Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos.

BACKGROUND: The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stage in vitro, while the others arrest at cleavage to late morula or early blastocyst stages. METHODS: To achieve a more complete view of the impacts of aneuploidy, we applied low-coverage sequencing-based PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time-lapse imaging (n = 843). RESULTS: The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20 to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. CONCLUSIONS: We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryos in vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage.

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.

Shared intent in third-party donation will underpin the success of new surrogacy laws.

The demands for surrogacy treatments continue to grow worldwide. However the legal guidance for non-commercial surrogacy treatments remains inadequate, and this commentary argues how the forthcoming guidance on surrogacy from the UK Law Commissions would benefit from a bold decision based on previous experience derived from similar developments in three other areas of assisted conception.

First clinical report of 179 surrogacy cases in the UK: implications for policy and practice.

RESEARCH QUESTION: What implications for policy and practice can be derived from outcomes and trends observed across 8 years of a surrogacy programme in two UK-regulated IVF centres (London, Cardiff)? DESIGN: Retrospective cohort study analysing surrogacy treatments undertaken between 2014 and September 2021. RESULTS: Surrogacy continues to rise in popularity in the UK despite the inability of those supporting safe and professional practice to advertise to recruit surrogates. In two IVF centres regulated by the Human Fertilisation and Embryology Authority (HFEA), both the number of surrogacy treatments and the proportion of those undertaken on behalf of same-sex male intended parents increased year on year in the period studied. From a cohort of 108 surrogates, 71 babies were born to 61 surrogates (with five pregnancies ongoing) by February 2022. No statistically significant difference in live birth rates (LBR) was observed between the heterosexual couples and same-sex male couples. Sample sizes of single and transgender intended parents were too small (n < 5) to compare. The use of vitrified oocytes in surrogacy treatments has increased year on year, while fresh oocyte use has declined since peaking in 2019. There was no significant difference in LBR between fresh and vitrified oocyte usage across the cohort. CONCLUSIONS: The number of surrogacy treatments steadily increased, with clear evidence that the proportion of same-sex male couples accessing surrogacy is a major contributor to this growth. Vitrified/warmed oocyte use now outstrips the use of fresh oocytes in the surrogacy treatment cycles studied here. The results represent a strong basis for supporting the liberalization of regulatory reform expected to be introduced in the UK later in 2022.

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.

Cumulative live birth rates following insemination with donor spermatozoa in single women, same-sex couples and heterosexual patients.

RESEARCH QUESTION: What is the cumulative live birth rate (LBR) following donor intrauterine insemination (IUI-D) treatment in a large, retrospective, single-centre cohort of single women, same-sex couples and heterosexual patients? DESIGN: Outcomes from 8922 treatments performed in 3333 consecutive women (45% single, 43% from same-sex and 12% from heterosexual couples) were analysed in a 13-year retrospective study from a private, HFEA-regulated UK centre between January 2004 and December 2016. RESULTS: A total of 795 live births resulted in an overall delivery rate of 8.9% per cycle, including 24 (3%) twins. Age-specific crude and expected cumulative LBR calculated in four age groups (<35, 35-37, 38-39 and 40-42 years) were 29, 23, 21, 12% and 66, 49, 54, 28%, respectively. A plateau was reached after six cycles, beyond which there were few additional live births. There was no significant difference in cumulative LBR between single women and same-sex couples. In a multivariate analysis, female age (adjusted odds ratio [aOR] 0.92; 95% confidence interval [CI] 0.90-0.93; P < 0.0001), previous live birth following IUI-D (aOR 2.15; 95% CI 1.69-2.73; P < 0.0001) and mild stimulation (aOR 1.27; 95% CI 1.09-1.48; P = 0.02) had a significant effect on outcome, but relationship status or cycle rank did not. CONCLUSIONS: These results indicate there is little benefit performing more than six cycles of IUI-D in all women up to 40 years old, including those from same-sex relationships, while only three attempts seem reasonable in those aged 40-42 years. These results do not reflect current clinical guidelines in the UK. The authors found that consecutive IUI cycles, especially with mild stimulation, were an efficient treatment in all indications.

Vitrification and the demise of fresh treatment cycles in ART.

The advent of vitrification has transformed the therapeutic landscape in assisted reproductive technology. Clear evidence for this is provided by the dramatic rise in the number of frozen embryo transfer (FET) cycles being carried out annually. In this review, we examine the reasons that underlie this trend and the current evidence that points to the place FET cycles will come to inhabit in the future. Safety issues have been central to the narrative around the clinical application of vitrification and, as the evidence base grows, the risk benefit balance will become clearer for different patient groups. These will include recipients of donor eggs, as in some centres the use of cryopreserved donor eggs now exceeds that of fresh oocytes. Efficient cryopreservation techniques have also affected international transport of gametes and embryos, increasing international access. The profound changes that vitrification has created promises to fulfil a prediction made by this journal's founding Editor, Bob Edwards, that embryo and cryopreservation would solve many of the challenges presented by assisted reproductive technology.

