Higher blastocyst implantation in frozen versus fresh embryo transfers in good prognosis patients.

BACKGROUND: There is emerging evidence that frozen embryo transfers provide a more favorable environment for implantation as compared to fresh embryo transfers. Our objective was to determine if there is a clinical benefit to frozen versus fresh blastocyst transfers in good prognosis patients. METHODS: Subjects undergoing their first or second IVF/ICSI cycle <38 years of age in an OCP pretreated GnRH antagonist stimulation protocol with supernumerary embryos available for blastocyst cryopreservation were eligible for analysis. Primary transfer was exclusively blastocyst transfer. Exclusion criteria consisted of rescue ICSI, preimplantation genetic testing, donor oocytes, and surrogacy. The cohort was divided into two groups based on whether they underwent a fresh vs. frozen primary transfer. The implantation rates were compared using mixed-effects logistic regression. The clinical pregnancy and live birth rates were compared using logistic regression adjusted for number of oocytes retrieved and number of embryos transferred. All models included age, reason for treatment, and number of prior births as covariates. RESULTS: A total of 615 subjects were included in the study. There were no differences in the two groups with respect to age, BMI, baseline ovarian reserve testing, total gonadotropin dosage, and duration of stimulation. The implantation rate was higher in the frozen-embryo group as compared to the fresh-embryo group (59% and 48% respectively; OR 1.58; 95% CI 1.02-2.44). There was a trend towards higher clinical pregnancy and live birth rates in the frozen-embryo group. These differences persisted in the adjusted analysis. CONCLUSIONS: Among good prognosis patients undergoing IVF, frozen embryo transfer was associated with improved implantation rates. Consideration should be given to primary frozen blastocyst transfer in this population.

Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta.

PURPOSE: To describe the pregnancy and neonatal outcomes using fresh and vitrified/warmed blastocysts obtained from ovarian stimulation with follitropin delta in controlled trials versus follitropin alfa. METHODS: This investigation evaluated the outcome from 2719 fresh and frozen cycles performed in 1326 IVF/ICSI patients who could start up to three ovarian stimulations in the ESTHER-1 (NCT01956110) and ESTHER-2 (NCT01956123) trials, covering 1012 fresh cycles and 341 frozen cycles with follitropin delta and 1015 fresh cycles and 351 frozen cycles with follitropin alfa. Of the 1326 first cycle patients, 513 continued to cycle 2 and 188 to cycle 3, and 441 patients started frozen cycles after the fresh cycles. Pregnancy follow-up was continued until 4 weeks after birth. RESULTS: The overall cumulative take-home baby rate after up to three stimulation cycles was 60.3% with follitropin delta and 60.7% with follitropin alfa (-0.2% [95% CI: -5.4%; 5.0%]), of which the relative contribution was 72.8% from fresh cycles and 27.2% from frozen cycles in each treatment group. Across the fresh cycles, the ongoing implantation rate was 32.1% for follitropin delta and 32.1% for follitropin alfa, while it was 27.6% and 27.8%, respectively, for the frozen cycles. Major congenital anomalies among the live-born neonates up until 4 weeks were reported at an incidence of 1.6% with follitropin delta and 1.8% with follitropin alfa (-0.2% [95% CI: -1.9%; 1.5%]). CONCLUSIONS: Based on comparative trials, the pregnancy and neonatal outcomes from fresh and frozen cycles provide reassuring data on the efficacy and safety of follitropin delta. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01956110 registered on 8 October 2013; NCT01956123 registered on 8 October 2013.

Trophectoderm segmentation in human embryo images via inceptioned U-Net.

