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The occurrence of birth defects in relation to assisted reproductive technologies in the massachusetts outcomes study of assisted reproductive technology database
efficiency increased 2-fold. Spermatogenesis progression in males carrying Sxrb was more advanced, with clear spermatid elongation. This suggested that a gene/s encoded within Sxrb provides benefit for spermiogenesis and ROSI success. In this study our objective was to identify the gene responsible. We hypothesized that this gene might be Zfy2, a promoter of which drives the expression of Sxrb encoded Zfy2/1 fusion gene. DESIGN: Research study. MATERIALS AND METHODS: Mice lacking Y chromosome and transgenic for 3 Y-derived transgenes, Sry, Eif2s3y and Zfy2 (‘SEZ’ males), provided testes for the histological analyses and assisted reproduction trials. RESULTS: Spermiogenesis progression in ‘SEZ’ males was more advanced than in males with Sry and Eif2s3y only, with many seminiferous tubules containing elongated and condensed spermatids. Four ‘SEZ’ males provided testicular cells for injection. Three had testicular sperm, which when injected yielded live offspring. The efficiency of intracytoplasmic sperm injection (ICSI) measured as a proportion of offspring from embryos transferred was 23% (18/79), lower than that obtained after ICSI with testicular sperm from wild-type controls (57%, 32/56, P<0.001). The same ‘SEZ’ and control males provided round spermatids for injections. ROSI efficiency was 53% (48/90) for ‘SEZ’ and 23% (18/79) for control males (P<0.01). CONCLUSION: Zfy2 is essential for the formation of mature testicular sperm functional in assisted fertilization. In the presence of Zfy2, mice with testis determination driven by Sry and initiation of spermatogenesis warranted by Eif2s3y, are capable of producing sperm, which yield live offspring in ICSI. Therefore, in the mouse, only three Y encoded genes, Sry, Eif2s3y and Zfy2, constitute the minimum Y chromosome complement compatible with successful ICSI. Supported by: NIH HD072380 to MAW.
O-7 Monday, October 20, 2014 12:45 PM THE OCCURRENCE OF BIRTH DEFECTS IN RELATION TO ASSISTED REPRODUCTIVE TECHNOLOGIES IN THE MASSACHUSETTS OUTCOMES STUDY OF ASSISTED REPRODUCTIVE R. F. Liberman,a TECHNOLOGY DATABASE. K. D. Getz,a b c d aa B. Luke, J. E. Stern, E. Declercq, M. T. Anderka. Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health, Boston, MA; bDepartment of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, East Lansing, MI; cDepartment of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Lebanon, NH; dDepartment of Community Health Sciences, Boston University School of Public Health, Boston, MA. OBJECTIVE: To estimate and compare the prevalence of several specific cardiac and non-cardiac birth defects among deliveries to mothers who conceived using assisted reproductive technologies (ART) and those who conceived spontaneously. DESIGN: A longitudinal cohort study using a database of deliveries (live births and stillbirths) to Massachusetts residents during 2004-2008 created via a linkage of data from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System to the Pregnancy to Early Life Longitudinal data system. MATERIALS AND METHODS: Deliveries were classified as spontaneous conceptions (n¼324,148) or deliveries to mothers who received ART for the index pregnancy (n¼11,762). We used log-binomial regression to directly estimate prevalence ratios (PR) and associated 95% confidence intervals (CI) for cardiac and non-cardiac defects overall and for specific defects with at least four exposed and unexposed cases. RESULTS: The prevalence of cardiac defects was 82 per 10,000 among ART deliveries compared to 52 per 10,000 among spontaneous conceptions (PR¼1.60, 95% CI: 1.30, 1.96). The prevalence of non-cardiac defects was 180 per 10,000 among ART deliveries compared to 130 per 10,000 among spontaneous conceptions (PR¼1.33, 95% CI: 1.16, 1.52). Preliminary analyses of specific defects suggested elevated rates of tetralogy of Fallot, hypoplastic left heart syndrome, esophageal atresia, and rectal and large intestinal atresia among ART deliveries. Ongoing analyses will account for potential confounding, and evaluate biologic interaction with maternal age as well as potential mediation of observed associations through an increase in plural births. CONCLUSION: ART use is unlikely to be a major risk factor for birth defects. Preliminary analyses suggest that there may be modest associations between ART use and some birth defects; however, the prevalence of birth defects is low, even among ART-assisted conceptions. Supported by: NIH Grants R01HD064595 and R01HD067270.
