Frozen Embryo Transfer Cycles Research Articles

Circadian serum progesterone variations on the day of frozen embryo transfer in a modified natural cycle protocol.

Is there a circadian variation of serum progesterone (P) on the day of frozen embryo transfer (FET) in a modified natural cycle (mNC)? There is a statistically significant diurnal variation of serum P on the day of a FET in an mNC protocol. In recent years, the proportion of FET cycles has increased dramatically. To further optimize pregnancy outcomes after FET, recent studies have focused on serum luteal P levels in both natural and artificially prepared FET cycles. Despite the different cut-off values proposed to define low serum P in the NC, it is generally accepted that lower serum P values (<10 ng/ml) around the day of FET are associated with negative reproductive outcomes. However, a single serum P measurement is not reliable given that P levels are prone to diurnal fluctuations and are impacted by patients' characteristics. A prospective cohort study was conducted in a single university-affiliated fertility center, including 22 patients performing a single blastocyst mNC-FET from August 2022 to August 2023. Serum P levels were measured on the day of transfer at 08:00h, 12:00h, 16:00h, and 20:00h. Differences between P levels were compared using the Wilcoxon signed-rank test. The sample size was calculated to detect a difference of 15% between the first and last P measurements with a 5% false-positive rate and a 95% CI. Patients with a normal BMI, between 18 and 40 years old, without uterine diseases were eligible. Patients utilizing donated oocytes were excluded. The mNC-FET protocol involved monitoring the normal ovarian cycle and triggering ovulation with an injection of 250 μg of choriogonadotropin alfa when a pre-ovulatory follicle (16-20 mm diameter) was visualized. The blastocyst was transferred seven days later. The patients were not supplemented with exogenous P at any time before the day of the FET. The mean age and BMI of the study population were 33.6 ± 3.8 years and 22.7 ± 1.8 kg/m2, respectively. Mean P values at 08:00h, 12:00h, 16:00h, and 20:00h were 14.6 ± 4.5, 14.7 ± 4.1, 12.9 ± 3.5, and 14.6 ± 4.3 ng/ml, respectively. The mean P levels at 16:00h were significantly lower compared to all other time points (P < 0.05: P = 0.007 between P at 8:00h and 16:00h; P = 0.003 between P at 12:00h and 16:00h; P = 0.007 between P at 16:00h and 20:00h). No statistically significant difference was observed between P values at the other time points (P > 0.05: P = 0.88 between P at 8:00h and 12:00h; P = 0.96 between P at 8:00h and 20:00h; P = 0.83 between P at 12:00h and 20:00h). The study's limitations include the small sample size that may cause a bias when the results are extrapolated to a larger subfertile population undergoing mNC-FET. Ideally, larger prospective trials including a more heterogeneous patient population would be necessary to validate our findings. The current study demonstrates the existence of a diurnal fluctuation of serum P on the day of mNC-FET highlighting the importance of a standardized time point for its measurement. This is especially important for considering clinical actions, such as additional exogenous P supplementation, when encountering P values lower than 10 ng/ml on the day of FET. No funding was obtained for the study. The authors have no conflicts of interest to declare regarding the content of the study. NCT05511272.

Association between the length of in vitro embryo culture, mode of ART, and the initial endogenous hCG rise in ongoing singleton pregnancies.

