2007 Annual Meeting
ABSTRACT 1
Clinical Risk Factors Associated with Poor VBAC Outcome
By Invitation
Kimberly D. Gregory, MD, MPH
Lisa M. Korst, MD, PhD; Moshe Fridman, PhD; Ida Shihady, MPH; Paula Broussard, RN; Arlene Fink, PhD; Linda Burnes Bolton, RN, DrPH
OBJECTIVE: To identify VBAC success rates, and maternal and neonatal complication rates for selected antenatal conditions.
STUDY DESIGN: Population based cohort study using administrative discharge data for women delivering in California hospitals during 2002.
RESULTS: Among 41,450 women, 29.72% (12,320/41,450) had maternal, fetal, or placental conditions complicating pregnancy. Attempted VBAC rates and VBAC success rates varied widely by these clinical condition, ranging from 10%-73%. The VBAC success rate for low-risk women (no conditions) was 73.76%, versus 50.31% for high-risk women (at least one condition), p<0.0001. Absolute rates of maternal and neonatal complications were low (less than 1-2%), and the rate of adverse events was higher in the high-risk clinical group as compared to the low risk clinical group.
CONCLUSION: Variation in rates of VBAC success and childbirth morbidities can be partially attributed to clinical factors complicating pregnancy. Women without such conditions show improved VBAC success and fewer maternal and neonatal complications.
ABSTRACT 2
Gene Expression Profiling of Human Oocytes at Different Maturational Stages and After In Vitro Maturation
By Invitation
Pasquale Patrizio, MD, MBE
Dagan Wells, PhD
OBJECTIVE: To catalogue genes expressed in human oocytes at germinal vesicle (GV) or metaphase II (MII) stage and to compare gene profiles between oocytes matured in vivo (in vivo-MII) and in vitro (IVM-MII).
STUDY DESIGN: Research utilizing unfertilized oocytes analyzed for >29,000 genes with RNA amplification and microarray.
RESULTS: GV, in vivo-MII and IVM-MII oocytes expressed 14188, 16402 and 18299 genes, respectively. There was extensive overlap among the three groups, but some significant differences as well. In particular, in vivo-MII and IVM-MII oocytes shared expression of 11973 genes. However, some immature patterns of expression, reminiscent of GVs, persisted in IVM-MIIs.
CONCLUSIONS: This study provided a detailed insight into gene expression of human oocytes. Although IVM-MII oocytes closely resemble in vivo-MII oocytes for most of the pathways related to nuclear maturity, several others associated with cytoplasmic functions continue to be expressed in a GV-like manner. IVM-MII oocytes have significant differences in the expression of genes related to cellular storage and homeostasis.
ABSTRACT 3
Is There a Therapeutic Benefit to Regional Lymphadenectomy in the Surgical Treatment of Endometrial Carcinoma?
By Invitation
Richard R. Barakat, MD
Nadeem R. Abu-Rustum, MD; Dennis S. Chi, MD; Alexia Lasonos, PhD, Qin Zhou, Eniola Oke, Robert A. Soslow, MD; Kaled M. Alektiar, MD
OBJECTIVE: To evaluate whether surgical removal of regional lymph nodes influences the overall survival of women with endometrial carcinoma.
STUDY DESIGN: All patients with endometrioid-type endometrial cancer treated at our institution between 1/93 and 12/04 were reviewed. The Classification and Regression Tree (CART) method, a form of recursive partitioning, was used.
RESULTS: In all, 1035 patients were evaluated. FIGO stage included: stage I, 824; stage II, 65; stage III, 109; and stage IV, 37. Lymph nodes were removed in 524 cases (51%). Median number of nodes removed was 16. Using the CART hierarchically, stage, age, adjuvant therapy, and the removal of >10 lymph nodes emerged as predictors of overall survival.
CONCLUSIONS: In addition to well-known clinicopathologic risk factors for survival in endometrioid endometrial carcinoma, the removal of > 10 regional lymph nodes was associated with improved overall survival in lower-stage, older patients who received no adjuvant therapy or brachytherapy only.
ABSTRACT 4
Fetal Outcome in Motor-Vehicle Crashes: Effects of Crash Characteristics and Maternal Restraint
By Invitation
Mark D. Pearlman, MD
Kathleen DeSantis Klinich, PhD; Carol A. C. Flannagan, PhD; Jonathan D. Rupp, PhD; Mark Sochor, MD; Lawrence W. Schneider, PhD
OBJECTIVE: This project was undertaken to improve understanding of factors associated with adverse fetal outcomes of pregnant occupants involved in motor-vehicle crashes.