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ASRM Abstracts
REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY FELLOWS RESEARCH I O-8 Monday, October 20, 2014 04:15 PM THE EFFECT OF DONOR OOCYTE RECIPIENT OBESITY ON LIVE BIRTH: AN ANALYSIS OF 3,922 SHARED DONOR OOCYTE ASSISTED REPRODUCTIVE TECHNOLOGY (ART) CYCLES. S. M. Zarek,a E. M. Mitchell,a A. H. DeCherney,a b a b ba K. S. Richter, K. Devine, P. E. Browne, J. E. O’Brien. NIH, Bethesda, MD; bShady Grove Fertility, Rockville, MD. OBJECTIVE: Data regarding the effect of recipient obesity on donor oocyte cycle outcome are mixed. Prior analyses have not fully accounted for intrinsic variation between donors. Our objective was to isolate the impact of body mass index (BMI) on live birth in donor egg sharing cycles in which oocytes from the same donor are shared by recipients with differing BMI. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: Live births were analyzed in fresh, shared donor ART cycles from 2004-2012 in which recipients of oocytes from the same donor oocyte retrieval fell into disparate BMI categories. Recipients had normal endometrial cavities by both saline infusion sonography and hysterosalpingogram and all donors were of normal BMI. Analysis was via generalized estimating equations with adjusted standard errors for repeated measures and nesting of recipients with differing BMI receiving oocytes from the same donor retrieval. Recipients were compared using relative risk (RR) and 95% confidence intervals (CIs) adjusted for age of the recipient. RESULTS: There were 3,922 cycles identified with 2,425 (63%) with recipient BMI below 25 kg/m2 (control group), 961 (24%) with recipient BMI between 25-30 kg/m2, 344 (8%) with recipient BMI between 30-35 kg/m2 and 192 (5%) with recipient BMI above 35 kg/m2. Increasing recipient BMI was associated with decreased live birth rate, and the association persisted when adjusted for age of recipient, number of embryos transferred, embryo stage, embryo grade and presence of severe male factor (0.990, 95% CI 0.981-0.998). Live birth was further impacted in the subset of recipients with BMI greater than 35 kg/m2, (RR 0.790, 95% CI 0.6260.977) compared to normal weight recipients. Significant differences were not appreciated in recipients with BMI between 25-30 kg/m2 (0.958, 95% CI 0.872, 1.053) and in recipients with BMI between 30-35 kg/m2 (0.931, 95% CI 0.807, 1.072). CONCLUSION: To our knowledge, this is the first report of a unique analysis of shared donor oocyte cycles demonstrating that increasing BMI of donor oocyte recipients is negatively associated with live birth. These findings persist after controlling for potential confounders, suggesting diminished uterine receptivity. A clinically significant, 21% reduction in live birth was demonstrated when BMI exceeded 35 kg/m2. This large dataset suggests a benefit to counseling on weight modification in obese recipients, with the greatest potential benefit for recipients with morbid obesity. Supported by: Intramural Research, PRAE. O-9 Monday, October 20, 2014 04:30 PM DIET-INDUCED OBESITY IMPAIRS ENDOMETRIAL STROMAL CELL DECIDUALIZATION. J. S. Rhee, J. L. Saben, V. Klenov, K. H. Moley. OB/Gyn, Washington University in St. Louis, St Louis, MO. OBJECTIVE: There is strong evidence that decreased pregnancy rates and higher miscarriage rates exist in obese women. Whether these effects are secondary to abnormal implantation, embryo development, or poor oocyte quality are unknown, although all of these factors may contribute. Our study objective was to investigate, via an in vivo and in vitro model, whether exposure of endometrial stromal cells (ESC) to saturated fatty acids or a high fat environment impairs decidualization. DESIGN: To test the effects of diet-induced obesity on ESC decidualization in vivo, artificial deciduomas were induced in high fat-fed versus chowfed control mice. In vitro cell culture models were also used to determine the impact of saturated fatty acids on ESC differentiation. MATERIALS AND METHODS: Artificial Deciduoma: Six-week old C57BL/6 female were fed either a high fat diet (59.4% Kcal from fat, HFD) or chow (CON) for twelve weeks. To induce decidualization in vivo, a silk thread was placed in the left uterine horn of pseudopregnant CON (n¼5) and HFD (n¼6) mice on dpc 3.5. Three days after thread placement, uterine horns were collected, and deciduoma formation was evaluated by comparing the uterine masses and morphologic changes via histology.