Trophectoderm (TE) is one of the main components of a day-5 human embryo (blastocyst) that correlates with the embryo's quality. Precise segmentation of TE is an important step toward achieving automatic human embryo quality assessment based on morphological image features. Automatic segmentation of TE, however, is a challenging task and previous work on this is quite limited. In this paper, four fully convolutional deep models are proposed for accurate segmentation of trophectoderm in microscopic images of the human blastocyst. In addition, a multi-scaled ensembling method is proposed that aggregates five models trained at various scales offering trade-offs between the quantity and quality of the spatial information. Furthermore, synthetic embryo images are generated for the first time to address the lack of data in training deep learning models. These synthetically generated images are proven to be effective to fill the generalization gap in deep learning when limited data is available for training. Experimental results confirm that the proposed models are capable of segmenting TE regions with an average Precision, Recall, Accuracy, Dice Coefficient and Jaccard Index of 83.8%, 90.1%, 96.9%, 86.61% and 76.71%, respectively. Particularly, the proposed Inceptioned U-Net model outperforms state-of-the-art by 10.3% in Accuracy, 9.3% in Dice Coefficient and 13.7% in Jaccard Index. Further experiments are conducted to highlight the effectiveness of the proposed models compared to some recent deep learning based segmentation methods.

Live Birth Rate after Surgical and Expectant Management of Endometriomas after In Vitro Fertilization: A Systematic Review, Meta-Analysis, and Critical Appraisal of Current Guidelines and Previous Meta-Analyses.

Controversy exists regarding surgical management of endometriomas in infertile women before in vitro fertilization (IVF) because growing evidence indicates that surgery may impair the ovarian response. The objective of the present systematic review and meta-analysis was to compare surgical and expectant management of endometriomas regarding IVF outcomes. Prospective and retrospective controlled studies were found via the Cochrane Library, Embase, and MEDLINE databases. Thirteen studies (1 randomized controlled trial and 12 observational studies, N = 2878) were pooled, and similar live birth rates were observed in the surgically and expectantly managed groups (odds ratio = 0.83; 95% confidence interval [CI], 0.56-1.22; p = .98). The clinical pregnancy rates (odds ratio = 0.83; 95% CI, 0.66-1.05; p = .86), the number of mature oocytes retrieved, and the miscarriage rates were not statistically different between study groups. However, the total number of oocytes retrieved was lower in the surgery group (mean difference = -1.51; 95% CI, -2.60 to -0.43; p = .02). Findings suggest that surgical management of endometriomas before IVF therapy yields similar live birth rates as expectant management. However, future properly designed randomized controlled trials are warranted.

Effect of endometrial injury on in vitro fertilization pregnancy rates: a randomized, multicentre study.

PURPOSE: To determine if endometrial injury prior to the first or second in vitro fertilization (IVF) cycle affects clinical pregnancy rates. METHODS: This study was a randomized, multicentre, controlled study performed at three Canadian outpatient fertility clinics. Patients undergoing their first or second IVF cycle were randomized to a single endometrial injury 5-10 days prior to the start of gonadotropins in an IVF cycle compared to no injury. The primary outcome was clinical pregnancy rate. Secondary outcomes were live birth rates, implantation rate, endometrial thickness, number of oocytes retrieved and the rate of embryo cryopreservation. RESULTS: Fifty-one women were randomized (25 in the en dometrial injury group and 26 in the control group); however, the study was terminated prematurely due to slow recruitment (target 332 patients). Groups were similar at baseline for: age, duration of infertility, BMI, day 3 FSH, and the number having first IVF cycle. The groups were similar for gonadotropin dose, endometrial thickness, number of oocytes retrieved, and embryo cryopreservation rate. The clinical pregnancy rate in the endometrial injury group was 52% (13/25) and 46% (12/26) in the control group (p = 0.45). Live birth rate in the endometrial injury group was 52% (13/25) and 35% (9/26) in the control group (p = 0.17). The implantation rate was also similar (58% vs. 45%, p = 0.17). CONCLUSIONS: This study did not detect a difference in implantation, clinical pregnancy or live birth rates; however, the lack of difference in this study may be because it was underpowered. CLINICAL TRIALS REGISTRATIONS: gov: NCT01983423.

Predicting Human Embryos' Implantation Outcome from a Single Blastocyst Image.

Only one-third of embryo transfer cycles via invitro fertilization, the most common fertility treatment, leads to a clinical pregnancy. Identifying embryos with the highest potentials for transfer is an essential step to optimize in-vitro fertilization outcome. However, human embryos are complicated by nature and some of their developmental aspects has still remained a mystery to expert biologists. In this paper, the first-ever attempt is made to estimate probability of implantation using a single blastocyst image. First, a semantic segmentation system is proposed for human blastocyst components in microscopic images. Second, a multi-stream classification model is proposed for the prediction of embryos' implantation outcome. The proposed classification model features an architectural component, Compact-Contextualize-Calibrate (C3) to guide the feature extraction process and a slow-fusion strategy to learn cross-modality features. Experimental results confirm that the proposed method delivers the first-reported implantation outcome prediction via a single blastocyst image to date with a mean accuracy of 70.9%.