Is there an association between the length of in vitro culture, mode of ART and the initial endogenous hCG rise, in cycles with a foetal heartbeat after single embryo transfer (ET) and implantation? Both the length of in vitro culture and the mode of ART have an impact on the initial endogenous rise in hCG in singleton pregnancies. Different factors have been identified to alter the kinetics of hCG in pregnancies. Current studies show conflicting results regarding the kinetics of hCG after different types of ART (fresh vs frozen ET (FET)), the inclusion or not of preimplantation genetic testing (PGT), and the length of time in in vitro culture. This was a multicentre cohort study, using prospectively collected data derived from 4938 women (5524 treatment cycles) undergoing IUI (cycles, n = 608) or ART (cycles, n = 4916) treatments, resulting a in singleton ongoing pregnancy verified by first-trimester ultrasound scan. Data were collected from the Danish Medical Data Centre, used by the three participating Danish public fertility clinics at Copenhagen University hospitals: Herlev Hospital, Hvidovre Hospital, and Rigshospitalet, from January 2014 to December 2021. The fresh ET cycles included cleavage-stage (2 or 3 days in vitro) and blastocyst (5 days in vitro) transfers. FET cycles included cleavage-stage (3 days in vitro before cryopreservation) or blastocyst (5 or 6 days in vitro before cryopreservation) transfers. The IUI cycles represented no time in vitro. To attain a comparable interval for serum-hCG (s-hCG), the ovulation induction time was identical: 35-37 h before oocyte retrieval or IUI. The conception day was considered as: the insemination day for pregnancies conceived after IUI, the oocyte retrieval day for fresh ET, or the transfer day minus 3 or 5 as appropriate for FET of Day 3 or 5 embryos. Multiple linear regression analysis was used, including days post-conception for the hCG measurement as a covariate, and was adjusted for the women's age, the cause of infertility, and the centre. For FET, a sensitivity analysis was used to adjust for endometrial preparation. The study totally includes 5524 cycles: 2395 FET cycles, 2521 fresh ET cycles, and 608 IUI cycles. Regarding the length of in vitro culture, with IUI as reference (for no time in in vitro culture), we found a significantly lower s-hCG in pregnancies achieved after fresh ET (cleavage-stage ET or blastocyst transfer). S-hCG was 18% (95% CI: 13-23%, P < 0.001) lower after fresh cleavage-stage ET, and 23% (95% CI: 18-28%, P < 0.001) lower after fresh blastocyst transfer compared to IUI. In FET cycles, s-hCG was significantly higher after blastocyst transfers compared to cleavage-stage FET, respectively, 26% (95% CI: 13-40%, P < 0.001) higher when cryopreserved on in vitro Day 5, and 14% (95% CI: 2-26%, P = 0.02) higher when cryopreserved on in vitro Day 6 as compared to Day 3. Regarding the ART treatment type, s-hCG after FET blastocyst transfer (Day 5 blastocysts) cycles was significantly higher, 33% (95% CI: 27-45%, P < 0.001), compared to fresh ET (Day 5 blastocyst), while there was no difference between cleavage-stage FET (Days 2 + 3) and fresh ET (Days 2 + 3). S-hCG was 12% (95% CI: 4-19%, 0.005) lower in PGT FET (Day 5 blastocysts) cycles as compared to FET cycles without PGT (Day 5 blastocysts). The retrospective design is a limitation which introduces the risk of possible bias and confounders such as embryo score, parity, and ovarian stimulation. This study elucidates how practices in medically assisted reproduction treatment are associated with the hCG kinetics, underlining a potential impact of in vitro culture length and mode of ART on the very early embryo development and implantation. The study provides clinicians knowledge that the type of ART used may be relevant to take into account when evaluating s-hCG for the prognosis of the pregnancy. No funding was received for this study. AP has received consulting fees, research grants, or honoraria from the following companies: Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos, Merck A/S, and Organon. AZ has received grants and honoraria from Gedeon Richter. NLF has received grants from Gedeon Richter, Merck A/S, and Cryos. MLG has received honoraria fees or research grants from Gedeon Richter, Merck A/S, and Cooper Surgical. CB has received honoraria from Merck A/S. MB has received research grants and honoraria from IBSA. MPR, KM, and PVS all report no conflicts of interest. The study was registered and approved by the Danish Protection Agency, Capital Region, Denmark (Journal-nr.: 21019857). No approval was required from the regional ethics committee according to Danish law.

Abstract PO4-11-10: Comparison of frozen embryo transfer cycle (FET) outcomes between young women with breast cancer (YWBC) with and without pathogenic variants (PV), and breast cancer-free PV carriers