High implantation and clinical pregnancy rates with single vitrified-warmed blastocyst transfer and optional aneuploidy testing for all patients.

This study reports the results of a 2-year long IVF programme ('One by One') in which all patients (median age 40 years; range 27-45 years) were offered preimplantation genetic testing for aneuploidy (PGT-A) and had all blastocysts vitrified (freeze-only), followed later by single vitrified-warmed blastocyst transfer (vSET) in managed cycles. Between January 2016 and December 2017, a total of 155 patients started 222 treatment cycles and 99 (45%) cycles resulted in one or more vitrified blastocysts (untested or with normal copy number for all chromosomes) available for transfer. Seventeen patients (11%) aged ≤35 years opted out of PGT-A. Over this period, 85 vSETs in 74 patients resulted in an implantation rate of 80% (68/85) and a singleton clinical pregnancy rate of 66% (56/85). Cumulative live birth rates will not be known for 1-2 years. Nevertheless, these high success rates with vSET confirm larger studies using selected patients and are likely to deliver similar, if not higher, live birth rates per cycle started than rates typically reported in national registries with conventional IVF and transfer of one or more fresh and/or frozen embryos.

For whom the egg thaws: insights from an analysis of 10 years of frozen egg thaw data from two UK clinics, 2008-2017.

PURPOSE: To better understand the characteristics of patients who returned to thaw their frozen eggs to attempt conception and their outcomes. METHODS: A retrospective analysis of clinical records for all own egg thaw patients in two UK fertility clinics across 10 years, 2008-2017. RESULTS: There were 129 patients who returned to thaw their eggs, of which 46 had originally frozen their eggs for social reasons and 83 for a variety of clinical, incidental, and ethical reasons (which we have called "non-social"). Women who had frozen their eggs for social reasons were single at time of freeze, with an average age of 37.7. They kept their eggs in storage for just under 5 years, returning to use them at the average age of 42.5. 43.5% were single at time of thaw, and 47.8% used donor sperm to fertilise their eggs. Women whose eggs were frozen for non-social reasons were almost all (97.6%) in a relationship at both time of freeze and thaw. They had an average age of 37.2 at first freeze and 37.6 at thaw, having kept their eggs in storage for an average of 0.4 years. Overall, there was a 20.9% success rate among women attempting conception with frozen-thawed eggs. CONCLUSIONS: Despite widespread assumptions, many women attempting conception with thawed eggs had not initially frozen them for social reasons. Women who froze their eggs for social reasons presented distinctly and statistically different characteristics at both time of freeze and thaw to women whose eggs were frozen for non-social reasons.

Development of an Interprofessional Educational Electronic Health Record.

This paper identifies issues relating to academic health record systems and outlines a project currently underway to develop an open source educational clinical information system to better support interprofessional health education.

Reconceiving egg freezing: insights from an analysis of 5 years of data from a UK clinic.

RESEARCH QUESTION: What can we learn from 5 years of egg-freezing practice in the UK? What are the different categories of egg freezing, and what are the social and demographic characteristics of patients, and their decisions regarding subsequent storage or thawing? DESIGN: A retrospective analysis of clinical and laboratory data of all 514 cycles of 'own' egg freezing conducted at the London Women's Clinic in the 5-year period from the start of 2012 to the end of 2016. RESULTS: This analysis, the first of its kind, develops a clearer picture of egg-freezing trends in the UK and fills in the details behind the Human Fertilisation and Embryology Authority's national figures. Four different categories of egg freezing are identified and the appropriate category allocated to each of the 514 cycles undertaken by 352 patients. To the established categories of 'medical' and 'social' already discussed in the literature, we add the two new categories of 'clinical' and 'incidental' egg freezing. We show how each of these categories presents a distinct egg-freezing patient profile, and discuss the similarities and differences between them across variables such as age, relationship status, number of eggs frozen, number of egg-freezing cycles undertaken, and the current status of frozen eggs. CONCLUSIONS: The data require a reconceptualization of the phenomenon of egg freezing, and argue for the importance of clearly and accurately differentiating between different categories of egg-freezing practice in clinical and national data collection in order to adequately inform future practice, regulation and the decision-making processes of patients considering these procedures.

The UK´s anomalous 10-year limit on oocyte storage: time to change the law.

There has been a growing recognition in the UK that the statutory storage limit for frozen eggs, which currently stands at 10 years, requires a review. The UK regulator, the Human Fertilization and Embryology Authority (HFEA), has recognized the problem and the Equality and Human Rights Commission is also sympathetic with the demand to change the current legislation. There is also strong desire on the part of assisted reproductive technology (ART) professionals and patients to change the current guidelines. For many women, the available alternatives of transporting their eggs to an overseas destination or having them fertilized with donor sperm and then stored as embryos is objectionable.