Follitropin delta in repeated ovarian stimulation for IVF: a controlled, assessor-blind Phase 3 safety trial.

RESEARCH QUESTION: To evaluate the immunogenicity of follitropin delta in repeated ovarian stimulation. DESIGN: Controlled, assessor-blind trial in IVF/intracytoplasmic sperm injection patients undergoing repeated cycles of ovarian stimulation (cycles 2 and 3), following initial stimulation with follitropin delta or follitropin alfa (cycle 1) in a preceding randomized trial. In cycles 2 and 3, 513 and 188 women, respectively, were treated as randomized in cycle 1, with dosing based on ovarian response in the previous cycle. RESULTS: The incidence of treatment-induced anti-FSH antibodies with follitropin delta was 0.8% and 1.1% in cycles 2 and 3, respectively, which was similar to the incidence in cycle 1 (1.1%). No antibodies were of neutralizing capacity. Women with pre-existing anti-FSH antibodies were safely treated with follitropin delta without boosting an immune response. Treatment with follitropin delta and follitropin alfa gave similar outcomes for mean number of oocytes retrieved (9.2 versus 8.6 [cycle 2]; 8.3 versus 8.9 [cycle 3]), ongoing pregnancy (27.8% versus 25.7%; 27.4% versus 28.0%) and live birth rates (27.4% versus 25.3%; 26.3% versus 26.9%). The presence of anti-FSH antibodies did not affect the ovarian response. CONCLUSIONS: The trial demonstrated the low immunogenicity potential of follitropin delta in repeated ovarian stimulation, and confirmed the appropriateness of the follitropin delta dosing regimen in repeated cycles, with documented efficacy and safety.

A hybrid approach for multiple blastomeres identification in early human embryo images.

Automatic quality assessment of the human embryo paves the way to improve the outcome of the In Vitro Fertilization (IVF) treatment by selecting embryos with the highest implantation potentials. Analyzing the shape, size, and motion of the cells, as well as other time-related changes, facilitates embryo quality assessment. However, the ambitious 3D-like side-lit appearance of the embryo, occlusion, transparency of cells and artifacts such as fragmentation make automatic detection of blastomeres (embryonic cells) a challenging task. In this paper, an automated noninvasive approach is proposed to identify multiple blastomere cells inside an embryo at different growth stages. In particular, the proposed method aims to identify up to 8 blastomeres in microscopic human embryo images of days 1-3. The proposed system is a hybrid approach that aggregates both models and features capturing global and local characteristics to locate the boundaries of each blastomere. Experimental results on a large dataset of 271 embryo images with various blastomere numbers and sizes confirm that the proposed method identifies blastomeres with average Precision, Recall, and Overall Quality of 85.9%, 85.3%, and 76.5%, respectively.

Case report: an identical twin with Sertoli-Leydig cell tumor.

Our report details the workup and management of a 43-year-old woman with an identical twin who presented with 2 years of virilization and secondary amenorrhea. Serum total testosterone was elevated. An MRI did not identify adnexal or adrenal pathology. Subsequent ovarian vein sampling demonstrated unilateral testosterone elevation. The patient underwent laparoscopic unilateral oophorectomy resulting in the diagnosis of Sertoli-Leydig cell tumor (SLCT). Although SLCT is a rare sex-cord ovarian tumor, it is associated with endometrial hyperplasia and malignancy. Our goals are to review the workup of androgen-secreting tumors and discuss the clinical importance of the DICER1 mutation in the context of SLCT. In this case, an identical twin underwent DICER1 testing which was one of the essential steps in her clinical management.

Adverse perinatal outcomes associated with crown-rump length discrepancy in in vitro fertilization pregnancies.

