Subfertile Women Research Articles

O-296 Progesterone level is an alternative marker to detect ovulation time in natural cycle frozen-thawed embryo transfers

Abstract Study question Do serum progesterone or LH levels better predict the optimal timing for embryo transfer in true natural cycle frozen-thawed embryo transfers (NC-FET)? Summary answer Performing embryo transfer according to serum progesterone levels (PL) had similar ongoing pregnancy rates compared to embryo transfer according to serum LH levels. What is known already With efficient and safe embryo vitrification techniques, there is an increasing trend in frozen-thawed embryo cycles (FET) over fresh cycles. FET protocols are programmed cycle, NC-FET and modified NC-FET. NC-FET is increasing in popularity, since it is associated with favourable obstetric and perinatal outcomes. In NC-FETs, ovulation time is the critical parameter for synchronization of embryo and endometrium. In the literature, LH surge is the most commonly used test to define ovulation time. Study design, size, duration This prospective cohort study included 183 NC-FET cycles in an IVF clinic between March 2022 and November 2022. Main outcome measure is ongoing pregnancy. Participants/materials, setting, methods 183 subfertile women aged between 18-40, having regular menstruation with a cycle length between 24-38 days are included. Protocol for NC-FET included serial hormone measurements and ultrasound monitoring when the dominant follicle reached the diameter of 15-16 mm. Serum LH level ≥15 IU/l defined as ‘ovulation -1’ in Group 1 and blastocyst embryo transfer was performed after 6 days. Serum PL > 1 ug/ml was defined as the ‘ovulation day’ in Group 2. Main results and the role of chance: There were no significant differences in baseline characteristics including female age, female body mass index, infertility duration, infertility diagnosis and number of failed IVF cycles between two groups. Also, cycle characteristics regarding endometrial thickness, number of embryos transferred, embryo quality and PLs at transfer day were similar. The overall clinical pregnancy was 59.6% and ongoing pregnancy was 50.8%. The implantation rate was 61.7%. The clinical pregnancy and ongoing pregnancy of Group 1 and Group 2 were 49.5%, 50.5% and 47.3%, 52.7%, respectively (p > 0.05). PLs in order to detect ovulation time were calculated according to a mathematical modelling (PL(Ov )=a1 eb1 Ov )(Ov:ovulation day; a1,b1:regression coefficients; e:euler number≌2.718) described in our previous study. Embryo transfer timing was planned after 5,4 or 3 days based on PLs calculated by modelling. Limitations, reasons for caution Since this is the first study planning embryo transfer in NC-FET based on progesterone levels, sample size should be increased and also serial change of progesterone levels were unknown in women >40 years of age. Wider implications of the findings Progesterone has a particular increasing pattern that enables ovulation day prediction accurately and may be used instead of serum LH levels in timing of embryo transfer. Trial registration number NCT05690360

P-658 Clinical outcomes from ART in predicted hyperresponders: in-vitro maturation of oocytes versus conventional ovarian stimulation

Abstract Study question Do ongoing pregnancy rates (OPR) differ in predicted hyperresponders undergoing ART after in-vitro maturation of oocytes (IVM) compared with conventional ovarian stimulation (COS)? Summary answer One cycle of IVM is non-inferior to one cycle of COS in women with serum AMH levels >10ng/mL. What is known already Women with high antral follicle count (AFC) and elevated serum AMH levels, indicating an increased functional ovarian reserve, are prone to hyperresponse during ART treatment. To avoid iatrogenic complications of COS, IVM has been proposed as a mild-approach alternative treatment in predicted hyperresponders, including women with polycystic ovary syndrome (PCOS) who are eligible for ART. To date, inferior pregnancy rates from IVM compared to COS have hampered the uptake of IVM by ART clinics. However, it is unclear whether the efficiency gap between IVM and COS may differ depending on the extent of AMH elevation. Study design, size, duration This study is a retrospective cohort analysis of clinical and laboratory data from the first completed highly purified human menopausal gonadotropin (HP-hMG) primed, non-hCG triggered IVM or COS (FSH or HP-hMG stimulation in a GnRH antagonist protocol) cycle with ICSI in predicted hyperresponders ≤36 years of age at a tertiary referral university hospital. A total of 1707 cycles were included between January 2016 and June 2022. Participants/materials, setting, methods Predicted hyperresponse was defined as a serum AMH level >3.25ng/mL (Elecsys® AMH, Roche Diagnostics). The primary outcome was cumulative ongoing pregnancy rate (OPR) assessed 10-11 weeks after embryo transfer. The predefined non-inferiority limit was -10.0%. The analysis was adjusted for AMH strata. Time-to-pregnancy (TTP), defined by the time interval between egg retrieval and date of successful embryo transfer, was a secondary outcome. Statistical analysis was performed using a multivariable regression model controlling for potential confounders. Main results and the role of chance Data from 463 IVM cycles were compared with those from 1244 COS cycles. Women in the IVM group more often had a diagnosis of Rotterdam PCOS (434/463, 93.7%) compared to those undergoing COS (522/1193, 43.8%), were significantly younger (29.5 years vs 30.5 years, p ≤ 0.001), had a higher BMI (25.7kg/m² vs 25.1kg/m², p ≤ 0.01) and higher AMH (11.6ng/mL vs 5.3ng/mL, p ≤ 0.001). Although IVM cycles yielded more cumulus oocyte complexes (COCs) (25.8 COC vs 15.0 COC, p ≤ 0.001), both groups had similar numbers of mature oocytes (MII) (11.9 MII vs 10.6 MII, p = 0.9). In the entire cohort, non-adjusted cumulative OPR from IVM was significantly lower (198/463, 42.8%) compared to COS (794/1244, 63.8%), p ≤ 0.001. When analysing OPR across different serum AMH strata, cumulative OPR in both groups converged with increasing serum AMH, and OPR from IVM was non-inferior compared to COS from serum AMH levels >10ng/mL onwards (113/221, 51.1% [IVM]; 29/48, 60.4% [COS]). Time-To-Pregnancy was shorter in the IVM group compared to COS (11.3 weeks vs 21.0 weeks, p ≤ 0.001). Multivariable regression analysis adjusting for ART type, age, BMI, oocyte number and PCOS phenotype showed that the number of COCs was the only parameter associated with OPR in predicted hyperresponders with a serum AMH >10ng/mL. Limitations, reasons for caution These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. Patients enrolled in a clinical IVM program received one-to-one care, in contrast with COS patients who received standard care, which may have influenced TTP. Wider implications of the findings Among subfertile women who are eligible for ART, IVM and COS resulted in comparable reproductive outcomes in a subset of women with a serum AMH >10ng/mL. These findings should be corroborated by an RCT comparing both treatments in selected patients with elevated AMH. Trial registration number Not applicable

