Perinatal outcome of babies born after using a simplified IVF culture system versus ICSI with sibling oocytes: a prospective cohort study.

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.

Multiyear outcomes using sibling oocytes demonstrates safety and efficacy of a simplified culture system consistent with use in a low-cost IVF setting.

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.

International Consensus Statement for Recommended Terminology Describing Hysteroscopic Procedures.

OBJECTIVE: To develop a consensus statement of recommended terminology to use for describing different aspects of hysteroscopic procedures that can be uniformly used in clinical practice and research. DESIGN: Open forum discussion followed by online video meetings. SETTING: International community of hysteroscopy experts PATIENTS: Not applicable. INTERVENTIONS: Series of online video meetings to complete a previously established agenda until a final agreement for standardized nomenclature was obtained. MEASUREMENT AND MAIN RESULTS: The adoption and implementation of a common terminology to standardize reporting of hysteroscopic procedures was proposed to cover five domains: pain management, healthcare setting, model of care, type of hysteroscopic procedure and the hysteroscopic approach to the uterine cavity. A final agreement was obtained after 3 online video meetings. CONCLUSION: Hysteroscopy is the gold standard technique for the evaluation and management of uterine disorders. A clear definition and understanding of the terminology used to describe hysteroscopic procedures is lacking. The production of this international consensus statement for terminology to describe hysteroscopic procedures, covering pain management, setting, model of care, type of procedure and hysteroscopic approach, has the potential to enable more effective communication for both clinical and research purposes with the ultimate aim of improving patient care and clinical outcomes.

Long-Term Reproductive Outcomes after Hysteroscopic Treatment of Dysmorphic Uteri in Women with Reproductive Failure: An European Multicenter Study.

OBJECTIVE: To evaluate the long-term reproductive outcomes in patients with dysmorphic uterus treated by hysteroscopic metroplasty with miniaturized instruments. DESIGN: Retrospective multicenter cohort study. SETTING: Tertiary care university hospitals. PATIENTS: The study was conducted on 214 women with a dysmorphic uterus (T-shaped, infantilis, or other type of dysmorphic uterus according to the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy classification system) with history of primary unexplained infertility (group 1) or repeated (>2) early miscarriages (group 2). Dysmorphic uteri were diagnosed by office hysteroscopy and 3-dimensional transvaginal ultrasound (3D-TVS). INTERVENTIONS: All patients underwent in office hysteroscopic metroplasty using a continuous-flow hysteroscope with a 5 Fr operating channel introduced into the uterine cavity using the vaginoscopic approach. Longitudinal incisions were performed on the fibromuscular constriction rings in the isthmic area and in some cases on the other uterine walls with a 5 Fr bipolar electrode or scissors. At the end of the procedure, an antiadhesive gel was applied into the uterine cavity to minimize adhesion formation. Postsurgical assessment of the uterine cavity was carried out through office hysteroscopy and 3D-TVS. All patients were followed for at least 24 months. MEASUREMENTS AND MAIN RESULTS: The metroplasty was completed in all cases, resulting in a significant increase of uterine cavity volume (100%) and optimization of uterine morphology in 211 of 214 women (98.6%). After 60 months, the overall clinical pregnancy rate was 72.9% (n = 156/214), and the live birth rate was 80.1% (n = 125/156). Specifically, 74 of 156 women (47.4%) conceived spontaneously (with a median time to pregnancy of 5.5 months), of whom 32.4% had previously failed 1 or more attempts at in vitro fertilization/intracytoplasmic sperm injection. CONCLUSION: Our long-term follow-up data demonstrate that the hysteroscopic correction of dysmorphic uteri may result in a high live birth rate in women suffering from unexplained infertility or repeated miscarriages.

Resectoscopic Metroplasty with Uterine Septum Excision: A Histologic Analysis of the Uterine Septum.

