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  • 1.
    Brodin, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ovarian Reserve and Assisted Reproduction2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Treatment success in IVF-ICSI is mainly limited by female age, but differences in ovarian reserve (OR; the remaining pool of oocytes and their quality) between individuals modify treatment prerequisites among women of similar age. OR may be assessed by OR tests (ORTs). The main aims of this work were to study menstrual cycle length (MCL), basal levels of circulating gonadotrophins, antral follicle count (AFC) and serum Anti-Müllerian hormone (AMH) levels and their associations with and prognostic capacities regarding IVF-ICSI outcome in large cohorts of unselected women.

    Age-adjusted MCL was positively and linearly associated with pregnancy rates (PRs), live-birth rates (LBRs) and ovarian response to controlled ovarian hyperstimulation. An MCL of >34 days almost doubled the LBR compared with an MCL of <26 days.

    The grouped variable ‘combined FSH and LH levels’ was superior to both individual gonadotrophin levels and the LH:FSH ratio. The highest mean PR was seen in connection with a combination of FSH <6.7 U/l with LH >4.9 U/l; PRs were lowest when FSH-LH levels were opposite to this (high-low) and intermediate when FSH-LH levels were low-low or high-high. Associations with LBR and ovarian response were similar as those for PR.

    AFCs and serum AMH levels were positively and log-linearly associated with PR, LBR and ovarian response. Success rates levelled out above AFC 30 or AMH 5 ng/ml. Treatment outcome was superior among women with polycystic ovaries.

    Among the studied ORTs, logAFC and logAMH concentration correlated most strongly. After multivariate testing, entering all studied ORTs, AMH and female age remained independently associated with LBR. AMH + AFC + age predicted both poor and excessive ovarian responses with high accuracy.

    Adjusting for age and oocyte yield, all ORTs remained significant for LBR, implying that ORTs also capture information on oocyte quality.

    In conclusion, measures of OR are strongly associated with PR, LBR and ovarian response in a log-linear fashion, and partly reflect oocyte quality. The OR spectrum is continuous, from small ‘oligofollicular’ ovaries (the low extreme) to polycystic ovaries (the high extreme). Among the studied ORTs, AMH together with age provide the most powerful basal estimate for IVF/ICSI outcome.

    List of papers
    1. Menstrual cycle length is an age-independent marker of female fertility: results from 6271 treatment cycles of in vitro fertilization
    Open this publication in new window or tab >>Menstrual cycle length is an age-independent marker of female fertility: results from 6271 treatment cycles of in vitro fertilization
    Show others...
    2008 (English)In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 90, no 5, p. 1656-1661Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate whether menstrual cycle length correlates with success rates at IVF/intracytoplasmic sperm injection (ICSI) and could be used as a marker of ovarian reserve. DESIGN: Prospective observational study. SETTING: Private infertility centre. PATIENT(S): A total of 6271 IVF/ICSI treatment cycles. INTERVENTION(S): Self-reported mean number of menstrual days during the last year was recorded before initiation of IVF/ICSI treatment. MAIN OUTCOME MEASURE(S): Relations between menstrual cycle length and pregnancy and delivery rates. RESULT(S): Increasing age was associated with a subtle shortening of mean menstrual cycle length. Menstrual cycle length correlated linearly with pregnancy and delivery rates, even after age adjustment. The chance of delivery after IVF/ICSI was almost doubled for women with a menstrual cycle length >34 days compared with women with a menstrual cycle length <26 days. Menstrual cycle length was also significantly associated with ovarian response to FSH/hMG stimulation and embryo quality. CONCLUSION(S): Mean menstrual cycle length is highly related to success rates in assisted reproduction, independently of age. A precise menstrual cycle history could be used as a simple marker of ovarian reserve.