P-675 Analysis of a digitally integrated ovulation date kit to determine ovulation precisely

Abstract Study question Do digitally integrated ovulation prediction kits (OPK) predict the fertile window and the ovulation date accurately? And can this prediction be proven by sonography? Summary answer Particularly for subfertile women with irregular cycles, OPKs can help predict their fertile window and ovulation day, in accordance with vaginal sonography. What is known already The fertile window is defined as the period of five days before ovulation including the day of ovulation itself. Prediction based only on cohort observations or historical datasets may be inaccurate for women with irregular cycles, particularly when unforeseen changes of ovarian function occur during reproductive life. Urinary luteinizing hormone (LH) assays and smartphone applications are already widely used to detect the optimal time for conception, but can only predict a likelihood of ovulation without proof. Study design, size, duration 100 healthy women between the ages of 21 and 45, cycle length up to 42 days, trying to conceive and without hormone intake were to be recruited in the gynecological outpatient clinics of the Technical University of Munich (TUM) and of the University of Ulm. Each participant entered the study for up to three consecutive cycles. Two vaginal ultrasound scans were performed per cycle – before and after the ovulation date prognosis by the app. Participants/materials, setting, methods After informed consent, participants downloaded the smartphone application “Pearl Fertility” and received OPKs consisting of four different sets of lateral flow immunoassay test strips (LFIA): for luteinizing hormone, follicle-stimulating hormone, progesterone and human chorionic gonadotropin. Home measurements with LFIAs were performed with morning urine. The phone camera feed analyzed the color information of the LFIAs. Three differently prioritized algorithms calculated the ovulation date. Two questionnaires evaluated patient baseline characteristics and their perception of the app. Main results and the role of chance 89 women were recruited. Mean age was 34.6 yrs. (SD ± 4.2). On average, the included women had tried to conceive for 7.5 (±5) months before joining the study. 8% (n = 7) became pregnant before the first cycle started.140 completed cycles in 71 remaining women were analyzed so far. 46% of the recruited women completed the study after 3 cycles, the drop-out-rate was 32.4%. The app predicted ovulation for cycle day 14.3 (mean, SD ± 3.5). In 25 cycles the date of ovulation was before day 12 and in 33 cycles on day 16 or later. The first ultrasound was done on cycle day 13.5 (mean, SD ± 3), the second ultrasound on cycle day 17.6 (mean, SD ± 3.6). In several cycles at least one (up to three) corrections of the prognosis occurred by the app, resulting in the day of predicted ovulation being moved either backward (retrospectively) or forward by 2.5 (mean, SD ± 1.9) days. Urinary progesterone measured with the OPK and post-ovulatory ultrasound were in accordance in the majority of cycles. 17% (n = 12) of the women became pregnant in the current analysis (mean duration to pregnancy: 1.3 cycles). In the ITT population (after informed consent) the rate was 23%. Limitations, reasons for caution This study was performed without a control group. Therefore, as an intraindividual control, a follow-up is planned to calculate the pregnancy rates and outcomes with and after the use of the app. Wider implications of the findings Our study shows that digitally integrated OPK are able to predict the fertile window and the ovulation date in a slightly subfertile cohort unselected for mild cycle irregularities. An early and accurate prediction may help couples to conceive, particularly if the date of ovulation is divergent from standard information. Trial registration number Not applicable

