605: Transplacental transfer of Vancomycin and Telavancin

Poster Session IV

Epidemiology, Infectious Disease, Intrapartum Fetal Assessment, Operative Obstetrics, Obstetric Quality & Safety, Public Health-Global Health

sequestration, acting as host defense mechanism. We have showed earlier that NGAL is elevated by cytotrophoblast (CTs) treated with proinflammatory cytokines (Tadesse et al. Reprod Sci 2011;18:71322). This current study examines the possible protective role of iron and NGAL at the fetal-maternal interface in infection/inflammation. STUDY DESIGN: In order to establish whether NGAL is expressed in clinically defined cases of IAI, we measured levels of mRNA in extracts of frozen placental tissue from 6 preterm cases [positive IAI, n⫽3, GA: 25(24-32) wks, negative IAI, n⫽3, GA: 30(28-32) wks]. AF cultures and histology were used to confirm IAI. CTs were isolated from term uncomplicated placentas. To simulate IAI and to verify the likely role of NGAL in keeping iron homeostasis in CTs, cells were supplemented with iron (Fe) citrate (50M) and treated with IL1␤ (1ng/mL), TNF␣(10ng/mL), LPS (10g/mL), respectively for 24h. Protein and mRNA levels were measured by western blot and RT-qPCR. RESULTS: IAI tissues showed a 23-fold increase in NGAL mRNA vs GA matched idiopathic controls. Expression of NGAL mRNA in CTs supplemented with and without Fe, respectively, and IL1␤,TNF␣,and LPS were 4449-fold vs 4.8-fold, (p⬍0.001); 1318-fold vs 4.7-fold (p⫽0.003), and 3.3-fold vs 2.8-fold (p⫽0.01) compared to control. In the presence of Fe, NGAL protein levels in CTs were also markedly increased by treatment with IL1␤, TNF␣, LPS vs control (25-fold, 11-fold, 8-fold, respectively, all p⬍0.05). In the absence of Fe, IL1␤,TNF␣,LPS treatment alone promoted a small increase of NGAL protein levels. CONCLUSION: IAI results in enhanced NGAL expression in EVTs. In vitro studies revealed marked upregulation of NGAL expression in CTs treated with Fe and proinflammatory compounds known to be increased in IAI. These results imply that NGAL functions as a mediator of innate immune responses in CTs at the maternal-fetal interface in pregnancies complicated by IAI.

603 Association between parity and hemozoin-positive syncytiotrophoblasts and CD68ⴙ cells in Plasmodium falciparuminfected placentas Stephanie Valderramos1, Bethann Hromatka2, Jennifer Adibi3, Susan Fisher4 1 University of California, San Francisco, Department of Obstetrics, Gynecology & Reproductive Sciences, San Francisco, CA, 2University of California, San Francisco, Departments of Obstetrics and Gynecology, Anatomy, the Center for Reproductive Sciences, and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, 3University of California, San Francisco, Department of Obstetrics and Gynecology, San Francisco, CA, 4University of California, San Francisco, Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, San Francisco, CA

OBJECTIVE: Plasmodium falciparum malaria infection during pregnancy is estimated to account for up to 50% of low birth weight infants in endemic areas. P. falciparum-infected red blood cells sequester in the intervillous space of the placenta, and the malaria pigment hemozoin has been noted within intervillous maternal monocytes/macrophages, syncytiotrophoblasts (STBs) and villous mesenchymal cells. We aimed to further characterize these histopathological features of infection to identify potential pathophysiological mechanisms of placental malaria. STUDY DESIGN: We performed immunolocalization studies on 34 biopsies of P. falciparum-infected and uninfected placentas (n⫽17/ group) from the Democratic Republic of the Congo. A diagnosis of malaria was made at the time of delivery. Patients with other pregnancy complications, including hypertension, preeclampsia, chorioamnionitis, and maternal anemia, were excluded. Placental sections were scored for the number of pigmented STBs and mesenchymal cells per 400x field. RESULTS: Immunostaining with cytokeratin 7 (KRT7) and CD68 demonstrated that hemozoin was present within STBs and monocytes/macrophages, respectively. Regression analysis suggested that hemozoin-positive STBs and CD68⫹ cells were associated with pla-

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centas from primigravidae and secundigravidae. Quantification of intravillous CD68⫹ cells, corresponding to fetal Hofbauer cells, revealed an increased prevalence in infected placentas from first and second pregnancies, compared to uninfected, parity-matched controls. Interestingly, we did not observe an increase in CD68⫹ cells in case versus control placentas from multigravidae (parity ⱖ 3). CONCLUSION: These data suggest that STBs and CD68⫹ fetal Hofbauer cells engulf hemozoin or P. falciparum-infected RBCs. Furthermore, our findings of increased numbers of intravillous CD68⫹ Hofbauer cells in placentas from primigravidae and secundigravidae may suggest a heightened fetal immune response in these patients, which are more susceptible to severe complications from placental malarial.

