628: More large-for-gestational (LGA) neonates and fewer placental vascular lesions in late-onset preeclampsia: a role for the fetus?

Poster Session IV

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

STUDY DESIGN: This is a retrospective cohort study of gravidas with

CHTN who delivered at University Hospital, Newark, NJ from 1/1/ 2001 to 9/30/2011. Patients were identified by ICD-9 codes, and excluded if they had multifetal gestation, HIV, pregestational diabetes, renal or connective tissue disease. APO was defined as preeclampsia, placental abruption, intrauterine fetal demise and intrauterine growth restriction. PWT and SWT in patients with and without an APO were compared. Mann-Whitney and chi-square tests were used. Receiver operating characteristic curves (ROC) were constructed for PWT and SWT and Youden’s index was used for optimal cut-off determination. Medians and ranges are shown. RESULTS: Of 763 patients identified, 187(24.5%) met the inclusion criteria. 90(48%) developed an APO. Age, gestational age at the time of echocardiogram and ejection fractions did not differ between the two groups. Blood pressure closest to the time of echo was higher in the APO group(SBP: 141 and 130 mmHg; DBP: 83 and 76 mmHg, p⬍0.0001). Use of antihypertensive agents was higher in the APO group (40% and 25%, p⫽0.038). Gestational age at delivery was earlier and birthweight was lower in the APO group (38 and 36 weeks, p⬍0.0001; 3160 and 2713 g, p⫽0.0002). PWT and SWT were both greater in the APO group [PWT: 1.14 and 1.04 cm, p⫽0.0027; SWT: 1.10(0.7-2.4) and 1.10(0.8-1.57) cm, p⫽0.0026]. Area under the ROC for PWT and SWT was similar (0.63). Using maximum Youden’s index, PWT and SWT of ⬎1.2 cm had a specificity of 92% and 89% and sensitivity of 33% and 33% for predicting APO, respectively. CONCLUSION: In patients with CHTN, adverse pregnancy outcomes are associated with increased PWT and SWT. These findings may be useful to guide surveillance and counseling in this group of patients.

625 Withdrawn 626 Mechanism of renal injury in RAS preeclampsia model Jeff Denney1, Cynthia Shaw1, Annette Gendron-Fitzpatrick2, Dinesh Shah1 1 University of Wisconsin, Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Madison, WI, 2University of Wisconsin, The Comparative Pathology Laboratory, Research Animal Resource Center, Madison, WI

OBJECTIVE: Cross-breeding a female mouse transgenic for human an-

giotensinogen (hAGT) with a male mouse transgenic for human renin (hREN) has been described as a model of preeclampsia with hypertension (HTN), proteinuria, and seizures (Science 1996). Our objective was to investigate mechanism of renal injury in this model. STUDY DESIGN: Mice were genotyped as hAGT, hREN, or wild type (WT). Nongravid females underwent carotid artery catheterization and telemetric transmitter implantation for blood pressure (BP) measurement. Mice were cross-bred: hAGT x hRen for preeclampsia (n⫽11) and WT x hREN or WT x WT as controls (n⫽9). Blood and urine were collected on gestational day (GD) 12, 15, and 18. ELISA was performed for plasma VEGF and sFlt-1. Necropsies were performed on GD 19. Kidneys and conceptuses were sectioned and H&E and immunostained (IHC) for sFlt-1 and VEGF. Univariate analysis was performed where appropriate. RESULTS: Preeclamptic mice had higher BP with more frequent spikes. Analysis of 2069 hrs of telemetric BP data revealed: BP of controls and preeclamptics at rest are lower than previously reported (ie, tail cuff method creates excited state). 36% of preeclamptic mice had placental necrosis. Plasma sFlt-1 declined over gestation in controls (slope, ␤⫽⫺143.66) but increased in preeclamptic mice (slope, ␤⫽2539.94; p⫽0.017). Plasma VEGF levels and slope did not differ. Preeclamptic mice had glomerular endotheliosis (82% vs. 11%; p⫽0.015) and proteinosis (82% vs. 0%; p⫽0.002). IHC demonstrated sFlt-1 in glomeruli and collecting tubules of preeclamptic kidneys but not controls. Only preeclamptic mice had VEGF staining localized to glomeruli. CONCLUSION: Preeclamptic mouse BP profiles suggest increased vascular reactivity. Although sFlt-1 increases with placental injury and is excreted through kidney, this appears to be an ancillary event. VEGF

S266

www.AJOG.org

immunostaining on glomerular endothelial cells suggests VEGF as the primary culprit causing renal injury in this model. Thus, preeclamptic renal injury in this model is similar to human preeclampsia.