O-258 Characterization of vaginal microbiota during IVF fresh embryo transfer (IVF-ET) and in early pregnancy

Abstract Study question Does the composition of vaginal microbiota affect the success of IVF-ET? Does vaginal microbiota profile change intra-individually from IVF-ET to early pregnancy? Summary answer L. crispatus is associated with successful IVF outcome. The individual composition of vaginal microbiota tends to shift towards Lactobacillus-dominance between IVF-ET and early pregnancy. What is known already Lactobacilli are the most abundant species in healthy female reproductive tract microbiota and especially Lactobacillus crispatus is associated with good gynecological health. The composition of vaginal microbiota may also play an important role in infertility and the success of IVF. Women with Lactobacillus-dominated vaginal microbiota may have higher pregnancy rates after IVF-ET compared to women with non-Lactobacillus dominance, but the results have been controversial. In healthy pregnancy, vaginal microbiota is usually lactobacilli-dominated, whereas miscarriages are associated to a non-lactobacillus dominance. The intra-individual shift on the vaginal microbiota from ET to early pregnancy has not been studied earlier. Study design, size, duration This observational and longitudinal study investigates the effect of vaginal microbiota on the success of fresh IVF-ET. Another aim was to study the intra-individual changes in the microbiota profile between IVF-ET and early pregnancy. We recruited 76 subfertile women undergoing IVF with their own gametes between November 2019 and September 2021 in the Reproductive Medicine Unit, Helsinki University Hospital and in Oulu University Hospital. Main outcomes were clinical pregnancy and live birth. Participants/materials, setting, methods Study population composed of 76 subfertile women under 40 years of age. One IVF cycle including fresh embryo transfer was studied. Vaginal swabs were taken at the time of IVF-ET and at 8th gestational week. Samples were frozen in − 20 °C and moved to − 80 °C within four weeks. Microbiota analysis was performed with next-generation sequencing of 16S rRNA gene using Illumina MiSeq technology. Clinical data were collected from the patient registries and background questionnaires. Main results and the role of chance Altogether 30 (39.5%) of the 76 women achieved pregnancy after IVF-ET and 26 (34.2%) had live birth. The relative abundance of L. crispatus among women who achieved clinical pregnancy (46.9% vs. 19.1%, q = 0.003) and live birth (43.3% vs. 19.1%, q = 0.006) was significantly higher compared to women who did not. After adjusting for age, parity and gravidity, the results remained similar when comparing clinical pregnancy (q = 0.039), but in live birth, the difference lost significance (q = 0.14) Vaginal samples were taken at the 8th gestational week from 21 of 30 women who got pregnant. All samples were dominated by Lactobacillus species, mainly by L. crispatus (n = 16, 76.2%). Only two (9.2%) women had L. iners dominated microbiota at the early pregnancy. When comparing samples taken during fresh IVF-ET and early pregnancy, L. crispatus had significantly higher relative abundance in early pregnancy samples compared to the samples taken at the ET (71.5% vs. 43.4%, q = 0.001), whereas the relative abundance of L. iners (10.1% vs. 24.1%, q = 0.004), and G. vaginalis (0.8% vs. 14.7%, q = 0.004) decreased. Altogether 13 women had an intra-individual shift in their microbiota profiles. Limitations, reasons for caution The small sample size was the main limitation of our study. Larger studies are needed to confirm our findings and their relationship with the success of IVF-ET. Wider implications of the findings Vaginal microbiota at the time of fresh IVF-ET has an impact of the success of IVF treatment. Also, the intra-individual composition of vaginal microbiota between IVF-ET and early pregnancy changes in some women. The vaginal microbiota modification through probiotics in order to optimize the result of IVF warrants more studies. Trial registration number Not applicable

Clomiphene Supported Ovulation Induction in Subfertile Polycystic Ovary Syndrome Women: Role of Different Insulin Sensitizers

Objective: To compare Clomiphene Citrate, ovulation induction efficacy following using insulin sensitises, Metformin versus Myo-inositol in subfertile women with polycystic ovary syndrome.
 Study Design: Prospective comparative study.
 Place and Duration of Study: Department of Obstetrics and Gynaecology, Combined Military Hospital, Kharian Pakistan, from Jun to Nov 2021.
 Methodology: A total of 316 patients with polycystic ovary syndrome and infertility who were included in the study. Group-A was administered Metformin, whereas Group-B as given Myo-inositol. Both groups were given clomiphene citrate for ovulation induction and were followed for six months.
 Results: There were 316 patients (158 in each Group). The mean age was 29.2±0.5 years, and the BMI of 23.2±1.7 Kg/m2 in both. Ovulation recorded in Group-A (Metformin) was 141(44.6%) versus Group-B (Myo-inositol), 103(32.6%). The pregnancy test was positive 33(21.1%) patients of Group-A versus 29(18.4%) of Group-B. The common complaints seen in both groups were nausea and vomiting 2(0.6%), while headache 1(0.3%) and dizziness 2(0.6%) occurred only in Group-B.
 Conclusion: Clomiphene citrate with Metformin, as first-line therapy for sub-fertile women with polycystic ovary syndrome, improved ovulation and had fewer side effects than Myo-inositol.

