Predictive Modeling of Implantation Outcome in an In Vitro Fertilization Setting: An Application of Machine Learning Methods.

BACKGROUND: Multiple embryo transfers in in vitro fertilization (IVF) treatment increase the number of successful pregnancies while elevating the risk of multiple gestations. IVF-associated multiple pregnancies exhibit significant financial, social, and medical implications. Clinicians need to decide the number of embryos to be transferred considering the tradeoff between successful outcomes and multiple pregnancies. OBJECTIVE: To predict implantation outcome of individual embryos in an IVF cycle with the aim of providing decision support on the number of embryos transferred. DESIGN: Retrospective cohort study. DATA SOURCE: Electronic health records of one of the largest IVF clinics in Turkey. The study data set included 2453 embryos transferred at day 2 or day 3 after intracytoplasmic sperm injection (ICSI). Each embryo was represented with 18 clinical features and a class label, +1 or -1, indicating positive and negative implantation outcomes, respectively. METHODS: For each classifier tested, a model was developed using two-thirds of the data set, and prediction performance was evaluated on the remaining one-third of the samples using receiver operating characteristic (ROC) analysis. The training-testing procedure was repeated 10 times on randomly split (two-thirds to one-third) data. The relative predictive values of clinical input characteristics were assessed using information gain feature weighting and forward feature selection methods. RESULTS: The naïve Bayes model provided 80.4% accuracy, 63.7% sensitivity, and 17.6% false alarm rate in embryo-based implantation prediction. Multiple embryo implantations were predicted at a 63.8% sensitivity level. Predictions using the proposed model resulted in higher accuracy compared with expert judgment alone (on average, 75.7% and 60.1%, respectively). CONCLUSIONS: A machine learning-based decision support system would be useful in improving the success rates of IVF treatment.

Proposed guidelines on the nomenclature and annotation of dynamic human embryo monitoring by a time-lapse user group.

STUDY QUESTION: Can the approach to, and terminology for, time-lapse monitoring of preimplantation embryo development be uniformly defined in order to improve the utilization and impact of this novel technology? SUMMARY ANSWER: The adoption of the proposed guidelines for defining annotation practice and universal nomenclature would help unify time-lapse monitoring practice, allow validation of published embryo selection algorithms and facilitate progress in this field. WHAT IS KNOWN ALREADY: An increasing quantity of publications and communications relating to time-lapse imaging of in vitro embryo development have demonstrated the added clinical value of morphokinetic data for embryo selection. Several articles have identified similar embryo selection or de-selection variables but have termed them differently. An evidence-based consensus document exists for static embryo grading and selection but, to date, no such reference document is available for time-lapse methodology or dynamic embryo grading and selection. STUDY DESIGN, SIZE AND DURATION: A series of meetings were held between September 2011 and May 2014 involving time-lapse users from seven different European centres. The group reached consensus on commonly identified and novel time-lapse variables. PARTICIPANTS/MATERIALS, SETTING, METHODS: Definitions, calculated variables and additional annotations for the dynamic monitoring of human preimplantation development were all documented. MAIN RESULTS AND THE ROLE OF CHANCE: Guidelines are proposed for a standard methodology and terminology for the of use time-lapse monitoring of preimplantation embryo development. LIMITATIONS, REASONS FOR CAUTION: The time-lapse variables considered by this group may not be exhaustive. This is a relatively new clinical technology and it is likely that new variables will be introduced in time, requiring revised guidelines. A different group of users from those participating in this process may have yielded subtly different terms or definitions for some of the morphokinetic variables discussed. Due to the technical processes involved in time-lapse monitoring, and acquisition of images at varied intervals through limited focal planes, this technology does not currently allow continuous monitoring such that the entire process of preimplantation embryo development may be visualized. WIDER IMPLICATIONS: This is the first time that a group of experienced time-lapse users has systematically evaluated current evidence and theoretical aspects of morphokinetic monitoring to propose guidelines for a standard methodology and terminology of its use and study, and its clinical application in IVF. The adoption of a more uniform approach to the terminology and definitions of morphokinetic variables within this developing field of clinical embryology would allow practitioners to benefit from improved interpretation of data and the sharing of best practice and experience, which could impact positively and more swiftly on patient treatment outcome. STUDY FUNDING/COMPETING INTERESTS: There was no specific funding for the preparation of these proposed guidelines. Meetings were held opportunistically during scientific conferences and using online communication tools. H.N.C. is a scientific consultant for ESCO, supplier of Miri TL. I.E.A. is a minor shareholder in Unisense Fertilitech, supplier of the EmbryoScope. Full disclosures of all participants are presented herein. The remaining authors have no conflict of interest.