627 Timing of initiation of low-dose aspirin therapy and preeclampsia prevention in high-risk women Jessica Cantu1, Joseph Biggio1, Victoria Jauk1, Rodney Edwards1, John Owen1, Alan Tita1 1 University of Alabama at Birmingham, Obstetrics and Gynecology, Birmingham, AL

OBJECTIVE: To evaluate the hypothesis that low-dose aspirin (LDA) therapy more effectively prevents preeclampsia in high-risk women when initiated before 16 weeks’ gestational age (GA). STUDY DESIGN: We performed a secondary analysis of data from a placebo-controlled RCT designed to evaluate the efficacy of LDA (60 mg/day) therapy for preeclampsia prevention in high-risk gravidaspregestational diabetes (18.5%), chronic hypertension (30.5%), multiple gestations (27%), or prior preeclampsia (24%). Participants were randomized to LDA therapy or placebo between 13 and 26 weeks. We compared the effect of LDA on preeclampsia separately for women who initiated treatment prior to 16 weeks versus those who initiated treatment at or beyond 16 weeks GA. The Breslow-Day test for homogeneity was performed to assess for variation in effect of LDA by GA category at randomization. RESULTS: Of the 2503 eligible women, 461 (18.4 %) initiated LDA therapy prior to 16 weeks GA, while 2042 initiated LDA after 16 weeks. 1254 women received LDA and 1249 received placebo, and the treatment assignment was similar in both GA groups. The effect of LDA therapy on preeclampsia by GA at initiation is presented in the table. The GA at initiation did not modify the effect of LDA on the risk of preeclampsia. The results remained unchanged when the analyses were repeated separately for each of the 4 high-risk groups (all p-values for homogeneity ⬎0.10). CONCLUSION: In women at high-risk of developing preeclampsia, lowdose aspirin therapy was ineffective in preventing the disease, whether initiated prior to or after 16 weeks GA.

Incidence of preeclampsia stratified by timing of initiation of low-dose aspirin therapy in high-risk women

628 More large-for-gestational (LGA) neonates and fewer placental vascular lesions in late-onset preeclampsia: a role for the fetus? Jimmy Espinoza1, Wesley Lee2, Stephanie Martin2, Michael Belfort2 1 William Beaumont Hospital, Department of Obstetrics and Gynecology, Royal Oak, MI, 2Baylor College of Medicine and Texas Children’s Hospital Pavilion for Women, Department of Obstetrics and Gynecology, Houston, TX

OBJECTIVE: There are conflicting reports in regards to the association between preeclampsia and LGA neonates. This study compares two nomograms in the identification of LGA neonates in preeclampsia and determines the frequency of placental vascular lesions according to the onset of the disease STUDY DESIGN: This prospective cohort study included 118 consecutive patients with preeclampsia between 23-41 weeks. LGA neonates were classified using a national birthweight (BW) chart (Alexander, 1996) and customized growth curves (Gardosi, 2009). The frequency

American Journal of Obstetrics & Gynecology Supplement to JANUARY 2013

www.AJOG.org

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

Poster Session IV

of histological placental vascular lesions was compared between earlyand late-onset preeclampsia (ⱖ 34 weeks). Exclusion criteria were inadequate dating, multiple pregnancies, fetal anomalies, chronic hypertension, renal disease, diabetes mellitus or gestational diabetes. RESULTS: 1) Customized growth curves identified a significantly higher proportion of LGA neonates than BW curves [18.6% (22/118) vs. 9.3% (11/118); p⫽0.03]; 2) The frequency of LGA neonates was higher in late- than early-onset preeclampsia [26.9% (21/78) vs. 2.5% (1/40); p⫽0.001. In contrast, the frequency of placental vascular lesions was significantly lower in late- than in early-onset preeclampsia (41% (32/78) vs. 62.5% (25/40); p⫽0.03). CONCLUSION: Late-onset preeclampsia has more LGA neonates and fewer placental vascular lesions than early-onset preeclampsia. It is possible that a mismatch between placental supply and increased fetal demand for nutrients may be central to the development of late-onset preeclampsia

629 Can preeclampsia be preliminarily diagnosed or excluded when the urine protein:creatinine ratio (TPCR) is <300 mg/g? John Ethridge1, Brian Mercer1 1 MetroHealth Medical Center-Case Western Reserve University, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Cleveland, OH

