Low-molecular-weight heparin in thrombophilic women receiving in vitro fertilization/intracytoplasmic sperm injection: A meta-analysis.

INTRODUCTION: This meta-analysis aimed to evaluate the efficacy and safety of low-molecular-weight heparin (LMWH) on pregnancy outcomes in thrombophilic women receiving in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). MATERIAL AND METHODS: A systematic literature search of PubMed, EMBASE, the Cochrane Library, and China National Knowledge Infrastructure was performed to identify randomized controlled trials (RCTs) comparing LMWH with no treatment or placebo published from database inception until February 19, 2023. Primary outcomes were the clinical pregnancy rate and implantation rate, and secondary outcomes were the live birth rate, miscarriage rate, and the risk of bleeding events. The certainty of the evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system. Meta-analysis was conducted using STATA 14.0. RESULTS: Five RCTs involving 1094 thrombophilic women receiving IVF/ICSI were finally included. Administration of LMWH was associated with statistically higher clinical pregnancy rate (4 RCTs, risk ratio [RR] 1.50, 95% confidence interval [CI] 1.23-1.82, p < 0.001, low certainty evidence), implantation rate (5 RCTs, RR 1.49, 95% CI 1.25-1.78, p < 0.001, very low certainty evidence), and live birth rate (2 RCTs, RR 2.15, 95% CI 1.60-2.89, p < 0.001, very low certainty evidence), but with statistically lower miscarriage rate (2 RCTs, RR 0.36, 95% CI 0.15-0.86, p = 0.021, very low certainty evidence). However, using LMWH was linked to a higher risk of bleeding events (2 RCTs, RR 2.36, 95% CI 1.49-3.74, p < 0.001, very low certainty evidence). CONCLUSIONS: Very low certainty evidence suggests that administration of LMWH may benefit pregnancy outcomes in thrombophilic women receiving IVF/ICSI treatment, although it may also increase the risk of bleeding events. However, before putting our findings into practice, healthcare professionals should conduct an in-depth evaluation of the available evidence and specific patient situations. Furthermore, due to the low methodological quality of the included studies, more high-quality studies are needed to validate our findings in the future.

Should blastocyst transfer be performed in patients with 1-3 embryos available on day 3?

RESEARCH QUESTION: In patients with 1-3 embryos available on day 3, does blastocyst transfer reduce the chances of a clinical pregnancy by cancelling transfer cycles compared with cleavage transfer? DESIGN: This retrospective observational study included 423 IVF cycles performed from 1 January 2019 to 31 December 2020 at the Center for Reproduction and Fertility of the Second Affiliated Hospital of Kunming Medical University. Cleavage transfer was performed in 267 cycles and blastocyst transfer was performed in 156 cycles. The primary outcome was the ongoing pregnancy rate, and the secondary outcomes were clinical pregnancy rate and embryo cessation rate. Univariate analysis was performed to compare outcomes. A logistic regression analysis was performed to explore the association between transfer stage and ongoing pregnancy rate. RESULTS: No differences were observed in the ongoing pregnancy rate (25.84% versus 26.92%; odds ratio [OR] 0.95; 95% confidence interval [CI] 0.61-1.50; P = 0.82) and embryo cessation rate (83.48% versus 85.75%; OR 1.19; 95% CI 0.82-1.75; P = 0.40) between the two groups. Logistic regression analysis showed no association between transfer stage and ongoing pregnancy rate (OR 1.06; 95% CI 0.64-1.73). CONCLUSIONS: Blastocyst transfer does not reduce the chances of a clinical pregnancy. These results support the proposal of blastocyst transfer in patients with 1-3 embryos available on day 3.

Single-Dose Versus Multiple-Dose GnRH Agonist for Luteal-Phase Support in Women Undergoing IVF/ICSI Cycles: A Network Meta-Analysis of Randomized Controlled Trials.

Background: Although gonadotropin-releasing hormone (GnRH) agonist has been introduced as a beneficial luteal phase support (LPS), the optimal strategy of GnRH agonist remains unclear. This network meta-analysis was therefore performed to determine the comparative efficacy and safety of multiple-dose versus single-dose GnRH agonist protocol for LPS in patients undergoing IVF/ICSI cycles. Methods: We searched relevant studies in PubMed, Embase and the Cochrane Registry of Controlled Trials (CENTRAL) from their inception util to September 2021. Live birth, clinical pregnancy rate, multiple pregnancy rate, and clinical abortion rate was evaluated. Pairwise and network meta-analysis were conducted using RevMan and ADDIS based on random-effects model, respectively. Moreover, the prioritization of protocols based on ranking probabilities for different outcomes were performed. Results: Sixteen RCTs met our eligibility criteria. Pairwise meta-analysis showed that multiple-dose protocol of GnRH agonist was effective for increasing live birth rate (OR 1.80, 95% CI 1.15 to 2.83, p=0.01) and clinical pregnancy rate (OR 1.89, 95% CI 1.01 to 3.56, p=0.05) as well as decreasing clinical abortion rate (OR 0.55, 95% CI 0.34 to 0.90, p=0.02). Meanwhile, single-dose protocol of GnRH agonist was effective for increasing clinical pregnancy rate (OR 1.45, 95% CI 1.11 to 1.89, p=0.007) and multiple pregnancy rate (OR 2.55, 95% CI 1.12 to 5.78, p=0.03). However, network meta-analysis only confirmed that multiple-dose protocol of GnRH agonist was the best efficacious strategy for live birth rate (OR 2.04, 95% CrI 1.19 to 3.93) and clinical pregnancy rate (OR 2.10, 95% CrI 1.26 to 3.54). Conclusion: Based on the results of NMA, multiple-dose protocol may be the optimal strategy for patients undergoing IVF/ICSI cycles owing to its advantage in increasing live birth and clinical pregnancy rate. Moreover, single-dose protocol may be the optimal strategy for improving multiple pregnancy rate. However, with the limitations, more RCTs are required to confirm our findings.