Physician experience in performing embryo transfers may affect outcome.

The distribution of six physicians' pregnancy rates with cycle and patient demographics was investigated for 2,212 transfer cycles. The results indicate that when the patient and cycle characteristics are compromised, the level of physician experience may determine the outcome of embryo transfers.

Birth after 12 hours of oocyte refrigeration.

OBJECTIVE: To assess cycle outcome after oocyte refrigeration. DESIGN: Case report. SETTING: Private IVF center. PATIENT(S): One couple in a donor oocyte program. INTERVENTION(S): Intracytoplasmic sperm injection and blastocyst culture after refrigeration of oocytes for 12 hours. MAIN OUTCOME MEASURE(S): Birth. RESULT(S): Fourteen two-pronuclei zygotes from 17 metaphase II refrigerated oocytes resulted in transfer of two blastocysts at day 5 and cryopreservation of six excess embryos at day 6. The patient delivered one healthy male baby after 38 weeks' gestation. CONCLUSION(S): The successful outcome of oocyte refrigeration indicates that this protocol could be useful in circumstances in which a delay in obtaining spermatozoa arises.

In vitro culture under physiologic oxygen concentration improves blastocyst yield and quality: a prospective randomized survey on sibling oocytes.

A prospective randomized study was carried on sibling oocytes in which human gametes and embryos were cultured at physiologic (6% CO(2) + 5% O(2) + 89% N(2)) condition from insemination to day 6 or at atmospheric (6% CO(2) in air) condition until day 3 and at physiologic environment afterward. The results showed that physiologic oxygen concentration throughout culture period improved total blastocyst yield and day 5 embryo quality.

Preliminary study of embryo development following assessment of male and female gametes.

Gamete characteristics are likely to contribute to embryo development. In this preliminary study, early parameters were assessed in embryos generated following microinjection of hyaluronan-bound and unbound spermatozoa into 176 sibling oocytes, which had themselves been assessed using a polarizing light microscope imaging system. The fertilization and early cleavage rates, and day 3 embryo quality did not differ when oocytes displaying similar characteristics were inseminated with either bound or unbound sperm. Regardless of the binding characteristics of the sperm, early embryos displaying good and poor quality derived from oocytes displaying visible spindles and similar characteristics. These results indicate that early embryo developmental characteristics were independent from the hyaluronic acid binding capacity of the sperm when oocytes displayed a visible spindle.

Gonadotrophin therapy in combination with ICSI in men with hypogonadotrophic hypogonadism.

The aim of this study was to evaluate the impact of gonadotrophin therapy in combination with intracytoplasmic sperm injection (ICSI) in men with hypogonadotrophic hypogonadism (HH). Twenty-five azoospermic men were diagnosed with HH due to low FSH, LH and total testosterone concentrations. These patients were treated with human chorionic gonadotrophin for 1 month plus recombinant FSH the following month. Total testosterone concentrations were measured in the first and third months. Semen analyses were performed monthly after the third month of treatment. ICSI was performed when sperm production commenced. Total testosterone concentration and testicular volume were significantly increased after gonadotrophin therapy (P < 0.001). On average, spermatozoa were detected in the ejaculate after 10 months. Spontaneous pregnancies were achieved in four couples. Twenty-two ICSI cycles were performed in 18 couples using ejaculated or testicular spermatozoa, and 12 pregnancies (54.5% per cycle) were achieved. These results showed that HH could be treated successfully with hormonal therapy combined with ICSI using ejaculated spermatozoa. The use of ICSI made it possible to achieve pregnancy when spermatozoa appeared in the ejaculate, and shortened the duration of gonadotrophin therapy.

