Adverse childhood experiences are associated with increased risk of miscarriage in a national population-based cohort study in England

STUDY QUESTION: Is there an association between adverse childhood experiences (ACE) and the risk of miscarriage in the general population? SUMMARY ANSWER: Specific ACE as well as the summary ACE score were associated with an increased risk of single and recurrent miscarriages. WHAT IS KNOWN ALREADY: There is scarce evidence on the association between ACE and miscarriage risk. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective national cohort study. The sample consisted of 2795 women aged 55-89 years from the English Longitudinal Study of Ageing (ELSA). PARTICIPANTS/MATERIALS, SETTING, METHODS: Our study was population-based and included women who participated in the ELSA Life History Interview in 2007. We estimated multinomial logistic regression models of the associations of the summary ACE score and eight individual ACE variables (pertaining to physical and sexual abuse, family dysfunction and experiences of living in residential care or with foster parents) with self-reported miscarriage (0, 1, ≥2 miscarriages). MAIN RESULTS AND THE ROLE OF CHANCE: Five hundred and fifty-three women (19.8% of our sample) had experienced at least one miscarriage in their lifetime. Compared with women with no ACE, women with ≥3 ACE were two times more likely to experience a single miscarriage in their lifetime (relative risk ratio 2.00, 95% CI 1.25-3.22) and more than three times more likely to experience recurrent miscarriages (≥2 miscarriages) (relative risk ratio 3.10, 95% CI 1.63, 5.89) after adjustment for birth cohort, age at menarche and childhood socioeconomic position. Childhood experiences of physical and sexual abuse were individually associated with increased risk of miscarriage. LIMITATIONS, REASONS FOR CAUTION: Given the magnitude of the observed associations, their biological plausibility, temporal order and consistency with evidence suggesting a positive association between ACE and adverse reproductive outcomes, it is unlikely that our findings are spurious. Nevertheless, the observed associations should not be interpreted as causal as our study was observational and potentially susceptible to bias arising from unaccounted confounders. Non-response and ensuing selection bias may have also biased our findings. Retrospectively measured ACE are known to be susceptible to underreporting. Our study may have misclassified cases of ACE and possibly underestimated the magnitude of the association between ACE and the risk of miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Our study highlights experiences of psychosocial adversity in childhood as a potential risk factor for single and recurrent miscarriages. Our findings contribute to a better understanding of the role of childhood trauma in miscarriage and add an important life course dimension to the study of miscarriage. STUDY FUNDING/COMPETING INTEREST(S): ELSA is currently funded by the National Institute on Aging in USA (R01AG017644) and a consortium of UK government departments coordinated by the National Institute for Health Research. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. The authors have no actual or potential competing financial interests to disclose

Double vitrification and warming of blastocysts does not affect IVF implantation rates, or birth outcomes

Research question: Does double blastocyst vitrification and warming affect pregnancy rates from embryos subjected to PGT-A testing? Design: This is a retrospective observational analysis of embryo transfers performed at a single Centre between January 2017 and August 2022. The double vitrification (DV) 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: Comparison of the 84 DV blastocysts and 729 control SV blastocysts indicated that the DV embryos were frozen later in development and had expanded more than the SV embryos. Of the 813 embryo transfer procedures reported in this study, 452 resulted in the successful delivery of healthy infants (56%). There were however no significant differences between DV and SV embryos in the pregnancy rates achieved after single embryo transfer (55% vs 56%). Logistic regression indicated that while reduced pregnancy rates were associated with increasing maternal age at oocyte collection and at embryo transfer, and with longer culture prior to freezing, DV was not a significant predictor of outcome. Conclusions: Blastocyst DV was not shown to impact pregnancy rates. While caution is necessary due to the study size, no effects of DV on miscarriage rates, birth weight or gestation period were noted. These data offer reassurance given the absence of influence of DV on pregnancy rates after PGT-A

Rescue of late maturing oocytes in poor prognosis patients: delayed intracytoplasmic sperm injection (DICSI) results in more viable embryos