OBJECTIVE(S): To determine whether an association exists between small crown-rump length (CRL) and adverse obstetrical outcomes in pregnancies conceived by IVF and to compare a CRL reference based on IVF pregnancies to a reference based on spontaneous pregnancies. DESIGN: Retrospective cohort study. CRL was classified as small by comparing it with the local university hospital maternal fetal medicine standard and the Monash IVF reference chart. SETTING: University-affiliated fertility center. PATIENT(S): Singleton pregnancies conceived by IVF with ultrasounds performed between 7+0 and 8+6 weeks of gestational age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pregnancy loss, preterm birth, and low birth weight. RESULT(S): Included were 940 clinical pregnancies. The overall and CRL-discrepant miscarriage rates were 12.7% and 41%, respectively. When CRL was small, the maternal age-adjusted odds of miscarriage were 13.8 times higher (95% confidence interval [CI], 8.9-21.6). At age 30, small CRL was associated with a 30% risk of miscarriage, versus 61% at age 45. There was no association between small CRL and preterm birth or low birth weight. The sensitivity and specificity for predicting miscarriage from the optimal Monash cut point were 0.69 (95% CI, 0.61-0.77) and 0.84 (95% CI, 0.82-0.87), which were similar to those of the CRL reference based on spontaneous pregnancies. CONCLUSION(S): Small CRL in IVF pregnancy was strongly associated with miscarriage, especially in the context of advanced maternal age. Small CRL was not associated with preterm birth or low birth weight. A CRL reference based on IVF pregnancies was equivalent to the standard reference for predicting miscarriage.

Prevalence and Treatment Choices for Couples with Recurrent Pregnancy Loss Due to Structural Chromosomal Anomalies.

OBJECTIVE: Parental carriers of balanced structural chromosomal rearrangements such as reciprocal or Robertsonian translocations are at increased risk of recurrent pregnancy loss (RPL) due to the production of gametes with unbalanced non-viable chromosome variants. As a purported means of improving reproductive outcomes in this population, IVF and preimplantation genetic diagnosis (PGD) have been introduced as an alternative to natural conception and prenatal diagnosis. In this study, we evaluate the prevalence and treatment choices of couples with structural chromosomal rearrangement referred to a tertiary care RPL clinic. In addition, we compare the two methods of management in terms of live birth rate. METHODS: This is a retrospective chart review of 2321 couples who were referred to a highly specialized RPL clinic for ongoing clinical management between January 2005 and December 2013 (n = 23). Couples who pursued PGD through local fertility centres during this time were also included (n = 13). RESULTS: Thirty-six couples (1.6%) were found to be parental carriers of a structural chromosomal rearrangement. In this cohort, couples were twice as likely to pursue natural conception compared with IVF with PGD. No significant differences were observed in live birth rate between PGD and clinical management (66.6% vs. 53.3%, P = 0.717). With PGD management, six live birth outcomes were observed, with an incidence of one birth in 5.63 years of follow-up. With clinical management, 24 live birth outcomes were observed, with an incidence of one birth in 4.09 years of follow-up. Mean time to live birth was 17.5 months and 23.3 months in clinical management and PGD, respectively. CONCLUSIONS: Among couples presenting to a tertiary RPL clinic, parental carriers of structural chromosomal rearrangement and history of RPL are more likely to pursue natural conception over IVF and PGD. With regards to reproductive outcomes, no significant difference in miscarriage rate, time to live birth, or live birth rate was observed between couples who pursued PGD compared with expectant clinical management.

Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study.

OBJECTIVE: For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry. METHODS: This was a retrospective population-based cohort study of women under age 45 in British Columbia from 2003 to 2015 with CAH or grade I endometrioid EC who used progestins as initial management. Demographics, treatment type, response to treatment, determinants of definitive surgery (hysterectomy), pathologic findings, and obstetrical outcomes were reviewed. RESULTS: There were 50 women under age 45 with CAH (n = 29) and EC (n = 21). Median age at diagnosis was 36 years (range 25-41), and most were nulliparous (88%) with a median BMI of 32.9 (range 21-70). After 6 months of therapy, 58% of women had persistent disease, and only 35% had full resolution at last follow-up (median 23 months). There were 32 women who had a hysterectomy, including 27 because of persistent/recurrent disease, and 5 who chose surgery despite complete response to progestins. The majority of hysterectomy specimens (85%) had minimal or no residual pathology, even among those with disease on preoperative biopsy. Only 10% of women had successful pregnancies. CONCLUSION: There is a moderate to high risk of persistence of CAH or EC on progestin therapy. However, for those undergoing hysterectomy, the vast majority has low-risk disease confined to the endometrium, implying the possibility of further conservative management of persistent disease.

