Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the ...cumulative live-birth rate as compared with conventional in vitro fertilization (IVF).
In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A.
A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval CI, -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups.
Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).
To evaluate whether prolonged storage of vitrified blastocysts negatively impacts pregnancy and neonatal outcomes.
A retrospective cohort study.
University hospital.
A total of 6,900 patients who ...desired to transfer vitrified blastocysts from the same oocyte retrieval cycle as their last live birth met the inclusion criteria and were grouped according to the storage duration (1,890 patients in group 1 with storage duration < 3 years, 2,693 patients in group 2 with storage duration between 3 and 4 years, 1,344 patients in group 3 with storage duration between 4 and 5 years, 578 patients in group 4 with storage duration between 5 and 6 years and 395 patients in group 5 with storage duration ≥ 6 years but ≤ 10.5 years).
None.
Rates of blastocyst survival, biochemical pregnancy, clinical pregnancy, miscarriage, ectopic pregnancy, and live birth and neonatal outcomes.
The survival rates of the vitrified blastocysts significantly decreased with prolonged storage from group 1 to the subsequent groups 2, 3, 4, and 5. After adjusting for potential confounding factors, the rates of biochemical pregnancy, clinical pregnancy, and live birth were significantly decreased when the vitrified blastocysts were stored for more than 6 years (group 5) compared with these for less than 3 years (group 1) but no distinct differences were found in these above-mentioned indicators among group 1, 2, 3, and group 4 (group 1 as reference). However, no significant differences were noted in the rates of miscarriage and ectopic pregnancy and neonatal outcomes on prolonged storage of vitrified blastocysts.
Long-term blastocyst vitrification for more than 6 years can negatively affect the rates of biochemical pregnancy, clinical pregnancy, and live birth but does not impact neonatal outcomes.
Repeated implantation failure (RIF) leads to a waste of high-quality embryos and remains a challenge in assisted reproductive technology. During early human placentation, the invasion of trophoblast ...cells into the decidua is an essential step for the establishment of maternal-fetal interactions and subsequent successful pregnancy. Bone morphogenetic protein 2 (BMP2) has been reported to regulate endometrial receptivity and promote trophoblast invasion. However, whether there is dysregulation of endometrial BMP2 expression in patients with RIF remains unknown. Additionally, the molecular mechanisms underlying the effects of BMP2 on human trophoblast invasion and early placentation remain to be further elucidated.
Midluteal phase endometrial samples were biopsied from patients with RIF and from routine control in vitro fertilization followed by quantitative polymerase chain reaction and immunoblotting analyses. Human trophoblast organoids, primary human trophoblast cells, and an immortalized trophoblast cell line (HTR8/SVneo) were used as study models.
We found that BMP2 was aberrantly low in midluteal phase endometrial tissues from patients with RIF. Recombinant human BMP2 treatment upregulated integrin β3 (ITGB3) in a SMAD2/3-SMAD4 signaling-dependent manner in both HTR8/SVneo cells and primary trophoblast cells. siRNA-mediated integrin β3 downregulation reduced both basal and BMP2-upregulated trophoblast invasion and vascular mimicry in HTR8/SVneo cells. Importantly, shRNA-mediated ITGB3 knockdown significantly decreased the formation ability of human trophoblast organoids.
Our results demonstrate endometrial BMP2 deficiency in patients with RIF. ITGB3 mediates both basal and BMP2-promoted human trophoblast invasion and is essential for early placentation. These findings broaden our knowledge regarding the regulation of early placentation and provide candidate diagnostic and therapeutic targets for RIF clinical management.
