Clinical outcomes of vitrified-warmed autologous oocyte cycles with 15-year follow-up at a single UK centre: consistent and predictable results.

RESEARCH QUESTION: What were the clinical outcomes from 332 autologous vitrified- warmed oocyte cycles derived from 3182 elective autologous oocyte freeze cycles carried out between 2008 and 2022 in a single-centre series? DESIGN: In this retrospective observational study, outcomes in 299 patients returning to use their frozen oocytes between 2015 and 2023 were analysed. RESULTS: A total of 3328 elective oocyte vitrification cycles were performed in 2280 patients. The return rate to use oocytes was 14% (299/2171). Mean ages were 37.6 years at storage and 40 at warming. Ninety-three clinical pregnancies and 77 healthy live births were recorded. The live birth rate (LBR) was 24% (39/163) per fresh transfer and 17% (39/227) per embryo transferred. Stratified by age at freezing, the LBR per embryo transferred was 26% (12/47) in participants under 35 years, 20% (24/118) in those 35-39 years and 5% (3/62) in those 40+ years. Frozen embryo transfers (FET) achieved a 30% (24/80) LBR per embryo transfer and a 27% (24/90) LBR per embryo transferred. PGT-A for embryo selection doubled the LBR compared with FET from an untested embryo after one attempt (40% versus 21%). In patients aged over 40 years, the cumulative LBR reached 42% per patient in euploid FET. CONCLUSION: The proportion of patients who returned to use their stored oocytes and the clinical outcomes were consistent with other recent reports and challenges the prevalent critical narrative regarding elective oocyte freezing for fertility preservation. The results are now comparable to routine IVF. Not everyone who returns to use their oocytes will conceive, but for those choosing to preserve their fertility, oocyte freezing can provide reproducible and reassuring results.

Double vitrification and warming of blastocysts does not affect pregnancy, miscarriage or live birth rates.

RESEARCH QUESTION: Does double blastocyst vitrification and warming affect pregnancy, miscarriage or live birth rates, or birth outcomes, from embryos that have undergone preimplantation genetic testing for aneuploidies (PGT-A) testing? DESIGN: This retrospective observational analysis of embryo transfers was performed at a single centre between January 2017 and August 2022. The double-vitrification group included frozen blastocysts that were vitrified after 5-7 days of culture, warmed, biopsied (either once or twice) and re-vitrified. The single vitrification (SV) group included fresh blastocysts that were biopsied at 5-7 days and then vitrified. RESULTS: A comparison of the 84 double-vitrification blastocysts and 729 control single-vitrification blastocysts indicated that the double-vitrification embryos were frozen later in development and had expanded more than the single-vitrification embryos. Of the 813 embryo transfer procedures reported, 452 resulted in the successful delivery of healthy infants (56%). There were no significant differences between double-vitrification and single-vitrification embryos in the pregnancy, miscarriage or live birth rates achieved after single-embryo transfer (55% versus 56%). Logistic regression indicated that while reduced live birth rates were associated with increasing maternal age at oocyte collection, longer culture prior to freezing and lower embryo quality, double vitrification was not a significant predictor of live birth rate. CONCLUSIONS: Blastocyst double vitrification was not shown to impact pregnancy, miscarriage or live birth rates. Although caution is necessary due to the study size, no effects of double vitrification on miscarriage rates, birthweight or gestation period were noted. These data offer reassurance given the absence of the influence of double vitrification on all outcomes after PGT-A.

Relationships between mothers and children in families formed by shared biological motherhood.

