Higher Miscarriage Rate Research Articles

Multilevel Modelling of Individual, Community and Regional Level Factors Associated with Insecticide-Treated Net Usage among Pregnant Women in Ethiopia.

Background: Pregnant women who are infected with malaria usually have more severe symptoms and negative health outcomes than women who are not pregnant, with higher rates of miscarriage, intrauterine demise, premature delivery, low-birth-weight neonates, and neonatal death. Based on evidence from the 2016 Ethiopia Demographic and Health Survey, this study assessed the variation in insecticide-treated nets (ITNs) usage and its associated factors among pregnant women in Ethiopia. Methods: Data from a total of 1122 women who were pregnant at the time of the survey were included in the final analysis. Bivariate and multilevel analyses were conducted. Multilevel modeling with fixed and random coefficients was used to estimate the variation in pregnant women’s ITNs usage across communities (residence areas) and regions of Ethiopia. Results: Out of the total 1122 pregnant women, 58.37% slept under a net and 41.63% did not sleep under nets. Significant variations were observed in pregnant women’s ITNs usage across communities (residence areas) and regions of Ethiopia, with between variations in pregnant women’s ITNs usage across communities (residence areas) and regions. In addition, the region, place of residence, wealth index, educational level, and age of the women as well as whether they believed that mosquito bites cause malaria were significant factors in pregnant women’s usage of ITNs. Pregnant women in Ethiopia had moderate usage of ITNs with varied risk factors at the individual, community, and regional levels. Conclusion: Based on the factors identified, there is a need to implement and/or strengthen programs (e.g., regular sensitization) that intensify high coverage of ITNs for effective malaria prevention in Ethiopia, especially among pregnant women who do not use ITNs.

Influence of broodmare aging on its offspring's racing performance.

Maternal aging has negative influences on the development and racing performance of their offspring in racehorses. However, the mechanism by which pregnancy at old age reduces the race performance of the offspring is unknown. Here, two hypotheses were posited: 1) Foals born to older mares are more likely to have muscular, skeletal, and cognitive disadvantages (direct effects). 2) Foals born to older mares are more likely to be affected by non-physiological factors correlating with the mare’s age, such as the quality of sires (e.g. low-quality sires are likely to be chosen as partners of older broodmares). To test these hypotheses, the effect of the broodmare’s age on the offspring’s racing performance was examined, while controlling for the effects of the stallion’s quality, age, and ID, offspring’s sex, trainer, and the location of the training center. Information of racehorses registered to the Japan Racing Association were collected from the Japan Bloodhorse Breeders’ Association website. Overall, results showed that the racing performance of horses born from older mares was lower than that of horses born from younger mares. However, generalized linear mixed models (GLMM) indicated that the quality of sires was significantly associated with the offspring’s racing performance, rather than the broodmare’s age itself. Furthermore, the age of broodmares was negatively correlated with the quality of sires, although the variance inflation factor was low. Therefore, the effect of maternal aging was negligible or only limited, and rather, the sire’s quality had an important influence on the offspring’s racing performance. Low quality sires, or cheap stallions in other words, are likely to be chosen as partners of older blood-mares, which may have reproductive risks such as lower fertility and higher rate of miscarriages. The present study suggests that the conventional belief that racehorses born from older mares show lower performance may not always be accurate.

Maternal and Fetal Outcome of Normal and Abnormal Cardiotocographic Findings at A Tertiary Hospital in Ghana

Background: Cardiotocography (CTG) provides important information about the interaction between fetal cerebral and cardiac activities which are both modified by hypoxia. The duration and severity of hypoxia and associated biochemical abnormalities allinfluence the manifestations of fetal heart rate abnormalities. Antenatal fetal heart rate monitoring with CTG has potential in preventing intrauterine fetal death.Aim: The aim of the study was to compare the maternal and fetal outcome of pregnancies with normal and abnormal antepartum CTG tracings.Methodology: This descriptive retrospective review compared 200 consecutive women with normal and 200 with abnormal CTG tracings. The study lasted six months and spanned a period of time from beginning of January to end of June 2011. Demographic, pregnancy and delivery outcome data were retrieved from participants' charts and simple descriptive analysis was performed. Means and their standard deviations of continuous variables were calculated and difference between group mean were compared using the student test. Categorical variables were summarized as proportions and the chi-square test used to test for difference between groups. A p-value < 0.05 was considered statistically significant.Results: Women with normal and abnormal CTG tracings were comparable in their demographic characteristics. Abnormal CTG tracings were associated with higher rate of preterm delivery (38.8% vs 18.8%, p = 0.001), caesarean section (77.9% vs 47.0%, p = 0.001)low birth weight (25.5% vs 9.1%, p = 0.001) and NICU admissions (36.5% vs 17.6%, p = 0.001). There was no difference in Apgar score or stillbirth rate between the two groups. Pregnancies with abnormal tracing were delivered about a week earlier than those with normaltracing. (37.8±2.9 vrs 38.3±2.6, p=0.001). Longer interval between tracing and delivery was associated with stillbirth.Conclusion: Abnormal antepartum CTG tracing was associated with higher preterm delivery, caesarean section, low birth weight and NICU admission. Longer interval between abnormal tracing and delivery was associated with higher stillbirth rate. Active and adequate resuscitation of babies with abnormal tracing can reduce perinatal morbidity.

