Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome?

OBJECTIVE: To investigate whether the duration of estrogen administration before euploid embryo transfer affects clinical outcome. DESIGN: Retrospective cohort study. SETTING: Private, academic fertility center. PATIENT(S): Patients (n = 1,439) undergoing autologous freeze-only in vitro fertilization with preimplantation genetic testing (PGT) followed by endometrial preparation with estrogen and progesterone in a frozen, euploid blastocyst transfer cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome was live birth, and secondary outcomes included implantation, clinical pregnancy, early pregnancy loss, live birth, infant birthweight, low birth weight, infant gestational age at delivery, and preterm birth. RESULT(S): The duration of estrogen administration (mean: 17.5 ± 2.9 days; range: 10-36 days) before frozen embryo transfer did not impact implantation (odds ratio [OR] 0.99; 95% confidence interval [CI], 0.95-1.03), clinical pregnancy (OR 0.98; 95% CI, 0.94-1.01), early pregnancy loss (OR 1.03; 95% CI, 0.95-1.12), or live birth (OR 0.99; 95% CI, 0.95-1.03). The duration of estrogen exposure did not affect infant birthweight (in grams) (ß= -10.65 ± 8.91) or the odds of low birth weight (OR 0.87; 95% CI, 0.68-1.13). For every additional day of estrogen administration, we observed a reduction in gestational age at delivery (in weeks) (ß= -0.07 ± 0.03), but the odds of preterm delivery were not affected (OR 1.05; 95% CI, 0.95-1.17). CONCLUSION(S): Variation in the duration of estradiol supplementation before progesterone initiation does not impact frozen, euploid blastocyst transfer outcome. The duration of estrogen administration was inversely correlated with gestational age at delivery, but this did not translate into an increase in preterm delivery. Further studies are required on the downstream effects of endometrial preparation on the placental-endometrium interface.

Reproductive outcome is optimized by genomic embryo screening, vitrification, and subsequent transfer into a prepared synchronous endometrium.

PURPOSE: The aim of this study is to compare implantation and live birth rates (LBR) between fresh euploid embryo transfers versus cryo-all cycles with a subsequent embryo transfer into a prepared endometrium. MATERIAL AND METHODS: This is a retrospective cohort study. Patients who underwent an IVF cycle with PGS with trophectoderm biopsy from January 2011 to July 2015 were included. Patients were divided into three groups: "Fresh Only," "Frozen Embryo Transfer ('FET) Only," and "Fresh ET then FET." For "Fresh Only" group (n = 345), PGS results were received within 24 h. For "FET Only" group (n = 514), results were expected after 24 h, and embryos were cryopreserved after biopsy; only FET was performed in this group (no fresh transfer). For "FET with a previous fresh ET" (n = 139) group, patients underwent a fresh ET with a subsequent FET, in which the same cohort of embryos was utilized. The main outcome measures were pregnancy rate (PR), clinical PR, implantation rate (IR), LBR, and early pregnancy loss rate. RESULTS: IRs were statistically higher in the "FET Only" group when compared to the "Fresh Only" group (59.5 vs. 50.6%, p < 0.01) and the "FET with a previous fresh ET" (59.5 vs. 50.6%, p < 0.05). LBR was statistically significant in the "FET Only" group when compared to the "Fresh Only" group (57.6 vs. 46.5 %, p < 0.005) but not when compared to "FET with a previous fresh ET" group (57.6 vs. 47.7%, p = 0.07). CONCLUSIONS: This analysis suggests euploid embryos to be more likely to implant and achieve a LBR in a synthetic FET cycle than in a fresh cycle.

Maximum basal FSH predicts reproductive outcome better than cycle-specific basal FSH levels: waiting for a "better" month conveys limited retrieval benefits.