OBJECTIVE: TPCR ⱖ300 mg is highly predictive of significant proteinuria (ⱖ300 mg) on 24 hour urine collection (24hrUP). However, despite an initial negative TPCR (nTPCR), half of gravidas will have significant proteinuria when preeclampsia (PET) is suspected. Our goal was to identify clinical and laboratory characteristics, among those with a nTPCR during evaluation for suspected PET, that differentiate those with and without significant proteinuria on 24hrUP. STUDY DESIGN: Retrospective electronic medical record review was performed for women evaluated for suspected PET after 24 weeks gestation between July 2009 and December 2011, with a nTPCR and a 24hrUP collected within 7 days. Those with chronic hypertension, diabetes, chronic renal disease, or prior 24hrUP during the pregnancy were excluded. Demographic and clinical characteristics, and laboratory data at initial evaluation for PET were collected. RESULTS: 241 patients met eligibility criteria. Mean EGA at evaluation was 36.0 weeks. The cohort was 51% African American and 58% nulliparous. 103 patients had 24hrUP ⱖ300 mg (Group 1) and 138 had 24hrUP⬍300 mg (Group 2). Maternal age, ethnicity, parity, weight, BMI, systolic BP, heart rate, tobacco use, platelets, Hct, Hgb, MCV, Na, Cl, K, albumin, total bilirubin, AST, ALT, and LDH did not differ significantly between the groups. Group 1 had higher plasma uric acid (5.1 vs 4.7 mg/dl, p⫽0.004), creatinine (0.61 vs 0.57 mg/dl, p⫽0.01), diastolic BP (85.1 vs 82.4 mmHg, p⫽0.04), and TPCR (212 vs 157 mg/g, p⬍0.0001) than Group 2. TPCR was the most discriminating of all individual characteristics (ROC AUC 0.768; Sens 77%, Spec 65%, Optimal cutoff 175.5 mg/g, Figure). Composites of 1, 2, 3 or 4 of these parameters above the 75th %ile or the optimal cutoff were not more discriminating than TPCR alone. CONCLUSION: Clinical and laboratory findings, alone or in combination, are not superior to TPCR alone in discriminating preeclamptic from non-preeclamptic women when the initial TPCR is below 300 mg/g.

630 Flt-1 expressing microparticle levels correlate with plasma sFlt-1 concentrations and may contribute to VEGF regulation in preeclampsia Jonathan O’Brien1, Wendy White1, Elizabeth Baldwin1, Arij Faksh1, Peter Boseman2, Muthuvel Jayachandran3, Virginia Miller4, Brian Brost1, Carl Rose1, Norman Davies1, Vesna Garovic2 1

Mayo Clinic College of Medicine, Maternal Fetal Medicine, Rochester, MN, Mayo Clinic College of Medicine, Nephrology and Hypertension, Rochester, MN, 3Mayo Clinic College of Medicine, Cardiovascular Surgery Research, Rochester, MN, 4Mayo Clinic College of Medicine, Physiology and Biomedical Engineering, Rochester, MN 2

OBJECTIVE: Flt-1 is expressed on a variety of cells and circulates free as soluble Flt-1 (sFlt-1). SFlt-1 binds pro-angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The plasma concentration of sFlt-1 is increased in preeclampsia. Microparticles (MPs) are small vesicles, 100 nm-1.0 um in size, which are released by many cells and express different membrane bound proteins. Our goal was to determine if Flt-1could be detected on plasma MPs and whether the levels were elevated in preeclampsia. We also compared levels of total, platelet and endothelial MPs between preeclamptic and normal pregnancies. STUDY DESIGN: Blood was collected from properly consented women with preeclampsia (n⫽8) and normal controls (n⫽12). Plasma MP and MP free plasma were obtained using differential centrifugation. Fluorescence activated cell sorting flow cytometry was used to analyze MPs. MP free plasma sFlt-1 levels were determined using ELISA. RESULTS: Flt-1 positive MPs were detected in all samples, and were elevated in preeclampsia when compared to controls. Median Flt-1 positive MPs per ul of plasma were 30.0 (14.3-81.0) in preeclampsia vs. 12.0 (8.0-14.0) in controls (p ⫽ .0066). MP free plasma levels of sFlt-1 were increased in preeclampsia. The mean concentration of sFlt-1 was 27165.5 pg/ml (6899.3-47432) in preeclampsia vs. 3905.5 pg/ml (2816.1-4995) in controls (p⫽.0035). There was a statistically significant correlation between MP free plasma levels of sFlt-1 and Flt-1 expressing MPs (r⫽.51, p⫽.021). There were no differences in numbers of total, platelet and endothelial MPs between the two groups. CONCLUSION: The increase in Flt-1 expressing MPs in preeclampsia is accompanied by an increase in MP free plasma sFlt-1 concentrations. These two forms of circulating receptors can potentially bind free VEGF and PlGF, thus limiting their ability to bind to endothelial cells. This could potentially regulate PlGF and VEGF signaling in preeclampsia.

Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology

S267