P-078 The role of male factor accompanying PGT-A as possible complementary strategies to control miscarriage

Abstract Study question Considering maternal influence or management of male factor, should only PGT-A be indicated to reduce miscarriage? Summary answer The finest cost-effective treatment for each patient to improve ART success, is a good, tailored, and individualized indication for choosing the best IVF technique. What is known already Advanced maternal age is related with fertility decline, oocyte quality and the increased risk of aneuploid embryos. Aneuploid embryos lead to a reduced implantation potential and higher miscarriage rate. PGT-A is a screening method to determine the chromosomal status of the embryos and it’s the most expanded technique used to reduce the miscarriage rates in most clinics. Common sperm capacitation techniques used in IVF laboratories could cause sperm DNA damage, leading to a smaller number of blastocysts obtained per cycle and a higher miscarriage rate. Microfluidics devices or sperm selection centrifugation-free (Swim-up modified techniques) could reduce sperm DNA fragmentation. Study design, size, duration This is a retrospective study from 2018-2020 including patients using their own oocytes fertilized by ICSI. No major differences on male factor were found between male patients. In all cycles at least one good quality blastocyst was obtained to biopsy on blastocyst stage in cycles with PGT-A or to transfer without PGT-A. Live-Birth Rate (LBR) per cycle is compared and analyzed by the t-Student and X2 test between groups. Participants/materials, setting, methods A total of 308 cycles were included in this study. Three groups of patients were formed: Group 1: 76 cycles with PGT-A; Group 2: 191 cycles without PGT-A and sperm samples processed by Swim-Up technique; and Group 3: 41 cycles without PGT-A and a centrifugation free sperm selection (IO-Lix) used for ICSI. The main indication for PGT-A was maternal age. No differences between male or other female infertility factors were found between groups. Main results and the role of chance When we compare the 3 groups, no statistically significant differences were obtained in fertilization rate (79.8%; 73.5%; 72.6%; p = 0.28); development to the blastocyst stage (48.7%; 43.1%; 44.9%; p = 0.11) and pregnancy rate per transfer (48.8%; 45.6%; 52.8%; p = 0.55). It seems that PGT-A doesn’t affect the viability, or the implantation potential of the biopsied embryos and a special sperm capacitation technique is useful for daily clinical use. If we include only patients with ages >38 years old to avoid age differences, comparing Group 1 (PGT-A) and Group 3 (no-PGT-A and IO-lix) (LBR=19.7% vs 50%), we obtain statistically significant differences between both groups (p = 0.01). No differences were found between Group 2 (LBR=26.4%; p = 0.25) and the Group 1. To summarize, the female age appears to be the most important factor for IVF success and the PGT-A can help to avoid a miscarriage, however when we compare women with advanced maternal age, the LBR is increased when PGT-A is non performed, and the sperm DNA is not damaged by the capacitation technique. Why not PGT-A to be complemented with efficient sperm selection? Limitations, reasons for caution Although sperm selection techniques to decrease sperm DNA damage could reduce miscarriage rates, PGT-A is the only used technique that allows us to ensure that euploid embryos are transferred. Wider implications of the findings A better understanding of male factor in IVF treatments can reduce miscarriage. Male factor assessment is a cost-effective technique to improve LBR in those patients without a clear indication for PGT-A, (advanced maternal age). Patient must be studied individually, and PGT-A shouldn’t be used indiscriminately to ensure a healthy new-born. Trial registration number Not Applicable

O-058 Obstetric outcomes of twin gestation after In-Vitro Fertilization and Embryo Transfer (IVT-ET) treatment in patients who underwent hysteroscopic septoplasty for subseptate uterus

