Sunny H. Jun

Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer

OBJECTIVE To evaluate the incidence of monozygotic twinning (MZT) in pregnancies conceived after blastocyst transfer compared to cleavage-stage transfer. DESIGN Retrospective study. SETTING University IVF program. PATIENT(S) All IVF patients with viable pregnancies conceived during a 4-year period. INTERVENTION(S) Blastocyst transfer or day 3 ET. MAIN OUTCOME MEASURE(S) Incidence of MZT assessed by transvaginal ultrasound. RESULT(S) There were 11 incidences of MZT in 197 viable pregnancies (5.6%) with blastocyst transfer compared to 7 of 357 viable pregnancies (2%) with day 3 ET. In 10 of 18 pregnancies, MZT was observed in the setting of a higher order multiple gestation (6 of 11 for blastocyst transfer and 4 of 7 for day 3 ET). In the day 3 ET group, assisted hatching or intracytoplasmic sperm injection (ICSI) did not increase MZT (4 of 213, 1.9%) compared to cycles without zona breaching (3 of 144, 2.1%). Similarly, in the blastocyst-transfer group, ICSI did not increase the incidence of MZT (4 of 74, 5.5% for ICSI and 7 of 123, 5.7% for non-ICSI IVF). CONCLUSION(S) Compared to day 3 ET, blastocyst transfer appears to significantly increase the incidence of gestations with MZT. This information should be taken into account when counseling patients about the pros and cons of extended culture.

A Novel and Critical Role for Oct4 as a Regulator of the Maternal-Embryonic Transition

Background Compared to the emerging embryonic stem cell (ESC) gene network, little is known about the dynamic gene network that directs reprogramming in the early embryo. We hypothesized that Oct4, an ESC pluripotency regulator that is also highly expressed at the 1- to 2-cell stages in embryos, may be a critical regulator of the earliest gene network in the embryo. Methodology/Principal Findings Using antisense morpholino oligonucleotide (MO)-mediated gene knockdown, we show that Oct4 is required for development prior to the blastocyst stage. Specifically, Oct4 has a novel and critical role in regulating genes that encode transcriptional and post-transcriptional regulators as early as the 2-cell stage. Our data suggest that the key function of Oct4 may be to switch the developmental program from one that is predominantly regulated by post-transcriptional control to one that depends on the transcriptional network. Further, we propose to rank candidate genes quantitatively based on the inter-embryo variation in their differential expression in response to Oct4 knockdown. Of over 30 genes analyzed according to this proposed paradigm, Rest and Mta2, both of which have established pluripotency functions in ESCs, were found to be the most tightly regulated by Oct4 at the 2-cell stage. Conclusions/Significance We show that the Oct4-regulated gene set at the 1- to 2-cell stages of early embryo development is large and distinct from its established network in ESCs. Further, our experimental approach can be applied to dissect the gene regulatory network of Oct4 and other pluripotency regulators to deconstruct the dynamic developmental program in the early embryo.

Uterine leiomyomas and their effect on in vitro fertilization outcome: a retrospective study.

Purpose: The effect of uterine leiomyomas on the outcome of in vitro fertilization (IVF) treatment has been controversial. This study was undertaken to clarify influence of fibroids on IVF success, in a large population with age and other potential confounding variables controlled for in the analysis.Methods: A population of 141 patients with and 406 without leiomyomata undergoing their first IVF cycle was studied.Results: The association between uterine leiomyomas and assisted reproduction treatment outcome was not statistically significant (OR = 0.73, 95% CI: 0.49−1.19, p = 0.21) after controlling for age and other risk factors. Also, fibroids neither affected the risk of spontaneous abortion (OR = 1.06, 95% CI: 0.44−2.60) nor the risk of ectopic pregnancy (OR = 0.78, 95% CI: 0.08−8.02). Location of fibroids (intramural vs. submucosal/subserosal) and their size had no significant effect on pregnancy outcome.Conclusions: Results from our analyses indicated that in vitro fertilization outcome was not affected by the presence of uterine leiomyomas. Therefore, in patients with normal uterine cavities and fibroids less than a certain size (i.e., <7 cm), undergoing myomectomies as a prerequisite for assisted reproduction treatment is seriously questionable.

Comparison of the sex ratio with blastocyst transfer and cleavage stage transfer.

AbstractPurpose: To evaluate the sex ratio in births conceived with blastocyst transfer compared to day 3-ET. Methods: A retrospective analysis of IVF patients who became pregnant after blastocyst or cleavage stage transfer at Stanford University Hospital and a literature review were performed. Result(s): In the day 3-ET group, the male-to-female (M/F) ratio was 157/139 (53%/47%) compared to 97/66 (59.5%/40.5%) in the blastocyst group (P = 0.18). Similar trends have been found in individual studies in the literature but reached statistical significance in only one out of six reports reviewed. The combined data from our study and the literature show a male-to-female ratio of 797/594 (57.3%/42.7%) in blastocyst transfer compared to 977/932 (51.2%/48.8%) in day 3-ET (P = 0.001). Conclusion(s): Although individual studies may lack power to show an altered sex ratio with blastocyst transfer, the combined data presented in this report do suggest that the M/F ratio is higher with blastocyst transfer compared to cleavage stage transfer.

Defining human embryo phenotypes by cohort-specific prognostic factors.

