Planned oocyte cryopreservation: the state of the ART.

The objective of this review is to provide an update on planned oocyte cryopreservation. This fertility preservation method increases reproductive autonomy by allowing women to postpone childbearing whilst maintaining the option of having a biological child. Oocyte cryopreservation is no longer considered experimental, and its use has increased dramatically in recent years as more women delay childbearing for personal, professional and financial reasons. Despite increased usage, most patients who have undergone oocyte cryopreservation have not yet warmed their oocytes. Most women who cryopreserve oocytes wait years to use them, and many never use them. Studies have demonstrated that oocyte cryopreservation results in live birth rates comparable with IVF treatment using fresh oocytes, and does not pose additional safety risks to offspring. Based on current evidence, cryopreserving ≥20 mature oocytes at <38 years of age provides a 70% chance of one live birth. However, larger studies from a variety of geographic locations and centre types are needed to confirm these findings. Additional research is also needed to determine the recommended age for oocyte cryopreservation, recommended number of oocytes to cryopreserve, return and discard/non-use rates, cost-effectiveness, and how best to distribute accurate and up-to-date information to potential patients.

Fifteen years of autologous oocyte thaw outcomes from a large university-based fertility center.

OBJECTIVE: To review the outcomes of patients who underwent autologous oocyte thaw after planned oocyte cryopreservation. DESIGN: Retrospective cohort study. SETTING: Large urban university-affiliated fertility center. PATIENT(S): All patients who underwent ≥1 autologous oocyte thaw before December 31, 2020. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was the final live birth rate (FLBR) per patient, and only patients who had a live birth (LB) or consumed all remaining inventory (cryopreserved oocytes and resultant euploid/untested/no result embryos) were included. The secondary outcomes were laboratory outcomes and LB rates per transfer. RESULT(S): A total of 543 patients underwent 800 oocyte cryopreservations, 605 thaws, and 436 transfers. The median age at the first cryopreservation was 38.3 years. The median time between the first cryopreservation and thaw was 4.2 years. The median numbers of oocytes and metaphase II oocytes (M2s) thawed per patient were 14 and 12, respectively. Overall survival of all thawed oocytes was 79%. Of all patients, 61% underwent ≥1 transfer. Among euploid (n = 262) and nonbiopsied (n = 158) transfers, the LB rates per transfer were 55% and 31%, respectively. The FLBR per patient was 39%. Age at cryopreservation and the number of M2s thawed were predictive of LB; the FLBR per patient was >50% for patients aged <38 years at cryopreservation or who thawed ≥20 M2s. A total of 173 patients (32%) have remaining inventory. CONCLUSION(S): Autologous oocyte thaw resulted in a 39% FLBR per patient, which is comparable with age-matched in vitro fertilization outcomes. Studies with larger cohorts are necessary.

Planned oocyte cryopreservation-10-15-year follow-up: return rates and cycle outcomes.