STUDY OBJECTIVE: To evaluate the histology of the uterine septum after its complete hysteroscopic excision. DESIGN: Case series. SETTING: Second Gynecological and Obstetric Unit and Pathological Anatomy Department of the University of Bari, Italy. PATIENTS: Thirty-five patients aged between 25 and 41 years who were diagnosed with uterine septum by 3-dimensional ultrasound per the European Society for Human Reproduction and Embryology/European Society of Gastrointestinal Endoscopy 2013/Salim 2003 criteria. In addition, office hysteroscopy was performed to define the anatomy of the uterine cavity and to exclude the presence of other endometrial pathologic conditions. INTERVENTIONS: Operative hysteroscopic septum resection was performed. The septum was initially incised with an "L-shape" bipolar electrode with a 5-mm bipolar mini-resectoscope (KARL STORZ SE & Co. KG, Tuttlingen, Germany). Then, using the bipolar loop, 2 triangles of the septum were excised in parallel, obtaining uninterrupted entire septum-long strips from the fundus to the apex of the septum. These strips were immediately removed from the uterus and reassembled in vitro to reconstruct a macroscopic, 3-dimensional structure of the septum for complete morphologic and histologic evaluations. MEASUREMENTS AND MAIN RESULTS: Patients presented with an average body mass index of 24.8 kg/m2and were all nulliparous. Histologic evaluation of the uterine septa showed a different conformation of the muscle bundles along the septum. Muscle cells in the apex and edges of the septum were arranged in nodules circumscribed by a thin area of collagen fibers. Medium-sized vessels were distributed in the collagen fibers around the muscle cells. Only few capillary vessels were present in the muscle nodules. This pattern was very similar to the cell arrangement in leiomyomas. In the core of the septa, near the base, the muscle bundles showed a linear course with concurrent collagen fibers and vessels. All the aforementioned characteristics were consistently present in every patient. On high-power histologic fields (200×), the muscle portion accounted for 48.3% ± 1.8% (mean, 6%) area in the apex and borders to 48.5% ± 1.3% (mean, 6%) area in the core. Collagen fibers accounted for 27.1% ± 1.1% (mean, 4%) area in the apex and borders to 26.7% ± 1.3% (mean 5%) area in the core. CONCLUSION: By removing the septum as a whole structure, this study allowed us to redefine the concept of the septum as a complex structure according to the islands of muscle fibers irregularly arranged in vertex, in a context of collagen tissue and similar to the structure of myomas. It appears to deeply involve the anterior and posterior uterine walls, resembling a "reverse letter H."

Hysteroscopy in recurrent in-vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial.

BACKGROUND: The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation. METHODS: We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078. FINDINGS: Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported. INTERPRETATION: Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted. FUNDING: European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies.

STUDY QUESTION: What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? SUMMARY ANSWER: The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. WHAT IS KNOWN ALREADY: Accurate diagnosis of congenital anomalies still remains a clinical challenge because of the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. STUDY DESIGN, SIZE, DURATION: The ESHRE/ESGE CONgenital UTerine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. PARTICIPANTS/MATERIALS, SETTING, METHODS: The consensus is developed based on: (i) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy by performing a systematic review of evidence and (ii) consensus for the definition of where and how to measure uterine wall thickness and the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. MAIN RESULTS AND THE ROLE OF CHANCE: Uterine wall thickness is defined as the distance between the interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional (3D) US is recommended for the diagnosis of female genital anomalies in 'symptomatic' patients belonging to high risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine evaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the subgroup of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopically. LIMITATIONS, REASONS FOR CAUTION: The various diagnostic methods should always be used in the proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The role of a combined US examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity. STUDY FUNDING/COMPETING INTERESTS: None.

Survival, re-expansion and cell survival of human blastocysts following vitrification and warming using two vitrification systems.