Automatic Identification of Human Blastocyst Components via Texture.

Choosing the most viable embryo during human in vitro fertilization (IVF) is a prime factor in maximizing pregnancy rate. Embryologists visually inspect morphological structures of blastocysts under microscopes to gauge their health. Such grading introduces subjectivity amongst embryologists and adds to the difficulty of quality control during IVF. In this paper, we introduce an algorithm for automatic segmentation of two main components of human blastocysts named: Trophectoderm (TE) and inner cell mass (ICM). We utilize texture information along with biological and physical characteristics of day-5 human embryos (blastocysts) to identify TE or ICM regions according to their intrinsic properties. Both these regions are highly textured and very similar in the quality of their texture, and they often look connected to each other when imaged. These attributes make their automatic identification and separation from each other a difficult task even for an expert embryologist. By automatically identifying TE and ICM regions, we offer the opportunity to perform more detailed assessment of blastocysts. This could help in analyzing, in a quantitative way, various visual/geometrical characteristics of these regions that when combined with the pregnancy outcome can determine the predictive values of such attributes. Our work aids future research in understanding why certain embryos have higher pregnancy success rates. This paper is tested on a set of 211 blastocyst images. We report an accuracy of 86.6% for identification of TE and 91.3% for ICM.

Peak Serum Estradiol Level During Controlled Ovarian Stimulation Is not Associated with Lower Levels of Pregnancy-Associated Plasma Protein-A or Small for Gestational Age Infants: A Cohort Study.

OBJECTIVE: During controlled ovarian stimulation in IVF, supraphysiologic levels of estradiol (E2) have been associated with poor placentation and adverse pregnancy outcomes. This study aimed to investigate whether high peak E2 on the day of human chorionic gonadotropin trigger is associated with low pregnancy-associated plasma protein-A (PAPP-A) and adverse perinatal outcomes. METHODS: We performed a retrospective cohort study at a private, university-affiliated fertility centre in Vancouver, BC. We enrolled 216 patients with a singleton pregnancy after fresh embryo transfer who also underwent first trimester screening. Adverse perinatal outcomes were collected from a local registry and included preterm birth, hypertension in pregnancy, antepartum hemorrhage, intrauterine growth restriction, SGA, stillbirth, admission to the NICU, and neonatal death. RESULTS: High serum E2 (≥13 035 pmol/L) at controlled ovarian stimulation was not correlated with low PAPP-A (<0.4 multiples of the median) at first trimester screening (P = 0.46). When each adverse outcome was analysed separately, there was no association between high E2 and any of the outcomes (P > 0.05 for all). High peak E2 was not associated with a total composite of maternal and neonatal adverse birth outcomes (P = 0.30). CONCLUSION: Our results do not support the theory that high E2 at fresh embryo transfer impedes placentation. We found no association between peak E2 and low PAPP-A levels or adverse pregnancy outcomes.

Longer ovarian stimulation reduces embryo number and clinical pregnancy rate in long GnRH agonist cycles.

BACKGROUND: The aim of this study was to analyze whether the length of controlled ovarian stimulation affects in vitro fertilization (IVF) cycle outcomes. METHODS: This retrospective cohort study was performed at a private, university-affiliated fertility centre. We reviewed 1522 IVF cycles, comprising 979 long gonadotropin-releasing hormone (GnRH) agonist and 543 GnRH antagonist protocols. All subjects underwent controlled ovarian stimulation followed by fresh embryo transfer. Logistic regression analysis was used to examine the relationship between trigger day and the following cycle outcomes: normal fertilization rate (FR), proportion of mature oocytes, proportion of cycles with embryos for cryopreservation, and clinical pregnancy rate (CPR). RESULTS: In long agonist cycles, having more days of stimulation was associated with a lower clinical pregnancy rate (OR=0.87, 95% CI=0.80-0.96, P=0.01). Longer stimulation also resulted in fewer cycles with supernumerary embryos for cryopreservation (OR=0.84, 95% CI=0.77-0.92, P=0.0005), despite a having greater number of mature oocytes retreived (OR=1.05, 95% CI=1.01-1.10, P=0.04). For each additional day of stimulation in a long agonist protocol, the odds of achieving a clinical pregnancy were reduced by 13% and of achieving cryopreservation by 16%. In the antagonist protocol group, the length of ovarian stimulation did not have an effect on the clinical pregnancy and cryopreservation rates. CONCLUSIONS: Longer duration of ovarian stimulation appears to reduce clinical pregnancy and embryo cryopreservation rates in subjects undergoing long GnRH agonist cycles. The number of days of stimulation does not appear to affect those using the GnRH antagonist protocol.

