164: Midtrimester isolated polyhydramnios in monochorionic diamniotic multiple gestations
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We recently found that human trophoblast nanovesicles (exosomes) contain C19MC miRNAs, which can deliver C19MC miRNAs to non-placental recipient cells and attenuate viral infection (PNAS 2013). Here we hypothesized that C19MC miRNAs constitute a novel maternal-fetal signaling system. STUDY DESIGN: RNAseq, microarrays and qPCR were used to quantify miRNA expression in triads of placenta and maternal-fetal plasma, obtained at delivery of term healthy women (n¼30). Ul- tracentrifugation and fractionation, verified by nanoparticle tracking device, were used to analyze exosomes from primary human tro- phoblasts. To analyze miRNA trafficking to maternal and fetal tissues we engineered a transgenic mouse in which we introduced a 160 kb segment of human genomic DNA containing the C19MC cluster. RESULTS: Placenta-specific miRNA species, such as miR-517-3p, which we demonstrated to have an anti-viral activity, were found in both the maternal and fetal circulation, exhibiting an extraordinary species correlation (p <2.2e-16). Isolated trophoblastic exosomes also contain these miRNAs. Our “humanized” C19MC transgenic mouse lines constitutively expressed a low level of C19MC miRNAs. In contrast, during pregnancy C19MC miRNAs were found mainly in the placenta, and expression was >100-fold higher than in any other tissue (p<0.0001). Importantly, breeding of wild-type females with C19MC transgenic males confirmed high miRNA expression in transgenic placentas and also revealed the expression of C19MC miRNAs primarily in the circulation of wild type mothers, as well as in the fetal blood. CONCLUSION: Our data define an unprecedented, non-hormonal system of miRNA communication between the placenta and feto- maternal compartments, which may serve to limit the maternal-fetal spread of viruses. 163 Fetal gender-specific placental “endocannabinoidome” in maternal obesity Natalia Schlabritz-Loutsevitch 1 , Jacques Samson 1 , Sonali Gupta 1 , Mauro Schenone 1 , Brian Brocato 1 , Danielle Tate 1 , Raisa Krutilina 1 , Cezary Skobowiat 2 , Andrzej Slominski 2 , Bob Moore 3 , Giancarlo Mari 1 1 University of Tennessee Health Science Center, Obstetrics and Gynecology, Memphis, TN, 2 University of Tennessee Health Science Center, Pathology, Memphis, TN, 3 University of Tennessee Health Science Center, Pharmacology, Memphis, TN OBJECTIVE: Endocannabinoids (ECBs) represent a group of lipid signaling molecules, derived from polyunsaturated fatty acids. ECBs regulation is critical for embryo development and pregnancy maintenance. Dysregulation of peripheral ECBs is a hallmark of obesity. We previously reported the changes in placental “endo- cannabinoidome” in obese non-human primates (Brocato et al., 2013). There are no data available regarding placental ECBs system in maternal obesity (MO) in human pregnancy. In light of the epidemic proportion of MO, these data are urgently needed. The goal of this study was to evaluate the expression of key enzymes and receptors of ECBs in placentas of the male fetuses, exposed to MO. STUDY DESIGN: Four non-obese and three obese patients without pregnancy-related complications and diabetes were included into this study based on their pre-pregnancy BMI (24.1 2 kg/m2 and 39.1 7 kg/m2). Placentas were collected at the time of cesarean delivery at term. The Western Blot analyses and immunohisto- chemistry were performed with the commercially available anti- bodies. Data were analyzed using two tailed Student’ s t-test, significance was set at p<0.05. The study was approved by the institutional review board (10-01129-XP). RESULTS: The expressions of ECBs receptors: CB1 and CB2 and N-arachidonoyl-phosphatidylethanolamine, cleaved by phospholi- pase D (NAPE-PLD) were significantly decreased in MO (Fig.1). The expressions of fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) were