PURPOSE: This study evaluated and compared survival, re-expansion, and percentage of live cells of individual Days 5 and 6 human blastocysts that were vitrified and warmed with the Vit Kit Freeze/Thaw (Irvine Scientific, CA), or with two protocols using the Global Fast Freeze/Thaw Kits (LifeGlobal, Canada). METHODS: Frozen/thawed Day 2-3 or discarded embryos were cultured to blastocyst (culture day 5-6). Group 1 blastocysts were vitrified with the Vit Kit (n = 29) and High Security Vitrification (HSV) devices. Group 2 (n = 47) and Group 3 (n = 48) blastocysts were cryopreserved with the Global Fast Freeze Kit and 0.25 ml straws, using a direct plunge or a -100 °C holding step, respectively. Group 4 (Controls, n = 30) were not vitrified. Blastocysts were subsequently cultured for 24 h, assessed for survival and expansion, and then stained individually with propidium iodide and Hoechst. Live and total cell number was assessed with ImageJ (NIH), and the percentage of live cells calculated for each blastocyst. RESULTS: The percentage of live cells was not different between vitrified and control (non-vitrified) blastocysts, thus vitrification did not affect cell survival. Survival (following thawing and after 24 h culture), re-expansion, and percentage of live cells were not different for blastocysts vitrified and warmed between the two vitrification/warming kits, or between the two protocols for the Global Fast Freeze/Thaw Kits. CONCLUSIONS: Blastocyst vitrification can be achieved with equal success using simplified protocols and cheaper and easy to load freezing straws, providing simultaneously increased safety, and efficiency with lower cost, when compared with vitrification using specialized embryo vitrification devices.

Influence of temperature and sperm preparation on the quality of spermatozoa.

This study investigated the effects of long-term (24h) in-vitro sperm incubation at room temperature (RT; 23°C) versus testis temperature (35°C) on various sperm-quality parameters. Semen samples (n=41) were prepared both by density-gradient centrifugation (DGC) and the swim-up technique in order to compare the influence of sperm preparation on sperm quality after incubation. Progressive motility and morphology were significantly higher after incubation at RT compared with 35°C (P<0.001 and P<0.01, respectively). The proportions of acrosome-reacted, apoptotic and dead spermatozoa were significantly lower in samples incubated for 24h at RT compared with 35°C (P<0.001, P=0.01 and P<0.001, respectively). The number of motile, morphologically normal, non-acrosome-reacted and nonapoptotic spermatozoa recovered after sperm preparation was significantly higher in DGC compared with swim-up samples (P<0.001). However, spermatozoa prepared by swim-up showed better survival after incubation compared with DGC-prepared spermatozoa, especially when incubated at 35°C. In conclusion, this study indicates a significantly better and longer preservation of sperm quality when incubation is performed at RT. These findings may convince laboratories to change the routinely used sperm storage conditions in order to maximize the quality of the prepared sperm sample.

Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies.

The clinical implications of congenital uterine anomalies (CUA), and the benefits of hysteroscopic resection of a uterine septum, were evaluated. Studies comparing reproductive and obstetric outcome of patients with and without CUA and of patients who had and had not undergone hysteroscopic resection of a uterine septum, were evaluated. Meta-analysis of studies indicated that the pregnancy rate was decreased in women with CUA (RR 0.85, 95% CI 0.73 to 1.00; marginally significant finding, P = 0.05). The spontaneous abortion rate was increased in women with CUA (RR 1.68, 95% CI 1.31 to 2.15). Preterm delivery rates (RR 2.21, 95% CI 1.59 to 3.08), malpresentation at delivery (RR 4.75, 95% CI 3.29 to 6.84), low birth weight (RR 1.93, 95% CI 1.50 to 2.49) and perinatal mortality rates (RR 2.43, 95% CI 1.34 to 4.42) were significantly higher in women with CUA. Hysteroscopic removal of a septum was associated with a reduced probability of spontaneous abortion (RR 0.37, 95% CI 0.25 to 0.55) compared with untreated women. Presence of CUA might be associated with a detrimental effect on the probability of pregnancy achievement, spontaneous abortion and obstetric outcome. Hysteroscopic removal of a septum may reduce the probability of a spontaneous abortion.

First births with a simplified culture system for clinical IVF and embryo transfer.

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.

The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies.

