Association between endometrial thickness and birthweight of singletons from vitrified-warmed cycles: a retrospective cohort study.

RESEARCH QUESTION: What is the association between endometrial thickness (EMT) and the birthweight of singleton infants born from frozen-thawed embryo transfer cycles? DESIGN: This retrospective cohort study was conducted from January 2016 to December 2019. Participants were categorized into a natural cycle (NC, n = 8132) group and hormone replacement therapy (HRT, n = 4975) group. Only singleton deliveries were included. The primary outcomes were measures of birthweight and relevant indexes. Multivariable logistic regression and multivariable-adjusted linear regression models that incorporated restricted cubic splines were used. RESULTS: In the HRT group, the risk of delivering a small for gestational age (SGA) infant was increased in women with an EMT <8.0 mm (adjusted odds ratio [aOR] 1.85, 95% confidence interval [CI] 1.17-2.91) compared with women with an EMT of 8.0 to <12.0 mm, and increased with an EMT ≥12.0 mm (aOR 1.85, 95% CI 1.03-3.33). An inverted U-shaped relationship was found between EMT and birthweight in women with HRT. No significant differences were shown in birthweight z-score, or being SGA or large for gestational age, in singletons among the three EMT groups in the natural cycles. CONCLUSIONS: A thinner endometrium seen in women undergoing HRT cycles was associated with a lower birthweight z-score, as well as a higher risk of SGA. However, no significant association was observed between EMT and birthweight z-score or SGA in the NC group. It is noteworthy that a thicker endometrium was not associated with a higher birthweight in frozen-thawed embryo transfer (FET) cycles. Women with a thin endometrium who achieve pregnancy require specialized attention, particularly if they are undergoing FET with HRT cycles.

Revitalizing female fertility: platelet-rich plasma - hype or hope?

Platelet-rich plasma (PRP) has gained popularity as an experimental tool in regenerative medicine, with potential applications in reproductive medicine. This review will assess the existing literature on the role of PRP in female fertility enhancement, focusing on ovarian rejuvenation and increased endometrial thickness. PRP is being explored as a treatment for recurrent implantation failure, primary ovarian insufficiency and poor ovarian response. While the influence of PRP on endometrial thickness and implantation success is postulated, its effectiveness remains the subject of debate due to protocol variability and unclear patient selection criteria. This narrative review includes 36 articles published before December 2022, and highlights the lack of comprehensive molecular studies examining the impact of PRP on reproductive capacity. This review underscores the importance of standardizing PRP preparation protocols in reproductive medicine. However, challenges persist, and there is a need for well-planned randomized controlled trials and a deeper understanding of the patient population that would gain the greatest benefit from PRP treatment. Clarifying these aspects is crucial to improve outcomes for low-prognosis patients undergoing assisted reproductive technology.

A sonographic endometrial thickness <7 mm in women undergoing in vitro fertilization increases the risk of placenta accreta spectrum.

BACKGROUND: The prevalence of placenta accreta spectrum, a potentially life-threatening condition, has exhibited a significant global rise in recent decades. Effective screening methods and early identification strategies for placenta accreta spectrum could enable early treatment and improved outcomes. Endometrial thickness plays a crucial role in successful embryo implantation and favorable pregnancy outcomes. Extensive research has been conducted on the impact of endometrial thickness on assisted reproductive technology cycles, specifically in terms of pregnancy rates, live birth rates, and pregnancy loss rates. However, limited knowledge exists regarding the influence of endometrial thickness on placenta accreta spectrum. OBJECTIVE: This study aimed to evaluate the association between preimplantation endometrial thickness and the occurrence of placenta accreta spectrum in women undergoing assisted reproductive technology cycles. STUDY DESIGN: A total of 4637 women who had not undergone previous cesarean delivery and who conceived by in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment and subsequently delivered at the Third Affiliated Hospital of Guangzhou Medical University between January 2008 and December 2020 were included in this study. To explore the relationship between endometrial thickness and placenta accreta spectrum, we used smooth curve fitting, threshold effect, and saturation effect analysis. Multivariate logistic regression analysis was performed to evaluate the independent association between endometrial thickness and placenta accreta spectrum while adjusting for potential confounding factors. Propensity score matching was performed to reduce the influence of bias and unmeasured confounders. Furthermore, we used causal mediation effect analysis to investigate the mediating role of endometrial thickness in the relationship between gravidity and ovarian stimulation protocol and the occurrence of placenta accreta spectrum. RESULTS: Among the 4637 women included in this study, pregnancies with placenta accreta spectrum (159; 3.4%) had significantly thinner endometrial thickness (non-placenta accreta spectrum, 10.08±2.04 mm vs placenta accreta spectrum, 8.88±2.21 mm; P<.001) during the last ultrasound before embryo transfer. By using smooth curve fitting, it was found that changes in endometrial thickness had a significant effect on the incidence of placenta accreta spectrum up to a thickness of 10.9 mm, beyond which the effect plateaued. Then, the endometrial thickness was divided into the following 4 groups: ≤7, >7 to ≤10.9, >10.9 to ≤13, and >13 mm. The absolute rates of placenta accreta spectrum in each group were 11.91%, 3.73%, 1.35%, and 2.54%, respectively. Compared with women with an endometrial thickness from 10.9 to 13 mm, the odds of placenta accreta spectrum increased from an adjusted odds ratio of 2.27 (95% confidence interval, 1.33-3.86) for endometrial thickness from 7 to 10.9 mm to an adjusted odds ratio of 7.15 (95% confidence interval, 3.73-13.71) for endometrial thickness <7 mm after adjusting for potential confounding factors. Placenta previa remained as an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 11.80; 95% confidence interval, 7.65-18.19). Moreover, endometrial thickness <7 mm was still an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 3.91; 95% confidence interval, 1.57-9.73) in the matched cohort after PSM. Causal mediation analysis revealed that approximately 63.9% of the total effect of gravidity and 18.6% of the total effect of ovarian stimulation protocol on placenta accreta spectrum were mediated by endometrial thickness. CONCLUSION: The findings of our study indicate that thin endometrial thickness is an independent risk factor for placenta accreta spectrum in women without previous cesarean delivery undergoing assisted reproductive technology treatment. The clinical significance of this risk factor is slightly lower than that of placenta previa. Furthermore, our results demonstrate that endometrial thickness plays a significant mediating role in the relationship between gravidity or ovarian stimulation protocol and placenta accreta spectrum.

