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. The success of IVF majorly depends upon successful superovulation, defined by the number and uniformly high quality of eggs retrieved in a cycle. Currently, this step is executed using almost daily monitoring of the follicular development using ultrasound and blood test. The daily dosage of hormones is customized for each patient based on these tests. Although there are the general guidelines for dosage, the dose is not optimized for each patient, and complications, such as overstimulation, can occur. The cost of testing and drugs make this stage very expensive. To overcome the shortcomings of these general guidelines system, a mathematical model and software 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. The model is based on analogy between IVF superovulation and the particle processes in chemical engineering like seeded crystallization. Customized optimal drug dosage procedures are developed for each patient using optimal control methods with the targeted follicle size distribution (FSD) as the expected outcome. This paper describes the theory, model, and the optimal control procedure for improving outcomes of IVF treatment for one of the two 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 doctors. Additionally, the number of mature follicles obtained at the end of the cycle using the model-predicted dosage was significantly higher than the physician suggested dosage. These results were consistent with all patients in this clinical trial. The testing and monitoring requirements for patients using optimized drug dosage is reduced by 72%. We are currently working on patients from United States for both protocols and the results are promising.