    Keywords
    Fecundity, female age, infertility, IVF, menstrual cycle, ovarian reserve
    Identifiers
    urn:nbn:se:uu:diva-107097 (URN)10.1016/j.fertnstert.2007.09.036 (DOI)000260752000015 ()18155201 (PubMedID)
    Available from: 2009-07-16 Created: 2009-07-16 Last updated: 2017-12-13Bibliographically approved
    2. High basal LH levels in combination with low basal FSH levels are associated with high success rates at assisted reproduction
    Open this publication in new window or tab >>High basal LH levels in combination with low basal FSH levels are associated with high success rates at assisted reproduction
    Show others...
    2009 (English)In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 24, no 11, p. 2755-2759Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND The objective of this study was to evaluate the associations of basal gonadotrophins with pregnancy and delivery rates at IVF/ICSI. METHODS A prospective observational study was conducted at a university-affiliated private infertility centre. Patients were 745 women, who underwent 1328 IVF/ICSI treatment cycles. Basal FSH, basal LH and combinations of FSH and LH versus treatment data and pregnancy and delivery rates were measured. RESULTS Combinations of FSH and LH gave significantly better information than the LH:FSH ratio, or each gonadotrophin alone: highest mean pregnancy rate (39%) was achieved in women with low FSH (<6.7 U/l) and with high LH levels (>4.9 U/l), whereas pregnancy rate was lowest (22%) in women with high FSH and low LH levels. Pregnancy rates were intermediate (27-28%) if FSH and LH were either both low or both high (P for trend = 0.0004). Associations to delivery rates and measures of ovarian response and embryo quality followed the same pattern. CONCLUSIONS Basal LH modifies and improves the information given by basal FSH alone. Low FSH level combined with high LH probably reflects a well-preserved ovarian reserve and is associated with the highest success rates at IVF/ICSI.

    Keywords
    FSH, infertility, IVF, ICSI outcome, luteinizing hormone, ovarian reserve
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-107635 (URN)10.1093/humrep/dep254 (DOI)000271107700013 ()19617206 (PubMedID)
    Available from: 2009-08-20 Created: 2009-08-20 Last updated: 2017-12-13Bibliographically approved
    3. Antral follicle counts are strongly associated with live-birth rates after assisted reproduction, with superior treatment outcome in women with polycystic ovaries
    Open this publication in new window or tab >>Antral follicle counts are strongly associated with live-birth rates after assisted reproduction, with superior treatment outcome in women with polycystic ovaries
    Show others...
    2011 (English)In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 96, no 3, p. 594-599Article in journal (Refereed) Published
    Abstract [en]

    Objective: To evaluate the association of antral follicle count (AFC) with in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) outcome in a large unselected cohort of patients covering the entire range of AFC. Design: Prospective observational study. Setting: University-affiliated private infertility center. Patient(s): 2,092 women undergoing 4,308 IVF-ICSI cycles. Intervention(s): AFC analyzed for associations with treatment outcome and statistically adjusted for repeated treatments and age. Main Outcome Measure(s): Pregnancy rate, live-birth rate, and stimulation outcome parameters. Result(s): The AFC was log-normally distributed. Pregnancy rates and live-birth rates were positively associated with AFC in a log-linear way, leveling out above AFC similar to 30. Treatment outcome was superior among women with polycystic ovaries, independent from ovulatory status. The findings were significant also after adjustment for age and number of oocytes retrieved. Conclusion(s): Pregnancy and live-birth rates are log-linearly related to AFC. Polycystic ovaries, most often excluded from studies on ovarian reserve, fit as one extreme in the spectrum of AFC; a low count constitutes the other extreme, with the lowest ovarian reserve and poor treatment outcome. The findings remained statistically significant also after adjustment for the number of oocytes retrieved, suggesting this measure of ovarian reserve comprises information on oocyte quality and not only quantity.

    Keywords
    AFC, antral follicle count, infertility, IVF, ovarian reserve, PCO
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-158865 (URN)10.1016/j.fertnstert.2011.06.071 (DOI)000294417000026 ()
    Available from: 2011-09-20 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
    4. Antimüllerian hormone levels are strongly associated with live-birth rates after assisted reproduction
    Open this publication in new window or tab >>Antimüllerian hormone levels are strongly associated with live-birth rates after assisted reproduction
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    2013 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 3, p. 1107-1114Article in journal (Refereed) Published
    Abstract [en]