Abstract Study question Is there an associated increased risk of preterm birth (PTB) in patients who underwent hysteroscopic septoplasty for subseptate uterus (SSU) with twin gestation through IVF-ET? Summary answer This study suggests an increased risk of PTB in patients, who underwent hysteroscopic septoplasty for SSU, and subsequently conceived twins after IVF-ET treatment. What is known already In general, the incidence of PTB is higher after IVF-ET treatment. In addition, Müllerian uterine anomalies, such as unicornuate uterus, are considered risk factors for PTB, even with singleton pregnancy. Furthermore, historical data suggest that some patients with uterine anomaly may have cervical incompetence. Twin gestation is associated with PTB in approximately 50% of cases. It is assumed that the obstetric outcome of twin gestation after successful septoplasty should be no different from those with normal uterine cavity. The impact of previous septoplasty for SSU on the obstetric outcomes of twin gestation after IVF-ET treatment has not been adequately studied. Study design, size, duration This retrospective cohort study included 377 fertility patients who received treatment between 2006-2019. The study group included 162 patients who underwent hysteroscopic septoplasty for SSU and subsequently conceived dichorionic-diamniotic (DI-DI) twins after IVF-ET treatment (Group 1). The control group included 215 patients who had normal endometrial cavity on hysteroscopy (#109) or Transvaginal 3D ultrasound scan with saline sonohysterogram (#106) and subsequently conceived DI-DI twins after IVF-ET treatment (Group 2). Participants/materials, setting, methods This study was conducted at an infertility clinic affiliated with an academic hospital. Demographic, clinical, and obstetric outcome data were collected for both groups and compared using appropriate statistical methods. PTB, severe PTB, extreme PTB, and peri-viable birth were defined as < 37 weeks, <32 weeks, <28 weeks and between 20 weeks-25 weeks 6 days gestation respectively. Main results and the role of chance There was no significant difference in mean age, BMI and infertility duration or in the incidence of smoking, primary infertility, tubal factors and unexplained infertility between the two groups. There was significantly lower mean baseline FSH levels (p < 0.01), lower incidence of male infertility (p < 0.001) and higher incidence of ovulatory disorders (p < 0.001) and endometriosis (p < 0.05) in Group 1 compared to Group 2. As expected, there was past history of lower parity rate (p < 0.01) and higher miscarriage rate (p < 0.001) in Group 1 compared to Group 2 prior to septum division. There was significantly higher incidence of PTB (72.8% vs 56.3%, p < 0.01), severe PTB (20.3% vs 8.2%, p < 0.01), extreme PTB (8.3% vs 3.9%, p < 0.05), and peri-viable birth (6.3% vs 1.9%, p < 0.05) in Group 1 compared to Group 2. There was no significant difference in cesarean section rate (82.8% vs 87.5%, p = 0.349) between Group1 and Group 2 respectively. There was significantly lower gestational age at birth in weeks (34.0 + 4.0 vs 35.6 + 3.0, p < 0.001), birth weight of the first newborn (2180.5 + 717.9 vs 2436.4 + 606.6, p < 0.001), and the second newborn (2235.2 + 674.2 vs 2398.0 + 537.9, p < 0.05) in grams in Group 1 compared to Group 2. Limitations, reasons for caution Our study has limitations being retrospective in nature. Data on cervical length measurements via ultrasound, if performed, was not available. However, recall bias was prevented by retrieving data from that submitted to the Society of Assisted Reproductive Technology. Additionally, procedural variation was reduced as this was a single-center study. Wider implications of the findings Our study suggests that twin gestation after IVF-ET in patients who underwent successful hysteroscopic septoplasty for SSU may increase the likelihood of PTB. Such patients may require increased surveillance with ultrasound cervical length and signs for preterm labor. Future research should focus on measures to reduce PTB in such patients. Trial registration number Not Applicable

O-042 ESHRE good practice recommendations on chromosomal mosaicism

Abstract The implementation of high-resolution genome-wide methods, usually next-generation sequencing-based, in preimplantation genetic testing (PGT), has led to the frequent detection of embryos with chromosomal mosaicism (whole chromosome and/or segmental aberrations). Despite a growing series of papers showing the birth of healthy babies following the transfer of embryos indicating mosaicism on PGT-A analysis - albeit with lower implantation rates and higher miscarriage rates in comparison with euploid embryo transfer - many questions remain, making it difficult to decide on how to handle chromosomally mosaic embryos in the clinic. A dedicated ESHRE working group developed good practice recommendations on how to manage chromosomal mosaicism in clinical practice. The recommendations were formulated based on the expert opinion of the working group while taking into consideration the published data and outcomes of a survey on current practices in 239 PGT laboratories and ART clinics, mostly within Europe, Asia and America. The recommendations with regards to detection and management of chromosomal mosaicism were developed following the manual for development of ESHRE good practice recommendations with a stakeholder review of the paper on the ESHRE website. In addition to the recommendations, the working group identified missing information and scientific questions, which should guide further research in PGT, with relevance to the occurrence, detection and impact of chromosomal mosaicism. Trial registration number:

O-251 Defining the exclusive role of male genome integrity on conceptus development