Associations of Maternal Urinary Concentrations of Phenols, Individually and as a Mixture, with Serum Biomarkers of Thyroid Function and Autoimmunity: Results from the EARTH Study.

The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009-2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography-tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols-both individually and as a mixture-and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT3 (mean difference for a 1 log unit increase in concentration: -0.088; 95% CI [-0.151, -0.025]) and TT3 (-0.066; 95% CI [-0.112, -0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT3 concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: -0.19, 95% CI [-0.35, -0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system.

Iron status in women with infertility and controls: a case-control study.

Iron deficiency is a common problem in subfertile women. The influence of iron status on unexplained infertility is unknown. In a case-control study, 36 women with unexplained infertility and 36 healthy non-infertile controls were included. Parameters of iron status including serum ferritin and a serum ferritin <30 µg/dL served as main outcome parameters. Women with unexplained infertility demonstrated a lower transferrin saturation (median 17.3%, IQR 12.7-25.2 versus 23.9%, IQR 15.4-31.6; p= 0.034) and a lower mean corpuscular hemoglobin concentration (median 33.6 g/dL, IQR 33.0-34.1 versus 34.1 g/dL, IQR 33.2-34.7; p= 0.012). Despite the fact that there was no statistically significant difference in median ferritin levels (p= 0.570), women with unexplained infertility had ferritin levels <30µg/L more often (33.3%) than controls (11.1%; p= 0.023). In a multivariate model, unexplained infertility and abnormal thyroid antibodies were associated with ferritin <30µg/L (OR 4.906, 95%CI: 1.181-20.388; p= 0.029 and OR 13.099; 2.382-72.044; p= 0.029, respectively). Ferritin levels <30µg/L were associated with unexplained infertility and might be screened in the future. Further studies with a focus on iron deficiency and iron treatment on women with unexplained infertility are warranted.

FREQUENCY OF PELVIC PATHOLOGIES IN PRIMARY SUBFERTILITY ON DIAGNOSTIC LAPAROSCOPY

This study aimed to determine the frequency of pelvic pathologies in female primary subfertility by using diagnostic laparoscopy. A prospective study was conducted in the Department of Gynecology and Obstetrics of Nishtar Hospital, Multan, from April 2022- April 2023. A total of 100 women aged 20-40 years who were unable to get pregnant after unprotected sex for one year and had a normal pelvic examination and semen analysis of the husband were selected for the study. All the patients underwent laparoscopy. A tubal patency test was performed by using methylene blue dye. 50 patients (50%) had been subfertile for 1-5 years. Laparoscopy revealed that endometriosis was the most common cause of subfertility, as seen in 40% of patients. Tubal blockage was also observed in 8 patients (8%). Based on the results, it can be concluded that endometriosis followed and tubal occlusions are the most common causes of subfertility in women.

Cancer risk in children, adolescents, and young adults conceived by ART in 1983-2011.

Do children, adolescents, and young adults born after ART, including IVF, ICSI and frozen-thawed embryo transfer (FET), have an increased risk of cancer compared with children born to subfertile couples not conceived by ART and children from the general population? After a median follow-up of 18 years, the overall cancer risk was not increased in children conceived by ART, but a slight risk increase was observed in children conceived after ICSI. There is growing evidence that ART procedures could perturb epigenetic processes during the pre-implantation period and influence long-term health. Recent studies showed (non-)significantly increased cancer risks after ICSI and FET, but not after IVF. A nationwide historical cohort study with prospective follow-up was carried out, including all live-born offspring from women treated with ART between 1983 and 2011 and subfertile women not treated with ART in one of the 13 Dutch IVF clinics and two fertility centers. Children were identified through the mothers' records in the Personal Records Database. Information on the conception method of each child was collected through the mother's medical record. In total, the cohort comprises 89249 live-born children of subfertile couples, of whom 51417 were conceived using ART and 37832 were not (i.e. conceived naturally, through ovulation induction, or after IUI). Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry for the period 1989-2019. Cancer risk in children conceived using ART was compared with risk in children born to subfertile couples but not conceived by ART (hazard ratio (HR)) and children from the general population (standardized incidence ratios (SIRs)). In total, 358 cancers were observed after a median follow-up of 18 years. Overall cancer risk was not increased in children conceived using ART, when compared with the general population (SIR = 0.96, 95% CI = 0.81-1.12) or with children from subfertile couples not conceived by ART (HR = 1.06, 95% CI = 0.84-1.33). Compared with children from subfertile couples not conceived by ART, the use of IVF or FET was not associated with increased cancer risk, but ICSI was associated with a slight risk increase (HR = 1.58, 95% CI = 1.08-2.31). Risk of cancer after ART did not increase at older ages (≥18 years, HR = 1.26, 95% CI = 0.88-1.81) compared to cancer risk in children not conceived by ART. The observed increased risk among children conceived using ICSI must be interpreted with caution owing to the small number of cases. After a median follow-up of 18 years, children conceived using ART do not have an increased overall cancer risk. Many large studies with prolonged follow-up are needed to investigate cancer risk in (young) adults conceived by different types of ART. In addition, international pooling of studies is recommended to provide sufficient power to study risk of specific cancer sites after ART. This work was supported by The Dutch Cancer Society (NKI 2006-3631) that funded the OMEGA-women's cohort, Children Cancer Free (KIKA; 147) that funded the OMEGA-I-II offspring cohort. The OMEGA-III offspring cohort was supported by a Postdoc Stipend of Amsterdam Reproduction & Development, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD088393. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing interests. N/A.

