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Due to the physiological alteration during pregnancy, maternal gut microbiota changes following the metabolic processes. Recent studies have revealed that maternal gut microbiota is closely associated with the immune microenvironment in utero during pregnancy and plays a vital role in specific pregnancy complications, including preeclampsia, gestational diabetes, preterm birth and recurrent miscarriages. Some other evidence has also shown that aberrant maternal gut microbiota increases the risk of various diseases in the offspring, such as allergic and neurodevelopmental disorders, through the immune alignment between mother and fetus and the possible intrauterine microbiota. Probiotics and the high-fiber diet are effective inventions to prevent mothers and fetuses from diseases. In this review, we summarize the role of maternal gut microbiota in the development of pregnancy complications and the health condition of future generations from the perspective of immunology, which may provide new therapeutic strategies for the health management of mothers and offspring.

The aim of this study was to investigate the impact of a history of recurrent ectopic pregnancy (EP) on pregnancy outcomes of subsequent in vitro fertilization (IVF) treatment. A retrospective cohort study involving 457 women with a history of recurrent EP (REP group), 912 women with a history of single EP (SEP group), and 1169 women with a history of intrauterine pregnancy (IUP group) as the control group, was conducted. IVF outcomes were compared for each cohort. The incidence of EP in the REP group after IVF treatment was significantly lower than those in the SEP group (2.4% vs. 6.8%, P = 0.011), and similar to those in the IUP group (2.4% vs. 2.1%, P = 0.830). No significant differences were observed in the clinical pregnancy rate, miscarriage rate, and live birth rate among the three groups. There was no statistically significant difference in the recurrent EP rate between the salpingectomy and salpingostomy treatments. Adjusting for maternal and treatment factors did not influence live birth rates for women with previous REP compared with women with previous SEP and those with IUP. The odds of EP were 82.2% lower (OR 0.178, 95% CI 0.042-0.762; P = 0.020) in women who had blastocyst transfer compared with cleavage embryo transfer in the SEP group. The odds of EP were over six times (OR 6.260, 95% CI 1.255-31.220; P = 0.025) in women who underwent double embryo transfer as opposed to single embryo transfer in the IUP group. Our results indicate that women with previous recurrent EP have a lower risk of EP after IVF in comparison with women with previous single EP. Previous EP has no significant adverse effect on the main IVF outcomes. The salpingostomy and salpingectomy treatments of EP do not significantly affect the incidence of recurrent EP after IVF.

ObjectivesThe aim of this study was to investigate the impact of a history of recurrent ectopic pregnancy (EP) on pregnancy outcomes of subsequent in vitro fertilization (IVF) treatment.MethodsA retrospective cohort study involving 457 women with a history of recurrent EP (REP group), 912 women with a history of single EP (SEP group), and 1169 women with a history of intrauterine pregnancy (IUP group) as the control group, was conducted. IVF outcomes were compared for each cohort.ResultsThe incidence of EP in the REP group after IVF treatment was significantly lower than those in the SEP group (2.4% vs. 6.8%, P = 0.011), and similar to those in the IUP group (2.4% vs. 2.1%, P = 0.830). No significant differences were observed in the clinical pregnancy rate, miscarriage rate, and live birth rate among the three groups. There was no statistically significant difference in the recurrent EP rate between the salpingectomy and salpingostomy treatments. Adjusting for maternal and treatment factors did not influence live birth rates for women with previous REP compared with women with previous SEP and those with IUP. The odds of EP were 82.2% lower (OR 0.178, 95% CI 0.042-0.762; P = 0.020) in women who had blastocyst transfer compared with cleavage embryo transfer in the SEP group. The odds of EP were over six times (OR 6.260, 95% CI 1.255-31.220; P = 0.025) in women who underwent double embryo transfer as opposed to single embryo transfer in the IUP group.ConclusionOur results indicate that women with previous recurrent EP have a lower risk of EP after IVF in comparison with women with previous single EP. Previous EP has no significant adverse effect on the main IVF outcomes. The salpingostomy and salpingectomy treatments of EP do not significantly affect the incidence of recurrent EP after IVF.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated 1 . Gestational diabetes has profound and enduring effects on the long-term health of the offspring 2 , 3 . However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote 4 , is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene ( Gck ), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring. Pregestational hyperglycaemia in mothers increases the probability of glucose intolerance in the offspring, an effect controlled by TET3-dependent DNA demethylation of genes involved in insulin secretion.

