The effects of first-line pharmacological treatments for reproductive outcomes in infertile women with PCOS: a systematic review and network meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common causes of infertility in reproductive-age women. However, the efficacy and optimal therapeutic strategy for reproductive outcomes are still under debate. We conducted a systematic review and network meta-analysis to compare the efficacy of different first-line pharmacological therapies in terms of reproductive outcomes for women with PCOS and infertility. METHODS: A systematic retrieval of databases was conducted, and randomized clinical trials (RCTs) of pharmacological interventions for infertile PCOS women were included. The primary outcomes were clinical pregnancy and live birth, and the secondary outcomes were miscarriage, ectopic pregnancy and multiple pregnancy. A network meta-analysis based on a Bayesian model was performed to compare the effects of the pharmacological strategies. RESULTS: A total of 27 RCTs with 12 interventions were included, and all therapies tended to increase clinical pregnancy, especially pioglitazone (PIO) (log OR 3.14, 95% CI 1.56 ~ 4.70, moderate confidence), clomiphene citrate (CC) + exenatide (EXE) (2.96, 1.07 ~ 4.82, moderate confidence) and CC + metformin (MET) + PIO (2.82, 0.99 ~ 4.60, moderate confidence). Moreover, CC + MET + PIO (2.8, -0.25 ~ 6.06, very low confidence) could increase live birth most when compared to placebo, even without a significant difference. For secondary outcomes, PIO showed a tendency to increase miscarriage (1.44, -1.69 ~ 5.28, very low confidence). MET (-11.25, -33.7 ~ 0.57, low confidence) and LZ + MET (-10.44, -59.56 ~ 42.11, very low confidence) were beneficial for decreasing ectopic pregnancy. MET (0.07, -4.26 ~ 4.34, low confidence) showed a neutral effect in multiple pregnancy. Subgroup analysis demonstrated no significant difference between these medications and placebo in obese participants. CONCLUSIONS: Most first-line pharmacological treatments were effective in improving clinical pregnancy. CC + MET + PIO should be recommended as the optimal therapeutic strategy to improve pregnancy outcomes. However, none of the above treatments had a beneficial effect on clinical pregnancy in obese PCOS. TRIAL REGISTRATION: CRD42020183541; 05 July 2020.

Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) administration increased ovarian preantral follicles and anti-Müllerian hormone (AMH) in animal models with diminished ovarian reserve. We investigated whether G-CSF priming before treatment with assisted reproductive technology (ART) improved embryo development and pregnancy rate while increasing serum AMH in patients with poor ovarian reserve. METHODS: In this prospective randomized open-label controlled trial, 100 patients 20 to 42 years old with AMH below 2 ng/mL were randomized to priming or control groups (50 patients each). None had over 1 ART failure, day-3 follicle-stimulating hormone (FSH) above 30 IU/L, uterine anomalies, or a partner with azoospermia. All patients initially underwent conventional infertility treatment for 2 consecutive cycles in which the priming group but not controls received a subcutaneous G-CSF priming injection during the early luteal phase. Each group then underwent 1 cycle of in vitro fertilization/intracytoplasmic sperm injection and fresh embryo transfer (IVF/ICSI-fresh ET), followed by cryopreserved ET if needed until live birth or embryo depletion. AMH was measured before and after priming. RESULTS: Fertilization rate, embryonic development, and implantation rate by fresh ET were significantly improved by priming. Clinical and ongoing pregnancy rates by IVF/ICSI-fresh ET were significantly higher with priming (30% and 26% in 47 ART patients; 3 delivered with conventional treatment) than in controls (12% and 10% in 49 ART patients; 1 dropped out). With priming, significantly more patients achieved cryopreservation of redundant blastocysts. The cumulative live birth rate was 32% in 50 patients with priming, significantly higher than 14% in 49 controls (relative risk, 2.8; 95% confidence interval, 1.04-7.7). Infants derived from priming had no congenital anomalies, while infant weights, birth weeks, and Apgar scores were similar between groups. Among 4 variables (age, day-3 FSH, AMH, and priming), logistic regression significantly associated age and priming with cumulative live birth. Priming significantly increased serum AMH. No adverse effects of priming were observed. CONCLUSION: G-CSF priming improved embryonic development and pregnancy rate during ART treatment and increased AMH in patients with poor ovarian reserve. Enhanced preantral follicle growth likely was responsible. TRIAL REGISTRATION: UMIN registration in Japan (UMIN000013956) on May 14, 2014.  https://www.umin.ac.jp/ctr/index.htm .