    Context: Previous studies have suggested that antimullerian hormone (AMH) levels are positively associated with in vitro fertilization (IVF) outcome through their relationship with oocyte yield and not by reflecting oocyte or embryo quality. Objective: The aim was to investigate whether AMH levels are associated with pregnancy and live-birth rates and whether the results may also reflect qualitative aspects of oocytes and embryos. Design: The study was a prospective cohort study between April 2008 and June 2011. Setting: The study was done at a university-affiliated private infertility center. Patients: The study cohort consisted of 892 consecutive women undergoing 1230 IVF-intracytoplasmic sperm injection cycles. Intervention(s): AMH levels, analyzed using the DSL ELISA kit, were statistically adjusted for repeated treatments and age and analyzed for associations with treatment outcome. Main Outcome Measures: Pregnancy rates, live-birth rates, and stimulation outcome parameters were measured. Results: AMH was log-normally distributed with a mean (SD) of 2.3 (2.5) ng/mL. Live-birth rates per started cycle (mean [95% confidence interval]) increased log-linearly from 10.7% [7.2-14.1] for AMH < 0.84 ng/mL (25th percentile) to 30.8% [25.7-36.0] for AMH > 2.94 ng/mL (75th percentile), P-trend < .0001, being superior in women with polycystic ovaries. These findings were significant also after adjustments were made for age and oocyte yield. AMH was also associated with ovarian response variables and embryo scores. Conclusions: AMH is strongly associated with live-birth rates after IVF-intracytoplasmic sperm injection. AMH may therefore serve as a prognostic factor for the chance of a pregnancy and live birth. Treatment outcome was superior in patients with polycystic ovaries. The findings also indicate that AMH may partially comprise information about oocyte quality.

    Keywords
    Anti-Mullerian Hormone, Polycystic-Ovary-Syndrome, Antral Follicle Counts, Menstrual-Cycle, Women, Ivf; Reserve, Age, Stimulatio, Embryo
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-192987 (URN)10.1210/jc.2012-3676 (DOI)000316417200060 ()23408576 (PubMedID)
    Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2017-12-06Bibliographically approved
    5. A comparison of four different ovarian reserve tests (ORT) for predicting the ovarian response and chance of live birth after IVF-ICSI treatment
    Open this publication in new window or tab >>A comparison of four different ovarian reserve tests (ORT) for predicting the ovarian response and chance of live birth after IVF-ICSI treatment
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-192988 (URN)
    Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2013-03-05
  • 2.
    Brodin, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bergh, Torbjorn
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Holte, Jan
    Antimullerian hormone predicts pregnancy and live-birth rates after assisted reproduction and reflect oocyte quality besides oocyte quantity2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, p. 35-35Article in journal (Other academic)
  • 3.
    Brodin, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Antimüllerian hormone levels are strongly associated with live-birth rates after assisted reproduction2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 3, p. 1107-1114Article in journal (Refereed)
    Abstract [en]

    Context: Previous studies have suggested that antimullerian hormone (AMH) levels are positively associated with in vitro fertilization (IVF) outcome through their relationship with oocyte yield and not by reflecting oocyte or embryo quality. Objective: The aim was to investigate whether AMH levels are associated with pregnancy and live-birth rates and whether the results may also reflect qualitative aspects of oocytes and embryos. Design: The study was a prospective cohort study between April 2008 and June 2011. Setting: The study was done at a university-affiliated private infertility center. Patients: The study cohort consisted of 892 consecutive women undergoing 1230 IVF-intracytoplasmic sperm injection cycles. Intervention(s): AMH levels, analyzed using the DSL ELISA kit, were statistically adjusted for repeated treatments and age and analyzed for associations with treatment outcome. Main Outcome Measures: Pregnancy rates, live-birth rates, and stimulation outcome parameters were measured. Results: AMH was log-normally distributed with a mean (SD) of 2.3 (2.5) ng/mL. Live-birth rates per started cycle (mean [95% confidence interval]) increased log-linearly from 10.7% [7.2-14.1] for AMH < 0.84 ng/mL (25th percentile) to 30.8% [25.7-36.0] for AMH > 2.94 ng/mL (75th percentile), P-trend < .0001, being superior in women with polycystic ovaries. These findings were significant also after adjustments were made for age and oocyte yield. AMH was also associated with ovarian response variables and embryo scores. Conclusions: AMH is strongly associated with live-birth rates after IVF-intracytoplasmic sperm injection. AMH may therefore serve as a prognostic factor for the chance of a pregnancy and live birth. Treatment outcome was superior in patients with polycystic ovaries. The findings also indicate that AMH may partially comprise information about oocyte quality.