Prolonged duration of transfer does not affect outcome in cycles with good embryo quality.

The objective of investigating the impact of the time that embryos remain in the catheter on the outcome of cycles was assessed by measuring the period between loading the catheter and discharging the embryos in 300 transfer cycles. The pregnancy and implantation rates were similar in cycles with good embryo quality regardless of transfer duration.

Outcome of 1114 ICSI and embryo transfer cycles of women 40 years of age and over.

The purpose of this study was to contribute to the development of strategies to obtain acceptable outcomes in assisted reproduction treatments in women over 40 years of age. A retrospective study was carried out on the database of the German Hospital in Istanbul using data from the years 1997 to 2004. A total of 1114 embryo transfer cycles were assessed. The pregnancy, implantation and delivery rates of the assessed population were 18.2, 8.3 and 10.9% respectively. The results showed that the demographics and outcome of cycles of women at 40 years differed significantly from those over 40. Cycles in which six or more oocytes were retrieved displayed better characteristics and outcome than those with five or fewer. The clinical pregnancy and delivery rates after transfer of three embryos were similar to four or more. Therefore, women over 40 years with a good ovarian response and at least three embryos available for transfer have an acceptable pregnancy and delivery rate with a low multiple pregnancy risk.

Efficiency of changing the embryo transfer time from day 3 to day 2 among women with poor ovarian response: a prospective randomized trial.

OBJECTIVE: To compare the outcome of day 2 and day 3 embryo transfers in women demonstrating poor ovarian response. DESIGN: Prospective randomized clinical trial. SETTING: Private assisted reproductive technology center. PATIENT(S): Two hundred eighty-one women demonstrating poor ovarian response to controlled ovarian hyperstimulation. INTERVENTION(S): Women who were poor responders were randomly allocated to day 2 or day 3 embryo transfer following oocyte retrieval. MAIN OUTCOME MEASURE(S): Implantation rates and pregnancy rates per oocyte retrieval and embryo transfer. RESULT(S): The clinical pregnancy rates per oocyte retrieval (37.2% vs. 21.4%, respectively; P<.05) and per embryo transfer (38.9% vs. 24.1%, respectively; P<.05) were significantly higher in the day 2 embryo transfer group compared with day 3. On the other hand, implantation rates were not different between groups (23.9% vs. 17.2%, respectively; P=.08). CONCLUSION(S): Our results demonstrated that transfering embryos on day 2 could provide an alternative to the management of poor responder patients.

Effect of oxygen concentration during the incubation of embryos of women undergoing ICSI and embryo transfer: a prospective randomized study.

The hypothesis that ICSI outcome can be improved by culturing human embryos in an atmosphere of controlled O(2) concentration (5%) compared with 20% was tested in a prospective randomized study of 712 transfer cycles. The cycle characteristics and the embryology parameters were similar between groups. The embryo qualities were similar with day 2 transfers; however, they were better with day 3 transfers incubated in 5% O(2) than in 20% O(2). The clinical outcome parameters did not differ between groups according to the O(2) concentration. The results indicated that culture of embryos under atmospheric conditions of O(2) for the first 2 or 3 days did not alter the clinical outcome in ICSI cycles.

Transfer of early-cleaved embryos increases implantation rate in patients undergoing ovarian stimulation and ICSI-embryo transfer.

The hypothesis that inspection for early cleavage improves pregnancy rate by aiding selection of the best embryos for transfer was tested in this study. Inspection for early cleavage was performed randomly in women undergoing intracytoplasmic sperm injection (ICSI) cycles. No differences were observed between early cleavage-inspected and uninspected embryos. When the hypothesis that transfer of early-cleaved (EC) embryos yields a higher pregnancy rate than transfer of late-cleaved (LC) embryos was tested using early cleavage-inspected cycles, it was found that transfer of EC embryos resulted in a higher implantation rate than transfer of LC embryos. In transfers for which all embryos were EC (100% EC), transfer of fewer embryos yielded a higher implantation rate compared with LC and uninspected cycles. These results indicate that, when inspected, early cleavage increases the implantation rate in ICSI patients.