Prise en charge des fibromes utérins en présence d'une infertilité autrement inexpliquée.

OBJECTIF: Formuler des recommandations quant à la façon optimale d'assurer la prise en charge des fibromes dans le contexte de l'infertilité. Les options habituelles et novatrices de prise en charge des fibromes seront analysées en mettant l'accent sur leur applicabilité chez les femmes qui souhaitent obtenir une grossesse. OPTIONS: La prise en charge des fibromes chez les femmes qui souhaitent obtenir une grossesse met d'abord en jeu la documentation de la présence des fibromes en question et la détermination de la probabilité que ces derniers affectent le potentiel génésique. Dans un tel contexte, la prise en charge des fibromes s'effectue principalement de façon chirurgicale; toutefois, il faut s'assurer au préalable de mettre en balance les avantages factuels de l'approche chirurgicale en matière d'amélioration des issues cliniques et les risques propres à une telle approche. ISSUES: L'amélioration des taux et des issues de grossesse que permet la prise en charge des fibromes chez les femmes aux prises avec l'infertilité constitue l'issue principale sur laquelle nous nous sommes attardés. RéSULTATS: La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, CINAHL et Cochrane Systematic Reviews en novembre 2013 au moyen d'un vocabulaire contrôlé (p. ex. « leiomyoma ¼, « infertility ¼, « uterine artery embolization ¼, « fertilization in vitro ¼) et de mots clés (p. ex. « fibroid ¼, « myomectomy ¼) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais et français. Aucune restriction n'a été appliquée en matière de date. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en novembre 2013. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. VALEURS: La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). AVANTAGES, DéSAVANTAGES ET COûTS: Les présentes recommandations devraient permettre la prise en charge adéquate des femmes qui présentent des fibromes et qui sont aux prises avec l'infertilité, et ce, par la maximisation de leurs chances de grossesse grâce à la minimisation des risques mis en cause par la tenue de myomectomies inutiles. L'atténuation des complications et l'élimination des interventions inutiles devraient également mener à une baisse des coûts pour le système de santé. DéCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Altered gene expression of H19 and IGF2 in placentas from ART pregnancies.

INTRODUCTION: The aim of this study is to determine whether the gene expression and associated DNA methylation regulation of H19 and IGF2 are altered in placentas conceived by assisted reproductive technologies (ART) compared to natural conceptions. METHODS: 113 pregnancies were recruited resulting in 119 placentas (83 singletons and 36 twins), where 56 were conceived via in vitro fertilization (IVF), 41 via intracytoplasmic sperm injection (ICSI), and 22 naturally. Regulation of imprinting of H19 and IGF2 was determined by the DNA methylation status at three CpG sites within the H19 imprinting control region 1 (ICR1) using bisulphite pyrosequencing. Expression of H19 and IGF2 in 45 of these placentas (17 IVF, 14 ICSI, and 14 NC) was measured by determining the relative mRNA transcript levels using RT-qPCR in placental villi. RESULTS: Placental weight and birth weight were not significantly different between groups. H19 expression was significantly increased in both IVF and ICSI placentas when compared to controls (1.8 and 1.9 fold higher, respectively). Conversely, IGF2 was significantly decreased in both ART groups (0.8 and 0.7 fold lower, respectively). Mean DNA methylation at ICR1 was found to be similar between all groups. No correlation was found between DNA methylation at ICR1 and expression of either gene. However, a significant inverse relationship was found between H19 and IGF2 expression. CONCLUSION: We provide evidence of altered H19 and IGF2 expression in ART placentas. The altered expression pattern may suggest a loss of imprinting on the paternal allele. Furthermore, these alterations may not be entirely associated with DNA methylation at ICR1. We show further indirect evidence of the H19-IGF2 inverse expression pattern.