Background Unresponsive thin endometrium caused by Asherman syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease. Methods Eighteen infertile women with unresponsive thin endometrium, whose frozen–thawed embryo transfers (FETs) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then twenty million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FETs were performed in the following cycle. Pregnancy outcomes were followed up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment. Results Sixteen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.08 ± 0.26 mm to 5.87 ± 0.77 mm ( P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks’ gestation. One of 2 patients without FET had a natural pregnancy and gave birth normally after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alpha, and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones. Conclusion CS/UC-MSCs is a promising and potential approach for treating women with unresponsive thin endometrium caused by AS. Trial registration ClinicalTrials.gov NCT03724617 . Registered on 26 October 2018—prospectively registered, https://register.clinicaltrials.gov/

To evaluate the association between the number of oocytes retrieved and cumulative live birth rate (CLBR) in different female age strata. 17,931 women undergoing their first IVF/ICSI-ET cycle in the Sir Run Run Shaw Hospital of Zhejiang University were grouped by age (A: ≤ 35 years; B: ≥ 36 years) as well as the number of oocytes retrieved (a: ≤ 5; b:6–9; c:10–14; d: ≥ 15). Multivariate regression analysis was performed to assess the OR of CLBR for the variable ‘age’ and ‘number of oocytes retrieved’. The group ≥ 36 years exhibited lower cumulative pregnancy rates (CPRs) and cumulative live birth rates (CLBRs), which are proportional to the number of oocytes retrieved but opposite to increasing age. Multivariate logistic regression analysis revealed that the age and number of oocytes retrieved remain significant independent predictive factors (P < 0.001). Age and number of oocytes retrieved are two independent factors affecting the CLBR. The discrepancy of the minimum number of oocytes retrieved for patients with different ages to achieve ideal CLBR is instructive for clinical practice. The practice of controlling the stimulation dose is feasible for patients ≤ 35 years who can achieve over 60% CLBR once the number of oocytes obtained is more than 6. However, additional stimulation cycles and accumulation of embryos are necessary for elderly group especially those ≥ 38 years old who need more than 14 oocytes to obtain higher live birth rate.

We aimed to investigate the difference in the time to pregnancy (TTP) between women with previous ectopic pregnancy (EP) and control women following in vitro fertilization (IVF) treatment and the association between TTP and the number of oocytes retrieved and embryos available. A retrospective study involving 1097 women, 547 of which had previous EP and 550 were control women whose previous pregnancy were abortion, was conducted. Women in the EP group had significantly longer median TTP than those in the control group (36; range, 12–252 vs 28; range, 12–220; P = 0.019). For women with previous EP, > 48 months TTP was most likely associated with low numbers of oocytes retrieved and embryos available compared to TTP of ≤ 24 months or 25–48 months, and women with younger age had a shorter TTP, higher numbers of oocytes retrieved and embryos available. A Cox proportional hazards model showed that maternal age was significantly related to the pregnancy over the TTP (adjusted hazard ratio, 0.934; P < 0.001). In conclusion, women with previous EP have a significantly increased TTP than control women with previous abortion. For women with previous EP, TTP is negatively associated with the numbers of oocytes retrieved and embryos available.

Background Transcervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can release estrogen within the uterine cavity slowly. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUA. Methods This was a multicenter prospective randomized controlled 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion reduction in the two groups. The secondary outcomes included endometrial thickness at the ovulation period, menstrual improvement rates, and other reported adverse events during follow-up. Results The average daily drug release amount for all the tested stents was 0.21 mg/day. At 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, p  < 0.001). The endometrium of the experimental group was thicker than that of the control group ( p  < 0.001). Consistently, the rate of improvement in menstruation was greater in the experimental group than in the control group ( p  = 0.010). No grade 3–4 adverse events were found in the two groups during the 1-year follow-up. Conclusions In the cohort of patients with moderate to severe IUA, the intrauterine estrogen-releasing system was more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system provides a new option for the management of IUA after surgery. Trial registration The registration number is NCT04972032. Date of registration: August 15, 2021.