Abstract BACKGROUND: In vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A) and monogenic disorders (PGT-M) are valuable tools for YWBC with or without PV such as BRCA1/2, ATM, CHEK2, PMS2 to prevent variant transmission to offspring. However, to date, there is scarce data on the usability of these cryopreserved, tested embryos and on the outcomes of FET cycles within the cancer population. It has been suggested that PV may influence endometrial thickness which is associated with embryo implantation and ultimately FET success rates. Thus, this study aimed to compare reproductive outcomes of FET cycles between YWBC with an identified PV, breast cancer (BC) patients without a PV, and cancer-free PV-carriers who returned to use their cryopreserved oocytes or embryos derived from IVF ± PGT-A/M cycles. METHODS: Patients that underwent either fertility preservation (FP) prior to BC therapy or preventative IVF/PGT-A/M cycles from 2009-2023 were included. All IVF &amp; PGT-A/M was performed at academic IVF centre. Genetic testing was conducted using high resolution next generation sequencing on the Illumina platform. We compared reproductive outcomes between 3 groups: 1) YWBC with a known PV (BCPV), 2) YWBC without a PV (BCNV), 3) Cancer-free patients who had a PV (CFPV). Primary outcomes measured were endometrial thickness, and FET success rates (i.e., ongoing pregnancy or live birth) analyzed by chi-square, t-tests and ANOVA. RESULTS: 185 patients underwent 202 cycles for either oocyte or embryo freezing. Mean age was 33.8±4.6 years (range 21-45) and mean BMI was 24.6±5.0 kg/m2 (range 15.7-42.7). 64 patients had a PV including BRCA1 (n=22), BRCA2 (n=20) and others (n=22): ATM, BARD1, BRIP1, CHEK2, MLH1, P53, PALB2, PDL2, PMS2, PTCH1, &amp; RAD51D. When comparing the BCPV, BCNV &amp; CFPV groups, no significant differences were found in the mean age (33.7 ± 4.9 vs. 36.8 ± 4.3 vs. 34.3 ± 4.4 years, p=0.52), mean BMI (26.2 ± 4.9 vs. 24.3 ± 4.8 vs. 24.3 ± 4.8 kg/m2, p=0.13), and the proportion of smokers (23.1% vs. 35.0% vs. 36.4%, p=0.72). Only 60% of BCNV performed PGT-A due to their lack of PV. As of June 2023, 44 patients (12 in BCPV, 20 in BCNV, and 12 in CFPV) returned to undergo 81 FET cycles (range 1-5/patient). 12/81(14.8%) FETs involved a surrogate. When comparing the BCPV, BCNV &amp; CFPV who had FET, a significant difference was found in the mean age at oocyte retrieval between BCPV &amp; BCNV (32.9±4.4 vs. 37.0±4.0 years, p=0.001) but not with CFPV (33.5±4.4 years). The endometrial thickness at the time of FET between the BCPV, BCNV, and CFPV groups was similar (10.2±1.6 vs. 10.6±2.6 vs. 9.3±1.9 mm, p=0.12), as was the proportion of smokers (25.0% vs. 36.8% vs. 33.3%, p=0.79). YWBC had a mean delay from egg retrieval to their first FET of 37 months. Estrogen receptor positive (ER+) YWBC had a longer delay than ER- patients (40.1±23.8 months vs. 29.6±11.6 months, p=0.25). 29/44 (65.9%) had at least one successful FET and another 5 YWBC conceived naturally or with intrauterine insemination (IUI); the cumulative pregnancy rate was 77.3% (34/44). The clinical pregnancy rate of 81 FETs was 44.4%. The BCPV group (73.7%) had a significantly higher successful outcome than the BCNV (35.3%) and CFPV (35.7%) groups (p=0.01). CONCLUSIONS: FP done at the time of a BC diagnosis is an effective tool to preserve fertility potential. 77% of patients had at least one baby from either IVF, IUI or conceived naturally. We did not find a difference in endometrial thickness in PV carriers. While all YWBC had a delay to their first FET from the time of their retrieval, those who were ER+ had a longer delay than ER- because of their need for endocrine therapy. The BCPV group had the highest FET success rate which is likely due to their younger age and use of PGT-A/M thereby eliminating FETs of abnormal embryos that would fail to implant. The BCNV were older with more untested embryos. The CFPV group transferred euploid embryos and thus the lower success rate is puzzling and needs further investigation. Citation Format: Maya Sharon-Weiner, Amanda Kauffman, Adina Tanen, Samantha Yee, Svetlana Madjunkova, Karen Glass. Comparison of frozen embryo transfer cycle (FET) outcomes between young women with breast cancer (YWBC) with and without pathogenic variants (PV), and breast cancer-free PV carriers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-10.

Embryonic Parameters Associated With Outcomes of Single Blastocyst Frozen Transfer [ID 2683440

INTRODUCTION: It is unclear how various in vitro fertilization cycle characteristics may ultimately influence the fertility outcomes of patients utilizing assisted reproductive technology. This study investigates embryo characteristics to determine which features are most associated with clinical intrauterine pregnancy after frozen embryo transfer. METHODS: This retrospective study evaluates 535 single blastocyst frozen embryo transfers (FETs) in 2022 and received IRB approval from the University of Kansas. Logistic regression analyses were used to evaluate embryo characteristics and likelihood of clinical intrauterine pregnancy (IUP), defined as positive fetal cardiac activity on ultrasound after 12 weeks of gestation. Blastocyst survival (percentage of live cells), blastocoele re-expansion, and morphological grade were evaluated prior to embryo transfer. Significant embryonic parameters included blastocyst developmental stage and blastocyst grade before cryopreservation, usage of preimplantation genetic testing for aneuploidy (PGT-A), post-warm blastocyst survival (percentage of live cells), degree of blastocoele re-expansion, blastocyst grading before transfer, and presence of zona pellucida. RESULTS: Among 535 FET cycles, 257 (48.0%) resulted in clinical IUP. Multivariate logistic regression analysis showed a significant independent influence of blastocyst development time (day 5/6) (odds ratio [OR] 0.571; P=.003), morphological grade before cryopreservation (day 5/6) (OR 0.648; P=.013), usage of PGT-A (OR 1.704; P=.010), and percentage of post-thaw live cells (OR 0.322; P=.001) on embryo transfer success rates. While fully expanded blastocysts showed a significantly higher rate of clinical IUP, the degree of blastocoele re-expansion did not appear to be independently related to ongoing pregnancy when multivariate logistic regression analysis was employed (OR 2.886; 95% CI: 0.824–10.105; P=.097). CONCLUSION: In addition to blastocyst quality prior to cryopreservation, post-thaw blastocyst survival is an independent predictor of embryo recovery and further development potential. Additional understanding of the potential contributors to failed FETs can inform strategies for improvement. Further investigation is needed to determine how to minimize embryonic cell damage during the vitrification and warming process.