  • 4.
    Brodin, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Carl von Linne Clin, S-75183 Uppsala, Sweden..
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.;Carl von Linne Clin, S-75183 Uppsala, Sweden.;Ctr Reprod Biol Uppsala CRU, Uppsala, Sweden..
    Comparing four ovarian reserve markers: associations with ovarian response and live births after assisted reproduction2015In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 10, p. 1056-1063Article in journal (Refereed)
    Abstract [en]

    Introduction. We compared the ability of four different ovarian reserve tests (ORTs) to predict live births per started in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) cycle, and poor and excessive response to controlled ovarian hyperstimulation. Material and methods. This was a cohort study in a private infertility center in collaboration with Uppsala University, comprising 1230 IVF-ICSI cycles in 892 consecutive women between April 2008 and June 2011. Anti-Mullerian hormone (AMH) levels, antral follicle counts (AFC), combinations of basal levels of follicle-stimulating hormone and luteinizing hormone, and menstrual cycle lengths were analyzed for correlation and treatment outcome prediction in age-adjusted statistical models. Stepwise multivariable generalized estimating equation analyses were carried out in a sub-group with complete data on all four ORTs (620 cycles in 443 women). Odds ratios and c-statistics were calculated in the largest available set of data for each significant variable. Primary outcomes were live birth rate per started cycle and poor and excessive ovarian response to controlled ovarian hyperstimulation (defined by the ovarian sensitivity index). Results. All ORTs correlated significantly with each other, with the strongest correlation between AFC and AMH (r = 0.71, p < 0.0001). Univariately, AMH and age equivalently predicted live birth (c-statistic 0.61), and together they provided a significantly better model (c-statistic 0.64). For prediction of poor and excessive response the best model included AMH, AFC and age (c-statistic 0.89). Conclusions. AMH improves the ability to estimate live birth rates after assisted reproduction compared with female age alone. AMH, AFC and age together constituted the best model for prediction of ovarian response.

  • 5.
    Holte, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Brodin, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bergh, Torbjörn
    Carl von Linné Clinic, Uppsala Science Park.
    Antral follicle counts are strongly associated with live-birth rates after assisted reproduction, with superior treatment outcome in women with polycystic ovaries2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 96, no 3, p. 594-599Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the association of antral follicle count (AFC) with in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) outcome in a large unselected cohort of patients covering the entire range of AFC. Design: Prospective observational study. Setting: University-affiliated private infertility center. Patient(s): 2,092 women undergoing 4,308 IVF-ICSI cycles. Intervention(s): AFC analyzed for associations with treatment outcome and statistically adjusted for repeated treatments and age. Main Outcome Measure(s): Pregnancy rate, live-birth rate, and stimulation outcome parameters. Result(s): The AFC was log-normally distributed. Pregnancy rates and live-birth rates were positively associated with AFC in a log-linear way, leveling out above AFC similar to 30. Treatment outcome was superior among women with polycystic ovaries, independent from ovulatory status. The findings were significant also after adjustment for age and number of oocytes retrieved. Conclusion(s): Pregnancy and live-birth rates are log-linearly related to AFC. Polycystic ovaries, most often excluded from studies on ovarian reserve, fit as one extreme in the spectrum of AFC; a low count constitutes the other extreme, with the lowest ovarian reserve and poor treatment outcome. The findings remained statistically significant also after adjustment for the number of oocytes retrieved, suggesting this measure of ovarian reserve comprises information on oocyte quality and not only quantity.

