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The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Research Question: Can a novel closed simplified IVF culture system be used to achieve outcomes comparable to those obtained with intracytoplasmic sperm injection (ICSI) followed by conventional culturing?, Design: This analysis is part of a non-inferiority prospective study comparing ICSI and a simplified culture system (SCS) for gamete fertilization in a selected group of patients. According to protocol, sibling oocytes in intact cumulus-oocyte complexes were randomly distributed between ICSI and conventional insemination in the SCS. For women, selection criteria included being under 43 years of age and at least six eggs at retrieval. An inseminating motile sperm count ≥1 million was required. The primary outcome measure was ongoing pregnancy rate (>12 weeks) per cycle; secondary outcome measures included fertilization rate, miscarriage rate and implantation rate (ongoing pregnancy rate per embryo)., Results: From January 2016 until December 2019, 653 SCS/ICSI cycles were performed yielding a total of 7915 oocytes. The fertilization rate was 61.1% and 50.4% for SCS and ICSI (P < 0.0001), respectively. The ongoing pregnancy rate was 32.0% for SCS and 36.7% for ICSI (P = 0.27). Implantation rate was 30.6% for SCS and 34.4% for ICSI (P = 0.35). The miscarriage rate was 7.5% and 6.5% for SCS and ICSI, respectively (P = 0.75)., Conclusion: No difference was found in ongoing pregnancy rate, implantation rate and the miscarriage rate between SCS and ICSI in this selected patient cohort., (Copyright © 2022 Reproductive Healthcare Ltd. All rights reserved.)

Research Question: Is there a difference in perinatal outcome in the same patient cohort for babies conceived following randomization of sibling oocytes allocated to a simplified IVF culture system (SCS) or intracytoplasmic sperm injection (ICSI) followed by conventional culturing?, Design: The study compared the perinatal outcomes of 367 babies born from 1 January 2013 until 31 December 2020 after using split SCS and ICSI insemination of sibling oocytes in a selected group of normo-responsive women, excluding cases of severe male infertility. Primary outcome measures were preterm birth (PTB; <37 weeks' gestation), low birthweight (LBW; <2.5 kg) and small for gestational age (SGA) as a primary outcome parameter while secondary outcome measures included mean birthweight, mean gestational age, extreme prematurity (<32 weeks), very low birthweight (<1.5 kg), perinatal mortality, multiple pregnancy and Caesarean section rate., Results: A total of 105 and 103 singleton babies were born after fresh embryo transfer (FRET) and 71 and 50 singletons after frozen embryo transfer (FET) in the SCS and ICSI groups, respectively. For babies born after FRET, the LBW rate was 2.9% (3/105) for SCS and 7.8% (8/103) for ICSI (P = 0.10). LBW occurred in 4.2% (3/71) and 0% (0/50) of babies born after the transfer of cryopreserved-thawed SCS and ICSI embryos, respectively (P = 0.14). The rate of PTB was 3.8% and 6.8% for SCS and ICSI in FRET cycles (P = 0.33), and 8.5% and 6.0% for SCS and ICSI in FET cycles (P = 0.62). One congenital malformation was found in the SCS FET group., Conclusion: There was no difference in perinatal outcome for singleton and twin babies born after SCS and ICSI., (Copyright © 2022 Reproductive Healthcare Ltd. All rights reserved.)

