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Sperm DNA damage is prevalent among infertile men and is known to influence natural reproduction. However, the impact of sperm DNA damage on assisted reproduction outcomes remains controversial. Here, we conducted a meta-analysis of studies on sperm DNA damage （assessed by SCSA, TUNEL, SCD, or Comet assay） and clinical pregnancy after IVF and/or ICSI treatment from MEDLINE, EMBASE, and PUBMED database searches for this analysis. We identified 41 articles （with a total of 56 studies） including 16 IVF studies, 24 ICSI studies, and 16 mixed （IVF ＋ ICSI） studies. These studies measured DNA damage （by one of four assays： 23 SCSA, 18 TUNEL, 8 SCD, and 7 Comet） and included a total of 8068 treatment cycles （3734 IVF, 2282 ICSI, and 2052 mixed IVF ＋ ICSI）. The combined OR of 1.68 （95% Ch 1.49-1.89; P 〈 0.0001） indicates that sperm DNA damage affects clinical pregnancy following IVF and/or ICSI treatment. In addition, the combined OR estimates of IVF （16 estimates, OR = 1.65; 95% CI： 1.34-2.04; P 〈 0.0001）, ICSI （24 estimates, OR = 1.31; 95% Ch 1.08-1.59; P = 0.0068）, and mixed IVF ＋ ICSI studies （16 estimates, OR = 2.37; 95% Ch 1.89-2.97; P〈 0.0001） were also statistically significant. There is sufficient evidence in the existing literature suggesting that sperm DNA damage has a negative effect on clinical pregnancy following IVF and/or ICSI treatment.

Changes in the female genital tract microbiome are consistently correlated to gynecological and obstetrical pathologies, and tract dysbiosis can impact reproductive outcomes during fertility treatment. Nonetheless, a consensus regarding the physiological microbiome core inside the uterine cavity has not been reached due to a myriad of study limitations, such as sample size and experimental design variations, and the influence of endometrial bacterial communities on human reproduction remains debated. Understanding the healthy endometrial microbiota and how changes in its composition affect fertility would potentially allow personalized treatment through microbiome management during assisted reproductive therapies, ultimately leading to improvement of clinical outcomes. Here, we review current knowledge regarding the uterine microbiota and how it relates to human conception.

Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of N-nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.

The objective of this study was to assess bias in the body mass index (BMI) measure in the Canadian Maternity Experiences Survey (MES) and possible implications of bias on the relationship between BMI and selected pregnancy outcomes. We assessed BMI classification based on self-reported versus measured values. We used a random sample of 6175 women from the MES, which derived BMI from self-reported height and weight, and a random sample of 259 women who had previously given birth from the Canadian Health Measures Survey (CHMS), which derived BMI from self-reported and measured height and weight. Two correction equations were applied to self-reported based BMI, and the impact of these corrections on associations between BMI and caesarean section, small-for-gestational age (SGA) and large-for-gestational age (LGA) births was studied. Overall, 86.9% of the CHMS subsample was classified into the same BMI category based on self-reported versus measured data. However, misclassification had a substantial effect on the proportion of women in underweight and obese BMI categories. For example, 14.5% versus 20.8% of women were classified as obese based on self-reported data versus measured data. Corrections improved estimates of obesity prevalence, but over- and underestimated other BMI categories. Corrections had nonsignificant effects on the associations between BMI and SGA, LGA, and caesarean section. While there was high concordance in BMI classification based on selfreported versus measured height and weight, bias in self-reported based measures may slightly over- or underestimate the risks associated with a particular BMI class. However, the general trend in associations is unaffected.