Research question: Does the application of delayed intracytoplasmic sperm injection (DICSI) in late maturing oocytes have the potential to improve fertilisation, blastocyst formation, pregnancy, and live birth rates for poor prognosis patients? Design: Retrospective analysis of 2,243 oocytes collected from 250 poor prognosis patients that underwent 311 ART cycles. Patients were offered DICSI when: over 50% of oocytes collected were immature on Day 0, fewer than 50% of the injected oocytes were fertilised on Day 1 or when patients were undergoing PGT-A with a view to increase the number of embryos available for testing. Results: Fertilisation and blastulation rates differed depending on the original assessment of the oocyte maturation stage. Euploidy rate did not however differ between blastocysts derived from fertilised oocytes originally assessed as MI or MII, and a transferred blastocyst derived from a matured oocyte originally assessed as MI was as likely to result in a live birth as one derived from an MII oocyte. For births to date, no differences between intracytoclasmic sperm injection and DICSI were observed in delivery method, gestation period or birth weight. As a result of DICSI, at least 27 cycles (8.7%), which would have otherwise been unproductive resulted in live births with a further five ongoing pregnancies. Conclusions: MI and GV oocytes can both complete maturation in vitro. The blastocysts produced from fertilisation of these oocytes appear to be as likely to be chromosomally normal as their counterparts and to result in similar live birth rates as blastocysts derived from oocytes originally assessed as MII. With no evident differences in birth outcomes and DICSI apparently increasing overall ART cycle success, this approach is shown to have value for poor prognosis patients

P-191 Differences in morphokinetic patterns and clinical outcomes between fresh and frozen oocytes; a retrospective analysis

Abstract Study question Is there a difference in morphokinetics and clinical outcomes between embryos from fresh and vitrified oocytes? Summary answer Embryos from vitrified versus fresh oocytes showed a delay at the cellular stage, but no impact on time to blastulation or clinical outcomes was evident. What is known already Oocyte vitrification has greatly impacted assisted reproduction, with the number of treatments cycles using frozen oocytes more than doubling in the UK since 2013. Studies of thawed vitrified oocytes have shown similar success rates and outcomes compared to fresh, allowing the technique to be considered safe and effective. However, vitrification and thawing subjects the oocyte to stress and osmotic changes that may be evident in alterations in the timing of their morphological events. Analysis of morphokinetic markers using time-lapse incubators was performed to investigate this. Study design, size, duration Matched cohort study. A total of 823 embryos were analysed, 414 embryos from fresh oocytes and 409 from vitrified. The embryos were from the 288 ICSI treatment cycles performed at LWC in 2019. Fresh oocytes were from women less than 35 years old undergoing fertility treatment and vitrified oocytes were from egg donors under 35. Participants/materials, setting, methods Embryos graded AA, BB, BA, AB, were selected and annotated retrospectively on the Embryoscope for the following events: pronuclei appearance (tPNa) and disappearance (tPNf), time until two (t2), four (t4) and eight cells (t8), compaction initiation (tSC), the start of blastulation (tSB) and time to expanded blastocyst (tEB). PN duration, second and third embryo cell cycle (ECC), compaction and blastulation duration were also calculated as well as differences in clinical outcomes. Main results and the role of chance Embryos derived from vitrified oocytes (EVO) were observed to have a statistically significant delay in 4/8 morphokinetic events studied: t4 (p = 0.03), t8 (p &amp;lt; 0.01), tSC (p &amp;lt; 0.01) and tSB (p = 0.01). A mean delay of 1h50min was observed when compared to embryos from fresh oocytes (EFO). ECC duration showed a statistically significant difference with a delay of 48 minutes in the vitrified group. However, compaction occurred on average just 84min faster in this group, meaning no differences were observed in the time needed to achieve a full expanded blastocyst. Regression analysis revealed a correlation between the age of the oocyte and morphokinetic timings. Oocytes from older women demonstrated slower development, with age having a statistically significant impact in the following categories: tPNa, tPNf, t2 and t4. No differences found between fresh and vitrified groups in fertilization rate (80% EFO vs 79% EVO) (p = 0.841), embryo utilization rate (60% EFO and 61% EVO) (p = 0.432), implantation rate (54% EFO vs 52% EVO) (p = 0.837) and clinical pregnancy rates (49% EFO vs 42% EVO) (p = 0.502). Limitations, reasons for caution Limitations of the present study include the retrospective analysis, small sample size and the lack of adjustment for potential contributory/confounding factors such as semen quality, body mass index (BMI), antimüllerian hormone (AMH) levels, type of ovarian stimulation or type of infertility which are known possible influencers of embryo morphokinetics. Wider implications of the findings The delay observed at the cellular stage by EVO had no impact on the time the embryos needed to achieve full expansion. While vitrification affects embryo morphokinetics, it does not seem to impact the ability of the oocyte to be fertilized, activated, or to produce a viable blastocyst and pregnancy. Trial registration number Not applicable </jats:sec