The endometrial microbiota of women with or without a live birth within 12 months after a first failed IVF/ICSI cycle.

The endometrial microbiota composition may be associated with implantation success. However, a 'core' composition has not yet been defined. This exploratory study analysed the endometrial microbiota by 16S rRNA sequencing (V1-V2 region) of 141 infertile women whose first IVF/ICSI cycle failed and compared the microbiota profiles of women with and without a live birth within 12 months of follow-up, and by infertility cause and type. Lactobacillus was the most abundant genus in the majority of samples. Women with a live birth compared to those without had significantly higher Lactobacillus crispatus relative abundance (RA) (p = 0.029), and a smaller proportion of them had ≤ 10% L. crispatus RA (42.1% and 70.4%, respectively; p = 0.015). A smaller proportion of women in the male factor infertility group had ≤ 10% L. crispatus RA compared to women in the unexplained and other infertility causes groups combined (p = 0.030). Women with primary infertility compared to secondary infertility had significantly higher L. crispatus RA (p = 0.004); lower proportions of them had ≤ 10% L. crispatus RA (p = 0.009) and > 10% Gardnerella vaginalis RA (p = 0.019). In conclusion, IVF/ICSI success may be associated with L. crispatus RA and secondary infertility with endometrial dysbiosis, more often than primary infertility. These hypotheses should be tested in rigorous well-powered longitudinal studies.

The effects of hydroxychloroquine on pregnancy outcomes in infertile women: a systematic review and meta-analysis.

A promising strategy for controlling repeated implantation failure (RIF) may be the use of hydroxychloroquine (HCQ). To the best of our knowledge, no systematic review has been conducted on the effects of hydroxychloroquine on pregnancy outcomes. A systematic research of the following electronic databases was conducted: Cochrane, EMBASE-Ovid, PubMed, Web of Science, and Scopus from inception to December 2021, using the following keywords [hydroxychloroquine] AND [infertility]. Fertilization and rate of live birth were significantly higher in the HCQ+ prednisone (PDN) group than in the PDN alone group. However, the abortion rate was not different between the two groups. The meta-analysis of two studies revealed no statistical significance between the PDN group and HCQ+PDN group regarding clinical pregnancy rate (OR=.14 [95%CI: 0.4-4.370]; heterogeneity; P=0.13; I2=54%; random effect model) and implantation rate (OR=1.99 [95%CI: 0.94-4.2]; heterogeneity; P=0.37; I2=0%; fixed-effect model). While HCQ may help improve fertilization and live birth rates, adding it to prednisone did not improve overall pregnancy outcomes. This systematic review should be used with caution due to the small size, study design, and difference in the studies' population.

Paternal preconception modifiable risk factors for adverse pregnancy and offspring outcomes: a review of contemporary evidence from observational studies.

BACKGROUND: The preconception period represents transgenerational opportunities to optimize modifiable risk factors associated with both short and long-term adverse health outcomes for women, men, and children. As such, preconception care is recommended to couples during this time to enable them to optimise their health in preparation for pregnancy. Historically, preconception research predominately focuses on maternal modifiable risks and health behaviours associated with pregnancy and offspring outcomes; limited attention has been given to inform paternal preconception health risks and outcomes. This systematic review aims to advance paternal preconception research by synthesising the current evidence on modifiable paternal preconception health behaviours and risk factors to identify associations with pregnancy and/or offspring outcomes. METHODS: Medline, Embase, Maternity and Infant care, CINAHL, PsycINFO, Scopus, and ISI Proceedings were searched on the 5th of January 2023, a date limit was set [2012-2023] in each database. A Google Scholar search was also conducted identifying all other relevant papers. Studies were included if they were observational, reporting associations of modifiable risk factors in the preconception period among males (e.g., identified as reproductive partners of pregnant women and/or fathers of offspring for which outcomes were reported) with adverse pregnancy and offspring outcomes. Study quality was assessed using the Newcastle-Ottawa Scale. Exposure and outcome heterogeneity precluded meta-analysis, and results were summarised in tables. RESULTS: This review identified 56 cohort and nine case control studies. Studies reported on a range of risk factors and/or health behaviours including paternal body composition (n = 25), alcohol intake (n = 6), cannabis use (n = 5), physical activity (n = 2), smoking (n = 20), stress (n = 3) and nutrition (n = 13). Outcomes included fecundability, IVF/ISCI live birth, offspring weight, body composition/BMI, asthma, lung function, leukemia, preterm birth, and behavioural issues. Despite the limited number of studies and substantial heterogeneity in reporting, results of studies assessed as good quality showed that paternal smoking may increase the risk of birth defects and higher paternal BMI was associated with higher offspring birthweight. CONCLUSION: The current evidence demonstrates a role of paternal preconception health in influencing outcomes related to pregnancy success and offspring health. The evidence is however limited and heterogenous, and further high-quality research is needed to inform clinical preconception care guidelines to support men and couples to prepare for a health pregnancy and child.