Background Hundreds of thousands of human embryos are cultured yearly at in vitro fertilization (IVF) centers worldwide, yet the vast majority fail to develop in culture or following transfer to the uterus. However, human embryo phenotypes have not been formally defined, and current criteria for embryo transfer largely focus on characteristics of individual embryos. We hypothesized that embryo cohort-specific variables describing sibling embryos as a group may predict developmental competence as measured by IVF cycle outcomes and serve to define human embryo phenotypes. Methodology/Principal Findings We retrieved data for all 1117 IVF cycles performed in 2005 at Stanford University Medical Center, and further analyzed clinical data from the 665 fresh IVF, non-donor cycles and their associated 4144 embryos. Thirty variables representing patient characteristics, clinical diagnoses, treatment protocol, and embryo parameters were analyzed in an unbiased manner by regression tree models, based on dichotomous pregnancy outcomes defined by positive serum ß-human chorionic gonadotropin (ß-hCG). IVF cycle outcomes were most accurately predicted at ∼70% by four non-redundant, embryo cohort-specific variables that, remarkably, were more informative than any measures of individual, transferred embryos: Total number of embryos, number of 8-cell embryos, rate (percentage) of cleavage arrest in the cohort and day 3 follicle stimulating hormone (FSH) level. While three of these variables captured the effects of other significant variables, only the rate of cleavage arrest was independent of any known variables. Conclusions/Significance Our findings support defining human embryo phenotypes by non-redundant, prognostic variables that are specific to sibling embryos in a cohort.

Ectopic pregnancy rates with day 3 versus day 5 embryo transfer: a retrospective analysis

BackgroundBlastocyst transfer may theoretically decrease the incidence of ectopic pregnancy following IVF-ET in view of the decreased uterine contractility reported on day 5. The purpose of our study is to specifically compare the tubal pregnancy rates between day 3 and day 5 transfers.MethodsA retrospective analysis of all clinical pregnancies conceived in our IVF program since 1998 was performed. The ectopic pregnancy rates were compared for day 3 and day 5 transfers.ResultsThere were 623 clinical pregnancies resulting from day 3 transfers of which 22 were ectopic (3.5%). In day 5 transfers, there were 13 ectopic pregnancies out of 333 clinical pregnancies (3.9%). The difference between these rates is not statistically significant (P = 0.8).ConclusionsOur data suggests that the ectopic pregnancy rate is not reduced following blastocyst transfer compared to day 3 transfer. While there may be several benefits to extended culture in IVF, the decision to offer blastocyst transfer should be made independently from the issue of ectopic pregnancy risk.

Deep phenotyping to predict live birth outcomes in in vitro fertilization

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVFBT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003–2006, followed by external validation with 634 cycles from 2007–2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVFBT, that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p < 0.05), and increased discrimination by receiver–operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVFBT provided predictions that were more accurate for ∼83% of C1 and ∼60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.

Is there a role for preparatory cycle in ovum donation recipients

Purpose of review In ovum donation cycles, the role of preparatory cycles to ensure proper endometrial development in the recipient remains controversial. As evidenced in the literature, endometrial receptivity is critical in conception. Therefore, endometrial preparation with exogenous hormones in addition to synchronization of the recipient and donor are essential in achieving a successful outcome. Recent findings There are very limited data specifically examining the benefit of recipients undergoing preparatory cycles prior to their actual egg donation cycle. One study concluded that trial hormone replacement treatment cycles with endometrial biopsies may be useful in older reproductive-age women but not in younger women. Another study showed no difference in pregnancy rates between those who did and did not undergo preparatory cycles. Summary Since one of the integral elements of preparatory cycles is determining endometrial dating, with relatively conflicting data, these mock cycles may not be as beneficial as expected. Therefore, for those who routinely use preparatory cycles, the potential risks, benefits, and costs of these cycles, increased hormonal exposure, the relatively invasive nature of the procedure, and time prior to performing them must be considered.

The Role of Preparatory Cycles in Ovum Donation Recipients: A Retrospective Study

Purpose: To determine whether preparatory cycles affect in vitro fertilization (IVF) outcome in ovum donation.Methods: Medical records of 98 ovum donation recipients undergoing their first egg donation cycle were analyzed retrospectively. Preparatory cycles were performed in 50 patients with leuprolide acetate, estrogen, and progesterone. An endometrial biopsy was performed on day 10–12 of progesterone supplementation, to determine adequacy of the preparatory cycle.Results: Pregnancy rates in women with and without preparatory cycles were 42.0% and 43.8%, respectively. Among ovum donation recipients who underwent preparatory cycles, the percentages of adequate endometrial biopsies in pregnant versus nonpregnant groups were 76.2% and 84.3%, respectively. No results showed statistical significance.Conclusions: Preparatory cycles do not increase pregnancy rates in ovum donation recipients. In addition, no correlation was noted between adequate endometrial biopsies and higher pregnancy rates.

Predictors of in vitro fertilization outcomes in women with highest follicle-stimulating hormone levels ≥ 12 IU/L: a prospective cohort study.

Objective The purpose of this study is to evaluate factors predictive of outcomes in women with highest follicle-stimulating hormone (FSH) levels ≥12 IU/L on basal testing, undergoing in vitro fertilization (IVF). Methods A prospective cohort study was conducted at Stanford University Hospital in the Reproductive Endocrinology and Infertility Center for 12 months. Women age 21 to 43 undergoing IVF with highest FSH levels on baseline testing were included. Donor/Recipient and frozen embryo cycles were excluded from this study. Prognostic factors evaluated in association with clinical pregnancy rates were type of infertility diagnosis and IVF stimulation parameters. Results The current study found that factors associated with clinical pregnancy were: increased number of mature follicles on the day of triggering, number of oocytes retrieved, number of Metaphase II oocytes if intracytoplasmic sperm injection was done, and number of embryos developed 24 hours after retrieval. Conclusions Our findings suggest that it would be beneficial for women with increased FSH levels to attempt a cycle of IVF. Results of ovarian stimulation, especially embryo quantity appear to be the best predictors of IVF outcomes and those can only be obtained from a cycle of IVF. Therefore, increased basal FSH levels should not discourage women from attempting a cycle of IVF.