STUDY QUESTION: Does shared biological motherhood, in which a woman gives birth to the genetic child of her female partner, result in more positive mother-child relationships than donor insemination, in which only one mother is biologically related to the child? SUMMARY ANSWER: Mothers in both family types showed high levels of bonding with their children and viewed their relationship with their child positively. WHAT IS KNOWN ALREADY: There is some evidence of feelings of inequality regarding their relationship with their child between biological and non-biological mothers in lesbian mother families formed by donor insemination, with a qualitative longitudinal study showing a tendency for children to form stronger bonds with their biological than their non-biological mother. STUDY DESIGN, SIZE, DURATION: Thirty lesbian mother families created through shared biological motherhood were compared with 30 lesbian mother families formed by donor-IVF. All families had two mothers who both participated in the study, and the children were aged from infancy up to 8 years old. Data collection took place over 20 months beginning in December 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each mother in the family was interviewed separately using the Parent Development Interview (PDI), a reliable and valid measure of the nature of the parent's emotional bond with their child. The interviews were transcribed verbatim and coded separately by one of two trained researchers who were unaware of the child's family type. The interview produces 13 variables that relate to the parent's representations of themselves as a parent, 5 variables that relate to the parent's representations of the child, and a global variable that assesses the extent to which the parent can reflect on the child and their relationship. MAIN RESULTS AND THE ROLE OF CHANCE: Families formed through shared biological parenthood did not differ from families created by donor-IVF in terms of the quality of mothers' relationships with their children as assessed by the PDI. Neither were differences identified between birth mothers and non-birth mothers across the entire sample, or between gestational and genetic mothers within the families formed by shared biological parenthood. Multivariate analyses were conducted to minimize the role of chance. LIMITATIONS, REASONS FOR CAUTION: Ideally, larger samples of families and a narrower age range of children would have been studied, but this was not possible as we were reliant on the small number of families formed through shared biological motherhood in the UK when the study began. To maintain the anonymity of the families, it was not possible to request information from the clinic that may have shed light on differences between those who responded to the request to participate and those who did not. WIDER IMPLICATIONS OF THE FINDINGS: The findings show that shared biological motherhood is a positive option for lesbian couples who wish to have a more equal biological relationship to their children. One type of biological connection does not appear to have a greater influence on the quality of parent-child relationships than the other. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Economic and Social Research Council (ESRC) grant ES/S001611/1. KA is Director, and NM is Medical Director, of the London Women's Clinic. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

The true incidence of recurrent implantation failure.

PURPOSE OF REVIEW: To review the merits and limitations of current definitions of recurrent implantation failure (RIF), how they translate into estimates of incidence and to summarize how emerging concepts of individualizing the recognition of this condition can assist in changing the way RIF is identified, studied and managed. RECENT FINDINGS: The notion of a one size fits all definition of RIF is seen to be of limited clinical value, as the individual risk of repeated IVF failure has many determinants and causes. Novel approaches provide a means of identifying 'actionable' RIF in individual patients. SUMMARY: Uncertainties as to what constitutes, causes and defines RIF have served to limit progress in its management. A new approach promises to permit progress from the current impasse.

Peri-implantation glucocorticoid administration for assisted reproductive technology cycles.