Abstract Study question To determine the effect of sperm DNA fragmentation on embryo development by ruling out a female factor component. Summary answer By utilizing healthy donor oocytes, it is possible to quantify the sole deleterious effect of sperm DNA fragmentation and explore the ooplasmic repair mechanism. What is known already In approximately 50% of couples with unexplained ART failure, a subtle male factor is present that is missed in a conventional semen analysis assessing concentration, motility, and morphology. Additional information on male gamete competence can be acquired by assessing Sperm Chromatin Fragmentation (SCF). Indeed, a fragmented male genome can give rise to poorly developing embryos, leading to impaired implantation, lower pregnancy, and higher miscarriage rates. It has been previously seen that an oocyte, according to its age, can repair the damaged DNA contributed by the male gamete. Study design, size, duration In last decade, 316 couples, who have an elevated SCF, underwent ICSI cycles and resulted in disappointing clinical outcomes. To exclude an eventual confounding female factor, couples who utilized donor oocytes were identified and clinical outcome was compared to a control. To measure the role of an impaired sperm genome and a concurrent oocyte repair mechanism, we compared clinical outcomes between cycles in the same couples who used their own and subsequently donor oocytes. Participants/materials, setting, methods We included 381 couples screened for SCF; 65 underwent ICSI cycles with donor oocytes; of these, 46 underwent a previous ICSI cycle with their own oocytes. Fertilization, implantation, clinical pregnancy, and delivery rates were compared between above-mentioned groups. A TUNEL assay was used to measure SCF (≥500 spermatozoa were assessed/sample at a 15% threshold). Paired t and Chi-square tests were used to compare ages and clinical outcomes, respectively. Main results and the role of chance We included 381 couples (maternal age, 37.8 ± 4.2; paternal age, 41.8 ± 8.2), whose male partners had the following semen parameters: average volume of 2.5 mL, concentration of 25.4x106/mL, 33% motility, and normal morphology of 1.7. Of these, 316 had elevated average DNA fragmentation of 25.5% and utilized their own oocytes in 683 ICSI cycles, resulting in a 67.5% fertilization, 12.2% implantation, 27.9% clinical pregnancy, and a 22.5% ongoing/delivery. Of the 381 couples, 65 underwent ICSI utilizing donor oocytes (SCF of 24.3%) resulting in a significantly higher fertilization (78.4%) (P < 0.00001) and embryo implantation rates (34.2%) (P < 0.0001). Similarly, albeit not statistically significant, the clinical pregnancy and ongoing/delivery rates increased from 27.9% to 37.1% and from 22.5% to 30.0%, respectively. To further explore the exclusive role of the male gamete in embryo development, we identified a cohort of patients (n = 46), with an elevated average DNA fragmentation of 23.6%, who underwent an ICSI cycle using their own oocytes and a subsequent cycle using donor oocytes. Compared to cycles where couples used their own oocytes, fertilization, embryo implantation, clinical pregnancy, and ongoing/delivery rates rose from 67.5% to 76.6% (P < 0.0001), 2.8% to 24.7% (P < 0.00001), 8.4% to 38.8% (P < 0.0001), and 1.2% to 28.6% (P < 0.00001), respectively. Limitations, reasons for caution Although this study attempts to control for a concurrent confounding female factor, it cannot be completely excluded. It is difficult to assess the extent and contribution of the ooplasmic repair mechanisms on the male genome. Wider implications of the findings Ooplasmic repair mechanisms of healthy female gametes appear to repair or improve the deleterious impact of sperm DNA fragmentation on ART outcomes. Trial registration number not applicable

P-380 Single-cell transcriptome analysis reveales that expression changes of the endometrium in repeated implantation failure are altered by HPV-mediated CXCL chemokine secretion

Abstract Study question What are the mechanisms and molecular expression patterns of reduced endometrial receptivity in repeated implantation failure (RIF) after human papillomavirus (HPV) infection? Summary answer The single-cell transcriptomic analysis identifies the expression changes of endometrium in RIF via HPV-mediated CXCL chemokines secretion in single-cell resolution. What is known already Regardless of the advance of in vitro fertilization (IVF), RIF is still a formidable challenge for couples and physicians in clinical treatment. In infertile couples, a reduction in natural and assisted cumulative pregnancy rate and an increase in miscarriage rate are related to the HPV infection. Study design, size, duration Cross-sectional clinical studies with 322 infertile couples undergoing IVF were integrated to demonstrate the associations between HPV infection and reproductive outcomes (pregnancy rate and miscarriage). Descriptive analysis of single-cell transcriptome data of uteruses, and transcriptome profiles of mid-secretory endometrium from 16 healthy fertile women and 38 repeated IVF failure women were analyzed to identify the expression patterns of endometrium in RIF. In vitro assays were used to validate the expression patterns in endometrium. Participants/materials, setting, methods 322 infertile couples, single-cell transcriptome data of uteruses (human and mouse), and transcriptome profiles of endometrium (16 normal vs. 38 RIF) were used to analyze the association between HPV infection and reduced endometrial receptivity. HPV genes (E1, E2, E4, and E5) were transfected into a human normal endometrial epithelial cell line (hEM3), and immunohistochemistry, Westerns, quantitative PCR were used to validate the changes of CXCL chemokines in the endometrium in vitro. Main results and the role of chance Integrated cross-sectional studies demonstrate that HPV+ women exhibit a decreased pregnancy rate (83.09%) as compared with HPV- women (55.17%, P <0.001), and a higher miscarriage rate (62.5% vs. 16.7%, P <0.001) and the relative risk of spontaneous abortion (odd ratio=2.84, P <0.0001) were observed in HPV+ women. Transcriptome profiling analysis identified the enrichment of the processes related to viral protein interaction with cytokine and cytokine receptor and cytokine-cytokine receptor interaction, especially in the CXCL chemokine family. Further analysis of single-cell transcriptome demonstrated that the changed expression patterns were associated with endometrial epithelial cells and immune cells, including macrophage dendritic cells, monocytes, and granulocytes. Moreover, in vitro assays validated the HPV-mediated CXCL chemokines secretion, which played the role in recruiting immune cells. Limitations, reasons for caution The current findings are based on the single-cell profiling analysis in normal endometrium. In addition, the in vivo response of the HPV infection may differ from the in vitro assay, which should be validated in the HPV infection couples. Wider implications of the findings Our study demonstrated the expression changes of endometrium in RIF via HPV-mediated CXCL chemokines secretion, which provided insight into the mechanisms of HPV-induced reduced endometrial receptivity in single-cell resolution. Trial registration number not applicable

