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Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study.
Hum Reprod. 2018 09 01; 33(9):1684-1695.HR

Abstract

STUDY QUESTION

Are the published pre-treatment and post-treatment McLernon models, predicting cumulative live birth rates (LBR) over multiple complete IVF cycles, valid in a different context?

SUMMARY ANSWER

With minor recalibration of the pre-treatment model, both McLernon models accurately predict cumulative LBR in a different geographical context and a more recent time period.

WHAT IS KNOWN ALREADY

Previous IVF prediction models have estimated the chance of a live birth after a single fresh embryo transfer, thereby excluding the important contribution of embryo cryopreservation and subsequent IVF cycles to cumulative LBR. In contrast, the recently developed McLernon models predict the cumulative chance of a live birth over multiple complete IVF cycles at two certain time points: (i) before initiating treatment using baseline characteristics (pre-treatment model) and (ii) after the first IVF cycle adding treatment related information to update predictions (post-treatment model). Before implementation of these models in clinical practice, their predictive performance needs to be validated in an independent cohort.

STUDY DESIGN, SIZE, DURATION

External validation study in an independent prospective cohort of 1515 Dutch women who participated in the OPTIMIST study (NTR2657) and underwent their first IVF treatment between 2011 and 2014. Participants underwent a total of 2881 complete treatment cycles, with a complete cycle defined as all fresh and frozen thawed embryo transfers resulting from one episode of ovarian stimulation. The follow up duration was 18 months after inclusion, and the primary outcome was ongoing pregnancy leading to live birth.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Model performance was externally validated up to three complete treatment cycles, using the linear predictor as described by McLernon et al. to calculate the probability of a live birth. Discrimination was expressed by the c-statistic and calibration was depicted graphically in a calibration plot. In contrast to the original model development cohort, anti-Müllerian hormone (AMH), antral follicle count (AFC) and body weight were available in the OPTIMIST cohort, and evaluated as potential additional predictors for model improvement.

MAIN RESULTS AND THE ROLE OF CHANCE

Applying the McLernon models to the OPTIMIST cohort, the c-statistic of the pre-treatment model was 0.62 (95% CI: 0.59-0.64) and of the post-treatment model 0.71 (95% CI: 0.69-0.74). The calibration plot of the pre-treatment model indicated a slight overestimation of the cumulative LBR. To improve calibration, the pre-treatment model was recalibrated by subtracting 0.35 from the intercept. The post-treatment model calibration plot revealed accurate cumulative LBR predictions. After addition of AMH, AFC and body weight to the McLernon models, the c-statistic of the updated pre-treatment model improved slightly to 0.66 (95% CI: 0.64-0.68), and of the updated post-treatment model remained at the previous level of 0.71 (95% CI: 0.69-0.73). Using the recalibrated pre-treatment model, a woman aged 30 years with 2 years of primary infertility who starts ICSI treatment for male factor infertility has a chance of 40% of a live birth from the first complete cycle, increasing to 72% over three complete cycles. If this woman weighs 70 kg, has an AMH of 1.5 ng/mL and an AFC of 10 measured at the beginning of her treatment, the updated pre-treatment model revises the estimated chance of a live birth to 30% in the first complete cycle and 59% over three complete cycles. If this woman then has five retrieved oocytes, no embryos cryopreserved and a single fresh cleavage stage embryo transfer in her first ICSI cycle, the post-treatment model estimates the chances of a live birth at 28 and 58%, respectively.

LIMITATIONS, REASONS FOR CAUTION

Two randomized controlled trials (RCT) evaluating the effectiveness of gonadotropin dose individualization on basis of the AFC were nested within the OPTIMIST study. The strict dosing regimens, the RCT in- and exclusion criteria and the limited follow up time of 18 months might have influenced model performance in this independent cohort. Also, consistent with the original model development study, external validation was performed using the optimistic assumption that the cumulative LBR in couples who discontinue treatment without a live birth would have been equal to that of those who continue treatment.

WIDER IMPLICATIONS OF THE FINDINGS

After national recalibration to account for geographical differences in IVF treatment, the McLernon prediction models can be introduced as new counselling tools in clinical practice to inform patients and to complement clinical reasoning. These models are the first to offer an objective and personalized estimate of the cumulative probability of a live birth over multiple complete IVF cycles.

STUDY FUNDING/COMPETING INTEREST(S)

No external funds were obtained for this study. M.J.C.E., D.J.M. and S.B. have nothing to disclose. J.A.L, S.C.O, T.C.v.T. and H.LT. received an unrestricted personal grant from Merck BV. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck BV (the Netherlands) and Ferring pharmaceutics BV (the Netherlands), for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA).

TRIAL REGISTRATION NUMBER

Not applicable.

Authors+Show Affiliations

Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.Institute of Applied Health Sciences, Medical Statistics Team, University of Aberdeen, Foresterhill, Aberdeen, UK.School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Heath Park, Cardiff, UK.Department of Obstetrics and Gynaecology, Monash University, Scenic Blvd & Wellington Road, Clayton VIC, Australia.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, The Netherlands.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Validation Study