OBJECTIVE: To evaluate the outcomes of planned oocyte cryopreservation patients most likely to have a final disposition. DESIGN: Retrospective cohort study of all patients who underwent at least 1 cycle of planned oocyte cryopreservation between Jan 2005 and December 2009. SETTING: Large urban University-affiliated fertility center PATIENT(S): All patients who underwent ≥1 cycle of planned oocyte cryopreservation in the study period. INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Primary outcome was the disposition of oocytes at 10-15 years. Secondary outcomes included thaw/warming types, laboratory outcomes, and live birth rates. Outcomes and variables treated per patient. RESULT(S): A total of 231 patients with 280 cycles were included. The mean age at the first retrieval was 38.2 years (range 23-45). A total of 3,250 oocytes were retrieved, with an average of 10 metaphase II frozen/retrieval. To date, the oocytes of 88 patients (38.1%) have been thawed/warmed, 109 (47.2%) remain in storage, 27 (11.7%) have been discarded, and 7 (3.0%) have been transported elsewhere. The return rate (patients who thawed/warmed oocytes) was similar by Society for Assisted Reproductive Technology age group. The mean age of patients discarding oocytes was 47.4 years (range, 40-57). Of the 88 patients who thawed/warmed oocytes, the mean age at the time of thaw/warming was 43.9 years (range, 38-50) with a mean of 5.9 years frozen (range, 1-12). Nine patients (10.2%) thawed/warmed for secondary infertility. A total of 62.5% of patients created embryos with a partner, and 37.5% used donor sperm. On average, 14.3 oocytes were thawed/warmed per patient, with 74.2% survival (range, 0%-100%) and a mean fertilization rate of 68.8% of surviving oocytes. Of 88 patients, 39 (44.3%) planned a fresh embryo transfer (ET); 36 of 39 patients had at least 1 embryo for fresh ET, and 11 had a total of 14 infants. Forty-nine of 88 patients (55.7%) planned for preimplantation genetic testing for aneuploidy, with a mean of 4.2 embryos biopsied (range, 0-14) and a euploidy rate of 28.9%. Of the 49 patients, 17 (34.7%) had all aneuploidy or no embryos biopsied. Twenty-four patients underwent a total of 36 single euploid ET with 18 live births from 16 patients. Notably, 8 PGT-A patients had a euploid embryo but no ET, affecting the future cumulative pregnancy rate. Overall, 80 patients with thaw/warming embryos had a final outcome. Of these, 20 had nothing for ET (arrested/aneuploid), and of the 60 who had ≥1 ET, 27 had a total of 32 infants, with a live birth rate of 33.8% (27/80). CONCLUSION(S): We report the final outcomes of patients most likely to have returned, which is useful for patient counseling: a utilization rate of 38.1% and a no-use rate of 58.9%, similar across age groups. Further studies with larger cohorts as well as epidemiologic comparisons to patients currently cryopreserving are needed.

Pregnancy Outcomes After Fertility Preservation in Transgender Men.

BACKGROUND: Transgender individuals, individuals whose gender identity does not align with their sex assigned at birth, undergoing gender-affirming hormonal or surgical therapies may experience loss of fertility. Assisted reproductive technologies have expanded family-building options for transgender men who were assigned female at birth. CASES: Three transgender men underwent oocyte cryopreservation before gender-affirming hormonal therapy. One patient underwent fertility preservation as an adolescent. Two adult patients had children using their cryopreserved oocytes, with the pregnancies carried by their sexually intimate partners. CONCLUSION: Transgender men with cryopreserved gametes can build families in a way that affirms their gender identity. Obstetrician-gynecologists should be familiar with the fertility needs of transgender patients so appropriate discussions and referrals can be made.

Preimplantation Genetic Diagnosis (PGD) for Monogenic Disorders: the Value of Concurrent Aneuploidy Screening.

Pre-implantation genetic diagnosis (PGD) has changed the landscape of clinical genetics by helping families reduce the transmission of monogenic disorders. However, given the high prevalence of embryonic aneuploidy, particularly in patients of advanced reproductive age, unaffected embryos remain at high risk of implantation failure or pregnancy loss due to aneuploidy. 24-chromosome aneuploidy screening has become widely utilized in routine in vitro fertilization (IVF) to pre-select embryos with greater pregnancy potential, but concurrent 24-chromosome aneuploidy screening has not become standard practice in embryos biopsied for PGD. We performed a retrospective cohort study of patients who underwent PGD with or without 24-chromosome aneuploidy screening to explore the value of concurrent screening. Among the PGD + aneuploidy-screened group (n = 355 blastocysts), only 25.6 % of embryos were both Single Gene Disorder (SGD)-negative (or carriers) and euploid; thus the majority of embryos were ineligible for transfer due to the high prevalence of aneuploidy. Despite a young mean age (32.4 ± 5.9y), 49.9 % of Blastocysts were aneuploid. The majority of patients (53.2 %) had ≥1 blastocyst that was Single Gene Disorder (SGD)-unaffected but aneuploid; without screening, these unaffected but aneuploid embryos would likely have been transferred resulting in implantation failure, pregnancy loss, or a pregnancy affected by chromosomal aneuploidy. Despite the transfer of nearly half the number of embryos in the aneuploidy-screened group (1.1 ± 0.3 vs. 1.9 ± 0.6, p < 0.0001), the implantation rate was higher (75 % vs. 53.3 %) and miscarriage rate lower (20 % vs. 40 %) (although not statistically significant). 24-chromosome aneuploidy screening when performed concurrently with PGD provides valuable information for embryo selection, and notably improves single embryo transfer rates.