Impact of dydrogesterone use in cycles with low progesterone levels on the day of frozen embryo transfer.

This study aims to evaluate whether the clinical outcomes of cycles with frozen embryo transfer (FET) in hormonal replacement treatment supplemented with dydrogesterone (DYD) following detection of low circulating levels of progesterone (P4) were comparable to the results of cycles with otherwise normal serum P4 values. Extended analyses of a retrospective cohort that included FET cycles performed between July 2019 and March 2022 after a cycle of artificial endometrial preparation using valerate-estradiol and micronized vaginal P4 (400mg twice daily). Whenever the serum P4 value was considered low on the morning of the planned transfer, 10mg of DYD three times a day was added as a supplement. Only single-embryo transfers of a blastocyst were considered. The primary endpoint was live birth rate. Five-hundred thirty-five FET cycles were analyzed, of which 136 (25.4%) underwent treatment with DYD. There were 337 pregnancies (63%), 207 live births (38.6%), and 130 miscarriages (38.5%). The P4 values could be modeled by a gamma distribution, with a mean of 14.5ng/ml and a standard deviation of 1.95ng/ml. The variables female age on the day of FET, ethnicity, and weight were associated with a variation in the serum P4 values. There were no differences in the results between cycles with or without the indication for DYD supplementation. Live birth rate did not vary significantly in females with low and normal serum P4 levels on the day of FET when DYD was used as rescue therapy.

Enhancing endometrial receptivity in FET cycles: exploring the influence of endometrial and subendometrial blood flow along with endometrial volume.

Fetal health and a receptive and healthy endometrium are two essential factors in achieving successful implantation. If the endometrium is unreceptive, postponing the transfer cycle to a suitable time can enhance the chances of pregnancy. This study aims to assess the impact of endometrial and sub-endometrial blood flows measured by Doppler ultrasound, as well as endometrial volume, on endometrial receptivity in frozen embryo transfer (FET) cycles. 112 patients with a mean age of 33.93 ± 4.93 years underwent in vitro fertilization (IVF). Serum β-hCG level was used to confirm pregnancy, and among the participants, 50 (44.6%) achieved pregnancy after IVF. The study results revealed a significant difference in endometrial blood flow between the pregnant and non-pregnant groups, with a higher pregnancy rate observed in participants exhibiting multi-focal and spare endometrial blood flows (p < 0.05). Furthermore, there was a notable association between endometrial blood flow and pregnancy outcome, as indicated by higher ongoing pregnancy rates in those with multi-focal and spare endometrial blood flows (p < 0.05). However, no significant differences were observed in endometrial variables such as volume, length, width, thickness, and pattern between the pregnant and non-pregnant groups. Additionally, contextual parameters showed no significant relationship with pregnancy outcome (p > 0.05). The study also found that endometrial measurement indices did not have a significant impact on pregnancy outcomes, with no significant differences observed between the groups (p > 0.05). In conclusion, endometrial blood flow is crucial for a successful pregnancy after IVF, while the predictive value of the endometrial volume is limited for pregnancy outcomes.

IMPACT OF TIME INTERVAL FROM CESAREAN DELIVERY TO FROZEN EMBRYO TRANSFER ON REPRODUCTIVE AND NEONATAL OUTCOMES

To evaluate differences in reproductive and neonatal outcomes based on the time interval from cesarean delivery to subsequent frozen embryo transfer (FET) DESIGN: Retrospective cohort SUBJECTS: Women undergoing autologous elective single embryo transfer (eSET) FET following prior cesarean delivery EXPOSURE: Time from prior cesarean delivery to subsequent FET MAIN OUTCOME MEASURES: Live birth RESULTS: A total of 6,556 autologous eSET FET cycles were included. FET cycles were divided into eight groups based on the time interval from prior cesarean delivery to subsequent FET in months. Time was also evaluated as a continuous variable. The proportion of live births did not differ significantly across all time interval groups and over continuous time (range: 40.0% - 45.6%, adjusted (adj) p = 0.572, continuous adj p = 0.599). Mean gestational age at the time of delivery did not significantly differ as the time between prior cesarean delivery and subsequent FET increased (range: 37.3 - 38.4 weeks, adj p = 0.87, continuous adj p = 0.06). When time was evaluated continuously, the proportion of preterm births was higher with a shorter time between cesarean delivery and subsequent FET (p = 0.02). Mean birth weight ranged from 3181 grams to 3470 grams, with a statistically significant increase over time (continuous adj p = 0.01). However, the proportions of extremely low birth weight, very low birth weight, and low birth weight did not significantly differ. There were no significant differences in reproductive outcomes based on the time interval from cesarean delivery to FET, including live birth. The proportion of preterm deliveries decreased with a longer time between cesarean delivery and FET. Differences in mean neonatal birth weight were not clinically significant, as the proportion of low-birth-weight neonates was not significantly different over time. While large, this sample cannot address all outcomes associated with short interpregnancy intervals, particularly rarer outcomes such as uterine rupture. When counseling patients, the timing of FET following cesarean delivery must be balanced against the risks of increasing maternal age on reproductive and neonatal outcomes.