The management of uterine fibroids in women with otherwise unexplained infertility.

OBJECTIVE: To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. OPTIONS: Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. OUTCOMES: The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. EVIDENCE: Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system. Summary Statements 1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) 2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III) 3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) 4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) 5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) 6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations 1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D) 5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) 8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) 9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A) 10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E).

Objectif : Formuler des recommandations quant à la façon optimale d'assurer la prise en charge des fibromes dans le contexte de l'infertilité. Les options habituelles et novatrices de prise en charge des fibromes seront analysées en mettant l'accent sur leur applicabilité chez les femmes qui souhaitent obtenir une grossesse. Options : La prise en charge des fibromes chez les femmes qui souhaitent obtenir une grossesse met d'abord en jeu la documentation de la présence des fibromes en question et la détermination de la probabilité que ces derniers affectent le potentiel génésique. Dans un tel contexte, la prise en charge des fibromes s'effectue principalement de façon chirurgicale; toutefois, il faut s'assurer au préalable de mettre en balance les avantages factuels de l'approche chirurgicale en matière d'amélioration des issues cliniques et les risques propres à une telle approche. Issues : L'amélioration des taux et des issues de grossesse que permet la prise en charge des fibromes chez les femmes aux prises avec l'infertilité constitue l'issue principale sur laquelle nous nous sommes attardés. Résultats : La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, CINAHL et Cochrane Systematic Reviews en novembre 2013 au moyen d'un vocabulaire contrôlé (p. ex. « leiomyoma ¼, « infertility ¼, « uterine artery embolization ¼, « fertilization in vitro ¼) et de mots clés (p. ex. « fibroid ¼, « myomectomy ¼) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais et français. Aucune restriction n'a été appliquée en matière de date. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en novembre 2013. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. Valeurs : La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). Avantages, désavantages et coûts : Les présentes recommandations devraient permettre la prise en charge adéquate des femmes qui présentent des fibromes et qui sont aux prises avec l'infertilité, et ce, par la maximisation de leurs chances de grossesse grâce à la minimisation des risques mis en cause par la tenue de myomectomies inutiles. L'atténuation des complications et l'élimination des interventions inutiles devraient également mener à une baisse des coûts pour le système de santé. Déclarations sommaires 1. Les fibromes sous-séreux ne semblent pas exercer un effet sur la fertilité; la question de savoir si les fibromes intramuraux exercent un effet quelconque à cet égard demeure sans réponse définitive. Quoi qu'il en soit, si les fibromes intramuraux exercent bel et bien un effet sur la fertilité, ce dernier semble être faible et être encore moins significatif lorsque l'endomètre n'est pas mis en cause. (II-3) 2. Puisque la prise en charge médicale des fibromes est actuellement associée à la suppression de l'ovulation, à la diminution de la production d'œstrogènes ou à la perturbation de l'action ciblée des œstrogènes ou de la progestérone au niveau des récepteurs et qu'une telle prise en charge dispose du potentiel de nuire au développement endométrial et à l'implantation, elle ne peut être utilisée à titre traitement autonome pour contrer les fibromes au sein de la population infertile. (III) 3. La tenue d'une évaluation préopératoire des fibromes sous-muqueux constitue un facteur essentiel pour la prise d'une décision quant à la meilleure approche thérapeutique à adopter. (III) 4. Nous ne disposons que de peu de données probantes quant à l'utilisation de sondes de Foley, d'œstrogènes ou de dispositifs intra-utérins pour la prévention des adhérences intra-utérines à la suite d'une myomectomie hystéroscopique. (II-3) 5. Au sein de la population infertile, les approches laparoscopique