Introduction After incomplete healing of the uterine cesarean section scar, a niche can be observed; 24% of the women develop large niches with a residual myometrial thickness <3 mm. In these cases a laparoscopic resection is possible. The effect of this new treatment on fertility outcome is not known yet. This paper describes reproductive outcomes 2 years after a laparoscopic niche resection and compares women with or without secondary infertility at baseline. Material and methods A prospective cohort study was performed, with consecutive inclusion of women between 2011 and 2019. Women with a niche in the uterine cesarean scar, with a residual myometrial thickness of <3 mm and with a desire to become pregnant, were scheduled to undergo a laparoscopic niche resection because of one or more of the following problems (1) postmenstrual spotting; (2) midcycle intrauterine fluid accumulation diagnosed during the fertility workup or (3) difficulties with a previous embryo transfer and preferring a surgical therapy. The study is registered in the ISRCTN register (ref. no. ISRCTN02271575) on April 23, 2013. Results There were 133 (62%) women included with a desire to become pregnant, 88 with secondary infertility. In all, 83 had an ongoing pregnancy at the 2‐year follow‐up. The ongoing pregnancy rate in patients with previous fertility problems was 60.2% compared with 66.7% in patients without infertility (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.32–1.7). The OR for live births was 0.57 (95% CI 0.02–1.2). Overall, 8.3% of the pregnancies resulted in miscarriages by the 2‐year follow‐up. Conclusions The reproductive outcomes in women with and without previous fertility problems undergoing resection of a large niche are very promising and quite comparable in both groups. These results suggest, but do not prove, a beneficial effect of this therapy for these indications. The results support the design of future randomized controlled trials to evaluate the effect of niche resection vs expectant management to assess its additional value in women with or without fertility problems who desire pregnancy. Our results show positive reproductive outcomes and improved postmenstrual spotting with few complications and lend support for carrying out randomized controlled trials for fertility reasons only.

Background Abnormal BMI is associated with discouraging IVF outcomes in fresh autologous or oocyte donor cycles, whether or not such a relation also holds true for women undergoing frozen-thawed embryo transfer (FET) remains unknown. In addition, it remains unclear the detrimental effect of abnormal BMI on IVF outcomes occurs at the level of ovary or endometrium. Methods A retrospective study involved 22,043 first FET cycles of all women who had undergone a freeze-all policy during the period from January 2010 to June 2017. To control for the embryo factor, our analysis was restricted to women with high-quality embryo transfer. The main outcome measure was live birth rate per embryo transfer. The secondary endpoints included rates of implantation, clinical pregnancy, multiple pregnancy, and pregnancy loss. Multivariate logistic regression analysis was performed to detect the independent effect of BMI on live birth rate after adjusting for important confounding variables. Results In the crude analysis, reproductive outcomes were similar between underweight women and normal-weight controls whereas all parameter outcomes were significantly worse in patients with obesity. After adjustment for a number of confounding factors, underweight women had a marginally significant decrease in rates of implantation (adjusted odds ratio (aOR) 0.91; 95% CI 0.85–0.96), clinical pregnancy (aOR 0.91; 95% CI 0.83–0.99), and live birth (aOR 0.91; 95% CI 0.83–0.99) as compared to the women with normal weight. Obesity was significantly associated with decreased implantation (aOR 0.80; 95% CI 0.73–0.87), clinical pregnancy (aOR 0.81; 95% CI 0.71–0.91), and live birth rates (aOR 0.70; 95% CI 0.62–0.80). Moreover, the pregnancy loss rate, both in the first (aOR 1.46; 95% CI 1.15–1.87) and in the second trimester (aOR 2.76; 95% CI 1.67–4.58), was significantly higher in the obesity group than that in the reference group. Conclusions Among women undergoing first FET with high-quality embryo transfer, low BMI has limited impact on pregnancy and live birth rates. On the contrary, obesity was associated with worse IVF outcomes. Our findings further highlighted that endometrial receptivity played an important role in the poor reproductive outcomes of women with abnormal weight status.

Background Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regarding the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this systematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive outcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical pregnancy rate. Methods We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane Library) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes difference between the intervention (vitamin D) vs. the control (placebo or none). Mantel-Haenszel random effects models were used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database registration number: CRD42022304018. Results Twelve eligible studies ( n  = 2352) were included: 9 randomized controlled trials (RCTs, n  = 1677) and 3 cohort studies ( n  = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased clinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24–2.34; I 2  = 63%, P  = 0.001). However, the implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference (OR: 1.86, 95% CI: 1.00–3.47; I 2  = 85%, P  = 0.05; OR: 1.49; 0.98–2.26; I 2  = 63%, P  = 0.06; OR: 0.98, 95% CI: 0.63–1.53; I 2  = 0%, P  = 0.94 and OR: 3.64, 95% CI: 0.58–11.98; I 2  = 68%, P  = 0.21). The improvement of clinical pregnancy rate in the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, the duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vitamin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000–50,000 IU or 50,000–500,000 IU), or got vitamin D 1000–10,000 IU daily, lasting for 30–60 days could achieve better pregnancy outcome. Conclusion To the best of our knowledge, this is the first meta-analysis systematically investigated that moderate daily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported the effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high-quality RCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit from this therapy.