  • 6.
    Rhenman, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Brodin, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Milton, K.
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Which set of embryo variables is most predictive for live birth?: A prospective study in 6252 single embryo transfers to construct an embryo score for the ranking and selection of embryos2015In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 30, no 1, p. 28-36Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Vaegter, Katarina Kebbon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology. Carl von Linne Clin, Uppsala Sci Pk, Uppsala, Sweden; PCG Clin Serv, Uppsala, Sweden.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden;Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden.
    Tilly, Johanna
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics. PCG Clin Serv, Uppsala, Sweden.
    Hadziosmanovic, Nermin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Brodin, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology. Carl von Linne Clin, Uppsala Sci Pk, Uppsala, Sweden; PCG Clin Serv, Uppsala, Sweden.
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology. Carl von Linne Clin, Uppsala Sci Pk, Uppsala, Sweden; Univ Agr Sci Uppsala, Ctr Reprod Biol Uppsala, Uppsala, Sweden; PCG Clin Serv, Uppsala, Sweden.
    Construction and validation of a prediction model to minimize twin rates at preserved high live birth rates after IVF2019In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 38, no 1, p. 22-29Article in journal (Refereed)
    Abstract [en]

    Research question: Elective single-embryo transfer (eSET) at blastocyst stage is widely used to reduce the frequency of multiple pregnancies after IVF. There are, however, concerns about increased risks for the offspring with prolonged embryo culture. Is it possible to select embryos for transfer at the early cleavage stage and still achieve low twin rates at preserved high live birth rates? Design: A prediction model (PM) was developed to optimize eSET based on variables known 2 days after oocyte retrieval (fresh day 2 embryo transfers; double-embryo transfers 1999-2002 (n=2846) and SET 1999-2003 (n=945); n total=3791). Seventy-five variables were analysed for association with pregnancy chance and twin risk and combined for PM construction. This PM was validated in 2004-2016 including frozen-thawed transfers (FET), to compare cumulative live birth rate (CLBR) and twin rate before (1999-2002 fresh embryo transfers plus FET from the same oocyte retrievals until the end of 2007, n=3495) and after (2004-2011 fresh embryo transfers plus FET from the same oocyte retrievals until the end of 2016, n=11195) implementing the model. Results: The PM was constructed from four independent variables: female age, embryo score, ovarian sensitivity and treatment history. The calibration, i.e. the fit of observed versus predicted results, was excellent both at construction and at validation. Without compromising CLBR, twin rate was reduced from 25.2% to 3.8%, accompanied by profound improvements in perinatal outcome. Conclusion: The results provide the first successful construction, validation and impact analysis of a day 2 transfer PM to reduce multiple pregnancies.

  • 8.
    Vaegter, Katarina Kebbon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Carl von Linne Clin, Uppsala, Sweden..
    Ghukasyan Lakic, Tatevik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Univ Agr Sci Uppsala, Uppsala, Sweden..
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Berglund, Lars
    Univ Agr Sci Uppsala, Uppsala Clin Res Ctr, Uppsala, Sweden..
    Brodin, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Carl von Linne Clin, Uppsala, Sweden..
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Carl von Linne Clin, Uppsala, Sweden.; Center for Reproductive Biology in Uppsala, University of Agricultural Sciences and Uppsala University, Uppsala, Sweden..
    Which factors are most predictive for live birth after in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) treatments?: Analysis of 100 prospectively recorded variables in 8,400 IVF/ICSI single-embryo transfers2017In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 107, no 3, p. 641-+Article in journal (Refereed)
    Abstract [en]

    Objective: To construct a prediction model for live birth after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and single-embryo transfer (SET) after 2 days of embryo culture. Design: Prospective observational cohort study. Setting: University-affiliated private infertility center. Patient(s): SET in 8,451 IVF/ICSI treatments in 5,699 unselected consecutive couples during 1999-2014. Intervention(s): A total of 100 basal patient characteristics and treatment data were analyzed for associations with live birth after IVF/ICSI (adjusted for repeated treatments) and subsequently combined for prediction model construction. Main Outcome Measure(s): Live birth rate (LBR) and performance of live birth prediction model. Result(s): Embryo score, treatment history, ovarian sensitivity index (OSI; number of oocytes/total dose of FSH administered), female age, infertility cause, endometrial thickness, and female height were all independent predictors of live birth. A prediction model (training data set; n = 5,722) based on these variables showed moderate discrimination, but predicted LBR with high accuracy in subgroups of patients, with LBR estimates ranging from <10% to >40%. Outcomes were similar in an internal validation data set (n = 2,460). Conclusion(s): Based on 100 variables prospectively recorded during a 15-year period, a model for live birth prediction after strict SET was constructed and showed excellent calibration in internal validation. For the first time, female height qualified as a predictor of live birth after IVF/ICSI.

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