Deliveries from trophectoderm biopsied, fresh and vitrified blastocysts derived from polar body biopsied, vitrified oocytes.

This longitudinal study reports preliminary findings of six patients who underwent first polar body biopsy followed by oocyte vitrification. All oocytes were warmed, inseminated by intracytoplasmic sperm injection and cultured to blastocyst. All suitable blastocysts underwent trophectoderm biopsy for aneuploidy screening, and supernumerary blastocysts were vitrified. Euploid blastocysts were transferred either fresh or in a subsequent programmed cycle. Of the 91 metaphase II oocytes, 30 had euploid first polar bodies. Development to blastocyst was more likely in oocytes with a euploid first polar body (66.7% versus 24.6%; P < 0.001). Nineteen euploid blastocysts were produced: 10 from oocytes with a euploid first polar body and nine from oocytes with an aneuploid first polar body. Five out of six patients (83%) had a live birth or ongoing pregnancy at the time of analysis. Eleven euploid blastocysts have been transferred and seven implanted (64%). Although the chromosomal status of the first polar body was poorly predictive of embryonic ploidy, an association was found between chromosomal status of the first polar body and development to blastocyst. Further study is required to characterize these relationships, but proof of concept is provided that twice biopsied, twice cryopreserved oocytes and embryos can lead to viable pregnancies.

Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing.

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼ 100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.

Changing ovarian stimulation parameters in a subsequent cycle does not increase the number of euploid embryos.

OBJECTIVE: To compare the euploidy outcome in patients that underwent 2 ovarian stimulation cycles with trophectoderm biopsy. DESIGN: Retrospective repeated-measures cohort study. SETTING: University-based fertility center. PATIENT(S): A total of 116 patients, from 2011 through 2013, that underwent 2 ovarian stimulation cycles followed by trophectoderm biopsy with array comparative genomic hybridization. INTERVENTION(S): Days of stimulation, average diameter of the 2 lead follicles on day of trigger, dose of gonadotropins, type of cycle (gonadotropin-releasing hormone [GnRH] antagonist, GnRH-antagonist plus clomiphene citrate [CC], microdose GnRH agonist). MAIN OUTCOME MEASURE(S): Number of euploid embryos. RESULT(S): Patients were analyzed based on whether they had ≥1 euploid embryos in their first cycle vs. none. There was no increase in the number of euploid embryos with more days of stimulation or increases in the dose of gonadotropins in either group. Significantly more euploid embryos were seen in patients who had no euploid embryo(s) in the first cycle (Group 0) that had CC added to a GnRH-antagonist cycle (1.11 more euploid embryos) or were triggered when follicle sizes were 2 mm larger (0.40 euploid embryos), but these increases were not significant compared with a control group. Patients with euploid embryo(s) in the first cycle (Group 1) had significantly more euploid embryos when daily dose was increased by 75-149 international units, but this relationship was not significant compared with a control group with no increase in daily dose. CONCLUSION(S): No specific intervention increased the number of euploid embryos within the same patient any more than simply repeating a similar stimulation cycle. An attempt was made to control for interpatient variability, but individual patients have considerable intercycle variability.

Live birth from previously vitrified oocytes, after trophectoderm biopsy, revitrification, and transfer of a euploid blastocyst.