Obstetric and neonatal outcomes after natural versus artificial cycle frozen embryo transfer and the role of luteal phase support: a systematic review and meta-analysis.

The number of frozen embryo transfers (FET) has increased dramatically over the past decade. Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) in subfertile women. However, NC-FET seems to be associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET cycles. Currently, there is no consensus about whether NC-FET needs to be combined with luteal phase support (LPS) or not. The question of how to prepare the endometrium for FET has now gained even more importance and taken the dimension of safety into account as it should not simply be reduced to the basic question of effectiveness. The objective of this project was to determine whether NC-FET, with or without LPS, decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET. A systematic review and meta-analysis was carried out. A literature search was performed using the following databases: CINAHL, EMBASE, and MEDLINE from inception to 10 October 2022. Observational studies, including cohort studies, and registries comparing obstetric and neonatal outcomes between singleton pregnancies after NC-FET and those after AC-FET were sought. Risk of bias was assessed using the ROBINS-I tool. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. We calculated pooled odds ratios (ORs), pooled risk differences (RDs), pooled adjusted ORs, and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2. The conducted search identified 2436 studies, 890 duplicates were removed and 1546 studies were screened. Thirty studies (NC-FET n = 56 445; AC-FET n = 57 231) were included, 19 of which used LPS in NC-FET. Birthweight was lower following NC-FET versus AC-FET (mean difference 26.35 g; 95% CI 11.61-41.08, I2 = 63%). Furthermore NC-FET compared to AC-FET resulted in a lower risk of large for gestational age (OR 0.88, 95% 0.83-0.94, I2 = 54%), macrosomia (OR 0.81; 95% CI 0.71-0.93, I2 = 68%), low birthweight (OR 0.81, 95% CI 0.77-0.85, I2 = 41%), early pregnancy loss (OR 0.73; 95% CI 0.61-0.86, I2 = 70%), preterm birth (OR 0.80; 95% CI 0.75-0.85, I2 = 20%), very preterm birth (OR 0.66, 95% CI 0.53-0.84, I2 = 0%), hypertensive disorders of pregnancy (OR 0.60, 95% CI 0.50-0.65, I2 = 61%), pre-eclampsia (OR 0.50; 95% CI 0.42-0.60, I2 = 44%), placenta previa (OR 0.84, 95% CI 0.73-0.97, I2 = 0%), and postpartum hemorrhage (OR 0.43; 95% CI 0.38-0.48, I2 = 53%). Stratified analyses on LPS use in NC-FET suggested that, compared to AC-FET, NC-FET with LPS decreased preterm birth risk, while NC-FET without LPS did not (OR 0.75, 95% CI 0.70-0.81). LPS use did not modify the other outcomes. Heterogeneity varied from low to high, while quality of the evidence was very low to moderate. This study confirms that NC-FET decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET. We estimate that for each adverse outcome, use of NC-FET may prevent 4 to 22 cases per 1000 women. Consequently, NC-FET should be the preferred treatment in women with ovulatory cycles undergoing FET. Based on very low quality of evidence, the risk of preterm birth be decreased when LPS is used in NC-FET compared to AC-FET. However, because of many uncertainties-the major being the debate about efficacy of the use of LPS-future research is needed on efficacy and safety of LPS and no recommendation can be made about the use of LPS.