Embryo development and live birth resulted from artificial oocyte activation after microdissection testicular sperm extraction with ICSI in patients with non-obstructive azoospermia.

Introduction: The application of microdissection testicular sperm extraction (micro-TESE) to retrieve the sperm of patients with non-obstructive azoospermia (NOA) has greatly increased. Patients with NOA often have poor quality sperm. Unfortunately, there are few studies on artificial oocyte activation (AOA) performed on patients who successfully retrieved motile and immotile sperm by micro-TESE after intracytoplasmic sperm injection (ICSI). Therefore, this study sought to obtain more comprehensive evidence-based data and embryo development outcomes to aid consultation of patients with NOA who opted to receive assisted reproductive techniques and to determine whether AOA needs to be performed in different motile sperm after ICSI. Methods: This retrospective study involved 235 patients with NOA who underwent micro-TESE to retrieve adequate sperm for ICSI between January 2018 and December 2020. A total of 331 ICSI cycles were performed in the 235 couples. Embryological, clinical, and neonatal outcomes were demonstrated comprehensively between motile sperm and immotile sperm using AOA and non-AOA treatment. Results: Motile sperm injection with AOA (group 1) showed significantly higher fertility rate (72.77% vs. 67.59%, p=0.005), 2 pronucleus (2PN) fertility rate (64.33% vs. 60.22%, p=0.036), and miscarriage rate (17.65% vs. 2.44%, p=0.018) compared with motile sperm injection with non-AOA (group 2). Group 1 had comparable available embryo rate (41.29% vs. 40.74%, p=0.817), good embryo rate (13.44% vs. 15.44%, p=0.265), and without an embryo for transfer rate (10.85% vs. 9.90%, p=0.815) compared with group 2. Immotile sperm injection with AOA (group 3) displayed significantly higher fertility rate (78.56% vs. 67.59%, p=0.000), 2PN fertility rate (67.36% vs. 60.22%, p=0.001), without an embryo for transfer rate (23.76% vs. 9.90%, p=0.008), and miscarriage rate (20.00% vs. 2.44%, p=0.014), but significantly lower available embryo rate (26.63% vs.40.74%, p=0.000) and good embryo rate (15.44% vs. 6.99%, p=0.000) compared with group 2. In groups 1, 2, and 3, the rates of implantation (34.87%, 31.85% and 28.00%, respectively; p=0.408), clinical pregnancy (43.87%, 41.00%, and 34.48%, respectively; p=0.360) and live birth (36.13%, 40.00%, and 27.59%, respectively; p=0.194) were similar. Discussion: For those patients with NOA from whom adequate sperm were retrieved for ICSI, AOA could improve fertilization rate, but not embryo quality and live birth outcomes. For patients with NOA and only immotile sperm, AOA can help achieve acceptable fertilization rate and live birth outcomes. AOA is recommended for patients with NOA only when immotile sperm are injected.

Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen-thawed embryo transfer cycle: a retrospective cohort study.

BACKGROUND: GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression. METHODS: The retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups. RESULTS: Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20-3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20-3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69-12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59-11.65, P = 0.004). CONCLUSIONS: Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.

Live birth in woman with premature ovarian insufficiency and 46, XY karyotype after chemotherapy and bone marrow transplant: a case report.