Midluteal serum estradiol levels are associated with live birth rates in hormone replacement therapy frozen embryo transfer cycles: a cohort study

ObjectiveTo study whether mid-luteal serum estradiol (E2) levels are associated with the Live Birth Rate in Hormone Replacement Therapy FET cycles in patients with optimal mid-luteal serum progesterone (P4) levels. DesignObservational prospective cohort study of 412 women having a Hormone Replacement Therapy FET single blastocyst transfer from January 2020 to November 2022. SubjectsThe Hormone Replacement Therapy FET priming regimen included oral estradiol (6mg/24h) administered in the evening, followed by vaginal progesterone (400mg/12h). Serum E2 and P4 levels were measured in a standardized manner, 2-4 hours after the latest progesterone administration and 9-14 hours after estradiol administration on the day of blastocyst transfer, day 6 of progesterone administration. Patients with serum P4 <11ng/mL (35nmol/l) on the day of transfer received additional rectal progesterone (400mg/12h). No additional estradiol was administered. Main Outcome MeasuresThe primary outcome was Live Birth Rate in relation to E2 levels at blastocyst transfer day. ResultsThe optimal serum E2 range correlating with ongoing pregnancy was ≥292pg/ml <409pg/ml (≥1070pmol/l and <1500pmol/l). The Live Birth Rate was 59% (60/102) if E2 levels were within this range, whereas a significantly lower Live Birth Rate of 39% (101/260, p=0.001) was seen in patients if E2 levels were <292pg/ml (<1070pmol/l), and of 28% (14/50, p<0.001) if E2 levels were ≥409pg/ml (≥1500pg/mL). In a logistic regression analysis, adjusting for serum progesterone level ≥11ng/mL or <11ng/mL (≥35nmol or <35nmol/l) on the day of transfer, BMI, age at oocyte retrieval, day 5 or 6 vitrified blastocyst and blastocyst score, the adjusted risk difference (RD) of a live birth was -0.21 [-0.32; -0.10] when the E2 level was <292pg/mL (<1070pmol/l) and -0.31 [-0.45; -0.18] if the E2 level was ≥409pg/ml (≥1500pmol/l) compared to E2 levels ≥292pg/ml <409pg/ml (≥1070 <1500pmol/l). Importantly, only 25% of patents had optimal levels. ConclusionThe study shows a significant association between serum E2 levels and reproductive outcomes in a Hormone Replacement Therapy FET cohort in which optimal serum progesterone levels were secured. Mid-luteal serum E2 levels are associated with Live Birth Rate in Hormone Replacement Therapy FET cycles and E2 levels should neither be too high nor too low.

Current understanding of the pathogenesis of placenta accreta spectrum disorder with focus on mitochondrial function.

The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions. A literature search was performed in the PubMed and Google Scholar databases. Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics. The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer: potential etiologies and strategies for prevention.

In the first of two companion papers, we comprehensively reviewed the recent evidence in the primary literature, which addressed the increased prevalence of hypertensive disorders of pregnancy, late-onset or term preeclampsia, fetal overgrowth, postterm birth, and placenta accreta in women conceiving by in vitro fertilization. The preponderance of evidence implicated frozen embryo transfer cycles and, specifically, those employing programmed endometrial preparations, in the higher risk for these adverse maternal and neonatal pregnancy outcomes. Based upon this critical appraisal of the primary literature, we formulate potential etiologies and suggest strategies for prevention in the second article. Comprehensive review of primary literature. Presupposing significant overlap of these apparently diverse pathological pregnancy outcomes within subjects who conceive by programmed autologous FET cycles, shared etiologies may be at play. One plausible but clearly provocative explanation is that aberrant decidualization arising from suboptimal endometrial preparation causes greater than normal trophoblast invasion and myometrial spiral artery remodeling. Thus, overly robust placentation produces larger placentas and fetuses that, in turn, lead to overcrowding of villi within the confines of the uterine cavity which encroach upon intervillous spaces precipitating placental ischemia, oxidative and syncytiotrophoblast stress, and, ultimately, late-onset or term preeclampsia. The absence of circulating corpus luteal factors like relaxin in most programmed cycles might further compromise decidualization and exacerbate the maternal endothelial response to deleterious circulating placental products like soluble fms-like tyrosine kinase-1 that mediate disease manifestations. An alternative, but not mutually exclusive, determinant might be a thinner endometrium frequently associated with programmed endometrial preparations, which could conspire with dysregulated decidualization to elicit greater than normal trophoblast invasion and myometrial spiral artery remodeling. In extreme cases, placenta accreta could conceivably arise. Though lower uterine artery resistance and pulsatility indices observed during early pregnancy in programmed embryo transfer cycles are consistent with this initiating event, quantitative analyses of trophoblast invasion and myometrial spiral artery remodeling required to validate the hypothesis have not yet been conducted. Endometrial preparation that is not optimal, absent circulating corpus luteal factors, or a combination thereof are attractive etiologies; however, the requisite investigations to prove them have yet to be undertaken. Presuming that in ongoing RCTs, some or all adverse pregnancy outcomes associated with programmed autologous FET are circumvented or mitigated by employing natural or stimulated cycles instead, then for women who can conceive using these regimens, they would be preferable. For the 15% or so of women who require programmed FET, additional research as suggested in this review is needed to elucidate the responsible mechanisms and develop preventative strategies.