not different between two groups. CONCLUSION: The decreased expression of NAPE PLD-the enzyme, involved in the synthesis of ECBs ligand- anandamide (AEA), might result in the decreased AEA concentrations, as documented in the adipose tissue from obese subjects and pregnant non- human primates (Brocato et al., 2013). Taking in consideration the reported inhibitory role of AEA on the myometrial contraction and down regulation of placental CB1 receptors in labor, our data might hold the key to the mechanisms, leading to preterm deliveries in MO. 164 Midtrimester isolated polyhydramnios in monochorionic diamniotic multiple gestations Andrew Chon 1 , Lisa Korst 2 , Arlyn Llanes 2 , David Miller 2 , Joseph Ouzounian 2 , Ramen Chmait 2 1 Kaiser Permanente Los Angeles, Department of Obstetrics and Gynecology, Los Angeles, CA, 2 Keck School of Medicine, University of Southern California, Department of Obstetrics and Gynecology, Division of Maternal- Fetal Medicine, Los Angeles, CA OBJECTIVE: The natural history of monochorionic diamniotic mul- tiple gestations complicated by midtrimester isolated poly- hydramnios (iPoly), in which one amniotic sac has polyhydramnios but the other has normal amniotic volume, remains unclear. The objective of this study was to identify risk factors for development of overt twin-twin transfusion syndrome (TTTS) in patients diagnosed with midtrimester iPoly. STUDY DESIGN: Patients referred for possible TTTS between 16 and 26 weeks’ gestation were studied (2006-2013). The diagnosis of iPoly was established if the maximum vertical pocket of amniotic fluid measured 8 cm in the recipient’ s sac and >2 cm in the donor’ s sac at the consultative ultrasound. RESULTS: Of 628 consecutive patients referred for possible TTTS, 11.8% (74) were diagnosed with iPoly; 1 remained undelivered. The overall perinatal survival of at-least-one twin in the 73 iPoly Poster Session I Ultrasound, Fetus, Genetics www.AJOG.org S94 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2014
Transcript of 164: Midtrimester isolated polyhydramnios in monochorionic diamniotic multiple gestations
Poster Session I Ultrasound, Fetus, Genetics www.AJOG.org
We recently found that human trophoblast nanovesicles (exosomes)contain C19MC miRNAs, which can deliver C19MC miRNAs tonon-placental recipient cells and attenuate viral infection (PNAS2013). Here we hypothesized that C19MC miRNAs constitute anovel maternal-fetal signaling system.STUDY DESIGN: RNAseq, microarrays and qPCR were used toquantify miRNA expression in triads of placenta and maternal-fetalplasma, obtained at delivery of term healthy women (n¼30). Ul-tracentrifugation and fractionation, verified by nanoparticle trackingdevice, were used to analyze exosomes from primary human tro-phoblasts. To analyze miRNA trafficking to maternal and fetal tissueswe engineered a transgenic mouse in which we introduced a 160 kbsegment of human genomic DNA containing the C19MC cluster.RESULTS: Placenta-specific miRNA species, such as miR-517-3p,which we demonstrated to have an anti-viral activity, were found inboth the maternal and fetal circulation, exhibiting an extraordinaryspecies correlation (p <2.2e-16). Isolated trophoblastic exosomesalso contain these miRNAs. Our “humanized” C19MC transgenicmouse lines constitutively expressed a low level of C19MC miRNAs.In contrast, during pregnancy C19MC miRNAs were found mainlyin the placenta, and expression was >100-fold higher than in anyother tissue (p<0.0001). Importantly, breeding of wild-type femaleswith C19MC transgenic males confirmed high miRNA expression intransgenic placentas and also revealed the expression of C19MCmiRNAs primarily in the circulation of wild type mothers, as well asin the fetal blood.CONCLUSION: Our data define an unprecedented, non-hormonalsystem of miRNA communication between the placenta and feto-maternal compartments, which may serve to limit the maternal-fetalspread of viruses.