STUDY QUESTION: What classification system is more suitable for the accurate, clear, simple and related to the clinical management categorization of female genital anomalies? SUMMARY ANSWER: The new ESHRE/ESGE classification system of female genital anomalies is presented. WHAT IS KNOWN ALREADY: Congenital malformations of the female genital tract are common miscellaneous deviations from normal anatomy with health and reproductive consequences. Until now, three systems have been proposed for their categorization but all of them are associated with serious limitations. STUDY DESIGN, SIZE AND DURATION: The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) have established a common Working Group, under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system. A scientific committee (SC) has been appointed to run the project, looking also for consensus within the scientists working in the field. PARTICIPANTS/MATERIALS, SETTING, METHODS: The new system is designed and developed based on (i) scientific research through critical review of current proposals and preparation of an initial proposal for discussion between the experts, (ii) consensus measurement among the experts through the use of the DELPHI procedure and (iii) consensus development by the SC, taking into account the results of the DELPHI procedure and the comments of the experts. Almost 90 participants took part in the process of development of the ESHRE/ESGE classification system, contributing with their structured answers and comments. MAIN RESULTS AND THE ROLE OF CHANCE: The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into sub-classes expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into sub-classes having clinical significance. LIMITATIONS, REASONS FOR CAUTION: The ESHRE/ESGE classification of female genital anomalies seems to fulfill the expectations and the needs of the experts in the field, but its clinical value needs to be proved in everyday practice. WIDER IMPLICATIONS OF THE FINDINGS: The ESHRE/ESGE classification system of female genital anomalies could be used as a starting point for the development of guidelines for their diagnosis and treatment. STUDY FUNDING/COMPETING INTEREST(S): None.

Perinatal Outcome of Singletons Born after Using a Simplified Low-Cost IVF Culture System and All Singletons Born in Flanders (Belgium) between 2012 and 2020.

BACKGROUND: We developed a simplified IVF culture system (SCS) which has proven to be effective and safe in a selected IVF cohort. METHODS: Preterm birth (PTB) and low birth weight (LBW) of 175 singletons born after using the SCS, 104 after fresh embryo transfer (ET), and 71 after frozen embryo transfer, were compared with all singletons born in Flanders between 2012 and 2020 conceived after natural conception, ovarian stimulation (OS), and assisted reproduction (IVF/ICSI). FINDINGS: The proportion of preterm (<37 weeks) births was significantly higher in the case of IVF or ICSI, followed by hormonal treatment, compared to spontaneous pregnancies. There was no significant difference in PTB between SCS and any of the other groups. Concerning the average birth weight we found no significant difference between singletons born after natural conception and SCS. However, a significant difference in average birth weight was found between SCS singletons and singletons born after IVF, ICSI and hormonal treatment, with a significantly higher birth weight in the SCS group. This difference was also observed in the proportion of babies weighing less than 2500 g, with significantly more LBW babies in the IVF and ICSI group compared to the SCS newborns. INTERPRETATION: Taking into account the small series, PTB and LBW rates in SCS singletons were found to be comparable with singletons born after natural conception. Compared to babies born after ovarian stimulation and IVF/ICSI, SCS singletons had a lower PTB and LBW rates, although the differences were not significant for PTB. Our results confirm previous reports on reassuring perinatal outcomes after using the SCS technology.

Promising Perinatal Outcome after Using a Simplified Low-Cost IVF Culture System Specifically Designed for Resource-Poor Countries.

BACKGROUND: Assisted reproductive techniques services are often not accessible to the majority of infertile couples in Low and Middle Income Countries (LMIC) due to high costs. Lowering IVF laboratory costs is a crucial step to make IVF affordable for a larger part of the world population. We developed a simplified culture system (SCS) which has proven to be effective, and the next step is to prove its safety. METHODS: Preterm birth (PTB) and low birthweight (LBW) of 176 singletons born after using the SCS, 105 after fresh embryo transfer (fresh ET), and 71 after frozen embryo transfer (frozen ET) were compared with all IVF/ICSI singletons born in Belgium between 2013 and 2018. When comparing our 105 SCS babies born after fresh ET with all Belgian babies born after conventional IVF only, we also adjusted for 7 risk factors known to influence perinatal outcome, namelythe mother's age, day of transfer, pituitary inhibition protocol, rank of cycles, number of oocytes retrieved, number of embryos transferred, and gender of the baby. FINDINGS: Before adjustment, we found a significantly higher PTB (10.2% vs. 3.8%, OR 2.852, 95% CI [1.042-7.803], p-value 0.0413) and LBW (9.8% vs. 2.9%, OR 3.692, 95% CI [1.163-11.721], p-value 0.0267) in the conventional IVF group versus SCS after fresh ET. After adjusting for seven risk parameters, these differences remained significant (PTB: OR 2.627, 95% CI [1.013-6.816], p-value 0.0471) and LBW: OR 3.267, 95% CI [1.118-9.549], p-value 0.0305). PTB and LBW between both groups was not significantly different for singletons born after frozen ET. INTERPRETATION: Taking into account the small series, PTB and LBW rates in SCS singletons in FRET cycles are very reassuring and significantly lower compared to babies born after conventional IVF in Belgium. Being aware of its effectiveness, our results offer a good perspective for SCS to become an important tool to implement low-cost IVF in LMIC.