Our objective is to describe a successful live birth from oocyte vitrification followed by thaw, fertilization, blastocyst culture, trophectoderm biopsy, vitrification, and subsequent thaw. Fifteen mature oocytes were frozen from a patient with uterine factor infertility. Thirteen oocytes survived the thaw, and five underwent trophectoderm biopsy and were refrozen. Three euploid embryos were obtained. A single euploid embryo was transferred in the second thaw cycle to a known recipient leading to the delivery of a normal male infant. This case report is proof of the concept that preimplantation screening and diagnosis is an option for fertility preservation patients.

Supernumerary blastocyst cryopreservation: a key prognostic indicator for patients opting for an elective single blastocyst transfer (eSBT).

OBJECTIVE: To determine if patients, less than 40 years of age with or without day 5 cryopreservation (d5 cryo), compromise their pregnancy rate (PR) by choosing an eSBT. DESIGN: Retrospective analysis SETTING: University IVF center PATIENTS: 2,203 non-donor fresh IVF cycles in women <40 years of age from January 2004 to January 2010. INTERVENTIONS: None MAIN OUTCOME MEASURE(S): Eggs retrieved, Embryos cryopreserved, Implantation Rates, Clinical Pregnancy Rates, Live Birth Rates, Spontaneous Abortion Rates RESULTS: Pregnancy outcomes in women <40 years with or without d5 cryo were compared according to whether patients underwent an eSBT versus a 2BT in non-donor fresh IVF cycles. Overall, eSBT was associated with elimination of twinning while maintaining a high clinical pregnancy rate in both groups with d5 cryo (75 % eSBT versus 72 % 2BT) and groups without d5 cryo (48 % eSBT versus 56 % 2BT). CONCLUSIONS: In this study, patients <40 years of age have eliminated twinning by electively choosing to transfer a single blastocyst without compromising their PR if embryos are available for d5 cryo, and suffer only a non-statistically significant drop in their PR if there are no embryos available for d5 cryo in exchange for the benefit of eliminating the obstetrical risk of twinning.

Is intracytoplasmic sperm injection overused?

PURPOSE: We determined whether the use of intracytoplasmic sperm injection in couples who previously underwent intracytoplasmic sperm injection cycles elsewhere could be decreased without compromising the pregnancy rate. MATERIALS AND METHODS: At our university in vitro fertilization-embryo transfer center we retrospectively analyzed the records of 149 fresh, in vitro fertilization-embryo transfer cycles in patients who underwent intracytoplasmic sperm injection elsewhere and subsequent fertilization by insemination only (all insemination group) or half insemination and half intracytoplasmic sperm injection at our center. We compared fertilization, implantation, clinical pregnancy and live birth rates. RESULTS: The fertilization rate was 74% and 73% for the all insemination and the half intracytoplasmic sperm injection groups, respectively. In the latter group 69% of inseminated and 78% of intracytoplasmic sperm injected oocytes were fertilized. No cycle showed complete fertilization failure. No statistically significant difference in the live birth rate was found between the 2 groups. CONCLUSIONS: More stringent criteria for intracytoplasmic sperm injection do not compromise the clinical outcome and reasonable fertilization can be achieved whether or not intracytoplasmic sperm injection is performed. Thus, although intracytoplasmic sperm injection is one of the greatest advances in our field, it is overused and should only be done for clinically proven indications.

Effect of autoimmune thyroid disease in older euthyroid infertile woman during the first 35 days of an IVF cycle.

In this case-control study of euthyroid first-cycle IVF patients ≥ 38 years old with singleton baby, miscarriage, biochemical pregnancy, and no pregnancy outcomes from 2005-2008, we assayed frozen serum for autoimmune thyroid disease (AITD) and thyroid function at cycle start, trigger, and 4 and 5 weeks' gestation. AITD prevalence in older infertile women was similar across clinical outcomes, and although AITD was associated with a higher baseline TSH, TSH remained within acceptable ranges, suggesting that T(4) supplementation may not affect maternal outcomes in older euthyroid AITD patients through 5 weeks gestation.

Evaluating the necessity for universal screening of prospective oocyte donors using enhanced genetic and psychological testing.