The success of IVF is currently measured by pregnancy or live birth rate only, without any consideration given to health outcomes for the woman and baby and the total cost of treatment. A successful IVF cycle should be redefined as the birth of a healthy singleton baby at term, without compromising the health and safety of the woman and baby achieved at the lowest possible cost. We recommend that the performance indices for an IVF programme should be based on a weighted scoring system according to live birth per embryo transferred, cumulative live birth rate over 1 year, total cost of treatment cycle and maternal and perinatal outcomes. This holistic approach would prevent the use of unnecessary high stimulation, unproven add-ons without regard for the welfare of the patients and would increase accessibility to IVF treatment., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Research Question: How many oocytes or embryos are needed to optimize the live birth rate (LBR) per cycle and cumulative LBR (CLBR) following mild stimulation IVF (MS-IVF) in women with uncompromised ovarian reserve?, Design: Retrospective analysis of a 4-year database of five fertility centres. The study population included women with normal/high ovarian reserve, who underwent autologous MS-IVF (daily ≤150 IU gonadotrophin) with fresh and subsequent frozen embryo transfer(s) (FET) from surplus embryos. Only the first cycle of each patient was included. Cycles with >150 IU daily average of gonadotrophin were excluded. 'Freeze-all embryo' (FAE) cycles were analysed separately., Results: A total of 862 consecutive cycles fulfilled the inclusion criteria; 592 were eligible for fresh embryo transfer, 239 had non-elective 'freeze-all' cycles. Median age (25-75th percentile) of women who had fresh embryo transfer was 35 (32-37) years, median antral follicle count 19 (14-28) and anti-Müllerian hormone 19.2 (13-28.9) pmol/l. LBR/fresh cycle and CLBR inclusive of FAE cycles in the <35, 35-37, 38-39 and 40-42 year age groups were 37.8% and 45.1%, 36.0% and 41.6%, 18.4% and 29.1%, and 8.9% and 18.1%, respectively. The LBR following fresh embryo transfer plateaued after nine oocytes (40.3%) or four embryos (40.8%). The CLBR optimized when 12 oocytes (42.9%) or nine embryos (53.8%) were obtained. The LBR per oocyte peaked in women under 35 years when <5 oocytes were retrieved (11.4%), then declined with age and with higher oocyte yield. There were no cases of severe ovarian hyperstimulation syndrome (OHSS)., Conclusion: Nine oocytes, or four embryos, can optimize fresh transfer cycle LBR in MS-IVF. The CLBR are optimized with 12 oocytes, or nine embryos in predicted normal responders, while safeguarding against OHSS., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Mild ovarian stimulation is a treatment option for poor responders in IVF treatment. Our updated review evaluated mild IVF solely from randomized controlled trials (RCTs) that used genuine low-dose gonadotrophin (≤150 IU daily) alone or in combination with oral medications, comparing it with conventional-dose (>150 IU/ daily) IVF for poor responders. Electronic searches on MEDLINE, Embase, The Cochrane Central Register of Controlled Trials and PreMEDLINE, and hand searches from 2002 up to 31 January 2019, identified 14 RCTs, which were compiled with the above inclusion criteria. The risk of bias (ROB) and quality of evidence (QOE) were assessed as per Cochrane Collaboration. Meta-analyses found no difference in live birth rate (four RCTs, n = 1057, RR 0.91, CI 0.66 to 1.25) (moderate QOE), ongoing pregnancy rate (six RCTs, n = 1782, RR 1.01, CI 0.86 to 1.20) (moderate-high QOE) and cycle cancellation rates (14 RCTs, n = 2746, RR 1.38, CI 0.99 to 1.92) (low QOE). Fewer oocytes and embryos were obtained from mild IVF; however, the number and proportion of high-grade embryos were similar. Mild IVF resulted in reduced gonadotrophin use and cost. The inference remained unchanged when smaller studies with ROB were excluded, or whether gonadotrophin alone or combination with oral medication was used. The evidence of equal efficacy from a pooled population, which was adequately powered for live birth, supported a mild IVF strategy for poor responders in preference to more expensive conventional IVF. Although clinical heterogeneity remained a limiting factor, it increased the generalizability of the findings., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