604 Transplacental transfer of oseltamivir carboxylate Svetlana Patrikeeva1, Ying Zhan1, Tatiana Nanovskaya2, Gary D. Hankins1, Mahmoud S. Ahmed1 1 The University of Texas Medical Branch, Obstetrics and Gynecology, Galveston, TX, 2University of Texas Medical Branch, Obstetrics and Gynecology, Fetal Pharmacology, Galveston, TX

OBJECTIVE: Determine the transplacental transfer and metabolism of oseltamivir carboxylate (OC) and its distribution between the tissue, maternal and fetal circuits of the dually perfused placental lobule. STUDY DESIGN: The technique of dual perfusion of placental lobule (DPPL) was utilized to determine the Maternal-to-Fetal (n⫽11) and Fetal-to-Maternal (n⫽9) transfer of OC. The concentration of OC in the maternal reservoir (350 ng/mL) was equal to the mean plasma concentration of the drug in patients who received a dose of 75 mg of oseltamivir phosphate (OP). OC was co-perfused with its [3H]-isotope and the marker compound antipyrine (AP, 20 ug/mL) together with its [14C]-isotope. The concentration of OC and its possible metabolite(s) in the perfused tissue and both maternal and fetal circuits was determined by liquid scintillation spectrometry and High Performance Liquid Chromatography (HPLC). RESULTS: OC was transferred from the maternal to the fetal circuit. The distribution of OC after 4 hours of perfusion was as follows: 21⫹6% of the drug was retained by placental lobule, 66⫹4% remained in the maternal circuit, and 21⫹6% was transferred to the fetal circuit. The fetal/maternal concentration ratio of OC was 0.33⫹0.10%. The normalized transfer of OC (Clearance index) to AP in the Maternal-to-Fetal direction (0.47⫹0.11) was not different from its transfer from the Fetal-to-Maternal circuit (0.47⫹0.06). The absence of any detectable metabolites of OC in the aliquots obtained from the maternal and fetal circuits and placental tissue suggest that the drug was not metabolized during its perfusion. CONCLUSION: OC crosses human placenta. Since the transfer rate of OC is 47% of the freely diffusible AP, it is likely that the fetus will be exposed to OC. This work was supported by NICHD Obstetric-Pharmacology network U10HD047891.

605 Transplacental transfer of Vancomycin and Telavancin Svetlana Patrikeeva1, Ying Zhan1, Valentina Fokina1, Tatiana Nanovskaya2, Gary D. Hankins1, Mahmoud S. Ahmed1 1 The University of Texas Medical Branch, Obstetrics and Gynecology, Galveston, TX, 2University of Texas Medical Branch, Obstetrics and Gynecology, Fetal Pharmacology, Galveston, TX

OBJECTIVE: Determine the bidirectional transfer of Vancomycin (Van) and Telavancin (Tel) across the dually perfused term human placental lobule and their metabolism by the tissue. STUDY DESIGN: Placentas were obtained from healthy term pregnancies. The dual perfusion in its re-circulating mode was used to determine the Maternal-to-Fetal (n⫽10) and Fetal-to-Maternal (n⫽8) transfer of each antibiotic. The initial concentration of Van or Tel in the donor circuit was 25 ug/mL. The readily diffusible non metabolizable marker compound antipyrine (AP, 20 ug/mL) was co-perfused with each antibiotic to account for inter-placental variations. Each antibiotic was co-perfused with its radioactive isotope (tritium) together with [14C]-isotope AP to enhance the detection limits of each

American Journal of Obstetrics & Gynecology Supplement to JANUARY 2012

www.AJOG.org

Epidemiology, Infectious Disease, Intrapartum Fetal Assessment, Operative Obstetrics, Obstetric Quality & Safety, Public Health-Global Health

compound. The concentrations of each drug and any metabolites formed by the tissue during the perfusion period of 4 hours were determined in both the maternal and fetal circuits by liquid scintillation spectrometry. Separation of the drugs from their metabolites was achieved by High Performance Liquid Chromatography (HPLC). RESULTS: Following the perfusion period of 4 hours in the maternal to fetal direction,10⫹4% of Van and 6⫹2% of Tel (p⬍0.05) was transferred to the fetal circuit. Van remaining in the maternal circuit amounted to 59⫹5% as compared to 65⫹7% for Tel. The tissue retained 31⫹6% of Van and 29⫹6% for Tel. The fetal/maternal concentration ratio of Van at the end of experiment was 0.16⫹0.06 and for Tel 0.097⫹0.03 (p⬍0.05). This data suggest low transfer of the two antibiotics to the fetal circuit. The transfer of Van and Tel in the Maternal-to- Fetal direction was normalized to that of AP and did not reveal a significant difference with their transfer in the Fetal-to-Maternal direction. In addition, neither Van nor Tel was metabolized by the tissue during the perfusion period. CONCLUSION: The data obtained using the dual perfusion model system revealed lower transfer of Tel than Van across human placenta. Supported by NICHD OPRU U10HD047891.

