Cystatin C expression in the preeclamptic placenta
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563 FIRST TRIMESTER COMBINED SCREENING: OUTCOMES OF AN INSTANT RESULTS APPROACH LINDA HOPKINS (F) 1 , AARON CAUGHEY 1 , SHERRI PENA 1 , DAVID KRANTZ 2 , HEIDI JONATHAN 1 , MARY NORTON 1 , 1 University of California, San Francisco, Obstetrics, Gynecology, and Reproductive Sciences, San Fran- cisco, California, 2 NTD Laboratories, Inc., Huntington Station, New York OBJECTIVE: To determine how many women pursue invasive testing or screening after an instant results first trimester (1st tri) screening protocol with nuchal translucency (NT), free beta hCG and PAPP-A. STUDY DESIGN: Retrospective cohort analysis of women undergoing 1st tri screening between 11/1/03 and 5/31/05. Predictor variables included age (R35, !35yo) and 1st tri screen status. Outcome variables included initial diagnostic test chosen (CVS, amnio, or none), detection of aneuploidy, and AFP uptake. We also examined choices of women with discordant 1st tri screen and AFP results. RESULTS: 1,820 women underwent 1st tri screening (See Table). After a positive 1st tri screen result, 59% of the women R35yo chose invasive testing as compared to 83% of women !35yo (p=0.007) and 23% of the women R35yo obtained a CVS as compared to 47% of women !35yo (p=0.003). After a negative 1st tri screen, 12% of women R35yo chose invasive testing as opposed to 1% of the women !35yo (p!0.001). After a negative 1st tri screen but a positive AFP, 64.5% of women R35yo and 85.7% of women !35yo underwent amniocentesis (p=0.05). 1st tri screening identified 13/15 (87%) fetuses with aneuploidy. CONCLUSION: Women !35yo are more likely to pursue invasive testing after a positive 1st tri screen, but women R35yo are more likely to pursue invasive testing after a negative 1st tri screen. How women incorporate their a priori risk or their increased risk after a test into diagnostic decision making requires further investigation. Test choice Screen Status Screen C Screen C Screen ÿ Screen ÿ Age R35yo !35yo R35yo !35yo Totals 186/1107 (16.8%) 36/713 (5.1%) 921/1107 (83.2%) 677/713 (94.9%) Amnio 68 (36.6%) 13 (36.1%) 95 (10.3%) 6 (0.9%) CVS 42 (22.6%) 17 (47.2%) 14 (1.5%) 0 (0.0%) AFP 9 (11.8%) 2 (33.3%) 314 (38.7%) 382 (56.9%) 564 ANTI-INFLAMMATORY CYTOKINE GENE POLYMORPHISMS PREDICT MULTIFETAL PREGNANCIES ROBIN B. KALISH (F) 1 , STEVEN D. SPANDORFER 1 , STEVEN S. WITKIN 1 , 1 Weill Medical College of Cornell University, Obstetrics and Gy- necology, New York, New York OBJECTIVE: Ovulation and implantation are inflammatory processes. We hypothesized that genetic polymorphisms associated with increased pro- inflammatory activity would be associated with multifetal pregnancies. STUDY DESIGN: DNA from 267 women with singleton pregnancies and 155 women with multifetal gestations were tested for a length polymorphism in intron 2 of the interleukin-1 receptor antagonist (IL-1ra) gene and a single nucleotide polymorphism at position –590 in the interleukin (IL)-4 promoter. RESULTS: Homozygosity for IL-1ra allele 1 (IL1RN*1) was more prevalent in women with singleton pregnancies (60.7%) than in those with multifetal pregnancies (42.6%) (P!.0001). Allele 2 (IL1RN*2) was more common in multifetal pregnancies (31.3%) than in singletons (20.8%) (P=.0009). Similar differences were observed when only women who conceived by in vitro fertil- ization (IVF) were evaluated. The IL1RN*2 allele frequency was 33.8% in women with multifetal IVF pregnancies as opposed to 23.5% in women with singleton IVF pregnancies (P!.003). The IL1RN*2 allele frequency in women with spontaneously conceived twins (26.0%) did not differ statistically from that of IVF twin pregnancies. Homozygosity for the IL-4 C allele (IL4- 590*C) occurred in 57.4% of women with multifetal pregnancies as opposed to 39.8% of those with singleton gestations (P=.0018). IL-4 T allele (IL4-590*T) carriage was 37.3% in singleton and 25.6% in multiple pregnancies (P=.0019). CONCLUSION: IL1RN*2 and IL4-590*C are both associated with a reduc- tion in the ability to down-regulate pro-inflammatory immune activity. Car- riage of these genotypes is associated with multifetal gestations, possibly due to an increased susceptibility for multiple embryo implantation. Supported by NIH grant 41676. 