ICSI does not improve reproductive outcomes in autologous ovarian response cycles with non-male factor subfertility.

STUDY QUESTION: Does the method of fertilisation improve reproductive outcomes in poor ovarian response (POR) cycles when compared to all other ovarian response categories in the absence of male factor subfertility? SUMMARY ANSWER: ICSI does not confer any benefit in improving the clinical pregnancy or live birth (LB) outcome in autologous ovarian response cycles in the absence of male factor subfertility when compared to IVF. WHAT IS KNOWN ALREADY: ICSI is associated with an improved outcome when compared to IVF in patients with severe male factor subfertility. STUDY DESIGN, SIZE, DURATION: A retrospective study involving 1 376 454 ART cycles, of which 569 605 (41.4%) cycles fulfilled the inclusion and exclusion criteria for all autologous ovarian response categories: 272 433 (47.8%) IVF cycles and 297 172 (52.2%) ICSI cycles. Of these, the POR cohort represented 62 641 stimulated fresh cycles (11.0%): 33 436 (53.4%) IVF cycles and 29 205 (46.6%) ICSI cycles. PARTICIPANTS/MATERIALS, SETTING, METHOD: All cycles recorded on the anonymised Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All fresh cycles with normal sperm parameters, performed after 1998 were included: frozen cycles, donor oocyte and sperm usage, intrauterine insemination cycles, preimplantation genetic testing (PGT) for aneuploidies (PGT-A), PGT for monogenic/single gene defects (PGT-M), PGT for chromosomal structural arrangements (PGT-SR) cycles, where the reason for stimulation was for storage and unstimulated cycles were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: ICSI did not confer any benefit in improving the LB outcome when compared to conventional IVF per treatment cycle (PTC), when adjusted for female age, number of previous ART treatment cycles, number of previous live births through ART, oocyte yield, stage of transfer, method of fertilisation and number of embryos transferred in the POR cohort (adjusted odds ratio [a OR] 1.03, 99.5% confidence interval [CI] 0.96-1.11, P = 0.261) and all autologous ovarian response categories (aOR 1.00, 99.5% CI 0.98-1.02, P = 0.900). The mean fertilisation rate was statistically lower for IVF treatment cycles (64.7%) when compared to ICSI treatment cycles (67.2%) in the POR cohort (mean difference -2.5%, 99.5% CI -3.3 to -1.6, P < 0.001). The failed fertilisation rate was marginally higher in IVF treatment cycles (17.3%, 95% binomial exact 16.9 to 17.7%) when compared to ICSI treatment cycles (17.0%, 95% binomial exact 16.6 to 17.4%); however, this did not reach statistical significance (P = 0.199). The results followed a similar trend when analysed for all autologous ovarian response categories with a higher rate of failed fertilisation in IVF treatment cycles (4.8%, 95% binomial exact 4.7 to 4.9%) when compared to ICSI treatment cycles (3.2%, 95% binomial exact 3.1 to 3.3%) (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The quality of data is reliant on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst-stage embryo transfers. The inability to link the treatment cycle to the individual patient meant that we were unable to calculate the cumulative LB outcome per patient. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date which evaluates the impact of method of fertilisation in the POR patient and compares this to all autologous ovarian response categories. The results demonstrate that ICSI does not confer any benefit in improving reproductive outcomes in the absence of male factor subfertility, with no improvement seen in the clinical pregnancy or LB outcomes following a fresh treatment cycle. STUDY FUNDING/COMPETING INTEREST(S): The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Bayer AG, Wellbeing of Women, the European Union and Finox. TRIAL REGISTRATION NUMBER: Not applicable.

Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.

STUDY QUESTION: Does ART impact the secondary sex ratio (SSR) when compared to natural conception? SUMMARY ANSWER: IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. WHAT IS KNOWN ALREADY: The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. STUDY DESIGN SIZE DURATION: A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. PARTICIPANTS/MATERIALS SETTING METHODS: All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1-105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2-105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6-111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5-99.2; odds ratio (OR) 1.16, 95% CI 1.12-1.19, P < 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5-106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3-103.1; OR 1.03, 95% CI 1.01-1.06, P = 0.011) for all fertilization methods. LIMITATIONS REASONS FOR CAUTION: The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. STUDY FUNDING/COMPETING INTERESTS: The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. TRIAL REGISTRATION NUMBER: Not applicable.

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage.

When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM.

Oxfordshire Women and Their Children's Health (OxWATCH): protocol for a prospective cohort feasibility study.

INTRODUCTION: Some specific pregnancy disorders are known to be associated with increased incidence of long-term maternal ill health (eg, gestational diabetes with late onset type 2 diabetes; pre-eclampsia with arterial disease). To what degree these later health conditions are a consequence of the woman's constitution prior to pregnancy rather than pregnancy itself triggering changes in a woman's health is unknown. Additionally, there is little prospective evidence for the impact of pre-pregnancy risk factors on the outcome of pregnancy. To understand the importance of pre-pregnancy health requires the recruitment of women into a long-term cohort study before their first successful pregnancy. The aim of this feasibility study is to test recruitment procedures and acceptability of participation to inform the planning of a future large-scale cohort study. METHODS: The prospective cohort feasibility study will recruit nulliparous women aged 18-40 years. Women will be asked to complete a questionnaire to assess the acceptability of our recruitment and data collection procedures. Baseline biophysical, genetic, socioeconomic, behavioural and psychological assessments will be conducted and samples of blood, urine, saliva and DNA will be collected. Recruitment feasibility and retention rates will be assessed. Women who become pregnant will be recalled for pregnancy and postpregnancy assessments. ETHICS AND DISSEMINATION: The study protocol was approved by South Central Portsmouth REC (Ref: 12/SC/0492). The findings from the study will be disseminated through peer reviewed journals, national and international conference presentations and public events. TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov; NCT02419898.

Interleukin-1 family cytokines and their regulatory proteins in normal pregnancy and pre-eclampsia.

Maternal systemic inflammation is a feature of pre-eclampsia, a condition in pregnancy characterized by hypertension and proteinuria. Pre-eclampsia is caused by the placenta; many placental factors contribute to the syndrome's progression, and proinflammatory cytokines have been identified previously as one such mediator. The interleukin (IL)-1 family of cytokines are key regulators of the inflammatory network, and two naturally occurring regulatory molecules for IL-1 family cytokines, IL-1RA and sST2, have been found previously to be elevated in maternal blood from women with pre-eclampsia. Here we investigate more recently identified IL-1 family cytokines and regulatory molecules, IL-1RAcP, IL-37, IL-18BP, IL-36α/ß/γ/Ra and IL-38 in pre-eclampsia. Pregnant women have more circulating IL-18BP and IL-36Ra than non-pregnant women, and sIL-1RAcP is elevated from women with pre-eclampsia compared to normal pregnancies. The placenta expresses all the molecules, and IL-37 and IL-18BP are up-regulated significantly in pre-eclampsia placentas compared to those from normal pregnancies. Together, these changes contribute to the required inhibition of maternal systemic cytotoxic immunity in normal pregnancy; however, in pre-eclampsia the same profile is not seen. Interestingly, the increased circulating levels of sIL-1RAcP and increased placental IL-18BP and IL-37, the latter of which we show to be induced by hypoxic damage to the placenta, are all factors which are anti-inflammatory. While the placenta is often held responsible for the damage and clinical symptoms of pre-eclampsia by the research community, here we show that the pre-eclampsia placenta is also trying to prevent inflammatory damage to the mother.