Metformin ameliorates endometrial thickness in a rat model of thin endometrium.

Metformin, a well-established anti-diabetic drug, is also used in managing various other metabolic disorders including polycystic ovarian syndrome (PCOS). There are evidences to show that metformin improves endometrial functions in PCOS women. However, fewer studies have explored the direct effects of metformin on endometrium. Previous in vitro studies have shown that therapeutic serum concentrations of metformin enhance endometrial epithelial cell proliferation. The present study was undertaken to investigate in vivo effects of metformin on endometrial proliferation in a rat model of thin endometrium. Toward this, a rat model of thin endometrium was developed. Metformin (0.1% or 1% w/v) was administrated orally for 15 days in rats with thin endometrium. Oral metformin administration for three consecutive estrous cycles (15 days) in the thin endometrium rat model led to an increase in endometrial thickness compared to sham endometrium. Histological analysis showed a significant increase in the number of endometrial glands (P < 0.05), stromal cells (P < 0.01) and blood vessels (P < 0.01) in metformin-treated (n = 10 in each group) uterine horns compared to sham (saline-treated) uterine horns in rats. The expression of proliferating cell nuclear antigen and vascular epithelial growth factor was found to be upregulated on treatment with 1% metformin-treated group (n = 7). However, pregnancy outcomes in the rats treated with metformin remained unaltered despite the restoration of endometrial thickness. In conclusion, the study demonstrated that metformin ameliorates endometrial thickness in a rat model of thin endometrium by increasing endometrial proliferation and angiogenesis, without restoration of embryo implantation.

Short-term reproductive outcomes analysis and prediction of the modified uterine stent treatment for mild to moderate intrauterine adhesions: experience at a single institution.

BACKGROUND: To evaluate the efficacy of modified uterine stent in the treatment of mild-to-moderate intrauterine adhesions and explore the relative indicators affecting prognosis prediction. METHODS: A total of 115 patients with mild-to-moderate intrauterine adhesions received a modified uterine stent placement after hysteroscopy adhesiolysis. The second-look hysteroscopy operated after 3 months surgery, and the third-look hysteroscopy operated after 6 months surgery if necessary. The stent was removed when the cavity shape was repaired, then the reproductive outcomes were followed up one year. RESULTS: Menstrual blood volume, endometrial thickness and volume had increased significantly after 3 months surgery. The rates of cavity repaired were 86.96% (100/115) after 3 months surgery and 100% (115/115) after 6 months surgery cumulatively. Endometrial thickness after 3-months surgery was positively associated with uterine cavity shape repaired (P<0.01). The receive operating characteristic (ROC) curve showed the rate of uterine cavity shape repaired predicted by the model was 0.92, based on the endometrial thickness after 3-months surgery. The rate of pregnancy was 86.09% (99/115) in one year, while the rate of miscarriage accounted for 26.26% (26/99). The median time interval between stent removal and subsequent conception was 3 months. It showed adhesion recurrence was the risk factor for subsequent pregnancy (P<0.01). CONCLUSIONS: A modified uterine stent placement under hysteroscopy was an effective approach for mild-to-moderate intrauterine adhesions, which is easy to operate and worthy for clinical promotion. Endometrial thickness measured by ultrasonography probably has predictive value in adhesion recurrence and subsequent pregnancy. TRIAL REGISTRATION: ChiCTR2100051524. Date of registration (retrospectively registered): 26/09/2021.

The influence of radical trachelectomy on endometrial thickness in in vitro fertilization-embryo transfer.

AIM: Both morbidity and mortality rates of cervical cancer are increasing, especially in reproductive-aged women. Radical trachelectomy (RT) is an effective fertility-preserving surgery for early-stage cervical cancer. This study aimed to determine the influence of RT on endometrial thickness during in vitro fertilization-embryo transfer (IVF-ET). METHODS: Forty-four patients had undergone RT, and 23 women undergoing IVF-ET treatment (105 ET cycles) were included. Endometrial thickness during hormone replacement therapy (HRT) was retrospectively evaluated and compared between patients with and without RT. RESULTS: Eleven patients (50 ET cycles) in the RT group and 12 (52 ET cycles) in the control group were investigated. Compared with the control group, higher ET cancellation rates were observed in patients in the RT group (1 of 52 cycles [control group] vs. 8 of 50 cycles [RT group], p < 0.01). Endometrial thinning was not affected by patient age at first IVF-ET treatment, history of artificial abortion, preservation of uterine arteries during RT, or postoperative chemotherapy (p = 0.27, 1, 1, and 1, respectively). CONCLUSIONS: Our data revealed that RT influenced endometrial thickness in IVF-ET. This was not affected by the background of the patients or perioperative management in this study. We could not reveal the underlying mechanism, but it is postulated that the transient postoperative uterine blood flow status and postoperative infections may have some effect on the endometrium. To resolve these issues, accumulation of evidences are required. We recommend informing patients about the impact of RT on IVF-ET before starting assisted reproductive technology (ART).