565 TBX3 & TBX15 EXPRESSION IN THE LIMB BUD OF WILD TYPE & FGF10 KNOCKOUT MICE MARY KING (F) 1 , FRANK DIAZ 2 , ALEX BONDAREV 2 , VIMLA AGGARWAL 2 , ALAN SHANSKE 3 , BERNICE MORROW 2 , 1 Albert Einstein College of Medicine, ObGyn, Bronx, New York, 2 Albert Einstein College of Medicine, Molecular Genetics, Bronx, New York, 3 Montefiore Medical Center, Pediatric Genetics, Bronx, New York OBJECTIVE: The T-box gene family is a group of transcription factors, required for embryonic development. Several T-box genes, Tbx2,3,4,5,15 & 18, are expressed in the developing limbs. Fibrobast growth factor 10 (Fgf10) is another gene required for limb development and Fgf10 null mouse mutant embryos do not form limbs. There is feedback between Tbx5-Fgf10; by E10.5, Tbx5 expression is downregulated in Fgf10 null mutants. Our hypothesis is that expression of the other T-genes will be downregulated in Fgf10 null mutants. STUDY DESIGN: Fgf10G mice were intercrossed & embryos of each genotype isolated at E10.5. Whole mount in situ hybridization was performed using probes for Tbx3 & Tbx15. RESULTS: In the Fgf10 null embryos at E10.5, expression of Tbx3 & Tbx15 was present in the early limb mesenchyme. Expression patterns for the wildtype embryos were similar to previous reports, with Tbx3 present along the anterior & posterior margins of the limb buds, Tbx15 in the central limb bud mesenchyme. We are now examining multiple stages of Fgf10ÿ/ÿ embryos with Tbx2,3,4,5,15 & 18 probes. CONCLUSION: Although Fgf10ÿ/ÿ embryos did not form limb buds, both Tbx3 & Tbx15 were robustly expressed. This suggests that unlike Tbx5, their expression is in a genetic pathway independent of Fgf10. 566 CYSTATIN C EXPRESSION IN THE PREECLAMPTIC PLACENTA KARL KRISTENSEN 1 , IRENE LARSSON 1 , S. R. HANSSON 1 , 1 Lunds University Hospital, Dep. of OB- GYN, Lund, Sweden OBJECTIVE: In human placentation extravillous trophoblast invasion is regulated by proteinases and their inhibitors. Impaired trophoblast invasion appears to be involved in the pathogenesis of preeclampsia. Cystatin C (Cys C) is a strong inhibitor of lysosomal cysteine proteinases and has a widespread distribution in human tissues and body fluids. Maternal serum levels of Cys C are elevated in normal pregnancy and preeclampsia. The aim of this study was to investigate the expression of Cys C mRNA and protein in the human placenta from normal and preeclamptic pregnancies. STUDY DESIGN: Placental tissue was collected from 13 normal and 22 preeclamptic pregnancies at term. We used in situ hybridization and real-time PCR to study the gene expression of Cys C and immunohistochemistry to study protein localisation. RESULTS: Cys C mRNA was mainly detected in the extravillous tropho- blast cells, the intralobular septa and in cells of placental vessel adventitias. Quantitative analysis showed a significnatly higher expression of Cys C mRNA in pre-eclamptic placentae compared to the normal pregnancy group. CONCLUSION: The location of Cys C mRNA expression and the higher expression in preeclampsia indicates a potential role of this proteinase inhibitor in normal placentation and in the pathogenesis of preeclampsia. Elevated serum levels of Cys C in normal pregnancy and preeclampsia could be explained by increased synthesis in the placenta. More studies of cysteine proteinases and their inhibitors are needed to determine their role in normal and failed placentation. SMFM Abstracts S161
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Transcript of Cystatin C expression in the preeclamptic placenta
563 FIRST TRIMESTER COMBINED SCREENING: OUTCOMES OF AN INSTANT RESULTSAPPROACH LINDA HOPKINS (F)1, AARON CAUGHEY1, SHERRI PENA1,DAVID KRANTZ2, HEIDI JONATHAN1, MARY NORTON1, 1University of California,San Francisco, Obstetrics, Gynecology, and Reproductive Sciences, San Fran-cisco, California, 2NTD Laboratories, Inc., Huntington Station, New York
OBJECTIVE: To determine how many women pursue invasive testing orscreening after an instant results first trimester (1st tri) screening protocol withnuchal translucency (NT), free beta hCG and PAPP-A.