P-116 Clinical predictors of live birth rate (LBR) in donor-intrauterine insemination (D-IUI) cycles

Abstract Study question Which clinical parameters can predict LBR in D-IUI cycles? Summary answer Only age returned as a clinical predictor of D-IUI LBR. Total motile sperm count for insemination (TMSC) and stimulation protocol may help clinicians optimise LBR. What is known already D-IUI cycles are a popular treatment option for patients requiring male gamete donation. For both patient and clinician, identification of parameters that can guide clinical decision-making during fertility treatment is important to optimise clinical outcomes. To date, few studies have investigated D-IUI cycle parameters with live birth as the primary outcome. Moreover, previous studies can be limited from lack of control of covariates, as well not accounting for data skewing from inclusion of multiple cycles per patient. Study design, size, duration A retrospective analysis of 1925 D-IUI cycles in 638 patients between 2018-2020 at a single UK-based centre was performed. All donors were recruited by the London Sperm Bank as per the HFEA regulations. Inclusion criteria for donor sperm quality were all samples that met the WHO criteria. Exclusion criteria were cycles where live birth outcome was unknown. Participants/materials, setting, methods Patients underwent natural or stimulation cycle. Stimulation included clomiphene or letrozole, gonadotrophins +/- GnRH agonist, an hCG trigger or LH-monitoring to time insemination and micronised vaginal progesterone for luteal support. Insemination was scheduled 24 hours following surge detection/trigger administration. TMSC is presented per 0.5ml vial, which is post-preparation sample for insemination. T-test for continuous variables and Fisher’s Exact test for categorical variables were performed. For multivariate analysis, a generalised mixed effects logistic regression was performed. Main results and the role of chance Median cohort age was 36 ± SE 0.1, median TMSC was 14x106 ± SE 0.2x106. Of recipients, 53% were same sex couples, 41% were single women, 6.3% were heterosexual couples. There was no significant difference in TMSCs between cycles that produced a live birth and those that did not (14x106 and 13.9x106 respectively, P = 0.1). Dividing TMSC into 5x106 increments demonstrated that small increases in LBR per cycle occurred between 2.5-25x106. On average, LBR increased by 1.3% with each increment up to 25x106, reaching 15%. Beyond this, no further increase in LBR was observed. However, these incremental increases were not statistically significant (P = 0.6). Gonadotrophin stimulation (without agonist) achieved significantly higher LBRs than all other protocols (17.1%, P &amp;lt; 0.001). This persisted when stratifying by age (&amp;lt;35; 30%, 35-37; 29%, 38+; 12.6%). A mixed effects logistic regression model demonstrated that only age returned as a significant negative predictor of LBR (aOR 0.9, 95% CI 0.86-0.94, P &amp;lt; 0.001). There was no effect of TMSC on LBR (aOR 1.0, 95% CI 0.99-1.02, P = 0.7). Gonadotropin stimulation was associated with over double increased odds of achieving a live birth, which came close to significance (aOR 2.29, 95% CI 0.98-5.4, P = 0.06). Limitations, reasons for caution The choice of management regimen could have been influenced by uncontrolled factors, introducing bias in this retrospective study. Other semen parameters were not included in the multivariate analyses which could, in turn, have affected live birth outcome, which should be considered. Wider implications of the findings These findings demonstrate that increasing TMSC may be associated with small rises in LBR up to 25x106 in D-IUI cycles. While gonadotrophin stimulation appeared most effective, only age was shown to be an independent predictor of LBR. Collectively, these parameters may assist clinicians in optimising LBR in D-IUI cycles. Trial registration number None </jats:sec

Childhood experiences of parenting and age at menarche, age at menopause and duration of reproductive lifespan: Evidence from the English Longitudinal Study of Ageing