Different Dosages of Progesterone in Luteal Phase Support Reflect Varying Endometrial microRNA Expression in Frozen Embryo Transfer Cycles.

Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for guiding clinical decisions on progesterone dosages to maximize reproductive outcomes. This retrospective study explored the utility of microRNA (miRNA) biomarkers in guiding personalized progesterone dosage adjustments for frozen embryo transfer (FET) cycles in 22 in vitro fertilization (IVF) patients undergoing hormone replacement therapy. Utilizing MIRA, an miRNA-based endometrial receptivity test, we analyzed patients' miRNA expression profiles before and after progesterone dosage adjustments to determine suitable dosages and assess endometrial status. Despite patients receiving identical progesterone dosages, variations in miRNA profiles were observed in the initial cycle, and all patients presented a displaced window of implantation. Following dosage adjustments based on their miRNA profiles, 91% of patients successfully transitioned their endometrium towards the receptive stages. However, two patients continued to exhibit persistent displaced receptivity despite the adjustments. Given the evident variation in endometrial status and serum progesterone levels among individuals, analyzing miRNA expression profiles may address the challenge of inter-personal variation in serum progesterone levels, to deliver more personalized dosage adjustments and facilitate personalized luteal phase support in IVF.

Immediate application of frozen-thawed embryo transfer cycle in month following COVID-19 infection does not impair subsequent pregnancy outcomes.

To investigate whether immediate frozen embryo transfer (FET) in the next month following COVID-19 recovery affects the subsequent pregnancy outcomes. A retrospective cohort study was carried out at a university-affiliated reproductive medicine center. The study group (post-COVID-19 group) consisted of women who were afflicted with COVID-19 in December 2022 and immediately invested in FET in January 2023 after recovery, with embryos transferred and not exposed to the infection. The control group was composed of women treated during the pre-COVID-19 period (January 2019). Multivariable logistic regression analyses as well as a propensity score matching (PSM) approach were introduced to control for the potential confounders and selection bias. A total of 200 patients were included in the post-COVID-19 group while a total of 641 women were enrolled in the control group. The rate of ongoing pregnancy was comparable between the study cohorts in both the unadjusted and confounder-adjusted logistic regression models. The other reproductive outcomes, including the odds of the positive pregnancy test, implantation, clinical pregnancy, and early pregnancy loss were all similar between the comparison groups. Results from PSM models further confirmed the lack of significant differences in pregnancy outcomes between the post-COVID-19 group versus the control group. Our findings suggested that for patients who get infected with COVID-19, the immediate investment in a FET cycle in the next month after recovery did not seem to compromise the ongoing pregnancy outcomes in cases of transferred embryos resulting from the pre-infection stage. Thus, women who had frozen embryos from the pre-infection cycles should be counseled and encouraged to invest in IVF as soon as possible after recovering from COVID-19 infection. This article is protected by copyright. All rights reserved.

Impact of vaginal microecological differences on pregnancy outcomes and endometrial microbiota in frozen embryo transfer cycles.