Platelet-rich plasma infusion as an adjunct treatment for persistent thin lining in frozen embryo transfer cycles: first US experience report.

PURPOSE: To study effect of intrauterine infusion of platelet-rich plasma (PRP) on endometrial growth in the setting of thin endometrial lining in patients with prior cancelled or failed frozen embryo transfer (FET) cycles. MATERIALS AND METHODS: Single-arm cohort study of forty-six patients (51 cycles) with endometrial lining thickness (EMT) < 6 mm in prior cancelled or failed FET cycles requesting intrauterine PRP treatment in upcoming FET cycle. The primary outcomes were final EMT in FET cycle and change in EMT after PRP. The secondary outcomes were overall pregnancy rate, clinical pregnancy rate, miscarriage rate, ongoing pregnancy, and live birth rates. RESULTS: The mean pre-PRP EMT in all FET cycles was 4.0 ± 1.1 mm, and mean post-PRP EMT (final) was 7.1 ± 1.0 mm. Of 51 cycles, 33 (64.7%) reached ≥ 7 mm after PRP administration. There was a significant difference between pre-PRP EMT and post-PRP EMT in all FET cycles, with mean difference of 3.0 ± 1.5 mm. Three cycles were cancelled for failure to reach adequate lining. Total pregnancy rate was 72.9% in our cohort of 48 cycles that proceeded to transfer. Clinical pregnancy rate was 54.2% (26/48 FET cycles); clinical miscarriage rate was 14.3% (5/35 pregnancies). Twenty six women had live birth (18 with EMT ≥ 7 mm and 8 with EMT < 7 mm). Response to PRP was not correlated with any pre-cycle characteristics. CONCLUSION: We demonstrate a significant improvement in lining thickness and pregnancy rates in this challenging cohort of women after PRP infusion, with no adverse events. Cost-effectiveness of PRP with benefits and alternatives should be carefully considered.

Supplementation with vitamin D improves the embryo quality in in vitro fertilization (IVF) programs, independently of the patients' basal vitamin D status.

PURPOSE: The study aims to demonstrate the effects of Vitamin D (VD) supplementation, prior to oocyte pick-up within IVF protocols, in women with diverse VD status at the enrollment. METHODS: A total of 204 women eligible for intra-cytoplasmatic sperm injection (ICSI) cycles were included in the study and two homogeneous groups were selected from the database. Both group of patients with normal VD baseline level (> 40 ng/ml) and patients with low VD baseline level (< 20 ng/ml) were divided into control group and treatment group. The control group followed the standard procedure. The treatment group was supplemented with vitamin D3 as cholecalciferol in combination with Myo-Inositol, folic acid, and melatonin 3 months before standard procedure, once a day in the evening. RESULTS: VD levels significantly increased in the study group of low baseline VD, both in serum and in the follicular fluid compared to controls. The treatment induced a significant improvement of the embryo quality in both group of patients considered. CONCLUSION: Supplementation of VD in patients undergoing ICSI procedures significantly improved the number of top-quality embryos compared with the control group, either starting from VD normal baseline values or starting from low values. TRIAL REGISTRATION NUMBER: 07/2018.

A new method that facilitates the diagnosis of endometrial cancer: the ratio of endometrial thickness to the full thickness of the uterine wall and subcutaneous adipose tissue measurements.

Introduction: The aim of the present study was to investigate the association between some risk factors and endometrial pathologies determined by transvaginal sonography (TVS), as well as the diagnostic predictive values of serum oestradiol (E2) levels, subcutaneous adipose tissue (SAT) thickness, endometrium thickness (ET), and the ratio of ET to uterine wall full thickness (UWT) in differential diagnosis of malignant, precancerous, and benign pathologies of endometrium in patients with postmenopausal bleeding (PMB) or with asymptomatic increased endometrial thickness. Material and methods: The study was conducted with 211 women who applied to the hospital with complaints of PMB or ET of 5 mm or more in their routine controls. Venous blood samples were taken for complete blood count and the measurement of E2 levels. Patients also underwent TVS; ET, UWT, and the ratio of ET to UWT were measured. Results: Menopausal age and body mass index averages were significantly higher in atypical hyperplasia and endometrial cancer (EC) groups. Endometrial thickness and endometrial thickness/uterine wall full thickness ratio measured by TVS were significantly higher in all precancerous pathologies and EC. Subcutaneous adipose tissue thickness was significantly higher in all precancerous pathologies and EC. Oestradiol levels were higher in the atypical hyperplasia and EC groups. Conclusions: Postmenopausal bleeding is a common symptom of EC, but in some cases this disease may occur asymptomatically. Measurement of the endometrium thickness, and the ratio of endometrium thickness/uterine wall full thickness and SAT thickness by sonography has a high predictive value for this disease.

Impact of letrozole co-treatment during ovarian stimulation on oocyte yield, embryo development, and live birth rate in women with normal ovarian reserve: secondary outcomes from the RIOT trial.