O-229 To remove or not to remove - debate continues

Abstract Fibroids and Fertility - To remove or not to remove debate continues Uterine fibroids (leiomyomas or myomas) are the most common benign pelvic tumors in reproductive age women. Fibroids are increasingly found in women seeking infertility treatment because of longer reproductive timeline & current trend to postpone childbearing. Fibroids adversely affect the female fertility by distortion of uterine cavity, thinning of endometrium, reduced blood supply in endometrium & myometrium, increased contractility of uterus and hormonal changes. Fibroids also exert global effect on endometrial receptivity through molecular signaling. Women with submucosal myomas experience significantly lower implantation, clinical pregnancy, ongoing pregnancy, and live birth rates, and higher miscarriage rates. The need and effect of myomectomy on submucous myoma is acknowledged in literature. Subserosal fibroids, do not affect fertility and removal is not advisable prior to IVF. There is heterogenicity in the studies reporting the effect of intramural fibroids on fertility. Some have reported an association between intramural fibroids and reduced chance of pregnancy and increased rates of early pregnancy loss. The effect of fibroids which are in close proximity to the endometrium & are 100% intramural (FIGO type 3 and 4) on fertility has been investigated by many researchers. The endometrial cavity may not be distorted by these fibroids, yet they can affect fertility because of their proximity to the uterine cavity. Studies have shown that both size of the fibroid and distance of fibroid from endometrial cavity are important factors, which determine the effect of intramural fibroids on fertility. The production of transforming growth factor beta-3b (TGF- b3), is increased as size of the fibroid increases and impairs the endometrial receptivity. Fibroids causing menorrhagia are likely to affect endometrial receptivity. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (Evidence III-A) Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. ( III-B). In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. ( II-2A). Removal of subserosal fibroids is not recommended. (III-D). Whether to surgically remove intramural fibroids not distorting the endometrial lining (FIGO types 3–4) for improving fertility in asymptomatic infertile patients has been a subject of debate since long. The studies favoring myomectomy indicate that It is better to perform myomectomy prior to ART cycle women with reduced ovarian reserve, advanced maternal age, recurrent pregnancy loss or previous failed IVF cycles. Decision for a particular approach for myomectomy - via a laparotomy, laparoscopy or hysteroscopy should be based on the size and location of fibroid and experience of surgeon. There is fair evidence to recommend against myomectomy in women with intramural fibroids more than 3–4 cm before ART cycle (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size (II-2D). Surgery in patients with intramural fibroids presenting with infertility, should be considered to be a risky procedure, not only because of the limited evidence of the efficacy of myomectomy on reproductive outcomes but also because of the potential for several surgery-related complications. We need to investigate other modalities such as uterine artery embolization and magnetic resonance-guided focused ultrasound. The observed lack of consensus regarding recommendations for myomectomy in case of infertile patients with intramural fibroid is mainly because of heterogenicity of the studies. The decision to perform myomectomy on intramural fibroids should be individualized (III-C)

O-192 Concomitant autoimmunity in endometriosis-affected women and In Vitro Fertilization (IVF) outcomes: a cohort study

Abstract Study question To evaluate whether the presence of concomitant autoimmunity in endometriosis patients may affect In Vitro Fertilization (IVF)/Intracytoplasmic Injection (ICSI) outcomes. Summary answer In ‘normo-responders’ patients autoimmunity did not affected ovarian response to gonadotrophin stimulation yet was the only significant negative predictor of cumulative pregnancy rate (CPR). What is known already In the last years, endometriosis has been redefined as a multifactorial disease with a complex pathogenesis. In this setting, a role of both innate and adaptive immune systems have been proposed in endometriosis development. The coexistence of endometriosis and autoimmunity is well-documented. Also, an increased risk of more severe stages of endometriosis in patients with autoimmunity has been recently reported. Even if autoimmunity has been associated with lower pregnancy rates and higher miscarriage rates, whether the presence of autoimmunity in endometriosis patients could act as an additive factor worsening IVF/ICSI response is still not known. Study design, size, duration Single-center, retrospective, cohort study. First IVF/ICSI cycles of endometriosis patients with or without autoimmunity carried out from 2007 to 2021 at the Fertility Unit of IRCSS San Raffaele Hospital(Milan) were included. Patients with endometriosis and concomitant autoimmunity were age-matched to endometriosis only controls. Only patients with a complete disease control following endometriosis treatment were admitted to IVF/ICSI. A total of 471 patients were enrolled. The study was conducted according to STROBE guidelines for observational studies. Participants/materials, setting, methods Endometriosis diagnosis was surgical/histopathological, yet also ovarian endometriosis at ultrasound assessment by expert operators was included. Autoimmunity was assessed by blood tests for auto-antibodies and/or rheumatological records. Stratified analysis by “expected” ovarian response at baseline according to AFC and/or AMH were performed. Expected ‘poor-responders’ were defined according to Bologna Criteria. The primary outcome was CPR. Secondary outcomes included oocytes retrieved, metaphase II(MII)oocytes and ovarian sensitivity index(OSI), the latter defined as:(number of retrieved oocytes/total gonadotrophin dose)×1000. Main results and the role of chance 113/471 cases with endometriosis and concomitant autoimmunity and 358/471 age-matched endometriosis only controls were enrolled. The mean age was 35.70±3.75 and 35.95±3.72 (p = 0.543) in cases and controls respectively. No baseline differences in endometriosis disease stage (p = 0.414), surgical treatment for endometriosis prior to IVF (p = 0.617), BMI (p = 0.866) or type of infertility (p = 0.255) were observed when comparing the two groups. In “expected normo-responders”, cases with autoimmunity had significantly higher numbers of oocytes retrieved (p = 0.007), MII oocytes (p = 0.007) and OSI index (p = 0.013) when compared to controls with endometriosis only; the CPR was 12.5% in cases vs. 17.5% in controls, thus comparable between the two groups (p = 0.143). In “expected poor-responders” no significant differences were observed neither in the number of oocytes retrieved and MII oocytes, nor in OSI index; the CPR was 12% in cases with concomitant autoimmunity compared to 7.75% in controls with endometriosis only (p = 0.256). In the generalized linear models (GLMs) of independent predictors associated with CPR, in expected ‘normo-responders’ autoimmunity was the only significant negative predictor of CPR (p = 0.004) whereas in ‘poor-responders’ only age negatively affected CPR (p = 0.001). Limitations, reasons for caution This study has a retrospective design. The interpretation of results is based on the validated yet still debated definition of poor-responders according to Bologna Criteria. Results should be interpreted with caution until replicated by future research providing multi-centric and prospective design, larger sample size and more standardized data collection. Wider implications of the findings Autoimmunity does not seem to impact neither ovarian reserve nor ovarian response to gonadotropin, as it may act a ‘competitive’ rather than ‘additive’ risk factor for infertility in endometriosis. However, in ‘normo-responders’ autoimmunity seems to reduce the chances of pregnancy following IVF/ICSI perhaps impairing endometrial receptivity and embryo implantation. Trial registration number Due to the retrospective design of the study, full IRB approval at the institution was not needed.