Vol. 102, No. 3, Supplement, September 2014
O-7 Monday, October 20, 2014 12:45 PM THE OCCURRENCE OF BIRTH DEFECTS IN RELATION TO ASSISTED REPRODUCTIVE TECHNOLOGIES IN THE MASSACHUSETTS OUTCOMES STUDY OF ASSISTED REPRODUCTIVE R. F. Liberman,a TECHNOLOGY DATABASE. K. D. Getz,a b c d aa B. Luke, J. E. Stern, E. Declercq, M. T. Anderka. Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health, Boston, MA; bDepartment of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, East Lansing, MI; cDepartment of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Lebanon, NH; dDepartment of Community Health Sciences, Boston University School of Public Health, Boston, MA. OBJECTIVE: To estimate and compare the prevalence of several specific cardiac and non-cardiac birth defects among deliveries to mothers who conceived using assisted reproductive technologies (ART) and those who conceived spontaneously. DESIGN: A longitudinal cohort study using a database of deliveries (live births and stillbirths) to Massachusetts residents during 2004-2008 created via a linkage of data from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System to the Pregnancy to Early Life Longitudinal data system. MATERIALS AND METHODS: Deliveries were classified as spontaneous conceptions (n¼324,148) or deliveries to mothers who received ART for the index pregnancy (n¼11,762). We used log-binomial regression to directly estimate prevalence ratios (PR) and associated 95% confidence intervals (CI) for cardiac and non-cardiac defects overall and for specific defects with at least four exposed and unexposed cases. RESULTS: The prevalence of cardiac defects was 82 per 10,000 among ART deliveries compared to 52 per 10,000 among spontaneous conceptions (PR¼1.60, 95% CI: 1.30, 1.96). The prevalence of non-cardiac defects was 180 per 10,000 among ART deliveries compared to 130 per 10,000 among spontaneous conceptions (PR¼1.33, 95% CI: 1.16, 1.52). Preliminary analyses of specific defects suggested elevated rates of tetralogy of Fallot, hypoplastic left heart syndrome, esophageal atresia, and rectal and large intestinal atresia among ART deliveries. Ongoing analyses will account for potential confounding, and evaluate biologic interaction with maternal age as well as potential mediation of observed associations through an increase in plural births. CONCLUSION: ART use is unlikely to be a major risk factor for birth defects. Preliminary analyses suggest that there may be modest associations between ART use and some birth defects; however, the prevalence of birth defects is low, even among ART-assisted conceptions. Supported by: NIH Grants R01HD064595 and R01HD067270.
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ASRM Abstracts
REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY FELLOWS RESEARCH I O-8 Monday, October 20, 2014 04:15 PM THE EFFECT OF DONOR OOCYTE RECIPIENT OBESITY ON LIVE BIRTH: AN ANALYSIS OF 3,922 SHARED DONOR OOCYTE ASSISTED REPRODUCTIVE TECHNOLOGY (ART) CYCLES. S. M. Zarek,a E. M. Mitchell,a A. H. DeCherney,a b a b ba K. S. Richter, K. Devine, P. E. Browne, J. E. O’Brien. NIH, Bethesda, MD; bShady Grove Fertility, Rockville, MD. OBJECTIVE: Data regarding the effect of recipient obesity on donor oocyte cycle outcome are mixed. Prior analyses have not fully accounted for intrinsic variation between donors. Our objective was to isolate the impact of body mass index (BMI) on live birth in donor egg sharing cycles in which oocytes from the same donor are shared by recipients with differing BMI. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: Live births were analyzed in fresh, shared donor ART cycles from 2004-2012 in which recipients of oocytes from the same donor oocyte retrieval fell into disparate BMI categories. Recipients had normal endometrial cavities by both saline infusion sonography and hysterosalpingogram and all donors were of normal BMI. Analysis was via generalized estimating equations with adjusted standard errors for repeated measures and nesting of recipients with differing BMI receiving oocytes from the same donor retrieval. Recipients were compared using relative risk (RR) and 95% confidence intervals (CIs) adjusted for age of the recipient. RESULTS: There were 3,922 cycles identified with 2,425 (63%) with recipient BMI below 25 kg/m2 (control group), 961 (24%) with recipient BMI between 25-30 kg/m2, 344 (8%) with recipient BMI between 30-35 kg/m2 and 192 (5%) with recipient BMI above 35 kg/m2. Increasing recipient BMI was associated with decreased live birth rate, and the association persisted when adjusted for age of recipient, number of embryos transferred, embryo stage, embryo grade and presence of severe male factor (0.990, 95% CI 0.981-0.998). Live birth was further impacted in the subset of recipients with BMI greater than 35 kg/m2, (RR 0.790, 95% CI 0.6260.977) compared to normal weight recipients. Significant differences were not appreciated in recipients with BMI between 25-30 kg/m2 (0.958, 95% CI 0.872, 1.053) and in recipients with BMI between 30-35 kg/m2 (0.931, 95% CI 0.807, 1.072). CONCLUSION: To our knowledge, this is the first report of a unique analysis of shared donor oocyte cycles demonstrating that increasing BMI of donor oocyte recipients is negatively associated with live birth. These findings persist after controlling for potential confounders, suggesting diminished uterine receptivity. A clinically significant, 21% reduction in live birth was demonstrated when BMI exceeded 35 kg/m2. This large dataset suggests a benefit to counseling on weight modification in obese recipients, with the greatest potential benefit for recipients with morbid obesity. Supported by: Intramural Research, PRAE. O-9 Monday, October 20, 2014 04:30 PM DIET-INDUCED OBESITY IMPAIRS ENDOMETRIAL STROMAL CELL DECIDUALIZATION. J. S. Rhee, J. L. Saben, V. Klenov, K. H. Moley. OB/Gyn, Washington University in St. Louis, St Louis, MO. OBJECTIVE: There is strong evidence that decreased pregnancy rates and higher miscarriage rates exist in obese women. Whether these effects are secondary to abnormal implantation, embryo development, or poor oocyte quality are unknown, although all of these factors may contribute. Our study objective was to investigate, via an in vivo and in vitro model, whether exposure of endometrial stromal cells (ESC) to saturated fatty acids or a high fat environment impairs decidualization. DESIGN: To test the effects of diet-induced obesity on ESC decidualization in vivo, artificial deciduomas were induced in high fat-fed versus chowfed control mice. In vitro cell culture models were also used to determine the impact of saturated fatty acids on ESC differentiation. MATERIALS AND METHODS: Artificial Deciduoma: Six-week old C57BL/6 female were fed either a high fat diet (59.4% Kcal from fat, HFD) or chow (CON) for twelve weeks. To induce decidualization in vivo, a silk thread was placed in the left uterine horn of pseudopregnant CON (n¼5) and HFD (n¼6) mice on dpc 3.5. Three days after thread placement, uterine horns were collected, and deciduoma formation was evaluated by comparing the uterine masses and morphologic changes via histology.
Vol. 102, No. 3, Supplement, September 2014