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.

Predicting pregnancy in women undergoing in-vitro fertilization with basal serum follicle stimulating hormone levels between 10.0 and 11.9 IU/L.

OBJECTIVE: To evaluate the results of the in vitro fertilization (IVF) cycle outcomes in women whose borderline basal follicle stimulating hormone (FSH) levels were between 10.0 and 11.9 IU/L and to analyze the predictors of pregnancy in this population. MATERIAL AND METHODS: A prospective cohort study was performed at an academic teaching hospital; participants were infertile couples in which the women were undergoing IVF treatment and had borderline basal highest FSH levels between 10.0 and 11.9 IU/L. Statistical modeling was performed to determine risk factors for pregnancy and clinical pregnancy. RESULTS: A clinical pregnancy rate of 26.5% per cycle and 35% per patient was found in the study population. Among all subjects and non-intracytoplasmic sperm injection (ICSI) subjects, younger age, higher gravidity, higher number of mature follicles on day of Human Chorionic gonadotrophin (hCG) triggering, higher number of oocytes retrieved, and number of embryos produced were significant discriminators between individuals who conceived and those who did not. However, only the number of embryos predicted those who had a clinical pregnancy when compared with those who did not. Higher gravidity, and basal estradiol (E2) levels, and lower maximum basal FSH levels predicted clinical pregnancy in non-ICSI patients. Among ICSI patients, the only predictor of pregnancy was a thicker endometrium. A trend towards higher pregnancy rates was noted in ICSI patients. CONCLUSION: We showed that pregnancy rates per cycle and per patient in this population were not significantly different than those in patients with a basal FSH level below 10.0 IU/L. Preliminary evidence suggests that ICSI is the fertilization method of choice in these patients.

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, IVF(BT), 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 approximately 83% of C1 and approximately 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.

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 beta-human chorionic gonadotropin (beta-hCG). IVF cycle outcomes were most accurately predicted at approximately 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 frozen compared with fresh blastocyst transfer.

OBJECTIVE: To compare the rate of ectopic pregnancy (EP) with fresh versus frozen blastocyst transfer in our program during the same time period. DESIGN: Retrospective analysis. SETTING: University IVF program. PATIENT(S): Women who achieved a clinical pregnancy after IVF between 1998 and 2005. INTERVENTION(S): In our program, cryopreservation is performed at the blastocyst stage. Embryo transfer was performed 1 to 1.5 cm short of the fundus by abdominal ultrasound guidance. MAIN OUTCOME MEASURE(S): The incidence of EP was examined in relation to fresh versus frozen blastocyst transfer. RESULT(S): In the frozen blastocyst group, there were 5 EPs out of 180 clinical pregnancies (2.8%), and there were 10 EPs out of 564 clinical pregnancies (1.8%) in the fresh blastocyst group. CONCLUSION(S): The rate of EP is not significantly increased after the transfer of frozen thawed blastocysts compared with fresh blastocyst transfer.

Benefit of intracytoplasmic sperm injection in patients with a high incidence of triploidy in a prior in vitro fertilization cycle.

OBJECTIVE: To test the hypothesis that intracytoplasmic sperm injection (ICSI) overcomes a high incidence of tripronucleate zygotes resulting from standard insemination in a previous cycle. DESIGN: A retrospective analysis of matched-pair cycles. SETTING: Assisted reproductive technologies (ART) program of Brigham and Women's Hospital. PATIENT(S): Ninety-five patients with a > or = 20% incidence of tripronucleate zygotes in an IVF cycle with use of ICSI in a subsequent attempt. INTERVENTION(S): Cycles with either standard insemination or ICSI. MAIN OUTCOME MEASURE(S): Incidence of diploid (2pn) and triploid (3pn) zygotes and number and quality of embryos obtained. RESULT(S): Patient age, ampules of gonadotropin used, peak E2, number of follicles at hCG trigger, and total number of oocytes were all significantly higher in the ICSI cycles, but the number of mature oocytes did not differ. After ICSI, the percentage of 2pn was higher (65.0% vs. 34.1%) and the percentage of 3pn was lower (5.0% vs. 33.9%) than after IVF, and more diploid embryos were obtained with ICSI (5.5 +/- 3.7 vs. 3.4 +/- 2.2 [mean +/- SD]). There was no difference in embryo quality between the two groups. CONCLUSION(S): ICSI appears beneficial in women with a high 3pn occurrence from IVF because it increases the number of diploid zygotes without affecting embryo quality.

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.

Assisted hatching is associated with a higher ectopic pregnancy rate.

In a retrospective analysis of 623 clinical pregnancies conceived after IVF, a 5.4% ectopic pregnancy rate (14/258 clinical pregnancies) was found in cases where assisted hatching (AH) was performed compared to 2.2% (8/365) in the group without assisted hatching. In view of the widespread use of AH, it may be relevant to assess the effect of AH on the incidence of ectopic pregnancy in a large multicenter effort.

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.

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

BACKGROUND: Blastocyst 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. METHODS: A 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. RESULTS: There 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). CONCLUSIONS: Our 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.

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

PURPOSE: 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.

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.