This prospective study investigates the correlation between vaginal microecology and pregnancy outcomes and explores their impact on endometrial microbiota composition during frozen embryo transfer (FET) cycles. Additionally, the impact of transvaginal Lactobacillus supplementation on reproductive outcomes in patients with previous failed cycles was assessed. A total of 379 patients undergoing FET at a reproductive medicine center were categorized into clinical pregnancy (CP), miscarriage (MISC), and non-pregnant (NP) groups. Vaginal specimens were collected for microecological evaluation prior to embryo transfer. Endometrial microbiota samples were obtained during embryo transfer for 16S rRNA gene sequencing analysis to assess endometrial microbiota composition. Vaginal microecological indicators, including pH, Lactobacillus dominance, and leukocyte esterase activity, were measured. Transvaginal Lactobacillus supplementation was investigated in 60 patients with previous failed cycles. Vaginal microecology significantly correlated with pregnancy outcomes, with normal microecology associated with a higher clinical pregnancy rate. Vaginal pH and leukocyte esterase activity were significantly associated with clinical pregnancy. Furthermore, vaginal microecological differences significantly impacted endometrial microbiota composition. However, no significant differences were observed in endometrial microbiota composition among the CP, MISC, and NP groups. Notably, transvaginal Lactobacillus supplementation increased the clinical pregnancy rate without affecting the miscarriage rate. This study highlights that normal vaginal microecology, characterized by lower pH and leukocyte esterase negativity, is associated with a higher likelihood of clinical pregnancy following FET. Importantly, vaginal microecological differences influence endometrial microbiota composition. Moreover, transvaginal Lactobacillus supplementation appears promising in improving clinical pregnancy rates in patients with previous failed cycles. These findings contribute to a better understanding of the interplay between vaginal and endometrial microbiota and offer potential interventions to enhance reproductive success in assisted reproductive technologies.

Is large for gestational age in singletons born after frozen embryo transfer associated with freezing technique or endometrial preparation protocol? A longitudinal national French study.

Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. Data were collected from 35 French ART centres, leading to the inclusion of a total of 72789 fresh ET, 10602 slow-freezing FET, and 39062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. Transfers led to, respectively, 19006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21704) or artificial cycles (n = 34237), leading to 5910 and 10322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P < 0.001, in slow freezing groups and 31.6% versus 21.8%, P < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P < 0.001 and 22.8% versus 24.9%, P < 0.001, respectively). Among a total of 26585 live-born singletons, 16413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. N/A.

The combination of dydrogesterone and micronized vaginal progesterone can render serum progesterone level measurements on the day of embryo transfer and rescue attempts unnecessary in an HRT FET cycle.

To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.

Does embryo biopsy, independent of vitrification, impact perinatal outcomes? An analysis of perinatal outcomes following preimplantation genetic testing biopsy in fresh and frozen embryo transfer cycles

Does embryo biopsy, independent of vitrification, impact perinatal outcomes? An analysis of perinatal outcomes following preimplantation genetic testing biopsy in fresh and frozen embryo transfer cycles

A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle.

The aim of this study was to compare endometrial thickness with the use of transdermal estrogen (gel) versus oral estrogen (pills) for endometrial preparation in the frozen embryo transfer cycle and serum estrogen concentrations during the preparation cycle, side effects, and chemical and clinical pregnancy rates. This was a prospective, randomized controlled trial of women undergoing endometrial preparation for cryopreserved blastocyst transfer. A total of 88 women were randomized, of which 82 completed the study protocol. Of this group, 44 received 6 mg/day of estradiol valerate orally (pills group) and 38 received 4.5 mg/day of estradiol hemihydrate transdermally (gel group). Endometrial thickness was measured using transvaginal ultrasound between the 7 and 10th day of the cycle. Serum estradiol concentrations were measured on the day of initiating the cycle, on control transvaginal ultrasounds, and on the day of embryo transfer. Side effects were documented at each study visit. p<0.05 were adopted as statistically significant. The groups were compared using Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables. There were no significant group differences (p>0.05) in endometrial thickness, biochemical and clinical pregnancy rates, miscarriage rate, blood estradiol concentrations, duration of estradiol administration, or cycle cancellation rates. Endometrial preparation with transdermal estrogen yielded similar reproductive outcomes to oral estrogen with fewer side effects.

Association of duration of embryo culture with risk of large for gestational age delivery in cryopreserved embryo transfer cycles

To examine the relationship between the day of embryo cryopreservation and large for gestational age (LGA) infants in women undergoing frozen embryo transfers (FETs) after cryopreservation on days 2-7 after fertilization and to compare the risk of the day of embryo cryopreservation to other possible risk factors of LGA after FET cycles. Retrospective cohort study. Society of Assisted Reproduction Clinical Outcomes Reporting System. Women undergoing FET cycles. Day of cryopreservation. Singleton LGA infant. A total of 33,030 (18.2%) FET cycles in the study group (n = 181,592) resulted in LGA infants during the study period of 2014-2019. There was an increase in LGA risk when cryopreservation was performed from day 2 (13.7%) to days 3-7 (14.4%, 15.0%, 18.2%, 18.5%, and 18.9%). In the log-binomial model, the risk increased compared with days 2-3 combined when cryopreservation was performed on days 5-7 (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.22-1.44 for day 5, aRR 1.34, 95% CI 1.23-1.46 for day 6, and aRR 1.42, 95% CI 1.25-1.61 for day 7). Other factors most associated with LGA risk in the log-binomial model were preterm parity of >3 compared with 0 (aRR 1.82, 95% CI 1.24-2.69) and body mass index (BMI) of >35 kg/m2 compared with normal weight (aRR 1.94, 95% CI 1.88-2.01). Increasing gravity, parity, BMI, number of oocytes, and embryo grade were also associated with LGA in this model. Asian, Black, Hispanic, and combined Hawaiian and Pacific Islander were protective factors in the model compared with White patients. Low BMI (<18.5 kg/m2) was also considered a protective factor in the model compared with normal BMI. Duration of embryo culture was associated with an increased risk of LGA in this study cohort when controlling for known confounders such as maternal BMI and parity. This study sheds new light on the possible link between FET and LGA infants.