P-195 Do the presence of necrotic foci and/or separate blastomeres, the blastocoele expansion degree affect pregnancy outcomes of frozen-thawed euploid blastocysts transfer cycles?

Abstract Study question Do the presence of necrotic foci and/or the presence of separate blastomeres and the blastocoele expansion degree affect pregnancy outcomes of frozen-thawed euploid embryo transfer cycles? Summary answer Significant correlations were observed between pregnancy outcomes and the degree of blastocoele expansion, the presence of necrotic foci or separate blastomeres in the euploid embryo. What is known already Implantation failure and pregnancy losses may occur despite the selection of a healthy euploid embryo for transfer and the elimination of other risk factors. Blastocyst morphology is known to affect pregnancy outcomes, but the effect of necrotic foci and/or separate blastomeres in the embryo on pregnancy outcomes needs further investigation. Study design, size, duration This is a retrospective cohort study and was conducted at ART and Reproductive Genetics Centre, Memorial, Sisli Hospital, Istanbul, Turkey between January 2017 and September 2021. A total of 2758 frozen-thawed euploid embryo transfer cycles were included in the study. Participants/materials, setting, methods After thawing, the embryos were divided into groups according to their morphological grades, whether there were necrotic foci and whether there were separate blastomeres, and were evaluated in terms of pregnancy outcomes. Blastocysts were graded by using Gardner and Schoolcraft’s grading system. Ongoing pregnancy was defined as a pregnancy that had reached 20 weeks. Miscarriage was defined as a pregnancy loss occurring before the 20th gestational week. Main results and the role of chance Our data showed that the presence of necrotic foci in the inner cell mass or trophectoderm reduced the ongoing pregnancy rates and increased the miscarriage rates. The ongoing pregnancy rate was lower (41.0%, vs 60.0%, p < 0.001) and the miscarriage rate was higher (27.3% vs 19.8%, p < 0.05) in the group with necrotic foci than in the group without necrotic foci. The presence of separate blastomeres decreased the ongoing pregnancy rates (50.3% in the group with separate blastomeres, 61.8% in the group without separate blastomeres) (p < 0.001) and increased the miscarriage rates (25.3% in the group with separate blastomeres, 18.8% in the group without separate blastomeres) (p > 0.004). The ongoing pregnancy rates for blastocoele expansion degrees of 2, 3, 4, 5, and 6 were 39.5%, 38.3%, 59.3%, 59.8%, and 61.4%, respectively and the miscarriage rates for blastocoele expansion degrees of 2, 3, 4, 5, and 6 were 35%, 33.3%, 21%, 21.2%, 18.4%, respectively. Embryos with degrees of expansion grade ≤ 3 had lower ongoing pregnancy rates and higher miscarriage rates than those with degrees of expansion > 3 (p < 0.01). Limitations, reasons for caution Retrospective study. Wider implications of the findings When choosing the embryo to be transferred in cases with more than one euploid embryo, the selection should be made by considering the blastocoele expansion degrees and the presence of necrotic foci and separate blastomeres in the embryo. Trial registration number not applicable

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

Differential proteomics of placentas reveals metabolic disturbance and oxidative damage participate yak spontaneous miscarriage during late pregnancy

BackgroundHigh spontaneous miscarriage rate in yak, especially during late pregnancy, have caused a great economic loss to herdsmen living in the Qinghai-Tibet plateau. However, the mechanism underlying spontaneous miscarriage is still poorly understood. In the present study, placenta protein markers were identified to elucidate the pathological reasons for yak spontaneous miscarriage through isobaric tags for relative and absolute quantification (iTRAQ) proteomic technology and bioinformatic approaches.ResultsSubsequently, a total of 415 differentially expressed proteins (DEPs) were identified between aborted and normal placentas. The up-regulated DEPs in the aborted placentas were significantly associated with “spinocerebellar ataxia”, “sphingolipid signalling”, “relaxin signalling”, “protein export”, “protein digestion and absorption” and “aldosterone synthesis and secretion” pathway. While the down-regulated DEPs in the aborted placentas mainly participated in “valine, leucine and isoleucine degradation”, “PPAR signalling”, “peroxisome”, “oxidative phosphorylation”, “galactose metabolism”, “fatty acid degradation”, “cysteine and methionine metabolism” and “citrate cycle” pathway.ConclusionsThe results implied that the identified DEPs could be considered as placental protein markers for yak miscarriage during late pregnancy, and biomacromolecule metabolic abnormality and oxidative damage might be responsible for the high spontaneous miscarriage rate in yak. These findings provide an important theoretical basis for deciphering the pathologic mechanism of late spontaneous miscarriage in yak.