606 Maternal HBeAg status and hepatitis B viral activity in HBsAg positive mothers Terence T. Lao1, Tak Yeung Leung1, Stephen Sik Hung Suen1, Man Kin Chung1, Stephen Siu Chung Chim1, Theresa Ka Wa Cheung1, Vincent Wai Sun Wong2, Henry Lik Yuen Chan2 1 The Chinese University of Hong Kong, Obstetrics and Gynecology, Hong Kong, Hong Kong, 2The Chinese University of Hong Kong, Medicine and Therapeutics, Hong Kong, Hong Kong

OBJECTIVE: To determine the relationship between maternal hepatitis B e-antigen (HBeAg) status with activity of hepatitis B virus (HBV) in mothers screened positive for hepatitis B surface antigen (HBsAg) in order to explore the reported association between HBeAg positivity with risk of vertical transmission of HBV. STUDY DESIGN: A prospective observation study was conducted in a group of Chinese mothers identified from positive antenatal screening for HBsAg and recruited from the antenatal clinic. Maternal characteristics, blood count, liver function, and blood HBV DNA level measured by TaqMan real-time polymerase chain reaction using Eurohep standard with a range of detection from 20 to 200 x 10e6 IU/ml, were compared between mothers with positive and negative HBeAg. RESULTS: The study consisted of 56 women, 11 (19.6%) of whom were positive for HBeAg. There was no significant difference in maternal characteristics, liver function and blood count, except for gestational age at study and hematocrit levels (Table). However, the HBeAg positive mothers had higher incidence of detectable HBV DNA (OR 1.73, 95% CI 1.35-2.22) and levels of HBV DNA detected. Further analysis showed that this group of mothers was associated with high (log value ⱖ4.0, OR 65.0, 95% CI 7.00-603.3) and very high (log value ⱖ8.0, OR 96.8, 95% CI 12.0-780.3) HBV DNA levels. CONCLUSION: Maternal positive HBeAg status was associated not only with increased incidence of detectable HBV DNA, but also with high and very levels. This is likely to be the underlying explanation for the increased risk of vertical transmission of HBV infection to the offspring in these mothers.

Poster Session IV

607 Administsration of lamivudine in the third trimester to reduce the risk of perinatal transmission of hepatitis B: a cost-effectiveness analysis Unzila A. Ali1, Erika F. Werner2, Christina S. Han1, Christian M. Pettker1, Edmund F. Funai1, Stephen F. Thung1 1 Yale University, Ob/Gyn & Reprod Sci., New Haven, CT, 2Johns Hopkins University, Gynecology and Obstetrics, Baltimore, MD

OBJECTIVE: Antepartum antiviral prophylaxis to decrease hepatitis B perinatal transmission rates is currently not standard of care. The objective of this study was to determine whether routine administration of lamivudine to pregnant patients with chronic hepatitis B in the third trimester is a cost-effective strategy in preventing perinatal transmission. STUDY DESIGN: We developed a decision analysis model to compare the cost-effectiveness of two management strategies during pregnancy for chronic hepatitis B: (1) expectant management with no treatment and (2) administration of lamivudine in the third trimester. In the latter, women with chronic hepatitis B received lamivudine 100 mg daily from 28 weeks until delivery. We assumed that lamivudine would reduce the perinatal transmission rate by 62% (range 20-80%) and that all neonates received the currently recommended hepatitis B immunoglobulin and hepatitis B vaccine. The main outcome measure was incremental cost-effectiveness ratio (ICER) defined as marginal cost per quality-adjusted life year (QALY) gained. An ICER less than $50,000/QALY gained was considered cost-effective. RESULTS: Our model demonstrates that administration of lamivudine in the third trimester is the dominant strategy. For every 1000 chronically infected pregnant women treated with lamivudine, $337,000 is saved and 314 QALYs are gained. We predict that for every 1000 pregnancies with chronic hepatitis B, lamivudine treatment would prevent 21 cases of hepatocellular carcinoma and 5 liver transplants. Even when lamivudine efficacy is conservatively estimated to be 20%, administration of the medication is cost-effective. The model remains robust in univariate sensitivity analysis. Monte Carlo simulations demonstrate that lamivudine treatment is cost-saving 82% of the time and is cost-effective the remainder of the time. CONCLUSION: Administration of lamivudine in the third trimester to pregnant patients with chronic hepatitis B is cost-effective, and frequently cost-saving, under a wide range of circumstances.

608 Obesity as a risk factor for infectious processes of pregnancy Virginia Takagi1, Meredith Williams1, Gregory Steele2, David Haas1 1 Indiana University, Obstetrics and Gynecology, Indianapolis, IN, 2Indiana University, Epidemiology, Indianapolis, IN

OBJECTIVE: The increased risk for wound infection and pro-inflammatory state associated with obesity is well established. Our objective is to determine if obesity is a risk factor for other infectious processes of pregnancy. STUDY DESIGN: The Consortium on Safe Labor is a database from 12 institutions across the United States from 228,668 deliveries from Supplement to JANUARY 2012 American Journal of Obstetrics & Gynecology

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