Diagnostic value of colposcopy in patients with cytology-negative and HR-HPV-positive cervical lesions.

PURPOSE: High-risk human papillomavirus (HR-HPV)-positive but cytology-negative cervical cancer screening results are not uncommon. This study aimed to investigate colposcopy's accuracy and diagnostic value in patients with cytology-negative HR-HPV-positive screening results. METHODS: This retrospective study included patients with HR-HPV-positive cytology-negative screening results who underwent electronic colposcopy with acetic acid and multi-point cervical biopsy, HPV typing (24 HPV subtypes), and quantitative HPV detection. RESULTS: Among 229 patients, 130 had chronic cervicitis, and 99 had cervical lesions (CIN1, n = 37; CIN2/3, n = 55; invasive carcinoma, n = 7). Using colposcopy as a reference, the cervical cytology false-negative rate was 43.2% (99/229). Colposcopy was more accurate in patients with HR-HPV16/18 or high viral loads. Multivariable analyses showed HPV viral load and childbearing history were the independent factors affecting the accuracy of colposcopy (P < 0.05). CONCLUSION: Colposcopy in HR-HPV-positive cytology-negative patients has a moderate diagnostic accuracy. The type of cervical transformation zone and HPV viral load are independent factors affecting the accuracy of colposcopy-based diagnosis.

Significance of the viral load of high-risk HPV in the diagnosis and prediction of cervical lesions: a retrospective study.

BACKGROUND: The significance of HPV viral load in the detection of cervical lesions is still controversial. This study analyzed the correlation between the high-risk HPV viral load and different cervical lesion degrees. METHODS: This retrospective study included women positive for high-risk HPV DNA and screened for cervical lesions between 01/2015 and 06/2018. The high-risk HPV DNA load was measured by the second-generation Hybrid Capture technology and classified as low, moderate, and high. Colposcopy and biopsy were performed in all patients. The patients were grouped as normal, cervical intraepithelial neoplasia (CIN) grade 1, CIN grade 2, CIN grade 3, and cervical cancer. Multivariable logistic regression was performed to explore the association between high-risk HPV DNA load and cervical lesions. The odds ratios (ORs) represent the odds for increasing from low to high viral load. RESULTS: Finally, 265 patients were grouped as normal (n = 125), CIN 1 (n = 51), CIN 2 (n = 23), CIN 3 (n = 46), and cervical cancer (n = 20). Among them, 139 (52.5%) had a low viral load, 90 (34.0) had a moderate viral load, and 36 (13.4%) had a high viral load. Taking the normal control group as a reference, a high viral load was an independent factor for CIN 1 (OR = 3.568, 95% CI: 1.164-10.941, P = 0.026), CIN 2 (OR = 6.939, 95% CI: 1.793-26.852, P = 0.005), CIN 3 (OR = 7.052, 95% CI: 2.304-21.586, P = 0.001), and cervical cancer (OR = 8.266, 95% CI: 2.120-32.233, P = 0.002). CONCLUSIONS: Among women who underwent cervical biopsy, higher high-risk HPV viral load in cervical lesions was associated with a higher risk of high-grade cervical lesions.

What is the impact of granulocyte colony-stimulating factor (G-CSF) in subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles on recurrent implantation failure: a systematic review and meta-analysis?

BACKGROUND: Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients. METHOD: The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I2 index were analyzed. Stata 15 was used for statistical analysis. RESULTS: A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27-2.37, I2 = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14-1.81, I2 = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33-2.23, I2 = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09-1.78, I2 = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28-2.68; I2 = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25-5.21: I2 = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86-2.36; I2 = 52.5%; n = 372) when a random-effects model was employed. CONCLUSION: The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.

Interleukin 6 in follicular fluid reduces embryo fragmentation and improves the clinical pregnancy rate.