This study reports the outcome results from a pilot clinical trial using a simplified laboratory method for human IVF. This system reproducibly generates de novo the atmospheric and culture conditions that support normal fertilization and preimplantation embryogenesis to the hatched blastocyst stage without the need for specialized medical-grade gases or equipment. Development from insemination to the hatched blastocyst stage occurs undisturbed in a completely closed system that enables timed performance assessments for embryo selection in situ that, in this study, involved single-embryo transfers on day 3. With the simplified culture system, 8/23 embryos implanted, one miscarried at 8weeks of gestation and seven healthy babies have been born. The methodology and results are discussed with regard to how this simplified system can be adopted worldwide to meet the growing need for accessible and affordable IVF. A common notion concerning the demographics of infertility is that it is largely a phenomenon associated with developed countries, where infertility treatments are commonplace. In fact, most infertile couples reside in developing/low-resource countries where infertility diagnosis and treatment is nonexistent, inaccessible or unaffordable by the vast majority of young men and women in need. The irony of this situation is that bilateral tubal occlusions, for which IVF was originally indicated and is the most effective treatment, is by far the most common cause of their infertility. We have addressed one aspect of this issue, the IVF laboratory, as part of a wider effort by the Walking Egg Project to design and establish small, dedicated centres in developing countries to provide assisted reproduction technologies that are affordable and accessible to a wider proportion of the population in need. The methods for conventional IVF designed to addresses tubal obstructions are relatively simple and free of complex instrumentation and the highly developed infrastructure common to high-resource centres. This simplified IVF system self-generates culture conditions in a closed system. After prolonged preclinical testing, a pilot clinical study was initiated in 2012 in Genk, Belgium. The findings suggest that a significant first step has been achieved in the effort to bring advanced assisted reproduction to developed countries using a low-resource but highly effective IVF system capable of bringing modern reproductive medicine to infertile couples in low-resource societies., (Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Severe ovarian hyperstimulation syndrome (OHSS) is a rare but potentially fatal condition associated with conventional IVF treatment. It is found predominantly in women with polycystic ovaries who have an exaggerated response to exogenous FSH, leading to a large number of follicles and an overproduction of vascular endothelial growth factor with resultant excessive increases in vascular permeability. There is evidence to suggest that OHSS is also linked to the use of human chorionic gonadotrophin (HCG) to induce ovulation. Therefore, while HCG is essential for corpus luteum function, high amounts of HCG can lead to OHSS in high responders. In a pilot study, infertile patients at high risk of developing OHSS were given half the current minimum dose of HCG (i.e. 2500 IU). No woman developed moderate or severe OHSS; 13 women (61.9%) conceived and there were three twin pregnancies. In women at high risk of OHSS, a low dose of HCG appears to prevent the development of OHSS without compromising success rates.

The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) is founded to promote a more physiological, less drug-oriented, lower risk, less expensive and more patient friendly approach to Assisted Reproduction embracing not only natural cycle treatment but also gentle stimulation protocols and in-vitro maturation of oocytes. Recent research suggests that IVF in modified natural cycle/mild stimulation with antagonist is likely to replace the current conventional approach in down-regulated cycles. The Society will focus both on the basic science and clinical aspects of assisted reproduction. It will be committed to promoting international multi-centre scientific research, regular practical workshops for training and also seminars for educating assisted reproduction technology professionals. ISMAAR aims to establish a direct dialogue with the voluntary sector and politicians to campaign for IVF to be a safer, softer and affordable treatment globally.

Incubation of gradient purified human spermatozoa, which are routinely maintained in media prior to IVF and intracytoplasmic sperm injection (ICSI), induced DNA strand breaks (up to 89 nicks x 10(-3) bp) and chromatin release. Unlike highly dispersed Alu repeat sequences, the centromeric heterochromatin was much less susceptible to endonuclease attack. In addition to chromatin release, the permeability of the sperm membrane was altered as evidenced by reduced accessibility of sperm nuclei to decondensation factors in mouse embryo extracts. Hybridization of cDNA microarrays with DNA released from spermatozoa revealed a consistent hypersensitivity of certain genes to endogenous cleavage including TP53, VHL (tumour suppressors), BRCA1 (breast cancer), NOS1 (neurotransmitter), PECAM1, FLT1 (angiogenesis) and CDKN1C (cell cycle/imprinted). N-tert-butyl hydroxylamine (NTBH), a derivative of the anti-teratogenic alpha-phenyl-N-t-butyl nitrone (PBN) and synthetic superoxide dismutase (SOD)/catalase mimetics inhibited chromatin release and sustained or dissipated relative mitochondrial membrane potential. Together, these results show a link between the hyperactivation of sperm mitochondria and chromosomal damage of specific genes in vitro, and that the potential risk of disruption of paternally contributed genes can be circumvented by antioxidants which are known to target mitochondria.