A Rhenman1, L Berglund2, T Brodin3, M Olovsson4, K Milton3, N Hadziosmanovic2, J Holte5. 1. Department of Women's and Children's Health, Uppsala University, S-751 85 Uppsala, Sweden axelrhenman@yahoo.se. 2. Uppsala Clinical Research Center, Akademiska sjukhuset (UCR), S-751 85 Uppsala, Sweden. 3. Carl von Linné Clinic, Uppsala Science Park, S-751 83 Uppsala, Sweden. 4. Department of Women's and Children's Health, Uppsala University, S-751 85 Uppsala, Sweden. 5. Department of Women's and Children's Health, Uppsala University, S-751 85 Uppsala, Sweden Carl von Linné Clinic, Uppsala Science Park, S-751 83 Uppsala, Sweden Centre for Reproductive Biology in Uppsala (CRU), PO Box 7054, S-750 07 Uppsala, Sweden.
Abstract
STUDY QUESTION: Which embryo score variables are most powerful for predicting live birth after single embryo transfer (SET) at the early cleavage stage? SUMMARY ANSWER: This large prospective study of visual embryo scoring variables shows that blastomere number (BL), the proportion of mononucleated blastomeres (NU) and the degree of fragmentation (FR) have independent prognostic power to predict live birth. WHAT IS KNOWN ALREADY: Other studies suggest prognostic power, at least univariately and for implantation potential, for all five variables. A previous study from the same centre on double embryo transfers with implantation as the end-point resulted in the integrated morphology cleavage (IMC) score, which incorporates BL, NU and EQ. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study of IVF/ICSI SET on Day 2 (n = 6252) during a 6-year period (2006-2012). The five variables (BL NU, FR, EQ and symmetry of cleavage (SY)) were scored in 3- to 5-step scales and subsequently related to clinical pregnancy and LBR. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 4304 women undergoing IVF/ICSI in a university-affiliated private fertility clinic were included. Generalized estimating equation models evaluated live birth (yes/no) as primary outcome using the embryo variables as predictors. Odds ratios with 95% confidence intervals and P-values were presented for each predictor. The C statistic (i.e. area under receiver operating characteristic curve) was calculated for each model. Model calibration was assessed with the Hosmer-Lemeshow test. A shrinkage method was applied to remove bias in c statistics due to over-fitting. MAIN RESULTS AND THE ROLE OF CHANCE: LBR was 27.1% (1693/6252). BL, NU, FR and EQ were univariately highly significantly associated with LBR. In a multivariate model, BL, NU and FR were independently significant, with c statistic 0.579 (age-adjusted c statistic 0.637). EQ did not retain significance in the multivariate model. Prediction model calibration was good for both pregnancy and live birth. We present a ranking tree with combinations of values of the BL, NU and FR embryo variables for optimal selection of the embryo/s to transfer, providing a revised IMC score. The five embryo variables had similar effects over all age groups. LIMITATIONS, REASONS FOR CAUTION: Limitations of the present study are those inherent for real-time visual scoring, including risks of inter-observer variation and the hazards of fixed time-point scoring procedures in a dynamic process. The study is restricted to Day-2 transfers. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge this is the largest prospective, SET study performed with the explicit aim of constructing an evidence-based embryo score for the ranking and selection of early cleavage stage embryos. In line with previous research, our data suggest that the symmetry of cleavage variable may be omitted when scoring embryos in the early cleavage stage. We suggest that, following validation in other populations, the revised IMC score may be used when international standards for embryo scoring are discussed. STUDY FUNDING/COMPETING INTEREST: Carl von Linné Clinic, Uppsala and the Department of Women's and Children's Health and the Family Planning Fund in Uppsala, Uppsala University, Uppsala, Sweden financed this study. There are no competing interests to declare.
STUDY QUESTION: Which embryo score variables are most powerful for predicting live birth after single embryo transfer (SET) at the early cleavage stage? SUMMARY ANSWER: This large prospective study of visual embryo scoring variables shows that blastomere number (BL), the proportion of mononucleated blastomeres (NU) and the degree of fragmentation (FR) have independent prognostic power to predict live birth. WHAT IS KNOWN ALREADY: Other studies suggest prognostic power, at least univariately and for implantation potential, for all five variables. A previous study from the same centre on double embryo transfers with implantation as the end-point resulted in the integrated morphology cleavage (IMC) score, which incorporates BL, NU and EQ. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study of IVF/ICSI SET on Day 2 (n = 6252) during a 6-year period (2006-2012). The five variables (BL NU, FR, EQ and symmetry of cleavage (SY)) were scored in 3- to 5-step scales and subsequently related to clinical pregnancy and LBR. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 4304 women undergoing IVF/ICSI in a university-affiliated private fertility clinic were included. Generalized estimating equation models evaluated live birth (yes/no) as primary outcome using the embryo variables as predictors. Odds ratios with 95% confidence intervals and P-values were presented for each predictor. The C statistic (i.e. area under receiver operating characteristic curve) was calculated for each model. Model calibration was assessed with the Hosmer-Lemeshow test. A shrinkage method was applied to remove bias in c statistics due to over-fitting. MAIN RESULTS AND THE ROLE OF CHANCE: LBR was 27.1% (1693/6252). BL, NU, FR and EQ were univariately highly significantly associated with LBR. In a multivariate model, BL, NU and FR were independently significant, with c statistic 0.579 (age-adjusted c statistic 0.637). EQ did not retain significance in the multivariate model. Prediction model calibration was good for both pregnancy and live birth. We present a ranking tree with combinations of values of the BL, NU and FR embryo variables for optimal selection of the embryo/s to transfer, providing a revised IMC score. The five embryo variables had similar effects over all age groups. LIMITATIONS, REASONS FOR CAUTION: Limitations of the present study are those inherent for real-time visual scoring, including risks of inter-observer variation and the hazards of fixed time-point scoring procedures in a dynamic process. The study is restricted to Day-2 transfers. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge this is the largest prospective, SET study performed with the explicit aim of constructing an evidence-based embryo score for the ranking and selection of early cleavage stage embryos. In line with previous research, our data suggest that the symmetry of cleavage variable may be omitted when scoring embryos in the early cleavage stage. We suggest that, following validation in other populations, the revised IMC score may be used when international standards for embryo scoring are discussed. STUDY FUNDING/COMPETING INTEREST: Carl von Linné Clinic, Uppsala and the Department of Women's and Children's Health and the Family Planning Fund in Uppsala, Uppsala University, Uppsala, Sweden financed this study. There are no competing interests to declare.
Authors: Karin E Lindgren; Fatma Gülen Yaldir; Julius Hreinsson; Jan Holte; Karin Kårehed; Inger Sundström-Poromaa; Helena Kaihola; Helena Åkerud Journal: Ups J Med Sci Date: 2018-10-04 Impact factor: 2.384