STUDY QUESTION: Does letrozole (LZ) co-treatment during ovarian stimulation with gonadotropins for in IVF impact follicle recruitment, oocyte number and quality, embryo quality, or live birth rate (LBR)? SUMMARY ANSWER: No impact of LZ was found in follicle recruitment, number of oocytes, quality of embryos, or LBR. WHAT IS KNOWN ALREADY: Multi-follicle stimulation for IVF produces supra-physiological oestradiol levels. LZ is an aromatase inhibitor that lowers serum oestradiol thus reducing negative feedback and increasing the endogenous gonadotropins in both the follicular and the luteal phases, effectively normalizing the endocrine milieu during IVF treatment. STUDY DESIGN, SIZE, DURATION: Secondary outcomes from a randomized, double-blind placebo-controlled trial (RCT) investigating once-daily 5 mg LZ or placebo during stimulation for IVF with FSH. The RCT was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018 and pregnancy outcomes of frozen-thawed embryo transfers (FET) registered until May 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred fifty-nine women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) were randomized to either co-treatment with LZ (n = 80) or placebo (n = 79). In total 1268 oocytes were aspirated developing into 386 embryos, and morphology and morphokinetics were assessed. One hundred twenty-nine embryos were transferred in the fresh cycle and 158 embryos in a subsequent FET cycle. The effect of LZ on cumulative clinical pregnancy rate (CPR), LBR, endometrial thickness in the fresh cycle, and total FSH consumption was reported. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of usable embryos of retrieved oocytes was similar in the LZ group and the placebo group with 0.31 vs 0.36 (mean difference (MD) -0.05, 95% CI (-0.12; 0.03), P = 0.65). The size and number of aspirated follicles at oocyte retrieval were similar with 11.8 vs 10.3 follicles per patient (MD 1.5, 95% CI (-0.5; 3.1), P = 0.50), as well as the number of retrieved oocytes with 8.0 vs 7.9 oocytes (MD 0.1, 95% CI (-1.4; 1.6), P = 0.39) in the LZ and placebo groups, respectively. The chance of retrieving an oocyte from the 13 to 16 mm follicles at trigger day was 66% higher (95% CI (24%; 108%), P = 0.002) in the placebo group than in the LZ group, whilst the chance of retrieving an oocyte from the ≥17 mm follicles at trigger day was 50% higher (95% CI (2%; 98%), P = 0.04) in the LZ group than in the placebo group. The proportion of fertilized oocytes with two-pronuclei per retrieved oocytes or per metaphase II oocytes (MII) (the 2PN rates) were similar regardless of fertilization with IVF or ICSI with 0.48 vs 0.57 (MD -0.09, 95% CI (-0.24; 0.04), P = 0.51), and 0.62 vs 0.64 (MD -0.02, 95% CI (-0.13; 0.07), P = 0.78) in the LZ and placebo groups, respectively. However, the MII rate in the ICSI group was significantly lower with 0.75 vs 0.88 in the LZ vs the placebo group (MD -0.14, 95% CI (-0.22; -0.06), P = 0.03). Blastocysts on Day 5 per patient were similar with 1.5 vs 2.0, P = 0.52, as well as vitrified blastocysts per patient Day 5 with 0.8 vs 1.2 in (MD -0.4, 95% CI (-1.0; 0.2), P = 0.52) and vitrified blastocysts per patient Day 6 with 0.6 vs 0.6 (MD 0, 95% CI (-0.3; 0.3), P = 1.00) in the LZ vs placebo group, respectively. Morphologic evaluation of all usable embryos showed a similar distribution in 'Good', 'Fair', and 'Poor', in the LZ vs placebo group, with an odds ratio (OR) of 0.8 95% CI (0.5; 1.3), P = 0.68 of developing a better class embryo. Two hundred and ninety-five of the 386 embryos were cultured in an embryoscope. Morphokinetic annotations showed that the odds of having a high KIDscore™ D3 Day 3 were 1.2 times higher (CI (0.8; 1.9), P = 0.68) in the LZ group vs the placebo group. The CPR per transfer was comparable with 31% vs 39% (risk-difference of 8%, 95% CI (-25%; 11%), P = 0.65) in the LZ and placebo group, respectively, as well as CPR per transfer adjusted for day of transfer, oestradiol and progesterone levels at trigger, progesterone levels mid-luteal, and number of oocytes retrieved (adjusted OR) of 0.8 (95% CI (0.4; 1.6), P = 0.72). Comparable LBR were found per transfer 28% vs 37% (MD -9%, 95% CI (-26%; 9%), P = 0.60) and per randomized women 24% vs 30% (MD of -6%, CI (-22%; 8%), P = 0.60) in the LZ group and placebo group, respectively. Furthermore, 4.8 years since the last oocyte aspiration, a total of 287 of 386 embryos have been transferred in the fresh or a subsequently FET cycle, disclosing the cumulative CPR, which is similar with 38% vs 34% (MD 95% CI (8%; 16%), P = 0.70) in the LZ vs placebo group. LIMITATIONS, REASONS FOR CAUTION: Both cleavage stage and blastocyst transfer and vitrification were permitted in the protocol, making it necessary to categorize their quality and pool the results. The study was powered to detect hormonal variation but not embryo or pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The similar utilization rate and quality of the embryos support the use of LZ co-treatment for IVF with specific indication as fertility preservation, patients with previous cancer, or poor responders. The effect of LZ on mature oocytes from different follicle sizes and LBRs should be evaluated in a meta-analysis or a larger RCT. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from EU Interreg for ReproUnion, Sjaelland University Hospital, Denmark, Ferring Pharmaceuticals, and Gedeon Ricther. Roche Diagnostics contributed with assays. A.P. has received grants from Ferring, Merck Serono, and Gedeon Richter, consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, speakers fees from Gedeon Richter, Ferring, Merck A/S, Theramex, & Organon, and travel support from Gedeon Richter. The remaining authors declare that they have no competing interests in the research or publication. TRIAL REGISTRATION NUMBERS: NCT02939898 and NCT02946684.

Thin endometrial lining: is it more prevalent in patients utilizing preimplantation genetic testing for monogenic disease (PGT-M) and related to prior hormonal contraceptive use?