BACKGROUND: Elevated follicle stimulating hormone (FSH) is associated with poor vaginal oocyte retrieval (VOR) outcomes and cycle cancellations but intercycle variability in basal FSH reportedly does not predict ovarian response. METHODS: We conducted a retrospective cohort study of basal FSH (n = 15573 cycles) in couples (n = 9132) who initiated IVF cycle(s) with basal estradiol (E2) <100 pg/mL between 2002 and 2014 to reevaluate this hypothesis. The most recent (current) FSH, maximum FSH (Max FSH) and prior cycle maximum basal FSH (PMax FSH) were computed for each cycle. Metaphase II (MII) oocyte counts were modeled by age, stimulation type, prior peak E2 level, prior MII count, Max FSH, PMax FSH and current FSH. Antral follicle counts, pregnancy, clinical pregnancy and live birth rates were modeled as secondary outcomes. RESULTS: Max FSH level distinguished completed cycles from cancelled cycles better than PMax FSH or current FSH (AUC of 0.72, 0.71 and 0.61, respectively, p < 0.001). Fewer MIIs were retrieved (5.7 ± 3.8) in cycles with Max FSH >13 mIU/mL (n = 1475) than those with ≤13 mIU/mL (n = 11978) (11.6 ± 7.1) (p < 0.001). Max FSH was a better predictor of MII count than PMax FSH or current FSH after controlling for age, stimulation type, prior peak E2 level and prior MII count. Additional MIIs were retrieved on average in cycles with PMax FSH >13 mIU/mL (n = 1930) whose current FSH was ≤13 mIU/ml rather than >13 mIU/ml (p < 0.01) after controlling for age, cycle number and stimulation type. However, no improvement in pregnancy or live birth rate was detected. CONCLUSIONS: Max FSH is the best FSH-based predictor of ovarian reserve. Retrieval benefits from waiting for a "better" month appear to exist but are limited.

Endometrial pattern, but not endometrial thickness, affects implantation rates in euploid embryo transfers.

OBJECTIVE: To evaluate the relationship of endometrial thickness (EnT) and endometrial pattern (EnP) to euploid embryo transfer (ET) outcomes. DESIGN: Retrospective cohort. SETTING: Private academic clinic. PATIENT(S): Patients (n = 277; age 36.1 ± 4.0 years) whose embryos (n = 476) underwent aneuploidy screening with fresh (n = 176) or frozen (n = 180) ET from July 2010 to March 2014. INTERVENTION(S): The EnT and EnP were measured on trigger day and at ET. Patients were stratified by age and cycle type (fresh or frozen). Cycle data were combined at trigger day, but separated at ET day. MAIN OUTCOME MEASURE(S): Outcome measures were implantation rate, pregnancy rate, and clinical pregnancy rate. Analysis was conducted using χ(2) analysis and Fisher's exact test. RESULT(S): A total of 234 gestational sacs, 251 pregnancies, and 202 clinical pregnancies resulted from 356 cycles. The EnT (9.6 ± 1.8 mm; range: 5-15 mm) at trigger day (n = 241 cycles), as a continuous or categorical variable (≤8 vs. >8 mm), was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. The EnT at day of fresh ET (9.7 ± 2.2 mm; range: 4.4-17.9 mm) (n = 176 cycles) or frozen ET (9.1 ± 2.1 mm; range: 4.2-17.7 mm) (n = 180 cycles) was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. Type 3 EnP at trigger day was associated with increased serum progesterone at trigger and a decreased implantation rate, compared with type 2 EnP. The EnP at fresh or frozen ET was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. CONCLUSION(S): Within the study population, EnT was not significantly associated with clinical outcomes of euploid ETs. A type 3 EnP at trigger day suggests a prematurely closed window of implantation.

In-vitro maturation of germinal vesicle and metaphase I eggs prior to cryopreservation optimizes reproductive potential in patients undergoing fertility preservation.

PURPOSE OF REVIEW: To evaluate current and previous findings related to a timely implementation of in-vitro maturation (IVM) of germinal vesicle, metaphase I and metaphase II oocytes with an optimal cryopreservation to determine whether IVM should be attempted prior to (fresh IVM) or IVM after cryopreservation (postthaw IVM). Mitochondrion, chromatin and spindle formation in both groups were interpreted from referenced studies to establish best management of all oocytes. RECENT FINDINGS: The postthaw survival of germinal vesicle, metaphase I, fresh IVM-metaphase II and control metaphase II oocytes did not differ significantly [83.3% (n=9), 86.7% (n=12), 83% (n=57) and 86% (n=68), respectively]. Overall, combined survival and maturation were significantly higher (P<0.05) in the fresh IVM group at 63.8% (44 of 69) compared with the postthaw IVM group at 33.3% (nine of 27). SUMMARY: Conservation of retrieved immature oocytes after vaginal oocyte retrieval has become a major concern for patients, as they strive to maximize the reproductive viability of all oocytes obtained during treatment. Oocyte cryopreservation is important for patients at risk of ovarian cancer, elective fertility preservation and potentially for ovum donation. The superior maturation rate of germinal vesicle and metaphase I oocytes in the fresh IVM vs. postthaw groups provides strong impetus to mature oocytes to the metaphase II stage prior to cryopreservation.

Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved?

PURPOSE: To determine if patients with a low response to controlled ovarian hyperstimulation during IVF benefit from intracytoplasmic sperm injection (ICSI) METHODS: Retrospective analysis of 350 IVF cycles in which four or fewer oocytes were retrieved. Severe male factor cases were excluded from analysis. Conventional insemination (CI) and ICSI were compared, with primary outcome measures of fertilization rate, implantation rate, clinical pregnancy rate per embryo transfer, and pregnancy loss rate. RESULT(S): Fertilization rates per oocyte retrieved for CI and ICSI were comparable (51.5% vs. 51.8%). Parallel implantation rates (22% vs. 25%), clinical pregnancy rates (32.8% vs. 33.3%), and loss rates (26.7% vs. 39.5%) were also noted. No difference in cancelled cycles was reported. CONCLUSION(S): Our results demonstrate that in the presence of normal semen parameters, low egg number is not an indication to perform ICSI.

Parental karyotype may reveal the source of a pregnancy loss even in the presence of a reportedly euploid fetal karyotype.

OBJECTIVE: To present a case of a fetal loss in which a normal fetal karyotype was obtained by banding studies. Identification of an abnormal maternal karyotype prompted subsequent reanalysis using fluorescence in situ hybridization (FISH). DESIGN: Case report. SETTING: University-affiliated IVF center. PATIENT(S): A 32-year-old woman, G1 P0, underwent a fetal loss at 8 weeks, and a suction curettage was performed. The patient had a previous first-trimester loss. INTERVENTION(S): The fetal tissue was evaluated by banding studies and found to be normal. Parental karyotyping was performed, and the fetal tissue was reanalyzed by FISH. MAIN OUTCOME MEASURE(S): Analysis of fetal karyotype by targeted FISH. RESULT(S): Maternal karyotype demonstrated a translocation [46,XX, t(8;10)(q24.3:q25.2)]. The fetal tissue was reanalyzed by FISH, and a segment of chromosome 10 was found on chromosome 8. CONCLUSION(S): A normal fetal karyotype, as measured by banding, does not exclude a genetic etiology for pregnancy loss. In this case, maternal translocation prompted the genetics laboratory to search for a small segment of translocated extra chromosomal material. This demonstrated that despite the finding of a normal fetal karyotype, in some cases parental karyotyping may have value.

Paternal age and assisted reproductive technology outcome in ovum recipients.

This study suggests that paternal age may be inversely associated with reproductive outcome, as demonstrated by a decline in fertilization, blastocyst formation, implantation and cryopreservation rates with advancing age.

Redefining in vitro fertilization success: should triplets be considered failures?

OBJECTIVE: To evaluate how the ranking of IVF programs changes if high-order multiple pregnancies (HOMPs) are considered negative outcomes. DESIGN: Retrospective analysis. SETTING: The 2004 Society for Assisted Reproductive Technology Clinic Outcome Reporting System. PATIENT(S): Two hundred seven programs that performed >50 IVF cycles were analyzed, and only patients 2.4 embryos decreased, as opposed to the programs that transferred fewer embryos (1.8-2.4). CONCLUSION(S): Reclassifying HOMPs as failed cycles will result in a reduced rank in programs that maintain high embryo replacements. Redefining success as a singleton or twin birth significantly changes the ranking order of programs and, potentially, how programs are perceived.

Moderately elevated levels of basal follicle-stimulating hormone in young patients predict low ovarian response, but should not be used to disqualify patients from attempting in vitro fertilization.