BACKGROUND: Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian function before the age of 40 years, characterized by elevated serum gonadotropin levels and decreased estrogen levels with menstrual disturbance. POI can be natural or iatrogenic such as after chemotherapy, radiotherapy and surgery. CASE PRESENTATION: In this study, we describe a successful live birth in a 31-year-old woman with POI and 46, XY Karyotype after being treated with chemotherapy and bone marrow transplant (BMT) for acute non-lymphocytic leukemia when she was 17 years old. With amenorrhea or oligomenorrhea for 11 years, her serum level of FSH was up to 35.0 IU/L and 53.0 IU/L taken 4 weeks apart, which can be diagnosed as POI. After controlled ovarian stimulation treatment for three cycles with different protocols and frozen-thawed embryo transfer (FET), she finally got a successful pregnancy and had a live birth later. CONCLUSIONS: This case report serves as a reminder that karyotype of peripheral blood may mislead the diagnosis as disorders of sex development (DSD). It also demonstrates that it is possible for a woman with chemotherapy and bone marrow transplant induced POI can have successful pregnancy and live birth with appropriate therapy. Furthermore, as age may plays a predominant role in fertility rather than residual ovarian reserve, active treatment may be concerned for women with POI at younger age.

Influencing factors and predictive model of live birth involving low-grade blastocyst frozen-thawed transfer: a retrospective study.

BACKGROUND: Whether only low-grade blastocysts should undergo freeze-thaw transfer during the in vitro fertilization/intracytoplasmic sperm injection cycle remains controversial; however, high-quality embryos cannot be obtained from some patients. Therefore, we aimed to identify factors that may affect the live birth. METHODS: A total of 662 couples with only low-grade blastocysts who voluntarily accepted freeze-thaw blastocyst transfer at a single reproductive center over a 7-year period were followed-up. According to the outcome after transfer, they were divided into live birth group and failed pregnancy group. A nomogram was constructed for predicting live births. RESULTS: Baseline information and clinical treatment characteristics of patients in the two groups were comparable. Fifty-two of the 662 cycles (7.9%) resulted in live birth. Paternal age, maternal basal luteinizing hormone level, endometrial preparation scheme, and blastocyst development days were independent factors that affected low-grade blastocyst freeze-thaw transfer outcomes. The predictive model constructed based on these four factors presented favorable calibration and discriminatory abilities (area under the curve, 0.734; 95% confidence interval, 0.781-0.813). CONCLUSIONS: For patients who exclusively underwent low-grade blastocyst freeze-thaw transfer, advanced paternal age and a high level of maternal basal luteinizing hormone adversely affected low-grade blastocyst freeze-thaw transfer outcomes. Artificial cycle preparation of the endometrium and day 5 blastocyst selection may improve the probability of live birth.

The impact of weight loss for obese infertile women prior to in vitro fertilization: A retrospective cohort study.

Obesity is detrimental to general health and also reproductive health. This study aimed to evaluate whether weight reduction in obese infertile women prior to in vitro fertilization reduces the total gonadotropin dose and improves pregnancy outcomes. This retrospective cohort study was performed at the Jiaxing Maternity and Child Health Care Hospital between January 2017 and January 2022, and 197 women were enrolled. The women were divided into 2 groups according to the weight loss goal of 5%: weight reduction group A (≥weight loss goal of 5%) and control group A (

Endometrial Injury Upregulates Expression of Receptivity Genes in Women with Implantation Failure.

BACKGROUND: Homeobox genes A10 (HOXA10) and A11 (HOXA11), members of the abdominal B gene family, are responsible for embryonic survival and implantation. This study was planned to investigate whether endometrial injury alters the expression of both transcripts in women with implantation failure. METHODS: A total of 54 women with implantation failure were divided into two equal groups as experimental (scratching) and sham (no scratching). Participants in the scratching group were exposed to endometrial injury in the mid-luteal phase, and those in the sham group were exposed to endometrial flushing. The scratching group, but not the sham group, underwent prior endometrial sampling. A second endometrial sampling was performed on the scratching group in the mid-luteal phase of the following cycle. The mRNA and protein levels of the HOXA10 and 11 transcripts were determined in endometrial samples collected before and after injury/flushing. Participants in each group underwent IVF/ET in the cycle after the second endometrial sampling. RESULTS: Endometrial injury caused a 60.1-fold (p < 0.01) increase in HOXA10 mRNA and a 9.0-fold increase in HOXA11 mRNA (p < 0.02). Injury resulted in a significant increase in both HOXA10 (p < 0.001) and HOXA11 protein expression (p < 0.003). There was no significant change in HOXA10 and 11 mRNA expressions after flushing. Clinical pregnancy, live birth, and miscarriage rates of the both groups were similar. CONCLUSIONS: Endometrial injury increases homeobox transcript expression at both mRNA and protein levels.

Brief and long co-incubation of sperm and oocytes for in vitro fertilization: a meta-analysis of randomized controlled trials.