This retrospective cohort study aimed to assess the effect of chromosomal reciprocal translocation on meiotic segregation products of non-translocation chromosomes. A total of 744 reciprocal ...translocation carriers and 875 non-carriers were included in this study. A total of 6,832 blastocysts were biopsied and tested by next-generation sequencing. Blastocysts from the carrier group were classified into five subgroups according to the theoretical segregation pattern of quadrivalent structure. For carrier patients, normal meiotic segregation products of the non-translocation chromosome were classified after excluding the segregation modes of the quadrivalent structure. The proportion of normal non-translocation chromosome meiotic segregation products was similar between the carrier and noncarrier groups (p = 0.69). The generalized Estimation Equation revealed that there was no correlation between reciprocal translocation and meiotic segregation products of non-translocation chromosomes. Moreover, subgroup analyses showed that the segregation modes of quadrivalent structure (p = 0.00) and carrier's gender (p = 0.00) may affect the meiotic segregation products of non-translocation chromosomes. In conclusion, reciprocal translocation does not directly reduce the proportion of normal segregation products of non-translocation chromosomes. The difference among subgroups of different quadrivalent segregation patterns implied that interchromosomal effect may exist but the high incidence of chromosomal abnormalities for reciprocal translocation carriers should not be attributed to interchromosomal effect.
To explore the prognostic impact of a previous late miscarriage (LM) on the subsequent pregnancy outcomes of women with infertility.
This retrospective cohort study included couples who had ...experienced LM following their first embryo transfer during an in vitro fertilization (IVF) cycle from January 2008 to December 2020. Subgroup analysis and binary logistic regression were performed to evaluate the associations between LM due to different causes and subsequent pregnancy outcomes.
A total of 1072 women who had experienced LM were included in this study, comprising 458, 146, 412, and 56 women with LM due to unexplained factors (unLM), fetal factors (feLM), cervical factors (ceLM; i.e. cervical incompetence), and trauma factors (trLM), respectively. Compared with the general IVF (gIVF) population, the early miscarriage rate was significantly higher in the unLM group (8.28% vs. 13.47%, adjusted odds ratio OR 1.60, 95% confidence interval 95% CI 1.12-2.28; P = 0.01). Furthermore, women in the unLM and ceLM groups had a dramatically increased risk of recurrent LM (unLM: 4.24% vs. 9.43%, aOR 1.91, 95% CI 1.24-2.94; P = 0.003; ceLM: 4.24% vs.15.53%, aOR 2.68, 95% CI 1.82-3.95; P < 0.001) and consequently a reduced frequency of live birth (unLM: 49.96% vs. 43.01%, aOR 0.75, 95% CI 0.61-0.91; P = 0.004; ceLM: 49.96% vs. 38.59%, aOR 0.61, 95% CI 0.49-0.77; P < 0.001) compared with the gIVF population.
A previous LM due to an unexplained factor or cervical incompetence was significantly associated with a higher risk of miscarriage and a lower live birth rate after subsequent embryo transfer.
Repeated implantation failure (RIF) is a major problem that limits the pregnancy rate associated with assisted reproductive technology. However, the pathogenesis of RIF is still unknown. Recently, ...the expression levels of circular RNAs (circRNAs) were profiled in the endometrial tissues of patients with RIF. However, the exact role of circRNAs in RIF remains unclear. In our study, we found that circFAM120A levels were significantly down‐regulated in the endometrium at the window of implantation in RIF patients compared with non‐RIF controls. The suppression of circFAM120A expression inhibited decidualization in human endometrial stromal cells (hESCs). Furthermore, RNA‐seq analysis after circFAM120A knockdown revealed ABHD5 as a potential downstream target gene of circFAM120A. As expected, down‐regulating ABHD5 in hESCs also inhibited decidualization. Using the starBase and TargetScan databases, we predicted that miR‐29 may interact with ABHD5, based on nucleotide sequence matching. Luciferase reporter assay showed that miR‐29 bound to the 3′ UTR of ABHD5 at the predicted complementary sites. Moreover, miR‐29 mimics efficiently reduced ABHD5 expression levels and suppressed the decidualization process, whereas a miR‐29 inhibitor partly rescued ABHD5 mRNA expression level and decidualization reduced by the knockdown of circFAM120A. Therefore, circFAM120A modulated decidualization in RIF through the miR‐29/ABHD5 axis.
Abstract
Context
Some studies have reported the early miscarriage rate is higher in polycystic ovary syndrome (PCOS) women. However, there is a lack of evidence as to whether the risk of embryo ...abnormalities increases in PCOS women.