BACKGROUND: To minimize the potential for harmful inheritable conditions, donors are rigorously screened according to standard guidelines, yet such guidelines may not be sufficient to exclude egg donors with certain known inheritable conditions. We compared universal screening of oocyte donors with Tay-Sachs, Fragile X, karyotype and Minnesota Multiphasic Personality Inventory-2 (MMPI-2) versus standard American Society of Reproductive Medicine (ASRM) guidelines that do not include such testing. METHODS: In this 12 year retrospective cohort study, results of enhanced universal screening of all anonymous oocyte donor candidates from 1997 to 2008 at a university hospital oocyte donation program were reviewed. Primary outcomes were the frequency of oocyte donor candidates excluded as a result of enhanced universal screening (Tay-Sachs, Fragile X, karyotypic analysis and MMPI-2) versus basic screening according to ASRM guidelines. RESULTS: Of 1303 candidates who underwent on-site evaluation, 47% passed the screening process, 23% were lost to follow-up and 31% were excluded. Genetic and psychological factors accounted for the most common reasons for candidate exclusion. Enhanced genetic screening excluded an additional 25 candidates (19% of all genetic exclusions) and enhanced psychological screening excluded an additional 15 candidates (12% of all psychological exclusions). Altogether enhanced screening accounted for 40 candidates (10%) of the total pool of excluded candidates. CONCLUSIONS: Although our study is limited by its retrospective nature and center-specific conclusions, we show that enhanced comprehensive screening can exclude a significant number of candidates from an oocyte donor program and should be encouraged to assure optimal short-term and long-term outcomes for pregnancies achieved through oocyte donation.

Fate of cryopreserved donor embryos.

OBJECTIVE: To review a center's experience with cryopreserved embryos generated from donor eggs and to analyze their long-term disposition. DESIGN: Retrospective analysis of donor egg cycles with cryopreserved embryos. SETTING: University-based IVF program. PATIENT(S): Eight hundred twenty-nine women undergoing oocyte donation. INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): Factors affecting the decision regarding disposition of donor frozen embryo transfer (dFET) and the association between fresh and dFET cycles. RESULT(S): From January 2000 to December 2004, donor egg recipients underwent 829 fresh embryo transfer cycles that resulted in a 54% live birth rate. Of the 444 recipients who delivered, 177 (40%) also cryopreserved embryos at transfer; however, only 37 (21%) returned for a dFET by August 2009 and only 18 women had children from fresh and frozen transfers. In contrast, 128 of the 385 recipients who failed the fresh transfer (33%) cryopreserved embryos and 111 (87%) returned for a dFET. Of these, 44 had children from the dFET. Frozen cycle success rates between these recipient groups did not depend on fresh cycle outcome or prior parity. CONCLUSION(S): Donor oocyte recipients often initiate treatment with a desire to cryopreserve embryos for future use and family expansion. However, our data demonstrates that most recipients with a child from the fresh transfer do not return to use their cryopreserved embryos. Although fresh transfer success correlated with embryo disposition, it did not correlate with the outcome of thawed embryo transfer.

Optimizing embryo selection with day 5 transfer.

OBJECTIVE: To compare rates of implantation, pregnancy, miscarriage, multiple gestation, and selective reduction between patients undergoing day 5 (d5) and day 3 (d3) ETs. DESIGN: Retrospective cohort study. SETTING: University-based IVF center. PATIENT(S): The first d5 ET cycle of patients 42 years of age from 2003 to 2006 was compared with a historical control of first cycle d3 ET patients 42 years of age from 1996 to 1999 who would have met current d5 ET criteria. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of implantation, clinical pregnancy, miscarriage, live birth, high order multiple pregnancy (HOMP), and selective reduction. RESULT(S): D5 ET patients had higher implantation rates (39% vs. 30%), with no difference in the no-transfer rate. D5 ET patients had lower rates of HOMP (2.5% vs. 11%) and HOMP delivery (0.7% vs. 3.5%), multiple pregnancy (27% vs. 33%), multiple delivery (19% vs. 26%), and twin delivery (18% vs. 23%). There were fewer selective reductions of HOMP with d5 ET (1.7% vs. 3.8%). CONCLUSION(S): Extended culture improves embryo selection through increased implantation, facilitating fewer embryos per transfer, which lowers multiple gestation rates and the need for HOMP reduction.