Background Various luteal phase supports (LPSs) have been proven to increase the pregnancy rate in fresh cycles of in vitro fertilization or intracytoplasmic sperm injection; however, there is still significant debate regarding the optimal use of LPS. Methods A systematic review with the use of a network meta-analysis was performed via electronic searching of Ovid MEDLINE, the Cochrane Library, Embase, Web of Science, ClinicalTrials.gov and Google Scholar (up to January 2021) to compare the effectiveness and safety of various LPSs, as well as to evaluate the effects of different initiations of LPSs on pregnancy outcomes. The primary outcomes included live birth and ongoing pregnancy, with the results presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results Eighty-nine randomized controlled trials with 29,625 women comparing 14 interventions or placebo/no LPS treatments were included in the meta-analyses. No significant differences were found in terms of the pregnancy outcomes when LPS was started within 48 h after oocyte retrieval versus a delayed initiation between 48 h and 96 h after oocyte retrieval. The addition of gonadotropin-releasing hormone (GnRH) agonists to progesterone vaginal pessaries showed a significant benefit in terms of live birth (OR 1.39, 95% CI 1.08 to 1.78). Only human chorionic gonadotropin (HCG) was found to be more efficacious than the placebo/no LPS treatment in terms of live birth (OR 15.43, 95% CI 2.03 to 117.12, low evidence). Any active LPSs (except for rectal or subcutaneous progesterone) was significantly more efficacious than the placebo/no LPS treatment in terms of ongoing pregnancy, with ORs ranging between 1.77 (95% CI 1.08 to 2.90) for the vaginal progesterone pessary and 2.14 (1.23 to 3.70) for the intramuscular progesterone treatment. Among the comparisons of efficacy and tolerability between the active treatments, the differences were small and very uncertain. Conclusion Delays in progesterone supplementation until 96 h after oocyte retrieval does not affect pregnancy outcomes. The safety of GnRH agonists during the luteal phase needs to be evaluated in future studies before the applications of these agonists in clinical practice. With comparable efficacy and acceptability, there may be several viable clinical options for LPS.

Early embryonic arrest and fragmentation (EEAF) is a common phenomenon leading to female infertility, but the genetic determinants remain largely unknown. The Moloney sarcoma oncogene ( MOS ) encodes a serine/threonine kinase that activates the ERK signaling cascade during oocyte maturation in vertebrates. Here, we identified four rare variants of MOS in three infertile female individuals with EEAF that followed a recessive inheritance pattern. These MOS variants encoded proteins that resulted in decreased phosphorylated ERK1/2 level in cells and oocytes, and displayed attenuated rescuing effects on cortical F‐actin assembly. Using oocyte‐specific Erk1/2 knockout mice, we verified that MOS‐ERK signal pathway inactivation in oocytes caused EEAF as human. The RNA sequencing data revealed that maternal mRNA clearance was disrupted in human mature oocytes either with MOS homozygous variant or with U0126 treatment, especially genes relative to mitochondrial function. Mitochondrial dysfunction was observed in oocytes with ERK1/2 deficiency or inactivation. In conclusion, this study not only uncovers biallelic MOS variants causes EEAF but also demonstrates that MOS‐ERK signaling pathway drives human oocyte cytoplasmic maturation to prevent EEAF. SYNOPSIS Biallelic variants in MOS gene cause recurrent early embryonic arrest and fragmentation (EEAF) and female infertility. MOS variants impair activation of MOS‐ERK signal cascade, prevent substantial maternal mRNAs decay and hamper embryonic development both in human and mice. Four rare variants in MOS gene were identified in three Chinese infertile females displaying EEAF followed recessive inheritance pattern. Mutant MOS proteins failed to activate ERK1/2 cascade, and Erk1/2 ‐deficient mice also exhibited EEAF, confirming the human diagnostic. MOS‐ERK1/2 signal cascade is required for maternal mRNA clearance during human oocyte maturation, especially of transcripts relative to mitochondrial function. Inactivation of human or mouse MOS‐ERK1/2 signal cascade caused mitochondrial dysfunction in mature oocytes. Graphical Abstract Biallelic variants in MOS gene cause recurrent early embryonic arrest and fragmentation (EEAF) and female infertility. MOS variants impair activation of MOS‐ERK signal cascade, prevent substantial maternal mRNAs decay and hamper embryonic development both in human and mice.