship between urinary tract infection and circulating angiogenic factors in patients with preeclampsia Sarah Rae Easter1, Kee-Hak Lim2, Samuel Parry3, Thomas McElrath4 1 Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Department of Obstetrics and Gynecology, Boston, MA, 2 Beth Israel Deaconess Medical Center, Harvard Medical School, Division of Maternal-Fetal Medicine, Boston, MA, 3Hospital of the University of Pennsylvania, Division of Maternal-Fetal Medicine, Philadelphia, PA, 4 Brigham and Women’s Hospital, Harvard Medical School, Division of Maternal-Fetal Medicine, Boston, MA

OBJECTIVE: The association between preeclampsia (PE) and urinary tract infection (UTI) has been described. Aberrancies in circulating angiogenic factors, specifically sFlt-1 and P1GF, are associated with development of preeclampsia. We tested the hypothesis that UTI and the resulting inflammation causes changes in these markers leading to the development of PE. STUDY DESIGN: Pregnancies (n⫽2,619) were followed prospectively from the initiation of prenatal care through delivery at three U.S., regional academic centers. Plasma sFlt-1 and PlGF concentrations were quantified at 10, 17, 25 and 35 weeks gestational age (GA). Presence of UTI was abstracted from the medical record. PE was defined by ACOG criteria. Median sFlt-1 and PlGF concentrations were compared in early-onset (⬍34 weeks GA, n⫽29), late-onset (34⫹ weeks

American Journal of Obstetrics & Gynecology Supplement to JANUARY 2013