Chronic isolated fallopian tube torsion.

OBJECTIVE: To describe a case of chronic isolated fallopian tubal torsion in a woman without identifiable risk factors and discuss the difficulty of diagnosis. DESIGN: Case report. SETTING: University-based reproductive endocrinology and infertility center. PATIENT(S): Multiparous woman with no risk factors of torsion of the fallopian tube presenting with chronic right lower quadrant pain. INTERVENTION: Laparoscopy with subsequent salpingectomy. MAIN OUTCOME MEASURE(S): Resolution of symptoms. Preservation of ovary and future fertility. RESULT(S): Patient's symptoms resolved after salpingectomy. Information regarding future fertility is pending. CONCLUSION(S): Isolated fallopian tube torsion is rare and often difficult to diagnose. Despite ultrasonographic evidence of arterial and/or venous flow to the adnexa, adnexal torsion cannot be ruled out. If clinical suspicion for torsion is high, early diagnosis and treatment via laparoscopy is encouraged as a means of preserving fallopian tube integrity and maintaining fertility, especially in reproductive-age women.

Programmatic implementation of blastocyst transfer in a university-based in vitro fertilization clinic: maximizing pregnancy rates and minimizing triplet rates.

To assess whether the use of extended embryo culture can reduce the incidence of high-order multiple gestations, a retrospective analysis of 7,418 fresh ETs performed in a university-based IVF clinic from 1997-2003 was conducted, comparing program results before and after institution of a protocol to select patients for extended culture of in vitro fertilized embryos. The incidence of triplet pregnancies was significantly reduced in patients at highest risk for high-order multiple gestations, i.e., those at <35 years of age (16.8% versus 6.8%), those at 35-37 years of age (13.0% versus 5.6%), and recipients of donated oocytes (11.2% versus 4.5%).

Isolated teratozoospermia does not affect in vitro fertilization outcome and is not an indication for intracytoplasmic sperm injection.

OBJECTIVE: To reevaluate clinical management of isolated teratozoospermia, in couples initiating IVF. DESIGN: Retrospective analysis of fertility indices in 535 cycles. SETTING: A large, university-based fertility center. PATIENT(S): Consecutive couples (n = 495) who had a semen analysis using Kruger/Tyberberg strict criteria at our center within 12 months before undergoing their first and/or second IVF cycle in 2002-2004 with >2 million postwash, motile sperm on the day of egg retrieval. INTERVENTION(S): Eggs were fertilized either by conventional IVF or ICSI. Semen analysis and gamete/embryo manipulation was standardized in all cases. MAIN OUTCOME MEASURE(S): Fertilization, fertilization failure, pregnancy, and live birth rates. RESULT(S): There was no statistical difference in fertilization, fertilization failure, pregnancy, and live birth rates in the first or second IVF cycle when comparing couples with isolated teratozoospermia (<5% normal morphology) to those with a normal semen analysis. Furthermore, no improvement in these outcomes was noted when ICSI was used to treat these teratozoospermic couples. CONCLUSION(S): Because isolated teratozoospermia generally does not impact on the major indices of IVF, these patients need not be subjected to the unnecessary cost and potential risks of ICSI. Future studies, however, should focus on different sperm morphologic and biochemical parameters to determine if they are important for clinical management in IVF.

Low ectopic pregnancy rates after in vitro fertilization: do practice habits matter?

In a 6-year review of ectopic pregnancies (EPs) after fresh and frozen embryo transfers in IVF cycles conducted at a large university-based program, we report an overall 0.9% rate of EP that seems to have increased with the programmatic shift to routine blastocyst transfer, but remains lower than nationally reported rates. Aggressive management of tubal disease may contribute to low rates of EP, whereas blastocyst transfer may increase the rate.