PURPOSE: The aim of this study was to evaluate the role of interleukin 6 in embryo development in the in vitro fertilization cycles. METHODS: This was a retrospective cohort study. One hundred and three women undergoing in vitro fertilization and embryo transfer due to a tubal factor were included in the study. The follicular fluid IL-6 levels on oocyte retrieval day from each patient were determined by ELISA. The relationships between follicular fluid IL-6 levels and IVF cycle parameters were investigated. RESULTS: The levels of follicular fluid IL-6 were not affected by the use of drugs for superovulation or by estrogen. In addition, follicular fluid IL-6 levels did not affect the number of oocytes retrieved or the MII oocyte rate. High levels of follicular fluid IL-6 correlated with a significant increase in the rates of clinical pregnancy. Follicular fluid IL-6 levels did not affect the cell number or the blastomere symmetry of day 3 embryos, but it did significantly reduce the embryo fragmentation rate. CONCLUSIONS: High levels of follicular fluid IL-6 improved the rates of clinical pregnancy and reduce embryo fragmentation.

Menopausal Hormone Replacement Therapy and the Risk of Ovarian Cancer: A Meta-Analysis.

Background: Findings by epidemiologic studies on menopausal hormone replacement therapy (HRT) and the risk of ovarian cancer are inconsistent. This study aimed to assess the association of menopausal HRT with the risk of ovarian cancer by histological subtype. Methods: A literature search was performed in PubMed, Web of Science, and EmBase for relevant articles published from inception to August 2018. Pooled relative risk ratios (RRs) with 95% confidence intervals (CIs) were determined with a random-effects model. Results: Thirty-six studies involving 4, 229, 061 participants were included in this meta-analysis. The pooled RR of ovarian cancer was 1.29 (95%CI 1.19-1.40, I 2 = 57.4%) for menopausal HRT. In subgroup analysis by study design, pooled RRs of ovarian cancer in cohort and case-control studies were 1.35 (95%CI 1.19-1.53) and 1.24 (95%CI 1.11-1.38), respectively. In subgroup analysis by continent, association of menopausal HRT with ovarian cancer was significant for North America (1.41 [1.23-1.61]), Europe (1.22 [1.12-1.34]), and Asia (1.76 [1.09-2.85]), but not Australia (0.96 [0.57-1.61]). Association differed across histological subtypes. Increased risk was only found for two common types, including serous (1.50 [1.35-1.68]) and endometrioid (1.48 [1.13-1.94]) tumors. Conclusion: This meta-analysis suggests that menopausal HRT may increase the risk of ovarian cancer, especially for serous and endometrioid tumors.

No association of TP53 codon 72 SNP with male infertility: a study in a Chinese population and a meta-analysis.

Genetic polymorphisms may affect human male fertility. Even though TP53 plays a role in spermatogenesis we know little about the association of the functional polymorphism at codon 72 of TP53 with respect to susceptibility to male infertility. We conducted a case-control study to investigate this association in a Chinese population and performed a meta-analysis in different populations to clarify this association. The single nucleotide polymorphism (SNP) of TP53 codon 72 (rs1042522 G>C) was genotyped by PCR-RFLP in 83 Chinese male infertility patients and 401 healthy controls. Meta-analysis was performed using the data from four currently available studies. The data from our study were overlayed using the v.9.0 STATA software package. We observed no association between the TP53 codon 72 polymorphism and male infertility (p = 0.84, OR = 1.04, 95% CI, 0.74-1.45). Meta-analysis confirmed the case-control result that there was no significant association between the codon 72 polymorphism of TP53 and male infertility (Pro vs. Arg; p = 0.31, OR = 0.86, 95% CI, 0.65-1.15; Pro/Pro vs. Arg-carriers; p = 0.65, OR = 0.91, 95% CI, 0.61-1.36; Pro-carriers vs. Arg/Arg: p = 0.15, OR = 0.75, 95% CI, 0.51-1.11). The data presented in this communication supports the view that the codon 72 polymorphism of TP53 may not contribute to male infertility susceptibility in the Chinese population.

Effect of HCG-day serum progesterone and oestradiol concentrations on pregnancy outcomes in GnRH agonist cycles.

This study analysed the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, group 4 had lower clinical pregnancy and live birth rates as well as the highest ectopic pregnancy rate (29.15% versus 45.91%; 18.67% versus 34.34%; 18.10% versus 5.82%; P<0.05). Group 3 had lower clinical pregnancy and live birth rates per embryo-transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively; P<0.05). Clinical pregnancy rates were similar in frozen-thawed embryo transfers (FET) among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. High serum oestradiol concentration on HCG day did not affect the IVF pregnancy outcome. In combination with the elevated progesterone, high oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes. The aim of this study was to analyse the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to their serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, patients in group 4 had lower clinical pregnancy (29.15% versus 45.91%) and live birth rates (18.67% versus 34.34%) as well as the highest ectopic pregnancy rate (18.1% versus 5.82%) (all P<0.05). Those in group 3 had lower clinical pregnancy and live birth rates per embryo transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively, P<0.05). Embryo quality appeared to be unaffected since similar clinical pregnancy rates in frozen-thawed embryo transfer (FET) cycles among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. A high serum oestradiol concentration on the day of HCG administration did not affect the IVF pregnancy outcome. In combination with the elevated progesterone and oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes.