Predicting cumulative live birth for couples beginning their second complete cycle of in vitro fertilization treatment.

study questionCan we develop an IVF prediction model to estimate individualized chances of a live birth over multiple complete cycles of IVF in couples embarking on their second complete cycle of treatment? SUMMARY ANSWER: Yes, our prediction model can estimate individualized chances of cumulative live birth over three additional complete cycles of IVF. WHAT IS KNOWN ALREADY: After the completion of a first complete cycle of IVF, couples who are unsuccessful may choose to undergo further treatment to have their first child, while those who have had a live birth may decide to have more children. Existing prediction models can estimate the overall chances of success in couples before commencing IVF but are unable to revise these chances on the basis of the couple's response to a first treatment cycle in terms of the number of eggs retrieved and pregnancy outcome. This makes it difficult for couples to plan and prepare emotionally and financially for the next step in their treatment. STUDY DESIGN, SIZE, DURATION: For model development, a population-based cohort was used of 49 314 women who started their second cycle of IVF including ICSI in the UK from 1999 to 2008 using their own oocytes and their partners' sperm. External validation was performed on data from 39 442 women who underwent their second cycle from 2010 to 2016. PARTICIPANTS/MATERIALS, SETTING,

methodsData about all UK IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA) database. Using a discrete time logistic regression model, we predicted the cumulative probability of live birth from the second up to and including the fourth complete cycles of IVF. Inverse probability weighting was used to account for treatment discontinuation. Discrimination was assessed using c-statistic and calibration was assessed using calibration-in-the-large and calibration slope. MAIN RESULTS AND THE ROLE OF CHANCE: Following exclusions, 49 314 women with 73 053 complete cycles were included. 12 408 (25.2%) had a live birth resulting from their second complete cycle. Cumulatively, 17 394 (35.3%) had a live birth over complete cycles two to four. The model showed moderate discriminative ability (c-statistic: 0.65, 95% CI: 0.64 to 0.65) and evidence of overprediction (calibration-in-the-large = -0.08) and overfitting (calibration slope 0.85, 95% CI: 0.81 to 0.88) in the validation cohort. However, after recalibration the fit was much improved. The recalibrated model identified the following key predictors of live birth: female age (38 versus 32 years-adjusted odds ratio: 0.59, 95% CI: 0.57 to 0.62), number of eggs retrieved in the first complete cycle (12 versus 4 eggs; 1.34, 1.30 to 1.37) and outcome of the first complete cycle (live birth versus no pregnancy; 1.78, 1.66 to 1.91; live birth versus pregnancy loss; 1.29, 1.23 to 1.36). As an example, a 32-year-old with 2 years of non-tubal infertility who had 12 eggs retrieved from her first stimulation and had a live birth during her first complete cycle has a 46% chance of having a further live birth from the second complete cycle of IVF and an 81% chance over a further three cycles. LIMITATIONS, REASONS FOR CAUTION: The developed model was updated using validation data that was 6 to 12 years old. IVF practice continues to evolve over time, which may affect the accuracy of predictions from the model. We were unable to adjust for some potentially important predictors, e.g. BMI, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. These were not available in the linked HFEA dataset. WIDER IMPLICATIONS OF THE

findingsBy appropriately adjusting for couples who discontinue treatment, our novel prediction model will provide more realistic chances of live birth in couples starting a second complete cycle of IVF. Clinicians can use these predictions to inform discussion with couples who wish to plan ahead. This prediction tool will enable couples to prepare emotionally, financially and logistically for IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.