Objective
This work aimed to evaluate the association between PCOS and embryo ploidy.
Methods
A secondary analysis of a multicenter, randomized controlled trial was conducted from July 2017 to June 2018. The original intent was to identify whether preimplantation genetic test for aneuploidy (PGT-A) improves the live birth rate as compared with in vitro fertilization (IVF). From 14 reproductive centers, 190 patients diagnosed with PCOS and 1:1 age-matched non-PCOS patients were chosen from a PGT-A group. A total of 380 patients with 1118 embryos were included in our study. Intervention included women diagnosed with PCOS, and the main outcome measures were embryonic aneuploidy and embryonic mosaic.
Results
After adjusting for potential confounders, the rate of embryonic aneuploidy and embryonic mosaic in the PCOS group were comparable with the control group (embryonic aneuploid rate PCOS group: 14.0% vs control group: 18.3%, adjusted OR 95% CI: 0.78 0.54, 1.12; P = .19; embryonic mosaic rate 10.9% vs 10.1%, adjusted OR 95% CI: 0.91 0.59, 1.40; P = .66). We further stratified PCOS women into 4 groups according to phenotype. The rate of aneuploid and mosaic embryos was comparable between each PCOS phenotype and control group. There was still no significant difference of embryonic aneuploid and embryo mosaic rates among the 4 phenotypes.
Conclusion
The risk of aneuploid and mosaic embryos did not increase in PCOS women. Thus, we suggest that the miscarriage rate arising from abnormal embryonic chromosomes could be similar between PCOS and non-PCOS women.
The cover image is based on the Original Article
Insufficient GDF15 expression predisposes women to unexplained recurrent pregnancy loss by impairing extravillous trophoblast invasion
by Chunzi Lyu ...et al.,
https://doi.org/10.1111/cpr.13514
.
image
Insufficient extravillous trophoblast (EVT) invasion during early placentation has been shown to contribute to recurrent pregnancy loss (RPL). However, the regulatory factors involved and their ...involvement in RPL pathogenesis remain unknown. Here, we found aberrantly decreased growth differentiation factor 15 (GDF15) levels in both first‐trimester villous and serum samples of unexplained recurrent pregnancy loss (URPL) patients as compared with normal pregnancies. Moreover, GDF15 knockdown significantly reduced the invasiveness of both HTR‐8/SVneo cells and primary human EVT cells and suppressed the Jagged‐1 (JAG1)/NOTCH3/HES1 pathway activity, and JAG1 overexpression rescued the invasion phenotype of the GDF15 knockdown cells. Induction of a lipopolysaccharide‐induced abortion model in mice resulted in significantly reduced GDF15 level in the placenta and serum, as well as increased rates of embryonic resorption, and these effects were reversed by administration of recombinant GDF15. Our study thus demonstrates that insufficient GDF15 level at the first‐trimester maternal–foetal interface contribute to the pathogenesis of URPL by impairing EVT invasion and suppressing JAG1/NOTCH3/HES1 pathway activity, and suggests that supplementation with GDF15 could benefit early pregnancy maintenance and reduce the risk of early pregnancy.
By performing experiments using clinical samples from healthy pregnancies and unexplained RPL (URPL) patients, immortalized human trophoblast cells (HTR‐8/SVneo) and lipopolysaccharide (LPS)‐induced abortion mouse models, we discovered that growth differentiation factor 15 (GDF15), which is derived from human trophoblasts, was downregulated in villi and maternal sera from URPL patients. In addition, GDF15 could serve as a pro‐invasive factor in human extravillous trophoblasts and upregulate JAG1/NOTCH3/HES1 pathway activity as well as rescue the embryo absorption phenotype observed in the LPS‐induced abortion mouse model. Our findings demonstrate that insufficient GDF15 levels at the first‐trimester maternal–foetal interface contribute to the pathogenesis of URPL by impairing EVT invasion and suppressing JAG1/NOTCH3/HES1 pathway activity, therefore holding promise for diagnostic and therapeutic target applications for the clinical management of URPL.