STUDY DESIGN: In-depth investigations of crashes involving 57 pregnant occupants were performed. Maternal and fetal injuries, restraint information, measures of external and internal vehicle damage, and details about the crash circumstances were collected. Crash severity was calculated using vehicle crush measurements. Chi-square analysis and logistic regression models were used to determine factors with a significant association with fetal outcome.
RESULTS: Fetal outcome is most strongly associated with crash severity (p < 0.001) and maternal injury (p=0.002). Proper maternal belt-restraint use (with or without airbag deployment) is associated with favorable fetal outcome (Odds ratio=4.5, p=0.033).
CONCLUSIONS: Crash severity, maternal injury, and lack of proper seat belt use are associated with a higher risk of adverse fetal outcome. These results strongly support recommendations that pregnant women use properly positioned seatbelts.
ABSTRACT 5
Epidemiology of Low Grade Serous Ovarian Cancer
By Invitation
Steven C. Plaxe, MD
OBJECTIVE: To determine if the epidemiology of low grade ovarian serous cancers is distinct from that of high grade ovarian serous cancers.
STUDY DESIGN: SEER data are analyzed in order to compare the descriptive epidemiologies of low and high grade lesions.
RESULTS: Mean survival (99 vs. 57 months) and age (55.5 vs. 62.6 years), trends in annual incidence rate (-3.8% vs. 1.4%), rate ratio of advanced to early disease (1.9 vs. 10.2), rate ratio of post- to pre- menopausal incidence (5.0 vs. 13.0) and difference in average age between advanced and early stage (none vs. 2.5 years) are significantly different for patients with low grade, compared to high grade, disease.
CONCLUSION: Epidemiology of low grade tumors appears sufficiently different from that of high grade lesions to support the concept that low grade ovarian serous cancers constitute a distinct clinical, and perhaps biologic, entity.
ABSTRACT 6
Reliability and Validity of Reflection Exercises for Obstetrics and Gynecology Residents
By Invitation
Lee A. Learman, MD, PhD
Amy M. Autry, MD, Patricia O’Sullivan, EdD
OBJECTIVE: Self-evaluation is an essential skill throughout physicians’ careers, and reflection is thought to be a necessary mechanism for effective self-evaluation. The aim of our study was to establish the reliability and validity of structured assessments of critical self-reflection.
STUDY DESIGN: 32 residents completed 6 exercises that were scored from 0 (no description of event) to 6 (deep reflection). We calculated inter-rater and internal consistency reliability for the exercises, and compared scores by postgraduate year (PGY) and with other competency assessments.
RESULTS: Residents completed 183 reflections. Inter-rater reliability was 0.89. Surgical skill reflections scored highest (3.2, sd 0.91). Five exercises had adequate internal consistency reliability (0.62). Senior residents received higher reflection scores than junior residents; the magnitude of difference was similar for other competency measures and not statistically significant. Reflection scores were correlated with professionalism and communication skill assessments (0.36-0.37, p<0.01) but not with medical knowledge.
CONCLUSIONS: Self-reflection can be reliably assessed using scored exercises that demonstrate concurrent validity with other assessments. We encourage further research including multiple training programs to further evaluate our approach for assessing reflection in postgraduate education.
ABSTRACT 7
Group B Streptococcus and Pregnancy
By Invitation
John W. Larsen, MD
John L. Sever, MD, PhD
In the 1960s early onset neonatal sepsis due to GBS had an attack rate of 2/1000 live births and a 50% case fatality rate. Early treatment and then antibiotic prophylaxis were shown to reduce morbidity and mortality; however, GBS remains a leading cause of perinatal infection. This paper will review our investigations and related studies, including our studies in monkeys that have contributed to current diagnosis, treatment and prevention of disease due to GBS. While it has not been possible to eradicate GBS colonization intravenous antibiotic prophylaxis (IAP) given during parturition has been effective in preventing vertical transmission in animals and humans. Recently, diagnostic tests using polymerase-chain-reaction (PCR) have offered promise for rapid accurate detection. This could lead to a major shift in the timing of diagnosis from the office setting to delivery suite. The potential for immunization remains a challenge.
ABSTRACT 8
Protection against Cisplatin Induced Ovarian Damage by the Antioxidant Sodium 2-Mercaptoethanesulfonate (Mesna) in Female Rats
By Invitation
John Yeh, MD
Beom Su Kim, PhD, Jennifer Peresie, BS
OBJECTIVE: The hypothesis tested was that administration of the antioxidant mesna (sodium 2- mercaptoethanesulfonate) during chemotherapy would protect ovaries against follicular damage.
STUDY DESIGN: Sprague-Dawley rats were treated with saline, mesna plus cisplatin, or cisplatin. Immunohistochemistry was used to evaluate the Müllerian inhibiting substance (MIS) positive follicles. Serum and ovarian MIS were measured using ELISA and Western blot analysis, respectively. Apoptosis in ovaries was studied by TUNEL.