BACKGROUND: The use of peri-implantation glucocorticoids has been advocated to improve embryo implantation during assistive reproductive technology (ART) cycles such as in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). It has been proposed that glucocorticoids may improve the intrauterine environment by acting as immunomodulators to reduce the uterine natural killer (NK) cell count and activity, normalising the cytokine expression profile in the endometrium and by suppression of endometrial inflammation. OBJECTIVES: To evaluate the effectiveness and safety of glucocorticoids versus no glucocorticoids administered around the time of anticipated implantation in women undergoing IVF or ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL (now also containing output from two trial registers and CINAHL), MEDLINE and Embase, on 20 December 2021, together with reference checking, contact with experts in the field and relevant conference proceedings to identify additional studies. This review is an update of the review first published in  2007 and last updated in 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the efficacy of supplementary systemic administration of glucocorticoids in the peri-implantation period with a placebo or no glucocorticoids in subfertile women undergoing IVF or ICSI were included. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth rate and multiple pregnancy. MAIN RESULTS: We included 16 RCTs (2232 couples analysed). We are uncertain whether glucocorticoids improved live birth rates (odds ratio (OR) 1.37, 95% confidence interval (CI) 0.69 to 2.71; 2 RCTs, n = 366; I2 = 7%; very low-certainty evidence). This suggests that if the chance of live birth following no glucocorticoids/placebo is assumed to be 9%, the chance following glucocorticoids would be between 6% and 21%. We are also uncertain whether there was a difference between peri-implantation glucocorticoids on multiple pregnancy rates per couple (OR 0.86, 95% CI 0.33 to 2.20; 4 RCTs, n = 504; I2 = 53%; very low-certainty evidence). The I2 of 53% may represent moderate statistical heterogeneity and results have to be interpreted with caution. With regard to pregnancy rates, we are uncertain whether there was a difference between ongoing pregnancy rates after glucocorticoids versus no glucocorticoids/placebo (OR 1.19, 95% CI 0.80 to 1.76; 3 RCTs, n = 476; I2 = 0%; very low-certainty evidence) and clinical pregnancy rates after glucocorticoids versus no glucocorticoids/placebo (OR 1.17, 95% CI 0.95 to 1.44; 13 RCTs, n = 1967; I2 = 0%; low-certainty evidence). This suggests that if the chance of clinical pregnancy following no glucocorticoids/placebo is assumed to be 25%, the chance following glucocorticoids would be between 24% and 32%. Furthermore, we are also uncertain whether peri-implantation glucocorticoids influenced miscarriage rates per couple (OR 1.09, 95% CI 0.63 to 1.87; 6 RCTs, n = 821; I2 = 0%; very low-certainty evidence), the incidence of ectopic pregnancies per couple (OR 2.28, 95% CI 0.33 to 15.62; 3 RCTs, n = 320; I2 = 0%; very low-certainty evidence) and ovarian hyperstimulation syndrome (OHSS) per couple (OR 1.07, 95% CI 0.60 to 1.90; 3 RCTs, n = 370; I2 = 0%; very low-certainty evidence) compared to no glucocorticoids/placebo. The evidence was very low to low certainty: the main limitations were serious risk of bias due to poor reporting of study methods, and serious imprecision. AUTHORS' CONCLUSIONS: Overall, there was insufficient evidence that administration of peri-implantation glucocorticoids in IVF/ICSI cycles influenced clinical outcomes. These findings were limited to the routine use of glucocorticoids in subfertile women undergoing IVF or ICSI.

Smartphone-based lifestyle coaching modifies behaviours in women with subfertility or recurrent miscarriage: a randomized controlled trial.

RESEARCH QUESTION: Is an online lifestyle coaching platform more effective at modifying periconceptional behaviours than standard advice offered by the UK National Health Service (NHS)? DESIGN: Women with subfertility or recurrent miscarriage were recruited to a two-centre randomized controlled trial. They were randomized to either the online lifestyle coaching platform Smarter Pregnancy (intervention) or periconceptional advice provided by NHS websites (control). Participants completed a lifestyle questionnaire at baseline, 6, 12, 18 and 24 weeks, and the results were used to tailor lifestyle coaching in the intervention group. At baseline, 12 and 24 weeks, composite risk scores (CRS) were calculated. A lower CRS corresponds to a healthier lifestyle. RESULTS: Of the 400 women recruited, 262 women were randomized (131 in each arm). At 12 weeks, a reduction in CRS (includes risk score for intake of folic acid, vegetables and fruits, smoking and alcohol) was observed in the intervention versus control arms. After correcting for baseline, the difference in the CRS between intervention and control was -0.47 (95% CI -0.97 to 0.02) at 12 weeks and -0.32 (95% CI -0.82 to 0.15) at 24 weeks. A statistically significant reduction in lifestyle risk scores was found in women with a body mass index (BMI) of 25 kg/m2 or above compared with those with a BMI below 25kg/m2. The odds of being pregnant at 24 weeks was increased in the intervention versus control (OR 2.83, 95% CI 0.35 to 57.76). CONCLUSIONS: The Smarter Pregnancy coaching platform is more effective in delivering lifestyle advice and modulating behaviours to support women with a history of subfertility or recurrent miscarriage than standard online NHS advice.