STUDY QUESTION: Is a thin endometrial lining before ovulation triggering more prevalent in patients utilizing preimplantation genetic testing for monogenic disease (PGT-M) compared to the regular IVF/ICSI population and is this associated with prior hormonal contraceptive use? SUMMARY ANSWER: Thin (<8 mm) endometrial lining is more prevalent in PGT-M patients compared to the regular IVF/ICSI population and is associated with both longer prior hormonal contraceptive use and a shorter cessation interval of hormonal contraceptives before IVF/ICSI treatment. WHAT IS KNOWN ALREADY: Thin endometrial lining has been associated with lower pregnancy rates in IVF/ICSI cycles and increased chances of miscarriage and low birth weight. Endometrial thinning and atrophy occur during hormonal contraceptive use. Patients utilizing PGT-M typically use hormonal contraceptives up until treatment to avoid the risk of conception of a genetically affected child. Whether this could negatively affect endometrial thickness achieved during subsequent IVF/ICSI cycles is not known. STUDY DESIGN, SIZE, DURATION: A retrospective case control study was performed, including all PGT-M patients attending the University Medical Centre Groningen (cases), between 2009 and 2018. The control group consisted of two non-PGT IVF/ICSI patients for each PGT-M patient, matched for age and treatment period. PARTICIPANTS/MATERIALS, SETTING, METHODS: First cycles of 122 PGT-M patients and 240 controls were included. Cessation interval of hormonal contraceptives was categorized as late cessation (cessation <1 year prior to treatment) or early cessation (>1 year prior to treatment). Endometrial thickness was routinely measured on the day of hCG triggering or 1 day prior. The prevalence of an endometrial lining <8 mm was compared between PGT-M patients and controls. Hormonal contraceptive use (both duration and cessation interval) was compared between both groups. Univariable and multivariable regression analyses were performed to identify risk factors for thin endometrial lining. In addition, cycle and pregnancy outcomes were compared within control/PGT-M groups between patients with endometrial lining > or <8 mm. MAIN RESULTS AND THE ROLE OF CHANCE: Thin endometrial lining on the day of hCG triggering was found significantly more often in the PGT-M group, compared to controls: 32% vs 11% (mean difference 21.0%, 95% CI: 11.7, 30.3%). As expected, more patients in the PGT-M group ceased their hormonal contraception late (<1 year): 64% vs 2% in the control group (mean difference 61.9%, 95% CI: 53.0, 70.8%). Average duration of hormonal contraceptive use was 10.6 years in the PGT-M group vs 9.3 years in controls (mean difference 1.3 years, 95% CI: 0.2, 2.3 years). Multivariable logistic regression analysis identified late cessation (OR: 6.0, 95% CI: 1.9-19.2) and duration of prior hormonal contraceptive use (OR per year increase 1.1, 95% CI: 1.0-1.2) as significant independent risk factors for a thin endometrial lining. In relation to outcome, we found a statistically significant increase in miscarriage rate in PGT-M patients with an endometrial lining <8 mm compared to those with an endometrial lining >8 mm (20.0% vs 1.7%, mean difference 18.3%, 95% CI: 2.3, 34.3%). A trend towards lower birth weight and gestation- and gender-adjusted birth weight (z-score) was also found in this group. No statistically significant differences were detected in pregnancy rate, live birth rate, or incidence of preterm delivery or SGA. Within the control group, no statistically significant differences were found in outcomes between patients with an endometrial lining <8 compared to an endometrial lining >8 mm. LIMITATIONS, REASONS FOR CAUTION: The study is retrospective. Various types of hormonal contraceptives were reported which possibly exert different effects on the endometrial lining. In relation to pregnancy outcome measures, numbers were very limited; therefore, no firm conclusions should be drawn. WIDER IMPLICATIONS OF THE FINDINGS: This study provides further insight into the role of prior hormonal contraceptive use as a possible contributor to the occurrence of thin endometrial lining during ART treatment. Future studies should provide more information on its clinical relevance, to determine whether PGT-M patients can be reassured, or should be counselled to stop hormonal contraceptive use and change to an alternative contraceptive method prior to PGT treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was used and no conflicts of interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Effect of endometrial thickness on obstetric and neonatal outcomes in assisted reproduction: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to explore the relationship of endometrial thickness (EMT) with obstetric and neonatal outcomes in assisted reproductive cycles. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched for eligible studies through April 2023. Obstetric outcomes include placenta previa, placental abruption, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and cesarean section (CS). Neonatal outcomes include birthweight, low birth weight (LBW), gestational age (GA), preterm birth (PTB), small for gestational age (SGA) and large for gestational age (LGA). The effect size was estimated as odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) using a random-effects model. Inter-study heterogeneity was assessed by the chi-square homogeneity test. One-study removal method was used to determine the sensitivity of the meta-analysis. RESULTS: Nineteen studies involving 76,404 cycles were included. The pooled results revealed significant differences between the thin endometrium group and the normal group in placental abruption (OR = 2.45, 95% CI: 1.11-5.38, P = 0.03; I2 = 0%), HDP (OR = 1.72, 95% CI: 1.44-2.05, P < 0.0001; I2 = 0%), CS (OR = 1.33, 95% CI: 1.06-1.67, P = 0.01; I2 = 77%), GA (MD = -1.27 day, 95% CI: -2.41- -1.02, P = 0.03; I2 = 73%), PTB (OR = 1.56, 95% CI: 1.34-1.81, P < 0.0001; I2 = 33%), birthweight (MD = -78.88 g, 95% CI: -115.79- -41.98, P < 0.0001; I2 = 48%), LBW (OR = 1.84, 95% CI: 1.52-2.22, P < 0.00001; I2 = 3%) and SGA (OR = 1.41, 95% CI: 1.17-1.70, P = 0.0003; I2 = 15%). No statistical differences were found in placenta previa, GDM, and LGA. CONCLUSION: Thin endometrium was associated with lower birthweight or GA and higher risks of placental abruption, HDP, CS, PTB, LBW and SGA. Therefore, these pregnancies need special attention and close follow-up by obstetricians. Due to the limited number of included studies, further studies are needed to confirm the results.