A randomized controlled trial to compare the live birth rate of the first frozen embryo transfer following the progestin-primed ovarian stimulation protocol vs. the antagonist protocol in women with an anticipated high ovarian response

ObjectiveTo compare the live birth rate of the first frozen embryo transfer following ovarian stimulation by the progestin-primed ovarian stimulation protocol versus the antagonist protocol in women with anticipated high ovarian response undergoing IVF DesignRandomized controlled trial SettingsA tertiary assisted reproduction center PatientsInfertile women aged <43 years undergoing the first IVF cycle and having antral follicle count >15 InterventionsMedroxyprogesterone 10 mg daily was given from the start of ovarian stimulation until the day of ovulation trigger in the progestin-primed ovarian stimulation protocol. In the antagonist protocol, an antagonist 0.25mg daily was given from 6th day of ovarian stimulation until the day of ovulation trigger. Blinding was not possible for women or physicians but the biostatistician was blinded to the group assignment. Main Outcome MeasuresLive birth rate of the first frozen embryo transfer cycle Results784 women were recruited from June 2020 and October 2021 and randomly assigned in a 1:1 ratio into two groups: progestin-primed ovarian stimulation group (n=392) and antagonist group (n=392). Embryo transfer was either cancelled or postponed in 62 (62/392, 15.8%) women in the progestin-primed ovarian stimulation group and 65 (65/392, 16.6%) in the antagonist group because of no transferable embryos or no frozen embryo transfer within 6 months following randomizaion. The two groups were similar in demographic characteristics and number of oocytes obtained/fertilized, the number of cleaving embryos, number of good quality embryos at day 3, number of blastocysts developed and number of embryo/blastocyst frozen. There was no statistically significant difference in the live birth rate of the first frozen embryo transfer cycle between the progestin-primed ovarian stimulation and antagonist groups based on both intention to treat [37.5.0% (147/392) versus 32.7% (128/392), RR 1.148 (95% CI=0.949–1.390), P=0.16] and per protocol analysis [44.5% (147/330) versus 39.1.% (128/327), RR 1.138 (95%CI = 0.950–1.364), P=0.16]. Both groups showed comparable clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cumulative live birth rates. ConclusionThe live birth rates of the first frozen embryo transfer following the progestin-primed ovarian stimulation and the antagonist protocol were comparable in women with an anticipated high ovarian response.

The use of combined hormonal contraceptive for in-vitro fertilization cycle priming is not associated with decreased pregnancy rate in frozen embryo transfer cycles: a cohort study.

The objectives of this study are to evaluate the cycle outcomes from IVF treatment preceded by oral contraceptive pills (OCP) priming compared to estradiol pretreatment and to determine if there is a role for OCP priming for those undergoing frozen embryo transfers. The study took place at a university-affiliated fertility center in Canada. The study included in-vitro fertilization (IVF) antagonist cycles from Jan 2016 to Jun 2019. Those with protocol deviation or treatment cancellation were excluded. There were 2237 cycles by 1958 patients; 27% of cycles utilized OCP priming. The average age in the OCP group was 34 years old compared to 36.5 in the estradiol group (P<0.01). AMH was reported in 43% of patients and was 3.7ng/mL in the OCP group versus 2.2 ng/mL in the estradiol group (P<0.01). The number of oocytes (15.2 vs. 12.5) and number of blastocysts (4.6 vs. 3.3) were higher in the OCP group (P all <0.01). After adjusting for age and AMH with linear regression for the 978 cycles with recorded AMH (24% with OCP prime), a significantly higher number of oocytes (13.8 vs. 11.9, P=0.002) was still noted in the OCP group. There were 866 euploid embryo transfer cycles (28% with OCP prime). There were no significant differences in implantation (77% vs. 76%) or ongoing pregnancy rates (56% vs. 54%) between those who had a frozen embryo transfer after OCP primed compared to estradiol primed stimulation cycles (P all >0.6). There were no differences in pregnancy outcomes from euploid frozen blastocyst transfers after OCP primed antagonist cycles compared to estradiol pretreatment. In fact, the use of OCP pretreatment was associated with increased oocyte yield, keeping in mind demographic differences with the OCP pretreatment group being younger with higher anti-Müllerian hormone and a higher prevalence of PCOS. Thus, OCP priming should still be considered in specific populations, such as those with oligo-ovulation or adequate ovarian reserve.