Language

eng

PubMed ID

30085143

Citation

Leijdekkers, J A., et al. "Predicting the Cumulative Chance of Live Birth Over Multiple Complete Cycles of in Vitro Fertilization: an External Validation Study." Human Reproduction (Oxford, England), vol. 33, no. 9, 2018, pp. 1684-1695.
Leijdekkers JA, Eijkemans MJC, van Tilborg TC, et al. Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study. Hum Reprod. 2018;33(9):1684-1695.
Leijdekkers, J. A., Eijkemans, M. J. C., van Tilborg, T. C., Oudshoorn, S. C., McLernon, D. J., Bhattacharya, S., Mol, B. W. J., Broekmans, F. J. M., & Torrance, H. L. (2018). Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study. Human Reproduction (Oxford, England), 33(9), 1684-1695. https://doi.org/10.1093/humrep/dey263
Leijdekkers JA, et al. Predicting the Cumulative Chance of Live Birth Over Multiple Complete Cycles of in Vitro Fertilization: an External Validation Study. Hum Reprod. 2018 09 1;33(9):1684-1695. PubMed PMID: 30085143.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study. AU - Leijdekkers,J A, AU - Eijkemans,M J C, AU - van Tilborg,T C, AU - Oudshoorn,S C, AU - McLernon,D J, AU - Bhattacharya,S, AU - Mol,B W J, AU - Broekmans,F J M, AU - Torrance,H L, AU - ,, PY - 2018/03/05/received PY - 2018/07/11/accepted PY - 2018/8/8/pubmed PY - 2019/5/3/medline PY - 2018/8/8/entrez SP - 1684 EP - 1695 JF - Human reproduction (Oxford, England) JO - Hum Reprod VL - 33 IS - 9 N2 - STUDY QUESTION: Are the published pre-treatment and post-treatment McLernon models, predicting cumulative live birth rates (LBR) over multiple complete IVF cycles, valid in a different context? SUMMARY ANSWER: With minor recalibration of the pre-treatment model, both McLernon models accurately predict cumulative LBR in a different geographical context and a more recent time period. WHAT IS KNOWN ALREADY: Previous IVF prediction models have estimated the chance of a live birth after a single fresh embryo transfer, thereby excluding the important contribution of embryo cryopreservation and subsequent IVF cycles to cumulative LBR. In contrast, the recently developed McLernon models predict the cumulative chance of a live birth over multiple complete IVF cycles at two certain time points: (i) before initiating treatment using baseline characteristics (pre-treatment model) and (ii) after the first IVF cycle adding treatment related information to update predictions (post-treatment model). Before implementation of these models in clinical practice, their predictive performance needs to be validated in an independent cohort. STUDY DESIGN, SIZE, DURATION: External validation study in an independent prospective cohort of 1515 Dutch women who participated in the OPTIMIST study (NTR2657) and underwent their first IVF treatment between 2011 and 2014. Participants underwent a total of 2881 complete treatment cycles, with a complete cycle defined as all fresh and frozen thawed embryo transfers resulting from one episode of ovarian stimulation. The follow up duration was 18 months after inclusion, and the primary outcome was ongoing pregnancy leading to live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Model performance was externally validated up to three complete treatment cycles, using the linear predictor as described by McLernon et al. to calculate the probability of a live birth. Discrimination was expressed by the c-statistic and calibration was depicted graphically in a calibration plot. In contrast to the original model development cohort, anti-Müllerian hormone (AMH), antral follicle count (AFC) and body weight were available in the OPTIMIST cohort, and evaluated as potential additional predictors for model improvement. MAIN RESULTS AND THE ROLE OF CHANCE: Applying the McLernon models to the OPTIMIST cohort, the c-statistic of the pre-treatment model was 0.62 (95% CI: 0.59-0.64) and of the post-treatment model 0.71 (95% CI: 0.69-0.74). The calibration plot of the pre-treatment model indicated a slight overestimation of the cumulative LBR. To improve calibration, the pre-treatment model was recalibrated by subtracting 0.35 from the intercept. The post-treatment model calibration plot revealed accurate cumulative LBR predictions. After addition of AMH, AFC and body weight to the McLernon models, the c-statistic of the updated pre-treatment model improved slightly to 0.66 (95% CI: 0.64-0.68), and of the updated post-treatment model remained at the previous level of 0.71 (95% CI: 0.69-0.73). Using the recalibrated pre-treatment model, a woman aged 30 years with 2 years of primary infertility who starts ICSI treatment for male factor infertility has a chance of 40% of a live birth from the first complete cycle, increasing to 72% over three complete cycles. If this woman weighs 70 kg, has an AMH of 1.5 ng/mL and an AFC of 10 measured at the beginning of her treatment, the updated pre-treatment model revises the estimated chance of a live birth to 30% in the first complete cycle and 59% over three complete cycles. If this woman then has five retrieved oocytes, no embryos cryopreserved and a single fresh cleavage stage embryo transfer in her first ICSI cycle, the post-treatment model estimates the chances of a live birth at 28 and 58%, respectively. LIMITATIONS, REASONS FOR CAUTION: Two randomized controlled trials (RCT) evaluating the effectiveness of gonadotropin dose individualization on basis of the AFC were nested within the OPTIMIST study. The strict dosing regimens, the RCT in- and exclusion criteria and the limited follow up time of 18 months might have influenced model performance in this independent cohort. Also, consistent with the original model development study, external validation was performed using the optimistic assumption that the cumulative LBR in couples who discontinue treatment without a live birth would have been equal to that of those who continue treatment. WIDER IMPLICATIONS OF THE FINDINGS: After national recalibration to account for geographical differences in IVF treatment, the McLernon prediction models can be introduced as new counselling tools in clinical practice to inform patients and to complement clinical reasoning. These models are the first to offer an objective and personalized estimate of the cumulative probability of a live birth over multiple complete IVF cycles. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. M.J.C.E., D.J.M. and S.B. have nothing to disclose. J.A.L, S.C.O, T.C.v.T. and H.LT. received an unrestricted personal grant from Merck BV. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck BV (the Netherlands) and Ferring pharmaceutics BV (the Netherlands), for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). TRIAL REGISTRATION NUMBER: Not applicable. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/30085143/Predicting_the_cumulative_chance_of_live_birth_over_multiple_complete_cycles_of_in_vitro_fertilization:_an_external_validation_study_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dey263 DB - PRIME DP - Unbound Medicine ER -