A critical appraisal of studies on endometrial thickness and embryo transfer outcome.

A receptive endometrium is required for successful embryo implantation. Endometrial thickness, as measured by ultrasonography, is the most commonly used marker of endometrial receptivity in assisted reproductive technology cycles. Several factors simultaneously affect both endometrial thickness and probability of live birth, including age, oestradiol concentration and oocyte number, among others. Most of the studies investigating a relationship between endometrial thickness and embryo transfer outcomes are retrospective and do not adequately address confounding factors, in addition to other limitations. Despite multiple meta-analyses and studies with large numbers of cycles, controversy still exists. The difference between the results from prospective and retrospective studies is also striking. This article presents a critical appraisal of the studies on endometrial thickness and embryo transfer outcomes in order to highlight methodological issues and how they can be overcome in future studies. Currently available evidence does not seem to support a modification of management just because endometrial thickness is below an arbitrary threshold.

A decrease in endometrial thickness before embryo transfer is not associated with preterm birth and placenta-mediated pregnancy complications.

RESEARCH QUESTION: Does a decrease in endometrial thickness (compaction ≥10%) before embryo transfer prognosticate the risk for preterm birth and placenta-mediated pregnancy complications among IVF pregnancies? DESIGN: Retrospective cohort study at a large private fertility practice. Patients with a singleton live birth after a fresh or frozen embryo transfer between 2016 and 2019 were included. The primary outcome was preterm birth (delivery before 37 weeks gestational age). Secondary outcomes included gestational hypertension, pre-eclampsia, intrauterine growth restriction and placental abruption. RESULTS: Of the 252 patients that met the study criteria, 122 (48%) demonstrated endometrial compaction (≥10%) and 130 (52%) did not. Age, body mass index (BMI), parity, history of preterm birth or history of pre-existing maternal conditions between the compaction and no-compaction groups were not significantly different. The overall prevalence of placenta-mediated complications across all participants was 25% (n = 62). The number of preterm births between the compaction and no-compaction groups (13% and 6%, respectively, P = 0.09) as well as the prevalence of placenta-mediated complications (29.5% and 20%, respectively, P = 0.08) were not significantly different. Findings for the primary outcome (preterm birth) persisted even after adjustment for potential confounding variables, including maternal age, parity, BMI, embryo score and type of embryo transfer (fresh versus frozen) (adjusted OR 1.86, 95% CI 0.64 to 5.38). CONCLUSIONS: Endometrial compaction (or decrease in endometrial thickness) before embryo transfer is not associated with preterm birth or placenta-mediated pregnancy complications.

Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: This study aimed to evaluate the risk of endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women concerning the endometrial thickness measured by stratified threshold categories used for performing subsequent endometrial sampling and histologic evaluation. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, SciELO, Embase, the Cochrane Central Register of Controlled Trials, LILACS, conference proceedings, and international controlled trials registries were searched without temporal, geographic, or language restrictions. STUDY ELIGIBILITY CRITERIA: Studies were selected if they had a crossover design evaluating the risk of atypical endometrial hyperplasia and endometrial carcinoma in postmenopausal asymptomatic women and calculated the diagnostic accuracy of transvaginal ultrasonography thresholds (at least 3.0 mm) confirmed by histopathologic diagnosis. METHODS: This was a systematic review and diagnostic test accuracy meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy and Synthesizing Evidence from Diagnostic Accuracy Tests guidelines. Endometrial thickness thresholds were grouped as follows: from 3.0 to 5.9 mm; between 6.0 and 9.9 mm; between 10.0 and 13.9 mm; and ≥14.0 mm. Quality assessment was performed using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 tool. Publication bias was quantified using the Deek funnel plot test. Coprimary outcomes were the risk of atypical endometrial hyperplasia or endometrial carcinoma according to the endometrial thickness and diagnostic accuracy of each threshold group. RESULTS: A total of 18 studies provided the data of 10,334 women who were all included in the final analysis. Overall, at an endometrial thickness threshold of at least 3.0 mm, the risk of atypical endometrial hyperplasia or endometrial carcinoma was increased 3-fold relative to women below the cutoff (relative risk, 3.77; 95% confidence interval, 2.26-6.32; I2=74%). Similar degrees of risk were reported for thresholds between 3.0 and 5.9 mm (relative risk, 5.08; 95% confidence interval, 2.26-11.41; I2=0%), 6.0 and 9.9 mm (relative risk, 4.34; 95% confidence interval, 1.68-11.23; I2=0%), 10.0 and 13.9 mm (relative risk, 4.11; 95% confidence interval, 1.55-10.87; I2=86%), and ≥14.0 mm (relative risk, 2.53; 95% confidence interval, 1.04-6.16; I2=78%) with no significant difference among subgroups (P=.885). Regarding diagnostic accuracy, the pooled sensitivity decreased from thresholds below 5.9 mm (relative risk, 0.81; 95% confidence interval, 0.49-0.85) to above 14.0 mm (relative risk, 0.28; 95% confidence interval, 0.18-0.40). Furthermore, the specificity increased from 0.70 (95% confidence interval, 0.61-0.78) for endometrial thickness between 3.0 and 5.9 mm to 0.86 (95% confidence interval, 0.71-0.94) when the endometrial thickness is ≥14.0 mm. For 3.0 to 5.9 mm and 10.0 to 13.9 mm thresholds, the highest diagnostic odds ratios of 10 (95% confidence interval, 3-41) and 11 (95% confidence interval, 2-49), with areas under the curve of 0.81 (95% confidence interval, 0.77-0.84) and 0.82 (95% confidence interval, 0.79-0.86), respectively, were retrieved. The summary point analysis revealed that the 3.0 to 5.9 mm cutoff point was placed higher in the summary receiver operator curve space than the other subgroups, indicating increased endometrial carcinoma or atypical endometrial hyperplasia diagnosis using these cutoffs. CONCLUSION: Both low and high endometrial thickness thresholds in postmenopausal asymptomatic women seem equally effective in detecting endometrial carcinoma and atypical endometrial hyperplasia. However, although using a 3.0 to 5.9 mm cutoff results in a lower specificity, the offsetting improvement in sensitivity may justify using this cutoff for further endometrial evaluation in patients with suspected endometrial malignancy.