BACKGROUND: There is still no consensus on the optimal time of oocyte-sperm co-incubation during in vitro fertilization and embryo transfer (IVF-ET). The aim of this meta-analysis was to compare the effects of brief (1-6 h) and long (16-24 h) gametes co-incubation time on IVF outcomes. METHODS: The study protocol was registered online through PROSPERO (CRD42022337503) and PRISMA guidelines were followed in the present study. The following databases were searched from inception to May 2022 for randomized controlled trials (RCTs): PubMed, Embase, Cochrane library, Web of Science, using search terms related to IVF, gametes, time of co-incubation and reproductive outcome measure. Studies comparing outcomes of brief co-incubation to that of long co-incubation during IVF, and reporting primary outcome (live birth rate), secondary outcomes (clinical pregnancy rate; ongoing pregnancy rate; miscarriage rate; normal fertilization rate; polyspermy rate; top-quality embryo rate; implantation rate) were searched. A total of 11 studies were included in the meta-analysis. Combined odds ratio (OR) and 95% confidence interval (CI) were calculated for the data. Statistical heterogeneity analysis between studies was assessed by Cochran Q and I2 statistic with a significant threshold of P < 0.05. Methodologic quality assessment of RCTs was made for potential risk of bias with Cochrane Risk of Bias Tool. RESULTS: Compared to long-term co-incubation, brief co-incubation had an advantage in increasing implantation rate (OR: 1.97, 95% CI: 1.52-2.57), ongoing pregnancy rate (OR: 2.18, 95% CI: 1.44-3.29) and top-quality embryo rate (OR: 1.17, 95% CI: 1.02-1.35). However, brief co-incubation of gametes had no advantages in the live-birth rate (OR: 1.09, 95% CI: 0.72-1.65), miscarriage rate (OR: 1.32, 95% CI: 0.55-3.18), clinical pregnancy rate (OR: 1.36, 95% CI: 0.99-1.87) and polyspermy rate (OR: 0.80, 95% CI: 0.48-1.33) than long-term co-incubation. Additionally, the brief co-incubation was associated with lower normal fertilization rate (OR: 0.89, 95% CI: 0.80-0.99), compared with long co-incubation. CONCLUSIONS: Brief co-incubation of gametes had the advantages in increasing implantation rate, ongoing pregnancy rate and top-quality embryo rate than long-term co-incubation. However, the live-birth rate displayed no difference between the two in vitro fertilization methods. Gametes co-incubation time should be individualized according to each patient's IVF history, infertility causes and the semen parameters.

Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: A nationwide cohort study.

BACKGROUND: Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes. METHODS AND FINDINGS: We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors. CONCLUSIONS: This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for <10 days, along with continued careful monitoring for any safety signals.

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.

One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks' gestation), fetal deaths (10-20 weeks' gestation) and stillbirths (≥ 20 weeks' gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

Serum levels of anti-Müllerian hormone influence pregnancy outcomes associated with gonadotropin-releasing hormone antagonist treatment: a retrospective cohort study.

As a specific predictor of ovarian reserve, serum anti-Müllerian hormone (AMH) has become an area of intense research interest in the field of assisted reproductive technology. We assessed the relationship between AMH levels and pregnancy outcomes in Chinese patients and investigate the influencing factors of cumulative live birth in patients with high AMH levels. A total of 1379 patients starting their IVF/ICSI cycle were divided into normal (Group A, 1.1-4.0 ng/ml, n = 639) and high (Group B, > 4.0 ng/ml, n = 740) groups by serum AMH levels. Live birth rate (LBR), cumulative live birth rate (CLBR) and cumulative clinical pregnancy rate (CCPR) were also investigated. Compared with Group A, Group B had a significantly higher CLBR (65.80% vs. 43.95%) and CCPR (76.77% vs. 57.14%), respectively. Binomial logistic regression analysis showed that age over 40 years, LH/FSH > 2.5, total Gn dose and Gn duration, and greater than 4000 ng/ml serum E2 levels on HCG day were significantly associated with CLBR in Group B. The AUC value of CLBR averaged 0.664 (ranging from 0.621 to 0.706) (p < 0.001). The patients with high AMH levels had higher CPR, higher LBR, and lower MR with no statistically significant differences, although there were significant improvements in CLBR. Advanced age (> 40 years) still impacted CLBR, even in women with good ovarian reserves. Consequently, it is still recommended that patients over 40 years old with high AMH levels actively receive IVF treatment if they seek to become pregnant. PCOS diagnoses did not influence the CLBR. In summary, this study showed that serum AMH levels could positively predict patient ovarian responses and further affect pregnancy outcomes.

