In vitro fertilization (IVF) is the most common technique in assisted reproductive technology and in most cases the last resort for infertility treatment. It has four basic stages: superovulation, egg retrieval, fertilization, and embryo transfer. Superovulation is a drug-induced method to enable multiple ovulation per menstrual cycle and key component towards a successful IVF cycle. Although there are the general guidelines for dosage, the dose is not optimized for each patient, and complications, such as overstimulation, can occur. To overcome the shortcomings of this general system, a mathematical procedure is developed which can provide a customized model of this stage regarding the size distribution of eggs (follicles/ oocytes) obtained per cycle as a function of the chemical interactions of the drugs used and the conditions imposed on the patient during the cycle, which provide a basis for predicting the possible outcome. Uncertainty and risk are modeled and included in optimal drug dosage decisions. This paper describes the theory, model, and the optimal control procedure for improving outcomes of IVF treatment for one of the four protocols used in real practice. The validation of the procedure is performed using clinical data from the patients previously undergone IVF cycles. Customized patient-specific model parameters are obtained by using initial two-day data for each patient. Subsequently, this model is used to predict the FSD for the remaining days of the cycle. This procedure was conducted for 49 patients. The results of the customized models are found to be closely matching with the observed FSD. These results thus validate the modeling approach and consequently its use for predicting the customized optimal drug dosage for each patient. Using the customized model and the optimized dosage, the FSD at the end of the cycle was determined. A small double-blind clinical trial was also conducted in India. The results from the trial show that the dosage predicted by using the model is 40% less than the suggestion made by the IVF clinicians. The testing and monitoring requirements for patients using optimized drug dosage is reduced by 72%. Work on the other three protocols and for patients in the USA is started and is showing promising results.
Keywords: Clinical trial; Crystallization; Customized medicine; IVF treatment; Optimal control; Superovulation.
Copyright © 2019. Published by Elsevier Ltd.