RESULTS: Immunofluorescence staining for MIS was higher in prenatal follicles in the mesna plus cisplatin group. The ovarian and serum MIS levels were higher in the mesna plus cisplatin than the cisplatin alone group. There were no differences statistically in the TUNEL and in the ovarian cyst analyses.
CONCLUSION: Mesna used at the time of cisplatin administration protected ovaries against damage. The data presented challenge the existing clinical paradigm that GnRH agonists represent the only medical method for protecting ovaries during chemotherapy. Alternative medical means to protect ovaries during chemotherapy may be achievable.
ABSTRACT 9
Early Preterm Birth: Association Between In Utero Exposure to AcuteInflammation and Severe Neurodevelopmental Disability at 6 Years of Age
By Invitation
William W. Andrews, MD, PhD
Suzanne P. Cliver, BA; Fred Biasini, PhD; A. Myriam Peralta-Carcelen, MD; Richard Rector, PhD; Ann I. Alriksson-Schmidt, MA, MSPH; Ona Faye-Petersen, MD; Waldemar Carlo, MD; Robert Goldenberg, MD; John C. Hauth, MD
OBJECTIVE: To determine the association between in utero exposure to acute inflammation and long-term major neurodevelopmental disability at age 6 years among children born prior to 32 weeks’ gestation.
STUDY DESIGN: This was a follow-up investigation of a cohort of maternal-infant dyads delivered between 23 and <32 weeks’ gestation. Surviving infants (and their mothers or caregivers) underwent a battery of psychological and neurodevelopmental tests between 5 and 8 years of age. Pregnancy and neonatal data were analyzed among children with versus those without major neurodevelopmental disability (including IQ <70 [n=41], cerebral palsy [CP, n=11] and a composite major disability [n=52]).
RESULTS: A total of 261 (70%) of the 375 maternal-infant dyads with surviving children were successfully recruited and evaluated at 6.8 ± 0.7 years. Mean delivery gestational age (GA) and birth weight were 28.8 ± 2.2 weeks’ and 1163 ± 382 grams, respectively. Neither surrogate indicators for nor direct markers of in utero exposure to acute inflammation were significantly associated with severe adverse outcomes. Delivery GA was significantly associated with outcome. Logistic regression indicated that each increasing gestational week was associated with a significantly decreased risk of an IQ <70 (OR 0.75, 95% C.I. 0.6 – 0.9). An average 1.9 point increase in IQ at 6 years of age was observed per gestational week gained (23 to 32 weeks’).
Periventricular leukomalacia was associated with a 9.6 point mean deficit in IQ. The perceptive vocabulary scores (IQ proxy) of primary caregivers were significantly lower among children with an IQ <70 vs. ≥70 (87.5 ± 11.5 vs. 92.1 ± 11.2, P=.016).
CONCLUSIONS: Among children born between 23 and 32 weeks’ gestation, neonatal complications, GA at delivery, and caregiver IQ, but not in utero exposure to acute inflammation was associated with increased risk of severe adverse neurodevelopmental outcomes.
ABSTRACT 10
Prediction of Preterm Birth in Symptomatic Women Using Decision Tree Modeling for Biomarkers
By Invitation
Alan D. Bocking, MD
Jacquelyn L. Hill, MSc; M. Karen Campbell, PhD;GuangYong Zou, PhD; John R.G. Challis, PhD;Gregor Reid, PhD; Hiroshi Chisaka, MD
OBJECTIVE: To use recursive partitioning (RP) to identify gestational-age-specific and threshold values for infectious and endocrine biomarkers of imminent delivery.
STUDY DESIGN: RP was developed using a previously collected dataset and then applied to a prospectively collected cohort of women in threatened preterm labor. Predictors of preterm birth were considered, including white blood cell count (WBC), corticotrophin-releasing hormone (CRH), cortisol, and maternal age.
RESULTS: At 22-27 weeks gestation, WBC of >12000/mL was the most accurate predictor of delivery within 48 hours; at 28-31 weeks gestation, CRH of >684 pg/mL was the most accurate predictor; and at 32-26 weeks gestation, CRH and maternal age were the most important variables.
CONCLUSIONS: These results indicate that maternal WBC >12,000/mL prior to 28 weeks gestation and CRH beyond 28 weeks are the most accurate biomarkers in predicting preterm birth within 48 hours. RP assists in establishing clinically relevant and gestational-age specific threshold levels for these variables.