Objectives: The parent-child relationship is critical for human development, yet little is known about its association with offsprings’ reproductive health outside the context of abuse and neglect. We investigated whether childhood experiences of poor-quality parenting (characterized as decreased parental care and increased parental overprotection) are associated with women&apos;s reproductive timing and lifespan. Study design: Observational study of 2383 women aged 55–89 years in 2007 from the English Longitudinal Study of Ageing (ELSA). Multinomial logistic regression models were estimated. Main outcome measures: Self-reported ages at menarche and menopause and duration of reproductive lifespan. Results: Increasing maternal and paternal overprotection were associated with later menarche (≥16 years) after adjustment for age and childhood socioeconomic position (relative risk ratio (RRR) 1.11, 95% CI 1.02–1.21 and 1.11, 95% CI 1.01–1.21, respectively, per unit increase in the predictor). Increasing parental overprotection and decreasing paternal care were associated with earlier menarche (≤10 years). However, these associations were marginally non-significant. Maternal and paternal overprotection were also inversely associated with age at natural menopause after adjustment for age, childhood socioeconomic position and age at menarche (p value for linear trend = 0.041 and 0.004, respectively). Further, increasing paternal overprotection was associated with a shorter reproductive lifespan (≤33 years) (RRR 1.09 (1.01–1.18), per unit increase in the predictor) after adjustment for age and childhood socioeconomic position. Adjustment for additional childhood and adult factors did not explain these associations. Conclusions: Women who experienced poor-quality parenting in childhood, especially increased levels of parental overprotection, might be at increased risk of an unfavourable reproductive health profile that is characterized by late or early menarche, premature menopause and a shorter reproductive lifespan. © 2019 The Author

P–690 Clinical predictors of a high oocyte maturation rate in IVF treatment cycles

Abstract Study question Which clinical parameters predict a high oocyte maturation rate in patients undergoing IVF treatment? Summary answer Time between oocyte collection and insemination demonstrated significant association with oocyte maturation and represents a parameter that could be optimised in IVF cycles. What is known already Oocyte maturation is an important factor determining IVF outcomes and can be a rate-limiting step for patients undergoing treatment. A number of clinical and laboratory variables may affect this process, including the choice of trigger prior to oocyte collection, and certain laboratory procedures. Identification of which of these are predictors of maturation in individual centres enables local protocols to be optimised. Study design, size, duration This is a retrospective study of 714 oocyte collections from 661 women between January 2020 to November 2020 treated in a large, single centre in the UK. Subsequent fertilisation on fresh oocytes consisted of 371 IVF and 343 ICSI cycles. Participants/materials, setting, methods Patient and treatment data was collected by clinical staff at time of treatment. Either GnRH agonist, hCG or double trigger were administered 36 hours before collection. Prior to ICSI, oocyte maturation was assessed by visualisation of polar body (PB) extrusion. After IVF, the number of 2PNs plus unfertilised oocytes with PB extrusion were assessed. Univariate analyses consisted of Mann-Whitney test, t-test, Fisher’s Exact test or ANOVA. Potential predictors were investigated by logistic regression. Main results and the role of chance The end point was maturation rate, defined as high (greater or equal to 70%) or low (less than 70%). Factors predictive of a high rate included insemination more than 4 hours after collection. Oocytes inseminated over 4 hours post-collection displayed significantly higher maturation rates than oocytes inseminated less than 2 hours after collection (69% and 61% respectively; P = 0.01). Oocytes inseminated between 2–4 hours also had higher maturation than those inseminated less than 2 hours post-collection, but this did not reach significance (67% and 61%, respectively; P = 0.06). Further, oocytes fertilised by ICSI had significantly higher maturation than conventional IVF (77% and 67%, respectively, P &amp;lt; 0.001). No significant difference in oocyte maturation between triggers was observed. Similarly, neither age, AMH, a diagnosis of PCOS or number of oocytes collected predicted oocyte maturation in univariate analysis. Logistic regression analysis showed only time between oocyte collection and insemination (aOR 2.12; 95% CI 1.03–4.38; P = 0.04) to be a significant independent predictor. Limitations, reasons for caution Varying means of data collection across clinics and between clinical staff inevitably leads to provision of incomplete data and should be taken into consideration alongside interpretation. Prescription bias of specific triggers to certain patient demographics should be noted. Wider implications of the findings: Collectively, these results suggest that greater time between oocyte collection and insemination could be recommended to IVF clinics that wish to optimise their oocyte maturation. Triggering final maturation with GnRH agonist versus hCG or dual trigger did not have a significant effect on oocyte maturation when adjusted for confounders. Trial registration number Not applicable </jats:sec

P–226 Failure of blastocoele expansion within the first two hours post thawing could halve the chances of implantation