An endometrium of type C along with an endometrial thickness of < 8 mm are risk factors for ectopic pregnancy after stimulated cycles with fresh embryo transfer.

BACKGROUND: The study investigated whether specific ultrasonographically observed endometrial features (including endometrium type and thickness) were linked to ectopic pregnancy after stimulated cycles with fresh embryo transfer. METHOD: Of 6246 pregnancy cycles after fresh embryo transfer, 6076 resulted in intrauterine pregnancy and 170 in ectopic pregnancy. The primary outcome of the study was ectopic pregnancy, with the main variables being endometrium type and endometrial thickness. Univariate and subsequent multiple-stepwise logistic regression analyses were used to identify the risk factors of ectopic pregnancy. RESULTS: 1. Compared with patients with an endometrial thickness ≥ 8 mm, the adjusted odds ratio for those with an endometrial thickness < 8 mm was 3.368 (P < 0.001). The adjusted odds ratio for women with a type-C endometrium was 1.897 (P = 0.019) compared with non-type C. 2. A larger dose of gonadotropin used during controlled ovarian hyperstimulation was a protective factor against ectopic pregnancy (P = 0.008). 3. The GnRH antagonist protocol (P = 0.007) was a risk factor for ectopic pregnancy, compared with the use of GnRH agonists. CONCLUSION: (1) An endometrial thickness < 8 mm coupled with a type C endometrium significantly increased the risk of ectopic pregnancy after fresh embryo transfer. (2) A thin endometrial thickness and a type C endometrium could be further related to an abnormal endometrial receptivity/peristaltic wave. (3) Patients at a high risk of ectopic pregnancy should therefore be given special attention, with early diagnosis during the peri-transplantation period may assist in the prevention of ectopic pregnancy.

Suitable endometrial thickness on embryo transfer day may reduce ectopic pregnancy rate and improve clinical pregnancy rate.

BACKGROUND: This retrospective study aimed to investigate the most suitable endometrial thickness (EMT) on the day of embryo transfer that could reduce ectopic pregnancy rate (EPR) and improve clinical pregnancy rate (CPR) in fresh embryo transfer patients with early follicular phase long-acting regimen. METHODS: A total of 11,738 IVF/ICSI cycles, comprising 4,489 non-clinical pregnancies, 7,121 intrauterine pregnancies, and 128 ectopic pregnancy cycles after fresh embryo transfer, recorded between September 2017 and December 2020. Clinical pregnancy (CP) and ectopic pregnancy (EP) were the primary outcomes. Multivariate logistic regression was used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for EP and CP. Patients were divided into three groups based on the EMT (6-10 mm, 11-15 mm, and 16-20 mm). CPR and EPR per millimeter of EMT were drawn into a line chart, and three groups were analyzed by Chi-square test. RESULTS: After controlling for potential confounders, EMT had a significant effect on CP (aOR = 1.07; 95% CI, 1.05-1.08; P = 0.00) and EP (aOR = 0.88; 95% CI, 0.82-0.94; P = 0.00). With the increase of EMT, CPR increased and EPR decreased. Pearson correlation coefficients were r = 0.708 (P = 0.00) and r =-0.558 (P = 0.03), respectively. Significant differenceswere detected in the CPRs and EPRs (all P = 0.00). The CPR in the 6-10 mm group (54.88%) was significantly lower than that in the 11-15 mm group (64.23%) and the 16-20 mm group (64.40%) (P = 0.00). The EPR in the 6-10 mm group (2.72%) was significantly higher than that in the other two groups (1.60% and 0.97%, P = 0.00). The difference in CPR and EPR between the 11-15 mm group and the 16-20 mm group was not statistically significant, which indicated that EMT ≥ 11 mm simultaneously reduced the EPR and increased the CPR. CONCLUSIONS: EMT was inversely proportional to EPR and directly proportional to CPR in fresh embryo transfer cycles. The EMT ≥ 11 mm on the day of embryo transfer could simultaneously achieve lower EPR and higher CPR. Accordingly, more attention should be given to the EMT of women who underwent ART treatment.

Novel application to evaluate endometrial blood flow using transvaginal superb microvascular imaging: A preliminary study describing physiological changes from ovulation to mid-luteal phase.