Perfluorohexane sulfonate (PFHxS) disturbs the estrous cycle, ovulation rate, oocyte cell communication and calcium homeostasis in mice

Perfluoroalkyl substances are man-made chemicals with ample consumer and industrial applications. They are widely used and are resistant to environmental and metabolic degradation. Several studies have evaluated the effects of Perfluorohexane sulfonate on reproduction. However, there are few reports exploring the cell and molecular mechanisms of its toxicity in the ovary. The aim of this study was to investigate the effects of PFHxS exposure on the estrous cycle, ovulation rate, and the underlying mechanisms of action in female mice in vivo. The animals received a single sub-lethal dose of PFHxS (25.1 mg/kg, 62.5 mg/kg) or vehicle and were stimulated to obtain immature cumulus cell-oocyte complexes (COCs) from the ovaries, or superovulated to develop mature COCs. To evaluate oocyte physiology, Gap-junction intercellular communication (GJIC) was analyzed in immature COCs and calcium homeostasis was evaluated in mature oocytes. PFHxS exposure prolonged the estrous cycle and decreased ovulation rate in female mice. Connexins, Cx43 and Cx37, were downregulated and GJIC was impaired in immature COCs, providing a possible mechanism for the alterations in the estrous cycle and ovulation. No morphological abnormalities were observed in the mature PFHxS-exposed oocytes, but calcium homeostasis was affected. This effect is probably due, at least partially, to deregulation of the endoplasmic reticulum calcium modulator, Stim1. These mechanisms of ovarian injury could explain the reported correlation among PFHxS levels and subfertility in women undergoing fertility treatments.

Selenomethionine protects against Escherichia coli-induced endometritis by inhibiting inflammation and necroptosis via regulating the PPAR-γ/NF-κB pathway

Endometritis, inflammation of the endometrium, is a major cause of subfertility in women. Selenomethionine (SeMet)is known to exert anti-inflammatory activity. We aimed to verify the protective roles of SeMet on Escherichia coli (E.coli)-induced endometritis. The extent of uterus damage was assessed by detecting histopathology and inflammatory mediators. The results revealed that SeMet significantly prevented E.coli-induced endometritis by attenuating uterine histopathology and inflammatory cytokine production. E.coli-induced MPO activity and MDA content were inhibited by SeMey. E.coli-induced ZO-1 and occludin were upregulated by SeMet. E.coli-induced necroptosis was also inhibited by SeMet. Additionally, E.coli-induced NF-κB activation was alleviated by SeMet. PPAR-γ expression was upregulated by SeMet. Notably, the protective effects of SeMet on endometritis were abolished by a PPAR-γ inhibitor. In conclusion, SeMet inhibits E.coli-induced endometritis by attenuating inflammation and necroptosis, which is mediated by the PPAR-γ/NF-κB signaling pathway.

How does letrozole compare with other agents for subfertile women with polycystic ovary syndrome (PCOS)?

How does letrozole compare with other agents for subfertile women with polycystic ovary syndrome (PCOS)?

Higher miscarriage rate in subfertile women with endometriosis receiving unbiopsied frozen-warmed single blastocyst transfers.

Background: Assisted reproductive technology treatment is recommended to overcome endometriosis-associated infertility but current evidence is controversial. Endometriosis is associated with lower antral follicle count (AFC) and oocyte yield but similar clinical outcomes compared to controls. Unaffected ovarian stimulation response and embryological outcomes but lower clinical pregnancy and live birth rates and higher miscarriage rates have been reported, implying direct impact on endometrial receptivity. With evidence emerging on the benefit of frozen-warmed and blastocyst stage transfer, we investigated ART outcomes in endometriosis using homogeneous case-control groups. Methods: This is a retrospective observational case-control study including n = 66 frozen-warmed unbiopsied single blastocyst transfers of patients with endometriosis and n = 96 of women exhibiting idiopathic sterility. All frozen-warmed transfers followed artificial endometrial preparation. Results: In control women, the mean number of oocytes recovered at oocyte pick up was higher compared to women with endometriosis (15.3 ± 7.1 vs. 12.7 ± 5.2, p = 0.025) but oocyte maturation index (mature oocytes/total oocytes at oocyte pick up) was significantly higher for endometriosis (48.2% vs. 34.0%, p = 0.005). The same was shown for the subgroup of 44 endometriosis patients after endometrioma surgery when compared with controls (49.1% vs. 34.0%, p = 0.014). Clinical pregnancy rate was not higher in endometriosis but was close to significance (47.0% vs. 32.3%, p = 0.059) while live birth rate was comparable (27.3% vs. 32.3%, p = 0.746). Miscarriage rate was higher in the endometriosis group (19.7% vs. 7.3%, p = 0.018). A significantly higher AFC was observed in the control group in comparison with the endometriosis group (16.3 ± 7.6 vs. 13.4 ± 7.0, p = 0.014). Live birth rate did not differ when comparing all endometriosis cases (p = 0.746), ASRM Stage I/II and Stage III/IV (p = 0.348 and p = 0.888) with the control group but the overall pregnancy rate was higher in ASRM Stage I/II (p = 0.034) and miscarriage rate was higher in ASRM Stage III/IV (p = 0.030) versus control. Conclusion: Blastocyst transfers in women with endometriosis originate from cycles with lower AFC but higher share of mature oocytes than in control women, suggesting that endometriosis might impair ovarian reserve but not stimulation response. A higher miscarriage rate, independent of blastocyst quality may be attributed to an impact of endometriosis on the endometrium beyond the timing of implantation.