[Analysis of reproductive outcomes in the first IVF-ET cycle after laparoscopic treatment in patients with endometriosis].

Objective: To explore the effect of endometriosis (EM) on reproductive outcomes of young patient with EM after laparoscopic treatment in the first in vitro fertilization-embryo transfer (IVF-ET) cycle. Methods: The clinical data and reproductive outcomes of 394 infertile patients with EM after laparoscopic treatment (EM group) and 3 242 infertile patients caused by gamete transport disorder (control group) in the first IVF-ET cycle were collected in Chongqing Health Center for Women and Children from January 2016 to June 2021. The information included baseline characteristics, oocyte retrieval, embryo development, clinical pregnancy, miscarriage, and live birth. Propensity score matching (PSM) method was used to perform 1∶2 matching between EM group and control group. The impact of EM on reproductive outcomes was analyzed in the retrospective observational study. Results: In the initial data, compared with control group, the number of two pronucleus (2PN) zygotes (9.7±4.8 vs 9.0±4.4), the number of transferable embryos (6.2±3.6 vs 5.5±3.4) and the rate of transferable embryos (64.0% vs 60.8%) on the third day were significantly lower in EM group, and the differences were statistically significant (all P<0.05). After PSM was performed, there were 394 and 787 cases in EM group and control group, respectively. Compared with control group, the number of 2PN zygotes (9.7±4.9 vs 9.0±4.4), the 2PN fertility rate (77.1% vs 75.3%), the number of transferable embryos on the third day (6.2±3.6 vs 5.5±3.4), the transferable embryos rate on the third day (63.8% vs 60.8%) were significantly lower in EM group, and the differences were statically significant (all P<0.05). The study did not find the effect of EM on embryo implantation rate, pregnancy rate, early miscarriage rate, live birth rate and preterm birth rate (all P>0.05). Conclusions: EM might interfere with the development of oocytes and embryos. Obtaining top-quality embryos may be an effective way to improve the prognosis of patients with EM after laparoscopic treatment.

Obstetric and perinatal outcomes following frozen and fresh embryo transfer in patients with endometrial hyperplasia and carcinoma: a retrospective study in a high-volume reproductive center.

BACKGROUND: There is ongoing debate regarding which embryo transfer procedure can achieve a higher live birth rate. Research has suggested that frozen ET might be beneficial for certain populations, such as hyper-responders. This study aimed to compare outcomes of pregnancies between frozen and fresh embryo transfer cycles in patients with endometrial hyperplasia and carcinoma. METHODS: This retrospective cohort study was conducted at a high-volume reproductive center from January 2010 to January 2022. Patients who were diagnosed with endometrial hyperplasia with atypia and endometrial carcinoma were included. They all underwent in vitro fertilization after conservative treatment. The primary outcome was live birth after frozen and fresh embryo transfer cycles, and secondary outcomes included perinatal complications and other pregnancy outcomes. RESULTS: Overall, 259 ET cycles (130 fresh and 129 frozen) were included. The rate of live births per embryo transfer cycle of the whole cohort was 20.8% (54/259), and no significant between-group difference was found after adjusting for potential confounding factors (23.8% vs. 17.8%; adjusted OR, 0.47; 95% CI, 0.21-1.06; p=0.068). Compared to fresh embryo transfer group, the incidence of total maternal complications in the frozen embryo transfer group was significantly higher (30.4% vs. 6.5%, p=0.019). Analyzing each complication as a separate entity, patients in the frozen embryo transfer group had a higher incidence of hypertensive disorders of pregnancy (p=0.028). Multiple logistic regression analysis showed that frozen embryo transfer was related with an increased occurrence of maternal complications (OR, 6.68, 95% CI, 1.01-44.19, p=0.040). CONCLUSIONS: Among patients with endometrial hyperplasia and carcinoma, the rate of live births was comparable between both embryo transfer procedures, while frozen embryo transfer might be associated with a higher risk of maternal complications compared to that with fresh embryo transfer.

The average gonadotrophin dosage per follicle is predictive of ovarian response and cumulative live birth chances after in vitro fertilization: a retrospective cohort study.