Abstract Study question The aim of this study was to evaluate the influence of blastocoele re-expansion time of warmed vitrified blastocysts on clinical pregnancy outcome. Summary answer Clinical pregnancy rate was significantly higher after transfer of warmed vitrified blastocysts that were fully expanded within 2 hours post thaw. What is known already The number of blastocysts being vitrified worldwide has increased dramatically over recent years. A combination of factors has led to this including the introduction of vitrification, an increase in freeze-all policies, single embryo transfer and an increase in preimplantation genetic testing. Currently, blastocyst re-expansion after thawing is used to indicate the survival status of the blastocyst and when combined with the morphology of blastocyst can predict its reproductive potential. While time taken for blastocoele re-expansion has been proposed to be a biomarker of viability, its value in clinical practice remains unclear. Study design, size, duration This retrospective study analysed outcomes in patients who had frozen embryo transfers between June-December 2020. 233 embryos were reviewed with time-lapse to assess their blastocoele expansion post-warming and three groups were identified. The first included fully expanded blastocysts post-warming. The second group included partially expanded blastocysts and the third non-expanded blastocysts. In addition, the groups were subcategorised into two further categories depending on whether they took less or more than 2 hours to complete expansion. Participants/materials, setting, methods 233 vitrified/warmed embryos from 216 patients were analysed using time-lapse incubators. The first group included 134 blastocysts, of which 70 were fully expanded within 2 hours and 64 after 2 hours post thaw. The second group had 70 embryos of which 45 expanded partially within 2 hours and 25 after 2 hours. The third had 28 embryos that had no expansion within the first 2 hours (n = 20) or after 2 hours (n = 8). Main results and the role of chance Blastocysts were collapsed by laser prior to vitrification. Single blastocyst transfer was performed for all patients. The mean transferred embryo age was 32.1± 5.5 and the recipient’s was 37.5± 5.9. Fully expanded blastocysts (n = 70) within 2 hours demonstrated a clinical pregnancy rate (CPR) of 57% compared with 38% from those that expanded fully after 2 hours (n = 64) (p = 0.02). Blastocysts with some form of expansion (full or partial) within 2 hours post-warming (n = 115) were associated a significantly higher CPR compared to those expanding after 2 hours (n = 89). The CPR was 55% and 39% respectively (p = 0.02). Embryos that showed no expansion (n = 20) within the first 2 hours post thaw resulted in CPR of 28%. Interestingly, embryos that showed no expansion after 2 hours resulted in no pregnancy. When combining morphology as a selection criterion, expansion within 2 hours of thawing was associated with a CPR of 62.5% for ≥4AB embryos, 50% for BB embryos and 45% for poorer embryos ≤CB.In conclusion, failure of blastocoele expansion post 2 hours reduced by half the chances of clinical pregnancy (p = 0.03). Combination of the degree of re-expansion and embryo morphology is an important predictor tool to improve clinical outcomes in frozen embryo transfers. Limitations, reasons for caution This study uses a small sample size of patients. The data are observational and were retrospectively analysed so unknown confounders could not be assessed. The addition of more cycles and further multivariate analysis, is essential for confirmation of the findings. However, initial results are very reassuring. Wider implications of the findings: The degree of speed of re-expansion post warming should be used as a predictor for prioritisation of embryos for transfer. Owing to these preliminary findings there is rationale for a larger scale study combining other morphological indicators that could further assess implantation indicators and assist patient counselling Trial registration number Not applicable </jats:sec

P–136 Factors predicting clinical outcomes of 511 recipients of vitrified oocyte donation from an UK-regulated egg bank

Abstract Study question Do established donor and recipient clinical markers predict recipient clinical pregnancy and live birth rates (LBRs) in a vitrified oocyte donation programme? Summary answer Recipient BMI and previous miscarriages predicted cumulative LBR. Likelihood of clinical pregnancy and LBR was higher in recipients of donors aged 23–29 than donors 18–22. What is known already The influence of age on ovarian reserve underlies the upper limit of 35 years for UK donors. However, recent evidence suggests that oocyte aneuploidy rates follow an inverse U-shaped curve in relation to a woman’s age. Conflicting evidence exists regarding the impact of other donor-related factors including BMI, AMH, oocyte yield and prior reproductive history on recipient outcomes. Moreover, the effect of recipient age, BMI, and reproductive history on oocyte donation outcome remains unclear. Study design, size, duration Retrospective cohort study of 325 altruistic oocyte donors matched to a total of 511 recipients. Only first donations taking place between January 2017 and December 2019 were included. Participants/materials, setting, methods All oocyte donors were altruistic volunteers aged 18–35 with no prior infertility diagnosis. Donor and recipient screening for suitability and safety was carried out according to the Human Fertilisation Embryology Authority guidelines. Backward stepwise logistic regression was used to identify donor, recipient and embryology parameters predictive of recipient primary outcomes defined as clinical pregnancy and live birth, either cumulative or after the first embryo transfer (ET). Main results and the role of chance A total of 705 fresh and frozen/thawed ETs were performed, of which 76% were elective single embryo transfers (eSETs) of blastocysts (96.5%), resulting in a cumulative clinical pregnancy and LBR of 83.5% and 70.5% respectively after 3 ETs. Recipient BMI and previous miscarriages were predictors of cumulative LBR (p &amp;lt; 0.05). The ratio of transferrable embryos per oocytes received/fertilised and the number of ETs needed to achieve the intended primary outcome were predictors of cumulative clinical pregnancy and LBR (p &amp;lt; 0.05). Donor age 18–22 was associated with lower incidence of recipient clinical pregnancy and live birth after the first ET, as compared to donor age 23–29 (p &amp;lt; 0.05). Limitations, reasons for caution The present study included only healthy oocyte donors, thus conclusions may not apply to subfertile or less healthy women. Male factors were not accounted for. Wider implications of the findings: We demonstrate the efficacy of vitrified oocyte donation treatment and identify recipient BMI, previous miscarriages and embryology parameters as predictors of cumulative LBR. Additionally, the choice of donors aged 18–22 instead of older donors is found not to be advantageous for increasing the chance of clinical pregnancy and live birth. Trial registration number Not applicable </jats:sec

P-335 How to define recurrent implantation failure and when to start investigating the endometrium? Lessons from three years’ experience in a dedicated unit

Abstract Study question Should we always define recurrent implantation failure (RIF) after three unsuccessful transfers and only then start investigating the endometrium? Summary answer Endometrial investigations can be beneficial for patients with RIF. However, waiting for three previous failures before instituting assessment might not be appropriate in every situation. What is known already The definition of unexplained recurrent implantation failure (RIF) continues to be debated. This usually implies a lack of embryo implantation after the transfer of three good quality blastocysts on an apparently responsive and anatomically normal endometrium. To deal with this frustrating and distressing situation for both the patient and the clinician, additional empirical interventions are often blindly used. This approach may exacerbate rather than ameliorate any underlying aetiology. There is a need therefore to base interventions on diagnostic rationale wherever possible. Study design, size, duration In order to base advice and any interventions for RIF on diagnostic rationale, we created a referral unit dedicated to the investigation and treatment of patients meeting the traditional criteria for RIF. Over three years, 395 patients were referred to this unit and 237 completed their investigations. Here we present the clinical outcomes and insights obtained over these three years. Participants/materials, setting, methods Blood sampling for serum progesterone level and endometrial pipelle biopsy were performed after five days of luteal support in a standardised substituted cycle. The samples underwent dating by gene expression (ERA test) and immune assessment describing the recruitment and activation of the uterine Natural Killer cells (MLI test, Matrice Lab Innove). A personalised treatment plan was thus derived and suggested to the referring clinician. The outcomes after the subsequent personalised single embryo transfer were monitored. Main results and the role of chance The patients referred had an average of 4.3 previous good quality blastocysts transferred in the past. 58% of the referred patients had used their own eggs, including 49% after conventional IVF or ICSI, and 9% after using PGT-A. 42% of the referred patients had used donor eggs. To date, 237 patients completed their endometrial assessment. 92% of the tested patients revealed at least one disrupted endometrial marker. With the subsequent personalised single embryo transfer, an implantation rate of 58% was observed. The ongoing pregnancy rate at 12 weeks was reported at 39%. Limitations, reasons for caution While confirmatory prospective controlled studies are required, these data indicate that more targeted rather than blind usage of simple known therapeutics could be beneficial for patients experiencing RIF. The clinical context these referred was highly variable, including patients undergoing PGT-A and egg donation. Wider implications of the findings Given the higher implantation rates to be expected in some groups, waiting for at least three embryos to fail before investigating the endometrium may be inappropriate and underlie the relatively high miscarriage rate observed. The investigation of implantation failure should be driven by context rather than arbitrary definition. Trial registration number Not Applicable </jats:sec