ROLE OF GENITAL TUBERCULOSIS IN SUB-FERTILE WOMEN

OBJECTIVE: To evaluate role of Acid fast bacilli culture (AFB) in sub-fertile women undergoing laparoscopy and dye test with endometrial biopsy. METHODS: This cross-sectional study was conducted from 1st January 2020 to 30th April 2021, on 108 cases of subfertility, enrolled through non-probability consecutive sampling technique, for diagnostic laparoscopy &amp; dye test with endometrial biopsy for AFB culture. We included all women of reproductive age with ≥2 years of subfertility, normal menstrual history, hormonal assay and normal male-factor. All women with comorbidities, women having contraindications for anaesthesia &amp; couple with male-factor subfertility were excluded. Data analysis was done by SPSS version-20. RESULTS: Seventy-two (66.7%) women had primary and 36 (33.3%) had secondary subfertility. Duration of subfertility was &gt;5 years in 63 (58.3%) cases. Ninety-seven (89.8%) patients had bilateral patent tubes. Majority of patients (n=46/108; 42.6%) were aging 32-38 years. Endometrial biopsy of 22 (20.4%) cases were positive for AFB culture. Out of AFB-positive cases, 17 (77.3%) had primary and 5 (22.7%) had secondary sub-fertility. All AFB-positive cases had patent tubes (unilateral n=5/22; bilateral n=17/22). Common laparoscopic findings were tortuous tubes (n=30; 27.8%) and clumped end fimbrial (n=24, 22.2%). CONCLUSION: In our study, endometrial sampling of 20.4% cases were positive for AFB culture. Although female genital tuberculosis constitutes a small proportion of extra-pulmonary tuberculosis, but it has an immense effect on fertility. Thus without challenging the superiority of laparoscopy, AFB culture could be considered a judicious part of subfertility workup in low resource countries carrying high burden of disease.

Comparing Vaginal and Endometrial Microbiota Using Culturomics: Proof of Concept.

It is generally accepted that microorganisms can colonize a non-pathological endometrium. However, in a clinical setting, endometrial samples are always collected by passing through the vaginal-cervical route. As such, the vaginal and cervical microbiomes can easily cross-contaminate endometrial samples, resulting in a biased representation of the endometrial microbiome. This makes it difficult to demonstrate that the endometrial microbiome is not merely a reflection of contamination originating from sampling. Therefore, we investigated to what extent the endometrial microbiome corresponds to that of the vagina, applying culturomics on paired vaginal and endometrial samples. Culturomics could give novel insights into the microbiome of the female genital tract, as it overcomes sequencing-related bias. Ten subfertile women undergoing diagnostic hysteroscopy and endometrial biopsy were included. An additional vaginal swab was taken from each participant right before hysteroscopy. Both endometrial biopsies and vaginal swabs were analyzed using our previously described WASPLab-assisted culturomics protocol. In total, 101 bacterial and two fungal species were identified among these 10 patients. Fifty-six species were found in endometrial biopsies and 90 were found in vaginal swabs. On average, 28 % of species were found in both the endometrial biopsy and vaginal swab of a given patient. Of the 56 species found in the endometrial biopsies, 13 were not found in the vaginal swabs. Of the 90 species found in vaginal swabs, 47 were not found in the endometrium. Our culturomics-based approach sheds a different light on the current understanding of the endometrial microbiome. The data suggest the potential existence of a unique endometrial microbiome that is not merely a presentation of cross-contamination derived from sampling. However, we cannot exclude cross-contamination completely. In addition, we observe that the microbiome of the vagina is richer in species than that of the endometrium, which contradicts the current sequence-based literature.

Fertility awareness education improves fertility cycle knowledge and may reduce time-to-pregnancy in subfertile women

Research suggests that low fertility awareness (FA) may be a contributing factor to infertility. The aim of this study was to determine whether education improves knowledge in FA and to explore the associations between FA knowledge and time to pregnancy (TTP). A 20-point self-administered FA questionnaire (FAQ) was completed by 180 subfertile women on their first visit to a hospital-based fertility assessment and research clinic, followed by an education session on FA. Women completed the same FAQ after receiving the education session. There was an increase in the FAQ score after the women received FA education (post-education FAQ score: mean, M = 15.68, SD = 1.8) compared with the score before the session [(pre-education FAQ score: M = 13.87, SD = 1.9), t(179)=–10.547, p < 0.001]. Pregnancy was achieved in 88 women (49%). Women with a higher post-education FAQ score (≥15 points) had a shorter TTP (M = 6.4 months, SD = 4.1) than women with post-education FAQ scores <15 [M = 8.8 months, SD = 6.0, t(86)=2.231, p = 0.028]. Greater time trying to conceive was negatively predictive of the hazard for achieving a pregnancy (b=–0.021, se = 0.008, p = 0.005), while age had no significant effect. FA knowledge in women attending a fertility clinic significantly improved after education. Higher FA may reduce TTP in subfertile women who are actively trying to conceive naturally.

Ovarian reserve of infertile women in Libreville: A retrospective analysis of 124 cases at the University Mother and Child Hospital in Libreville, Gabon.