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Fetal gender-specific placental “endocannabinoidome”in maternal obesityNatalia Schlabritz-Loutsevitch1, Jacques Samson1, Sonali Gupta1,Mauro Schenone1, Brian Brocato1, Danielle Tate1, Raisa Krutilina1,Cezary Skobowiat2, Andrzej Slominski2, Bob Moore3,Giancarlo Mari11University of Tennessee Health Science Center, Obstetrics and Gynecology,Memphis, TN, 2University of Tennessee Health Science Center, Pathology,Memphis, TN, 3University of Tennessee Health Science Center,Pharmacology, Memphis, TNOBJECTIVE: Endocannabinoids (ECBs) represent a group of lipidsignaling molecules, derived from polyunsaturated fatty acids. ECBsregulation is critical for embryo development and pregnancymaintenance. Dysregulation of peripheral ECBs is a hallmark ofobesity. We previously reported the changes in placental “endo-cannabinoidome” in obese non-human primates (Brocato et al.,2013). There are no data available regarding placental ECBs systemin maternal obesity (MO) in human pregnancy. In light of theepidemic proportion of MO, these data are urgently needed. Thegoal of this study was to evaluate the expression of key enzymes andreceptors of ECBs in placentas of the male fetuses, exposed to MO.STUDY DESIGN: Four non-obese and three obese patients withoutpregnancy-related complications and diabetes were included intothis study based on their pre-pregnancy BMI (24.1 �2 kg/m2 and39.1 �7 kg/m2). Placentas were collected at the time of cesareandelivery at term. The Western Blot analyses and immunohisto-chemistry were performed with the commercially available anti-bodies. Data were analyzed using two tailed Student’s t-test,
S94 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2
significance was set at p<0.05. The study was approved by theinstitutional review board (10-01129-XP).RESULTS: The expressions of ECBs receptors: CB1 and CB2 andN-arachidonoyl-phosphatidylethanolamine, cleaved by phospholi-pase D (NAPE-PLD) were significantly decreased in MO (Fig.1).The expressions of fatty acid amide hydrolase (FAAH) andmonoacyl glycerol lipase (MAGL) were not different between twogroups.CONCLUSION: The decreased expression of NAPE PLD-the enzyme,involved in the synthesis of ECBs ligand- anandamide (AEA), mightresult in the decreased AEA concentrations, as documented inthe adipose tissue from obese subjects and pregnant non-human primates (Brocato et al., 2013). Taking in considerationthe reported inhibitory role of AEA on the myometrial contractionand down regulation of placental CB1 receptors in labor, ourdata might hold the key to the mechanisms, leading to pretermdeliveries in MO.
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Midtrimester isolated polyhydramnios in monochorionicdiamniotic multiple gestationsAndrew Chon1, Lisa Korst2, Arlyn Llanes2, David Miller2,Joseph Ouzounian2, Ramen Chmait21Kaiser Permanente Los Angeles, Department of Obstetrics and Gynecology,Los Angeles, CA, 2Keck School of Medicine, University of SouthernCalifornia, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Los Angeles, CAOBJECTIVE: The natural history of monochorionic diamniotic mul-tiple gestations complicated by midtrimester isolated poly-hydramnios (iPoly), in which one amniotic sac has polyhydramniosbut the other has normal amniotic volume, remains unclear. Theobjective of this study was to identify risk factors for development ofovert twin-twin transfusion syndrome (TTTS) in patients diagnosedwith midtrimester iPoly.STUDY DESIGN: Patients referred for possible TTTS between 16 and26 weeks’ gestation were studied (2006-2013). The diagnosis of iPolywas established if the maximum vertical pocket of amniotic fluidmeasured �8 cm in the recipient’s sac and >2 cm in the donor’s sacat the consultative ultrasound.RESULTS: Of 628 consecutive patients referred for possible TTTS,11.8% (74) were diagnosed with iPoly; 1 remained undelivered.The overall perinatal survival of at-least-one twin in the 73 iPoly
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www.AJOG.org Ultrasound, Fetus, Genetics Poster Session I
patients was 89.1%. TTTS developed in 22 of the 73 patients(30.1%), of which almost two-thirds were of advanced Quinterostage. Of these 22, 19 underwent laser surgery; 30-day perinatalsurvival of at-least-one twin in this laser group was 84.2%. ThreeTTTS patients did not undergo laser: two had a fetal demise, andone was diagnosed with Stage I at 28 weeks and managed withamnioreduction. In the remaining 51 non-TTTS patients, 8 hadamnioreductions because of symptomatic iPoly and 43 weremanaged expectantly; 30-day perinatal survival of at-least-onetwin in the non-TTTS group was 92.9%. In a multivariatelogistic regression model, two gestational characteristics wereassociated with the development of TTTS: intrauterine growth re-striction (IUGR) of the normal twin (OR 7.88, 95%CI [1.83-33.88],P ¼ 0.0056), and gestational age< 20 weeks at the time of diagnosisof iPoly (OR ¼ 13.08, 95%CI [3.29-52.04], P ¼ 0.0003).CONCLUSION: Patients with midtrimester iPoly have a 30% risk ofdeveloping subsequent TTTS. Donor twin IUGR and/or earlydiagnosis (<20 weeks) are significant risk factors for development ofTTTS in iPoly patients.
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Clinically significant genomic alterations are enhancedin placentas from pregnancies with fetal growth restriction(FGR)epreliminary resultsTal Biron-Shental1, Rivka Sukenik-Halevy1, Michael Bonin3,Atalia Shtorch-Asor2, Meirav Kaiser2, Aliza Amiel11Meir Medical Center, Tel Aviv University, OBGYN, Kfar Saba, Israel, 2MeirMedical Center, Tel Aviv University, Genetics Institute, Kfar Saba, Israel,3University of Tuebingen, Department of Medical Genetics, Tuebingen,GermanyOBJECTIVE: Advances in microarray technology allow high-resolutiongenome wide evaluation for DNA copy number variations: deletionsor duplications. Fetal growth restriction (FGR) secondary toplacental insufficiency is associated with substantially increasedchildhood and adulthood morbidity and mortality. The long termoutcome is related to placental aberrations and intra-uterineprogramming.
Our aim was to demonstrate the usefulness of microarray testingin FGR placentas.STUDY DESIGN: Using Affimetix (California, USA) genetic chip forchromosomal microarray (CMA), we performed an analysis of 10placentas from pregnancies with FGR attributed to placental insuf-ficiency. We analyzed 5 placentas from FGR below the 5th percentileand 5 placentas of FGR between 5 and <10th percentile. All thefetuses had a normal anomaly scan and normal karyotypes. Theresults were compared to 4 placentas from uncomplicated preg-nancies with healthy neonates.RESULTS: Microarray analysis identified more clinically significantgenomic alterations in FGR placentas compared to healthy controls.There was a correlation to the severity of the FGR (see the table).The genomic alterations were below the resolution of normal kar-yotyping. Genes that were altered in the severe FGR placentas arerelated to adult human height, stress reaction and also to cellularmigration, differentiation and adhesion.CONCLUSION: Though very preliminary, our data supportplacental evaluation using CMA for FGR placentas. Larger datasets are needed for further evaluation of our findings and itsclinical implications.
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3D power Doppler vascularization indices of the wholeplacenta vs placental bed in the prediction of adversepregnancy outcomesKaren Hannaford1, Katherine Goetzinger1, Methodius Tuuli1,Linda Odibo1, Alison Cahill1, George Macones1, Anthony Odibo11Washington University in St. Louis, Obstetrics & Gynecology, St. Louis, MOOBJECTIVE: Previous literature has shown modest association be-tween 3D power Doppler indices in the placenta and adverse preg-nancy outcomes. We hypothesized that evaluating these indices atthe maternal-fetal interface (the placental bed) would be morepredictive.STUDY DESIGN: This is a secondary analysis of a prospective cohortstudy of women with singletons between 11-14 weeks who un-derwent ultrasounds for aneuploidy screening. We excluded fetalor chromosomal anomalies. Placental vascular indices (flow index(FI), vascularization index (VI), and vascularization flow index(VFI) of the whole placenta and of the placental bed werecalculated using 3D power Doppler imaging. Outcomes of in-terest were preeclampsia (PE), early PE (delivered<34 weeks),<10th% for gestational age (SGA), gestational hypertension(GHTN) and preterm birth (PTB<34wks). The predictive abilityof each variable was calculated using ROC curves, and area underthe ROC curve (AUC) were compared using non-parametricstatistics.RESULTS: From 651 women with 3D data, 56 (8.8%) had PE, 12(2%) had early PE, 57 (9%) had SGA, and 43 (6.7%) hadPTB<34 weeks. The mean values for PBVI, PBFI and PBVFIwere lower in those that developed PE, and both PBFI andPBVFI were lower in those with early PE. All placental bedvascular indices were lower among PTB<34wks compared tothose who delivered at term. None of the indices were statisticallydifferent in those with GH or SGA. The predictive ability of thevascular indices of the whole placenta versus the placental bedalone for predicting adverse pregnancy outcomes were notsignificantly different when compared using non-parametricstatistics (Table).CONCLUSION: This study confirms lower 3D power Dopplerplacental bed vascular flow indices in pregnancies that develop PE,especially early onset cases. Given the comparable predictive abilitybetween evaluation of the whole placenta and the placental bed, ourfindings question the need to focus on a specific region of theplacenta.
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