ABSTRACT 11
Diminished Survival of Human Cytotrophoblast Cells Exposed to Hypoxia/Reoxygenation Injury and Associated Reduction of Heparin-Binding EGF-Like Growth Factor
By Invitation
Richard E. Leach, MD
Brian A. Kilburn; Anelia Petkova, MD; Roberto Romero, MD; D. Randall Armant, PhD
OBJECTIVE: The anti-apoptotic action of HBEGF and its regulation by O2 constitutes a key factor for trophoblast survival. The hypothesis that cytotrophoblast survival is compromised by exposure to hypoxia–reoxygenation (H/R) injury may contribute to preeclampsia and some missed abortions prompted us to investigate HBEGF regulation and its role as a survival factor during H/R in cytotrophoblast cells.
STUDY DESIGN: A transformed human first trimester cytotrophoblast cell line HTR-8/SVneo was exposed to H/R (2% O2 followed by 20% O2) and assessed for HBEGF expression and cell death.
RESULTS: Cellular HBEGF declined significantly within 30 minutes of reoxygenation after culture at 2% O2. H/R significantly reduced proliferation and increased cell death when compared to trophoblast cells cultured continuously at 2% or 20% O2. Restoration of cell survival also was achieved by adding recombinant HBEGF during reoxygenation. HBEGF inhibited apoptosis through its binding to either HER1 or HER4, its cognate receptors.
CONCLUSION: These results provide evidence that cytotrophoblast exposure to H/R induces apoptosis and decreased cell proliferation. HBEGF accumulation is diminished under these conditions, while restoration of HBEGF signaling improves trophoblast survival.
ABSTRACT 12
Mechanical Homeostasis is Altered in Uterine Leiomyoma
By Invitation
James H. Segars, MD
Rebecca Rogers, BS; John Norian, MD; Mones Abu-Asab, PhD, Gregory Christman, MD; Minnie Malik, PhD; Faye Chen, PhD; Casey Korecki; James Iatridis; William H. Catherino, MD, PhD; Rocky S. Tuan; Phyllis C. Leppert, MD, PhD
OBJECTIVE: Uterine leiomyoma produce an extracellular matrix (ECM) that is abnormal in its volume, content, and structure. Alterations in ECM can modify mechanical stress on cells, leading to activation of Rho-dependent signaling. Here we sought to determine whether the altered ECM produced by leiomyoma was accompanied by an altered state of mechanical homeostasis.
STUDY DESIGN: Measurement of the mechanical response in paired leiomyoma and myometrium, immunogold, confocal microscopy, and immunohistochemical analyses.
RESULTS: Leiomyoma were significantly stiffer than matched myometrium. The increased stiffness was associated with a moderate increase in total sulfated glycosaminoglycan content and a slight increase in hydroxyproline. Levels of the Rho-GEF, AKAP13, were increased and subcellular localization was altered in leiomyoma. Phosphorylation of p38MAPK was greater in leiomyoma extracts.
CONCLUSIONS: Leiomyoma cells are exposed to increased mechanical stress and show structural and biochemical features consistent with activation of solid-state signaling. The altered state of stress may contribute to growth of leiomyoma.
ABSTRACT 13
Impact of Vessel Maturation on Anti-Angiogenic Therapy in Ovarian Cancer
By Invitation
Anil K. Sood, MD
Chunhua Lu, MD, PhD; Premal H. Thaker, MD; Yvonne G. Lin, MD; Whitney Spannuth, MD; Charles N. Landen, MD; William M. Merritt, MD; Nicholas B. Jennings, BS; Robert R. Langley, PhD; David M. Gershenson, MD; George D. Yancopoulos, MD, PhD; Lee M. Ellis, MD; Robert B. Jaffe, MD; Robert L. Coleman, MD
OBJECTIVE: To examine the functional and therapeutic significance of pericytes in ovarian cancer vasculature.
STUDY DESIGN: Tumor vessel morphology and efficacy of endothelial and pericyte targeting were examined using in vivo ovarian cancer models. The expression of platelet derived growth factor (PDGF) ligands and receptors was examined in endothelial, pericyte-like, and ovarian cancer cells.
RESULTS: Relative to normal vessels, tumor vasculature was characterized by loosely attached pericytes in reduced density. PDGF-BB was expressed predominantly by the endothelial and cancer cells whereas PDGFRβ was present in pericyte-like cells. PDGF-BB significantly increased migration of and VEGF production by pericyte-like cells while PDGFRβ blockade abrogated these effects. Dual VEGF (VEGF-Trap) and PDGF-B (PDGF-Trap) targeted therapy was more effective in inhibiting in vivo tumor growth than either agent alone.
CONCLUSIONS:Aberrations in the tumor microenvironment contribute to endothelial cell survival. Strategies targeting both endothelial cells and pericytes should be considered for clinical trials.