There has been an increasing number of sub-fertile women in Gabon during the last 20 years. Antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) are known as the most accurate markers of ovarian reserve in women and are related to age and weight. Therefore, the current study examines the relationship between AFC and serum AMH with age and weight among sub fertile Gabonese women. This is a retrospective study carried out in the assisted reproduction department of the Mother and Child University Hospital of Libreville. Over a period of 2 years, from 1st June 2019 to 30th May 2021. From the patient records we collected the following data, age, weight CFA and AMH of 124 women who had consulted for infertility. We excluded incomplete files. The average age and weight of women participating in the current study were 38 (±5.74) years and 76.3 (±14.59) kg. The average serum AMH concentration was 2.33 (±2.17) ng/mL) while the average AFC was 14.63 (±11.37). Significant negative correlation between the age and the serum AMH (r2= -0.368; p <0.0001) and between the age and the CFA (r2=-0.560; p <0.0001) were observed in the current study. This study suggests that sub-infertile women residing in Gabon generally have normal serum AMH concentration and AFC levels. Age significantly impact serum AMH and AFC levels.

Daily levels of sex hormones in 15 subfertile women formulate a menstrual cycle profile predominant with progesterone secretion.

Changes in sex hormone secretions during the menstrual cycle may affect fertility. It has been shown that a prematurely raised progesterone (P4) level after therapeutic injection of human chorionic gonadotropin caused changes in endometrial gene expression and lowered the pregnancy rate. The aim of the present study was to investigate the complete menstrual patterns of P4 together with its derivatives testosterone (T) and oestradiol (E2) in subfertile women during their natural cycles. Daily serum levels of P4 (ng/mL), T (ng/mL), E2 (pg/mL), and sex hormone binding protein (SHBG, nmol/L) were measured throughout a single 23-28-day menstrual cycle in 15 subfertile women aged 28-40 years with patent oviducts and normospermic partners. Knowing SHBG levels, the free androgen (FAI) and free oestrogen (FEI) indexes were calculated for each cycle day in each patient. Baseline (cycle day one) levels of luteinising hormone (LH), thyroid stimulating hormone (TSH), P4, and T were comparable with reference intervals for a normal cycle, whereas follicle stimulating hormone (FSH), E2, and SHBG exceeded those. During cycles, the levels of P4 correlated positively with E2 levels (r = 0.38, p < 0.05, n = 392) an negatively with T (r = -0.13, p < 0.05, n = 391). T correlated negatively with E2 (r = -0.19, p < 0.05, n = 391). Menstrual cycle phases were hidden. The curve of the mean/median daily levels of P4 rose prematurely, was parallel with the E2 rise, and culminated closely, but with more than 4 times greater amplitude of P4 (2571% of baseline levels in day 16) than of E2 (580% in day 14). In turn, the curve of T declined in a U-shaped manner with a nadir (-27%) on day 16. Averaged daily levels of FEI, but not FAI, varied significantly between 23 and 26 days long and the 27-28-day cycles. 1. Throughout the entire menstrual cycle length in subfertile women, P4 secretion predominates quantitatively over secretions of the remaining sex hormones when menstrual cycle phases are hidden. 2. The rise of E2 secretion is in parallel with the P4 rise, but with 4 times lower amplitude of E2. 3. T secretion declines and is inversely related to both P4 and E2 secretions. 4. Changes in E2 bioavailability are related to menstrual cycle length.

Effect of growth hormone cotreatment in sub-fertile women ≥ 40 years: A Meta-analysis.

Treatment of sub-fertile women aged ≥ 40 years old (AMA) is challenging. Co-treatment with growth hormone (GH) is suggested to improve reproductive outcomes in poor responders. However, few studies, and with conflicting results, focused on women with AMA. A systematic review and meta-analysis of randomized controlled trials (RCTs) and comparative retrospective trials (CRTs) of GH cotreatment in AMA women undergoing in vitro fertilization or intracytoplasmic injection treatment using their autologous oocytes was performed. The search included studies published in English up to the end of 2021. The primary outcome was the clinical pregnancy rate per embryo transfer. Secondary outcomes were the number of mature and retrieved oocytes and the rate of live birth. 406 studies were found. The final analysis included three RCTs and four CRTs with 481 patients who used GH and 400 patients who did not. Clinical pregnancy and live birth rates were significantly higher in the GH cotreatment group compared to the placebo as well as the group without GH co-treatment, (OR 2.2; 95% CI 1.34 - 3.61 and OR 4.12; 95% CI 1.82 - 9.32, respectively). Intriguingly, the subgroup analysis showed that poor-responder patients did not benefit from co-treatment with GH. There were no statistically significant differences in the number of mature or retrieved oocytes. GH cotreatment in a subgroup of women with AMA improves clinical pregnancy and live birth per fresh embryo transfer. However, this conclusion must be taken with caution and further research is needed. The review is registered in PROSPERO database (CRD42021252618). www.crd.york.ac.uk/prospero/.