STUDY DESIGN: Retrospective cohort analysis of women undergoing 1st triscreening between 11/1/03 and 5/31/05. Predictor variables included age (R35,!35yo) and 1st tri screen status. Outcome variables included initial diagnostictest chosen (CVS, amnio, or none), detection of aneuploidy, and AFP uptake.We also examined choices of women with discordant 1st tri screen and AFPresults.
RESULTS: 1,820 women underwent 1st tri screening (See Table). After apositive 1st tri screen result, 59% of the women R35yo chose invasive testingas compared to 83% of women !35yo (p=0.007) and 23% of the womenR35yo obtained a CVS as compared to 47% of women !35yo (p=0.003).After a negative 1st tri screen, 12% of women R35yo chose invasive testing asopposed to 1% of the women !35yo (p!0.001). After a negative 1st tri screenbut a positive AFP, 64.5% of women R35yo and 85.7% of women !35younderwent amniocentesis (p=0.05). 1st tri screening identified 13/15 (87%)fetuses with aneuploidy.
CONCLUSION: Women !35yo are more likely to pursue invasive testingafter a positive 1st tri screen, but women R35yo are more likely to pursueinvasive testing after a negative 1st tri screen. How women incorporate their apriori risk or their increased risk after a test into diagnostic decision makingrequires further investigation.
Test choice
Screen Status Screen C Screen C Screen � Screen �
Age R35yo !35yo R35yo !35yoTotals 186/1107
(16.8%)36/713(5.1%)
921/1107(83.2%)
677/713(94.9%)
Amnio 68 (36.6%) 13 (36.1%) 95 (10.3%) 6 (0.9%)CVS 42 (22.6%) 17 (47.2%) 14 (1.5%) 0 (0.0%)AFP 9 (11.8%) 2 (33.3%) 314 (38.7%) 382 (56.9%)
564 ANTI-INFLAMMATORY CYTOKINE GENE POLYMORPHISMS PREDICT MULTIFETALPREGNANCIES ROBIN B. KALISH (F)1, STEVEN D. SPANDORFER1, STEVENS. WITKIN1, 1Weill Medical College of Cornell University, Obstetrics and Gy-necology, New York, New York
OBJECTIVE: Ovulation and implantation are inflammatory processes. Wehypothesized that genetic polymorphisms associated with increased pro-inflammatory activity would be associated with multifetal pregnancies.
STUDY DESIGN: DNA from 267 women with singleton pregnancies and 155women with multifetal gestations were tested for a length polymorphism inintron 2 of the interleukin-1 receptor antagonist (IL-1ra) gene and a singlenucleotide polymorphism at position –590 in the interleukin (IL)-4 promoter.
RESULTS: Homozygosity for IL-1ra allele 1 (IL1RN*1) was more prevalentin women with singleton pregnancies (60.7%) than in those with multifetalpregnancies (42.6%) (P!.0001). Allele 2 (IL1RN*2) was more common inmultifetal pregnancies (31.3%) than in singletons (20.8%) (P=.0009). Similardifferences were observed when only women who conceived by in vitro fertil-ization (IVF) were evaluated. The IL1RN*2 allele frequency was 33.8% inwomen with multifetal IVF pregnancies as opposed to 23.5% in womenwith singleton IVF pregnancies (P!.003). The IL1RN*2 allele frequency inwomen with spontaneously conceived twins (26.0%) did not differ statisticallyfrom that of IVF twin pregnancies. Homozygosity for the IL-4 C allele (IL4-590*C) occurred in 57.4% of women with multifetal pregnancies as opposed to39.8% of those with singleton gestations (P=.0018). IL-4 T allele (IL4-590*T)carriage was 37.3% in singleton and 25.6% in multiple pregnancies (P=.0019).