No clinical relevance of the height of fundal indentation in subseptate or arcuate uterus: a prospective study.

The American Fertility Society has classified the arcuate uterus as a minor malformation with a benign clinical behaviour. The aim of this prospective study was to verify whether there is any scientific basis for this differentiation. Patients with at least one early miscarriage and a subseptate or arcuate uterus were admitted for hysteroscopic metroplasty. Patients were allocated to a subseptate uterus group, with an indentation of 1.5 cm or more, or an arcuate uterus group, with a smaller indentation. The miscarriage rates after metroplasty were similar between the two groups (14.0% in the subseptate uterus group versus 11.1% in the arcuate uterus group). Before metroplasty, the miscarriage rates were significantly higher in subseptate uterus group, as well as in the arcuate uterus group (both P<0.001). According to these results, there is no evidence to support that the arcuate uterus has a different effect on the reproductive outcome in comparison to the subseptate uterus, neither before nor after surgical correction of the anomaly. Since there is no scientific basis for a separate classification of the arcuate uterus, a review of the classifications of uterine congenital anomalies should be considered as necessary. Congenital uterine malformations have been classified by the American Fertility Society (AFS) since 1988. Although the AFS classification received wide acceptance and is still the most broadly used system, it is associated with various limitations in effective categorization of the anomalies. It is interesting that, until now, none of the other available options have been able to effectively replace the AFS system. Numerous papers indicate septate or subseptate (partial septate) uterus (AFS class V) is a possible cause of an unfavourable pregnancy outcome. Arcuate uterus (AFS class VI), a slight malformation similar to septate uterus, should differ from septate or subseptate uterus, because this 'minor' malformation should behave benignly with respect to the septate uterus. The aim of this study was to scientifically validate the difference between the arcuate and subseptate uterus in their effect on reproductive outcome through the results of a metroplasty in both groups of patients. A group of 96 patients, who underwent metroplasty after at least one early miscarriage, was divided into two groups according to the severity of the congenital uterine malformation. Our results indicate that there are no differences in pregnancy outcome after metroplasty either in patients with septate or arcuate utera. The poor pregnancy outcome in women with septate uterus seems not to be correlated to the dimension of the septum itself. There are no scientific bases for a separate classification of the arcuate uterus and it is proposed that a review of the classification of uterine congenital anomalies is necessary.

A multi-centre randomised controlled study of pre-IVF outpatient hysteroscopy in women with recurrent IVF implantation failure: Trial of Outpatient Hysteroscopy - [TROPHY] in IVF.

BACKGROUND: The success rate of IVF treatment is low. A recent systematic review and meta-analysis found that the outcome of IVF treatment could be improved in patients who have experienced recurrent implantation failure if an outpatient hysteroscopy (OH) is performed before starting the new treatment cycle. However, the trials were of variable quality, leading to a call for a large and high-quality randomised trial. This protocol describes a multi-centre randomised controlled trial to test the hypothesis that performing an OH prior to starting an IVF cycle improves the live birth rate of the subsequent IVF cycle in women who have experienced two to four failed IVF cycles. METHODS AND DESIGN: Eligible and consenting women will be randomised to either OH or no OH using an internet based trial management programme that ensures allocation concealment and employs minimisation for important stratification variables including age, body mass index, basal follicle stimulating hormone level and number of previous failed IVF cycles. The primary outcome is live birth rate per IVF cycle started. Other outcomes include implantation, clinical pregnancy and miscarriage rates.The sample size for this study has been estimated as 758 participants with 379 participants in each arm. Interim analysis will be conducted by an independent Data Monitoring Committee (DMC), and final analysis will be by intention to treat. A favourable ethical opinion has been obtained (REC reference: 09/H0804/32). TRIAL REGISTRATION: [corrected] The trial has been assigned the following ISRCTN number: ISRCTN35859078.