Embryos are exposed to a significant drop in temperature during the embryo transfer procedure: a pilot study.

RESEARCH QUESTION: During the embryo transfer procedure, to what degree of temperature drop are embryos exposed to between loading the transfer catheter and placing it into the uterus? DESIGN: Twenty-nine simulated embryo transfer procedures were carried out across five clinics. A thermocouple probe was used for standardized measurements inside the embryo transfer catheter to investigate the change in temperature that occurred in the time period between loading and placing the catheter in the uterus. RESULTS: In all cases, the temperature at the loaded catheter tip fell rapidly to ambient temperature during transit from the embryo transfer workstation in the laboratory to the procedure room, even though embryo transfer procedures, ambient temperatures and embryo transfer catheter temperatures at loading varied between clinics. CONCLUSIONS: Given the sensitivity of the pre-implantation embryo to its immediate environment, the rapid and profound drop in temperature observed at the catheter tip that houses the embryo during transit from laboratory to the uterus may affect embryo viability and health. This issue should be addressed to ensure that the tight temperature control aimed for by IVF laboratories continues throughout the embryo transfer procedure, and could improve clinical outcomes.

Factors predicting clinical outcomes from 494 vitrified oocyte donation cycles at a UK-regulated egg bank.

RESEARCH QUESTION: Do donor age, AMH, AFC, BMI and reproductive history predict response to ovarian stimulation? Do donor and recipient clinical markers and embryology parameters predict recipient pregnancy and live birth? DESIGN: Retrospective cohort study of 494 altruistic oocyte donors aged 18-35 years; 340 were matched to 559 recipients. Predictors of donor total oocyte yield and total mature oocyte yield were identified. Total and mature oocyte number were compared according to stratified donor AMH and age. Donor, recipient and embryology parameters predictive of recipient primary outcomes (clinical pregnancy and live birth) were identified. RESULTS: Donor age and AMH predicted total oocyte yield (P = 0.030 and P < 0.001)) and total mature oocyte yield (P = 0.011 and P < 0.001). Donors aged 30-35 years with AMH 15-29.9 pmol/l had lower total oocyte yield (P = 0.004) and mature oocyte yield (P < 0.001) than donors aged 18-24 years. Up to an AMH threshold of 39.9 pmol/l, increasing AMH levels predicted higher total oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.001; 15-29.9 pmol/l versus 30-39.9 pmol/l, P < 0.001; 30-39.9pmol/l versus ≥ 40 pmol/l, P = 1.0) and mature oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.005; 15-29.9 pmol/l versus 30-39.9 pmol/l, P = 0.006; 30-39.9 pmol/l versus ≥40 pmol/l, P = 1.0). In recipients, the rate of transferrable embryos per oocytes received, fertilized and number of embryo transfers needed to achieve the primary outcome were predictors of cumulative clinical pregnancy (P = 0.011, P = 0.017 and P < 0.001) and live birth (P = 0.008, P = 0.012 and P < 0.001) rates. Recipient BMI (P = 0.024) and previous miscarriages (P = 0.045) were predictors of cumulative live birth rate. Donor age 18-22 years was associated with a lower incidence of recipient clinical pregnancy (P = 0.004) and live birth (P = 0.001) after the first embryo transfer versus donor age 23-29 years. CONCLUSIONS: Donor age and AMH are independent predictors of oocyte yield. Raised recipient BMI and history of miscarriages reduce cumulative live birth rates, which may be increased by selecting donors aged 23-29 years, instead of younger donors.

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?

RESEARCH QUESTION: What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. DESIGN: A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. RESULTS: Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. CONCLUSIONS: The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.