BACKGROUND: With the development of assisted reproduction technology (ART), many indicators have been proposed to evaluate ovarian response, and then predict pregnancy outcomes. In general, the predictive values remain limited. OBJECTIVE: To further explore the indicators to evaluate ovarian sensitivity to gonadotrophin (Gn) stimulation more accurately. METHODS: This retrospective cohort study included 330 women who underwent an entire ART cycle. We aimed to assess whether a new index, termed as average Gn dosage per follicle, could be used as a marker for ovarian response and pregnancy outcomes. It was calculated as the ratio of total Gn dose during ovarian stimulation and the number of pre-ovulatory follicles (PFC) on the trigger day. Patients were divided into three subgroups according to the average Gn dosage per follicle: below the 33rd percentile (Group A), between 33rd and 67th percentiles (Group B), and above the 67th percentile (Group C). Then stimulation data, laboratory and clinical outcomes were compared among the groups. RESULTS: The results showed patients in Group A had the best ovarian response, the number of retrieved oocytes was significantly higher than in Group B and C. A multivariate regression analysis showed that average Gn dosage per follicle was an independent predictor of cumulative live birth rates (CLBRs) [adjusted odds ratio (OR): 0.96, 95% confidence interval (CI): 0.95-0.98, P < 0.01]. CONCLUSIONS: The present study showed that average Gn dosage per follicle appears to be a highly reliable index of ovarian response to exogenous Gn and can be useful to estimate CLBR.

Development and validation of a live birth prediction model for expected poor ovarian response patients during IVF/ICSI.

Background: A number of live birth predictive model during assisted reproductive technology treatment have been available in recent years, but few targeted evaluating the chances of live birth in poor ovarian response(POR) patients. The aim of this study was to develop a nomogram based on POSEIDON criteria to predict live birth in patients with expected POR. Methods: This retrospective cohort study using clinical data from 657 patients in POSEIDON Groups 3 and 4 (antral follicle count [AFC] ≤5 and AMH <1.2 ng/ml) in the Center for Reproductive Medicine, First Affiliated Hospital of Xinjiang Medical University, and Construction a nomogram model t. Results: Among 657 expected POR patients, 111 (16.89%) had live births, and 546 (83.11%) did not have live births. These were divided into a training set(n=438) and a validation set (n=219). Multivariate logistic regression analysis showed that the age (OR = 0.91, 95% CI: 0.86-0.97), BMI (OR = 1.98, 95% CI: 1.09-3.67), AMH (OR = 3.48, 95% CI: 1.45-8.51), normal fertilized oocytes (OR = 1.40, 95% CI: 1.21-1.63), and the basal FSH (OR = 0.89, 95% CI: 0.80-0.98) of the female were independent factors predicting live birth in patients with expected POR. Then, an individualized nomogram prediction model was built from these five factors. The area under the ROC curve of the live birth prediction model was 0.820 in the training set and 0.879 in the validation set. Conclusion: We have developed a nomogram combining clinical and laboratory factors to predict the probability of live birth in patients with an expected POR during IVF/ICSI, which can helpful for clinician in decision-making. However, the data comes from the same center, needs a prospective multicenter study for further in-depth evaluation and validation of this prediction model.

Gestational age: comparing estimation methods and live births' profile.

OBJECTIVE: To identify factors associated with the definition of the gestational age (GA) estimation method recorded in the live birth certificate (LBC), and to compare the results obtained according to the method in the city of São Paulo (CSP), between 2012 and 2019. METHODS: Cross-sectional population-based study using the Live Birth Information System. Descriptive and comparative analysis was performed according to the GA estimation method, followed by a univariate and multivariate logistic regression model to identify the predictor variables of the method used. RESULTS: The estimation of GA by the date of the last menstrual period (LMP) (39.9%) was lower than that obtained by other methods (OM) (60.1%) - physical examination and ultrasound, between 2012-2019. LMP registration in the LBC increased with the mother's age, it was higher among women who were white, more educated and with partners, in cesarean sections and with private funding. In the logistic regression, public funding was 2.33 times more likely than private funding to use OM. The proportion of preterm infants (<37 weeks) with GA by LMP was 26.5% higher than that obtained by OM. Median birth weight was higher among preterm infants with GA estimated by LMP. CONCLUSION: Prematurity was higher with the GA estimated by LMP in the CSP, which may indicate overestimation by this method. The source of funding was the most explanatory variable for defining the GA estimator method at the LBC. The results point to the need for caution when comparing the GA obtained by different methods.