CONCLUSION: IL1RN*2 and IL4-590*C are both associated with a reduc-tion in the ability to down-regulate pro-inflammatory immune activity. Car-riage of these genotypes is associated with multifetal gestations, possibly dueto an increased susceptibility for multiple embryo implantation.
Supported by NIH grant 41676.
565 TBX3 & TBX15 EXPRESSION IN THE LIMB BUD OF WILD TYPE & FGF10 KNOCKOUTMICE MARY KING (F)1, FRANK DIAZ2, ALEX BONDAREV2, VIMLA AGGARWAL2,ALAN SHANSKE3, BERNICE MORROW2, 1Albert Einstein College of Medicine,ObGyn, Bronx, New York, 2Albert Einstein College of Medicine, MolecularGenetics, Bronx, New York, 3Montefiore Medical Center, Pediatric Genetics,Bronx, New York
OBJECTIVE: The T-box gene family is a group of transcription factors,required for embryonic development. Several T-box genes, Tbx2,3,4,5,15 & 18,are expressed in the developing limbs. Fibrobast growth factor 10 (Fgf10) isanother gene required for limb development and Fgf10 null mouse mutantembryos do not form limbs. There is feedback between Tbx5-Fgf10; by E10.5,Tbx5 expression is downregulated in Fgf10 null mutants. Our hypothesis isthat expression of the other T-genes will be downregulated in Fgf10 nullmutants.
STUDY DESIGN: Fgf10G mice were intercrossed & embryos of eachgenotype isolated at E10.5. Whole mount in situ hybridization was performedusing probes for Tbx3 & Tbx15.
RESULTS: In the Fgf10 null embryos at E10.5, expression of Tbx3 & Tbx15was present in the early limb mesenchyme. Expression patterns for thewildtype embryos were similar to previous reports, with Tbx3 present alongthe anterior & posterior margins of the limb buds, Tbx15 in the central limbbud mesenchyme. We are now examining multiple stages of Fgf10�/�embryos with Tbx2,3,4,5,15 & 18 probes.
CONCLUSION: Although Fgf10�/� embryos did not form limb buds, bothTbx3 & Tbx15 were robustly expressed. This suggests that unlike Tbx5, theirexpression is in a genetic pathway independent of Fgf10.
566 CYSTATIN C EXPRESSION IN THE PREECLAMPTIC PLACENTA KARL KRISTENSEN1,IRENE LARSSON1, S. R. HANSSON1, 1Lunds University Hospital, Dep. of OB-GYN, Lund, Sweden
OBJECTIVE: In human placentation extravillous trophoblast invasion isregulated by proteinases and their inhibitors. Impaired trophoblast invasionappears to be involved in the pathogenesis of preeclampsia. Cystatin C (Cys C)is a strong inhibitor of lysosomal cysteine proteinases and has a widespreaddistribution in human tissues and body fluids. Maternal serum levels of Cys Care elevated in normal pregnancy and preeclampsia. The aim of this study wasto investigate the expression of Cys C mRNA and protein in the humanplacenta from normal and preeclamptic pregnancies.
STUDY DESIGN: Placental tissue was collected from 13 normal and 22preeclamptic pregnancies at term. We used in situ hybridization and real-timePCR to study the gene expression of Cys C and immunohistochemistry tostudy protein localisation.
RESULTS: Cys C mRNA was mainly detected in the extravillous tropho-blast cells, the intralobular septa and in cells of placental vessel adventitias.Quantitative analysis showed a significnatly higher expression of Cys CmRNA in pre-eclamptic placentae compared to the normal pregnancy group.
CONCLUSION: The location of Cys C mRNA expression and the higherexpression in preeclampsia indicates a potential role of this proteinaseinhibitor in normal placentation and in the pathogenesis of preeclampsia.Elevated serum levels of Cys C in normal pregnancy and preeclampsia couldbe explained by increased synthesis in the placenta. More studies of cysteineproteinases and their inhibitors are needed to determine their role in normaland failed placentation.
SMFM Abstracts S161