OBJECTIVE: To evaluate and compare IVF outcomes of patients within different age categories who had a normal basal FSH level with outcomes of patients with an elevated day 3 FSH level. DESIGN: Retrospective analysis. SETTING: Large, private IVF center. PATIENT(S): We analyzed 2,708 patients. Of these, 2,477 had normal basal FSH levels, and 231 had elevated basal FSH levels (> or =13.03 IU/L). Patients were segregated into various age groups. INTERVENTION: Follow-up. MAIN OUTCOME MEASURE(S): Outcomes of IVF overall, including cancellation rates, oocyte yield, and fertilization, implantation, and clinical pregnancy rates (PRs). RESULT(S): Cancellation rates were significantly higher in patients with elevated day 3 FSH levels compared with patients with normal FSH levels in all age groups. A significantly lower oocyte yield was observed in patients with elevated basal FSH. Fertilization rates were not affected by FSH levels. A significant decrease in the number of embryos available for transfer in patients > or =38 with an elevated day 3 FSH level was found. Implantation and clinical PRs were lower in patients >40 years of age who had an elevated day 3 FSH level when compared to same age patients with a normal day 3 FSH level. Loss rates were not significantly different. CONCLUSION(S): Young women with an elevated basal FSH level should be counseled differently than older women, and should be given adequate counseling and granted the opportunity to undergo an IVF cycle.

Report of four donor-recipient oocyte cryopreservation cycles resulting in high pregnancy and implantation rates.

OBJECTIVE: To determine the clinical potential of donor-oocyte cryopreservation and thaw techniques for recipient patients. DESIGN: Institutional review board-approved prospective study of donor oocyte cryopreservation. SETTING: A large, private infertility center. PATIENT(S): Four anonymous oocyte donors underwent ovarian hyperstimulation for the purpose of oocyte retrieval and cryopreservation. The oocytes were subsequently thawed, fertilized, and transferred to 4 recipient patients. INTERVENTION(S): Oocytes were obtained from young donor patients and were cryopreserved with a slow freeze/rapid thaw protocol in which 1,2-propanediol (PrOH) and sucrose were used as cryoprotectants. Oocytes that survived were inseminated using intracytoplasmic sperm injection (ICSI). Resulting embryos were replaced into the recipient patients on the third day post-insemination. MAIN OUTCOME MEASURE(S): Post-thaw survival rate, fertilization rate, cleavage rate, implantation and clinical pregnancy rates. RESULT(S): A total of 79 metaphase II oocytes were frozen, stored frozen overnight in liquid nitrogen, and then thawed. The post-thaw survival rate was 86.1%. Normal fertilization following ICSI occurred in 89.7% of the surviving oocytes. Cleavage was observed in 91.8% of normally fertilized oocytes. A total of 23 embryos were transferred to 4 recipient patients. A clinical pregnancy rate of 75% and an implantation rate of 26.1% were achieved. CONCLUSION(S): Human oocyte cryopreservation is an effective technique that can be applied in clinical situations with high oocyte survival and clinical pregnancy rates expected.

Blastocyst embryo transfer is associated with a sex-ratio imbalance in favor of male offspring.

OBJECTIVE: To evaluate the sex ratio of offspring born after blastocyst transfers. DESIGN: Retrospective data analysis. SETTING: A large assisted reproductive technology center. PATIENT(S): We included 1,284 offspring from 937 deliveries during the period August 2003-August 2005. INTERVENTION(S): Tabulation and statistical analysis of all births resulting from fresh IVF cycles. The sex of resulting offspring was compared in both day 3 and blastocyst transfers for all births and for singleton deliveries. In addition, the sex of children conceived with the use of autologous oocytes and donor oocytes was evaluated. MAIN OUTCOME MEASURE: Sex ratio of offspring born following embryo transfers (ETs) after day 3 of culture and sequential blastocycst culture. RESULT(S): The overall sex ratio was significantly shifted toward males when blastocyst transfers were performed. Blastocyst transfers with only the use of autologous oocytes resulted again in a significantly higher proportion of male offspring. An even greater proportional difference was encountered in singleton offspring from donor oocytes. However, significance was not reached because of the limited number of offspring in the subgroup. CONCLUSION(S): This is the first individual-center report of a significant sex-ratio imbalance after the sequential media culture of blastocysts. The large imbalance in singleton births associated with the use of donor oocytes, although not significant, is cautionary in regard to the use of elective single ETs. Observation and publication of phenomena such as the effects of extended culture on the sex ratio of live-borns will allow us a better understanding of early differences in sexual dimorphism of the embryo, and will allow us to counsel our patients more appropriately.