et par minilaparotomie donnent lieu à des taux de grossesse cumulatifs semblables; toutefois, l'approche « laparoscopique ¼ est associée à une récupération plus rapide, à une atténuation de la douleur postopératoire et à moins de cas de morbidité fébrile. (II-2) 6. Par comparaison avec la myomectomie, l'embolisation de l'artère utérine donne lieu à des taux moindres de grossesse, à des taux accrus de fausse couche et à plus d'issues de grossesse indésirables. (II-3) Des études laissent également entendre que l'embolisation de l'artère utérine est associée à une atténuation de la réserve ovarienne, particulièrement chez les patientes plus âgées. (III) Recommandations 1. Chez les femmes qui sont aux prises avec l'infertilité, des efforts devraient être déployés pour que l'évaluation et la classification des fibromes (plus particulièrement en ce qui concerne ceux qui exercent des effets sur la cavité endométriale) soient adéquatement menées au moyen de l'échographie transvaginale, de l'hystéroscopie, de l'hystéroéchographie ou de l'imagerie par résonance magnétique. (III-A). 2. L'évaluation préopératoire des fibromes sous-muqueux devrait non seulement comprendre la détermination de la taille des fibromes et de leur emplacement dans la cavité utérine, mais également la détermination de l'épaisseur du myomètre résiduel se situant entre ces fibromes et la séreuse et celle du degré d'envahissement de la cavité. À cette fin, les modalités à privilégier sont les suivantes : l'utilisation combinée de l'hystéroscopie et de l'échographie transvaginale ou l'hystéroéchographie. (III-B) 3. La prise en charge des fibromes sous-muqueux s'effectue par hystéroscopie. La taille des fibromes devrait être inférieure à 5 cm, et ce, bien que des fibromes de plus grandes dimensions aient déjà été pris en charge par hystéroscopie; toutefois, la tenue d'une deuxième intervention est souvent nécessaire. (III-B) 4. L'hystérosalpingogramme ne constitue pas une modalité adéquate pour l'évaluation et la classification des fibromes. (III-D) 5. Chez les femmes qui présentent une infertilité autrement inexpliquée, les fibromes sous-muqueux devraient être retirés de façon à permettre une amélioration des taux de conception et de grossesse. (II-2) 6. Le retrait des fibromes sous-séreux n'est pas recommandé. (III-D) 7. Nous disposons de données probantes assez bonnes pour nous prononcer contre le recours à la myomectomie chez les femmes qui présentent des fibromes intramuraux (l'intégrité de l'endomètre ayant été confirmée par hystéroscopie) et une infertilité autrement inexpliquée, peu importe la taille des fibromes en question. (II-2D) Lorsque la patiente ne dispose d'aucune autre option, les avantages de la myomectomie devraient être mis en balance avec les risques mis en cause; de plus, la prise en charge des fibromes intramuraux devrait alors être personnalisée. (III-C) 8. Lorsque les fibromes sont retirés par voie abdominale, l'utilisation d'une incision utérine antérieure devrait être favorisée pour minimiser la formation postopératoire d'adhérences. (II-2A) 9. L'élargissement du recours à l'approche laparoscopique en matière de myomectomie pourrait être limité par le degré de difficulté technique qui est associé à cette intervention. La sélection des patientes devrait être personnalisée en fonction du nombre, de la taille et de l'emplacement des fibromes utérins, ainsi qu'en fonction des habiletés du chirurgien. (III-A) 10. D'ordre général, les femmes (fertiles ou infertiles) qui cherchent à obtenir une grossesse ne devraient pas se voir offrir une embolisation de l'artère utérine à titre d'option pour la prise en charge de leurs fibromes utérins. (II-3E).

Automatic segmentation of trophectoderm in microscopic images of human blastocysts.

Accurate assessment of embryos viability is an extremely important task in the optimization of in vitro fertilization treatment outcome. One of the common ways of assessing the quality of a human embryo is grading it on its fifth day of development based on morphological quality of its three main components (Trophectoderm, Inner Cell Mass, and the level of expansion or the thickness of its Zona Pellucida). In this study, we propose a fully automatic method for segmentation and measurement of TE region of blastocysts (day-5 human embryos). Here, we eliminate the inhomogeneities of the blastocysts surface using the Retinex theory and further apply a level-set algorithm to segment the TE regions. We have tested our method on a dataset of 85 images and have been able to achieve a segmentation accuracy of 84.6% for grade A, 89.0% for grade B, and 91.7% for grade C embryos.