Preconception reproductive tract infections status and adverse pregnancy outcomes: a population-based retrospective cohort study

BackgroundReproductive tract infections can cause serious adverse outcomes for pregnant women such as spontaneous abortion and preterm birth. However, it is unclear whether maternal reproductive tract infection before pregnancy would also be related to any adverse pregnancy outcomes. This study aims to investigate the association of maternal preconception reproductive tract infections with subsequent adverse pregnancy outcomes.MethodsA retrospective cohort study was conducted in the Chongqing Municipality of China between April 2010 and December 2016. A total of 57,586 women (57,708 pregnancies) from all 39 counties of Chongqing who participated in the National Free Preconception Health Examination Project were included. They all took preconception examinations for gonorrhea, chlamydia, trichomoniasis, syphilis, bacterial vaginosis and candidiasis before pregnancy within one year. Primary outcomes included spontaneous abortion (< 28 weeks gestation), preterm birth (< 37 weeks gestation), macrosomia and low birthweight.ResultsOf the 57,708 pregnancies, 2438 (4.22%) had at least one type of reproductive tract infections. Compared with women who were not infected with any reproductive tract infection before pregnancy, women with reproductive tract infections had a higher rate of spontaneous abortion (7.88% vs. 5.62%, p < 0.001). After analyzing by each infection, there were few significant associations between pre-pregnancy infections and adverse outcomes. Preconception syphilis infection was significantly associated with increased odds of spontaneous abortion (aOR = 2.07, 95%CI 1.50–2.85), induced abortion/labour due to medical reasons (aOR = 1.60, 95%CI 1.01–2.54) and preterm birth (aOR = 1.60, 95%CI 1.12–2.30) after adjusting for potential confounders. Preconception trichomoniasis was intended to relate to a higher risk of spontaneous abortion (aOR = 1.65, 95%CI 1.01–2.71), but its impact seemed to be attributed to its co-infection with other RTIs. Women who were chlamydia or bacterial vaginosis positive before pregnancy showed higher odds of macrosomia (aOR = 2.00, 95% CI 1.07–3.74 for chlamydia; aOR = 1.58, 95% CI 1.06–2.34 for bacterial vaginosis). Preconception bacterial vaginosis might also be associated with higher risks of very preterm birth (aOR = 2.16, 95%CI 1.23–3.78) and large for gestational age (aOR = 1.36, 95%CI 1.02–1.81).ConclusionsWomen with infections of the genital tract before pregnancy might also have increased risks of subsequent adverse outcomes including spontaneous abortion, preterm birth and macrosomia.

Impact of various PCOS phenotypes on oocyte competence in an ART cycle

Introduction: PCOS is a common cause of female infertility. Although PCOS patients are characterized by producing an increased number of oocytes, they are often of poor quality, leading to lower fertilization, cleavage, and implantation and higher miscarriage rates. Aims: The present study aims to identify the effect of various PCOS phenotypes on oocyte competence in an ART cycle. Settings and design: A retrospective observational study. Methods and material: The study group included 102 women with PCOS as a main cause of infertility. Data was collected over a period of one year (2017-18). These women were divided into four groups on basis of PCOS phenotypes (A-D) and the relevant clinical data and the ART outcome were noted. Statistical analysis was done using SPSS statistical package. Data presented as mean ± SD which was compared using the ANOVA test. A p - value &lt; 0.05 was considered statistically significant. Results: Out of 102 PCOS women, 23.52% women had phenotype A, 11.76% had phenotype B, and 45.09% and 19.60% had phenotype C &amp; D respectively. Good quality embryos formed (p - value 0.01) were lower in Group B vs. other groups. However, clinical pregnancy rates were comparable in all groups. Conclusion: The reproductive potential of women with PCOS varies with the oocyte health and it largely depends on PCOS phenotype. Women with PCOS phenotype B might have poor IVF/ICSI outcomes with regard to the number of oocytes retrieved and embryos formed. PCO morphology might carry an advantage with regards to the number of oocytes retrieved and better quality embryos. It seems that hyperandrogenism in combination with chronic anovulation is associated with poor oocyte competence and hence, a negative impact on embryo quality and clinical pregnancy rate. Further studies with a larger sample size are required to further support it. Key messages: Oocyte competence in various PCOS phenotypes.