INTRODUCTION: We aimed to describe physiological changes in endometrial blood flow (minute arterioles running through the endometrium) from ovulation to the mid-luteal phase using superb microvascular imaging. MATERIAL AND METHODS: The study involved 17 women (median age, 32.5 years; first to third interquartile range, 29.8-40.0 years) with regular menstrual cycles who were managed in our institute from 2020 to 2021. The uterus was delineated at the sagittal section using transvaginal ultrasonography incorporated with superb microvascular imaging. For each participant, a total of 28 cycles were observed; 17 cycles observed within one day of ovulation and the implantation period, 5-7 days (D5-7) after ovulation in the same cycle, and nine cycles in which only ovulation was observed, and two cycles in which only D5-7 was observed. Therefore, 26 and 19 images at ovulation and D5-7, respectively, were acquired. Endometrial blood flow was evaluated by depth of the vascular signal in the endometrium and categorized as follows: signals only in the basal layer of the endometrium (grade 1), reaching up to half the endometrium (grade 2), and covering the whole endometrium (grade 3). Changes in the grade of endometrial blood flow from ovulation to D5-7 after ovulation, and the relationship between the grade of endometrial blood flow and the endometrial thickness on ovulation and D5-7 after ovulation, were analyzed. Statistical significance was set at p < 0.05. RESULTS: The endometrial blood flow from ovulation to D5-7 after ovulation during the same menstrual period showed a downgrade in 14 of 17 cycles (82.3%) and no change in the remaining three cycles (17.6%), indicating a decrease in the endometrial blood flow from ovulation to D5-7 after ovulation (p = 0.001). There were differences between the grade of endometrial blood flow and median endometrial thickness on ovulation (grade 1: 5.9 mm, grade 2: 9.1 mm, and grade 3: 11.2 mm); however, no differences in the endometrial thickness were found between the grades on D5-7 after ovulation. CONCLUSIONS: In the normal menstrual cycle, endometrial blood flow decreased from ovulation to the mid-luteal phase, and the endometrial thickness in the ovulatory phase was related to the endometrial perfusion.

The use of real time strain endometrial elastosonography plus endometrial thickness and vascularization flow index to predict endometrial receptivity in IVF treatments: a pilot study.

BACKGROUND: The usefulness of endometrium strain elastosonography (SE) for the evaluation of endometrial receptivity in women undergoing in vitro fertilization (IVF) remains controversial. The objective of this prospective, observational study was to evaluate the correlation between endometrial thickness (EMT) and its related strain (ESR) on the day of ovulation triggering (hCG-d) and in vitro fertilization outcomes. Additionally, 3D Power Doppler vascular indices (3DPDVI) were also analysed. METHODS: We included all the patients undergoing fresh IVF-single blastocyst transfer cycle from January 2021 to August 2021 at our center. On hCG-d, after B-mode scanning was completed to measure the EMT, the mode was changed to elastosonography to evaluate the ESR (ratio between endometrial tissue and the myometrium below). At the end of examination, the Endometrial Volume (EV) and 3DPDVI (vascularization index [VI], flow index [FI] and vascularization flow index [VFI]), were assessed. Statistical analysis was completed using STATA MP16 software. RESULTS: A total number of 57 women were included. Based on the EMT on hCG-d, women were divided into two groups, Group 1: <7 mm and Group 2 ≥ 7 mm. Women with EMT < 7 mm had a significantly higher ESR (p = 0.004) and lower pregnancy rate (p = 0.04). Additionally, low ESR values were correlated with high VFI values (rho = -0.8; 95% CI = -0.9- -0.6; p < 0.0001) and EMT ≥ 7 mm could be predicted by low ESR (OR = 0.01; 95% CI = 0.01-0.30; p = 0.008, area under the ROC curve: 0.70). After all, in multiple logistic regression analysis, low values of ESR (p = 0.050) and high values of EMT (p = 0.051) on hCG-d had borderline statistical effects on pregnancy rate. CONCLUSIONS: The ESR may be useful to improve the ultrasound evaluation of the endometrial quality in infertile women candidates to IVF/ICS. Given the small sample size of our study, the usefulness of strain elastosonography in this patients, needs further investigation.

Impact of biomimetic electrical stimulation combined with Femoston on pregnancy rate and endometrium characteristics in infertility patients with thin endometrium: a prospective observational study.

OBJECTIVE: To explore the impact of biomimetic electrical stimulation combined with Femoston (estradiol tablets/estradiol and dydrogesterone tablets) on pregnancy rate and endometrium characteristics (endometrial thickness and type) in patients with infertility and a thin endometrium. METHODS: This prospective study enrolled patients with infertility and a thin endometrium admitted to Urumqi Maternal and Child Health Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China, between May 2021 and January 2022. The patients received Femoston alone (Femoston group) or Femoston combined with biomimetic electrical stimulation (electrotherapy group). The outcomes were the pregnancy rate and endometrium characteristics. RESULTS: Finally, 120 patients were enrolled (60/group). Before treatment, the endometrial thickness (p = 0.515) and the percentages of patients with endometrial types A + B and C (p = 0.769) were comparable between the two groups. After treatment, the endometrium of the patients in the electrotherapy group was thicker than those in the Femoston group (6.48 ± 0.96 mm vs. 5.27 ± 0.51 mm, p < 0.001). Furthermore, the percentages of patients with endometrial types A + B and C in the electrotherapy group were larger than in the Femoston group (p = 0.027). In addition, the pregnancy rates between the two groups (28.33% vs. 16.67%, p = 0.126) were similar. CONCLUSIONS: The results suggest the possibility that biomimetic electrical stimulation combined with Femoston could improve endometrial type and thickness in patients with infertility and thin endometrium compared with Femoston alone, but the pregnancy rate showed no significant improvement. The results need to be confirmed.