Impact of introduction of the growth assessment protocol in a South Indian tertiary hospital on SGA detection, stillbirth rate and neonatal outcome

India has a high rate of stillbirths, and many deaths are due to fetal growth restriction and potentially preventable. Screening and identification of the small for gestational age (SGA) fetus during the antenatal period has been shown to reduce stillbirths. We set out to evaluate the impact of implementing the Growth Assessment Protocol (GAP), a programme designed for screening for SGA. Observational study comparing two-time epochs; before (years 2011-2014) and after (years 2015-2018) introduction of GAP. The programme includes identification of risk factors, risk categorization, serial fundal height measurement, customised fetal growth charts and appropriate referral protocols. Fetal growth charts and birth centiles were generated based on the hospital database of normal outcome pregnancies, customised to women's ethnicity, parity, height, and weight. The protocol was introduced following training of obstetric and midwifery care providers. We evaluated SGA detection rates, stillbirth rates (from 28weeks) and neonatal morbidity at term. There were 26,199 and 31,498 births, with 115 and 108 stillbirths in the pre and post-GAP implementation periods, respectively. SGA detection rates increased from 51.1 to 67.1%, representing a 31% improvement (p<0.001). Overall stillbirth rates declined from 4.4 to 3.4 per 1000 births (RR 0.78 CI 95% 0.60-1.02) and at term from 1.5 to 0.6 (RR 0.37 CI 95% 0.20-0.66). Neonatal intensive care admission and neonatal encephalopathy in term neonates also decreased significantly. Introduction of the GAP programme in an Indian tertiary maternity service was associated with improved antenatal detection of SGA and reduced stillbirth rates and neonatal morbidity.

Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis.

The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.

Risk of spontaneous abortion after antibiotic therapy for chronic endometritis before in vitro fertilization and intracytoplasmic sperm injection stimulation

To investigate whether cured chronic endometritis (CE) from antibiotic treatment would be associated with a higher risk of spontaneous abortion in the following invitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Prospective cohort study. Tertiary reproductive medicine center. Patients with infertility who underwent a routine hysteroscopy underwent an IVF/ICSI stimulation between January 1, 2019, and December 31, 2020. Women with CE (N = 338) underwent antibiotic therapy, and the assisted reproductive outcomes were then compared with women without CE (N = 7,962). Chronic endometritis was diagnosed through hysteroscopy and confirmed by histology and immunohistochemistry for CD138. Spontaneous abortion rate after the initial embryo transfer. A total of 7,218 patients underwent embryo transfer, with 330 in the cured CE group and 6,888 in the non-CE group. Women with cured CE had a higher rate of spontaneous abortion than did those without CE (11.8% vs. 9.2%; crude odds ratio [OR], 1.32 [0.94, 1.86]), and this difference was statistically significant after adjusting for confounding variables (adjusted OR, 1.49 [1.01, 2.19]). The live birth rate was 43.9% in the cured CE group and 50.5% in the non-CE group (crude OR, 0.77 [0.62, 0.96]; adjusted OR, 0.73 [0.59, 0.92]). The incidence of clinical pregnancy did not differ significantly between the 2 groups (56.1% vs. 60.0%; crude OR, 0.85 [0.68, 1.06]; adjusted OR, 0.83 [0.66, 1.03]). Sensitivity analyses stratified by initial fresh- or frozen-thawed embryo transfer cycles resulted in similar results. Chronic endometritis cured with antibiotic therapy was associated with an increased risk of spontaneous abortion among women undergoing IVF/ICSI treatment. The interpretation of the findings is limited by a potential confounding bias.

Effects of Climate and Environmental Changes on Women's Reproductive Health.

Effects of Climate and Environmental Changes on Women's Reproductive Health.

Corona and Reproduction, or Why the Corona Vaccination Does Not Result in Infertility.

Background As the COVID-19 pandemic persists and new vaccines are developed, concerns among the general public are growing that both infection with the SARS-CoV-2 virus and vaccinations against the coronavirus (mRNA vaccines) could lead to infertility or higher miscarriage rates. These fears are voiced particularly often by young adults of reproductive age. This review summarizes the current data on the impact of SARS-CoV-2 infection and corona vaccinations on female and male fertility, based on both animal models and human data. Method A systematic literature search (PubMed, Embase, Web of Science) was carried out using the search terms “COVID 19, SARS-CoV-2, fertility, semen, sperm, oocyte, male fertility, female fertility, infertility”. After the search, original articles published between October 2019 and October 2021 were selected and reviewed. Results Despite the use of very high vaccine doses in animal models, no negative impacts on fertility, the course of pregnancy, or fetal development were detected. In humans, no SARS-CoV-2 RNA was found in the oocytes/follicular fluid of infected women; similarly, no differences with regard to pregnancy rates or percentages of healthy children were found between persons who had recovered from the disease, vaccinated persons, and controls. Vaccination also had no impact on live-birth rates after assisted reproductive treatment. No viral RNA was detected in the semen of the majority of infected or still infectious men; however, a significant deterioration of semen parameters was found during semen analysis, especially after severe viral disease. None of the studies found that corona vaccines had any impact on male fertility. Discussion Neither the animal models nor the human data presented in recent studies provide any indications that fertility decreases after being vaccinated against coronavirus. However, there is a growing body of evidence that severe SARS-CoV-2 infection has a negative impact on male fertility and there is clear evidence of an increased risk of complications among pregnant women with SARS-CoV-2 infection. The counseling offered to young adults should therefore take their fears and concerns seriously as well as providing a structured discussion of the current data.