Background The decline in women's fertility becomes clinically relevant between 35–40 years old, when there is insufficient ovarian activity, and it becomes more difficult to achieve pregnancy naturally and through artificial reproductive technologies. A competent endometrium is required for establishing and maintaining a pregnancy to term, however, experts in the field underestimate the contribution of endometrial age and its impact on reproductive outcomes remains unclear. Study design A systematic search of full-text articles available in PubMed was conducted to retrieve relevant studies published until March 2023. Search terms included: endometrium, uterus, age, aging, pregnancy, and oocyte donation. Terms related to reproductive pathologies were excluded. Eligibility criteria included original, rigorous, and accessible peer-reviewed work, published in English on the effect of age on the uterus and endometrium. Results From 11,354 records identified, 142 studies were included for systematic review, and 59 were eligible for meta-analysis of endometrial thickness ( n  = 7), pregnancy rate ( n  = 22), implantation rate ( n  = 10), live birth rate ( n  = 10) and pregnancy loss rate ( n  = 11). Studies for the meta-analysis of reproductive outcomes only included transfers of embryos from ovum donation (ovum donors < 36 years old). Age shrinks the uterus; depletes endometrial blood supply through narrow uterine veins and a progressive loss of uterine spiral arteries; disrupts endometrial architecture and cellular composition; alters hormone production, shortening menstrual cycle length and impeding endometrial progression to the secretory stage; and dysregulates key endometrial functions such as adhesion, proliferation, apoptosis, and receptivity, among others. Women over 35–40 years old had significantly thinner endometrium (MD 0.52 mm). Advanced maternal age is associated with lower odds of achieving implantation (27%) and clinical pregnancy (20%), or higher odds of experiencing pregnancy loss (44%). Conclusion Due to the effect of age on endometrium reported in this review, managing patients with advanced maternal age may require considering the endometrial factor as a potential tissue to treat with anti-aging strategies. This review provides researchers and clinicians with an updated and in-depth summary of this topic, encouraging the development of new tailored anti-aging and preventive strategies for precision medicine in endometrial factor in infertility. Trial registration PROSPERO 2023 (CRD42023416947).

Endocrine-disrupting chemicals are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to endocrine-disrupting chemicals has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between these substances and disease outcomes has limitations. Epidemiological and experimental research on endocrine-disrupting chemicals faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and mechanistic insights, in particular regarding endocrine-disrupting chemicals' impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of chemical mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and chemical disruption mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of endocrine-disrupting chemicals on immune-reproductive health. Summary Sentence ENDOMIX integrates epidemiological, in vitro, and in vivo data to address life expanse exposure to chemical mixtures and their underlying mechanisms. Graphical Abstract

BackgroundAssisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) are often used to aid fertility in women with endometrioma; however, the implications of endometrioma on ART are unresolved.ObjectiveTo determine the effect of endometrioma on reproductive outcomes in women undergoing IVF or ICSI.MethodsA systematic review and meta-analysis was conducted to identify articles examining women who had endometrioma and had undergone IVF or ICSI. Electronic searches were performed in PubMed, BIOSIS and MEDLINE up to September 2019. The primary outcome was live birth rate (LBR). Secondary outcomes included clinical pregnancy rate (CPR), implantation rate (IR), number of oocytes retrieved, number of metaphase II (MII) oocytes retrieved, number of embryos and top-quality embryos and the duration of gonadotrophin stimulation and dose.ResultsEight studies were included. Where significant heterogeneity between studies was identified, a random-effects model was used. The number of oocytes (weighted means difference; WMD-2.25; 95% CI 3.43 to − 1.06, p = 0.0002) and the number of MII oocytes retrieved (WMD-4.64; 95% CI 5.65 to − 3.63, p < 0.00001) were significantly lower in women with endometrioma versus controls. All other outcomes, including gonadotrophin dose and duration, the total number of embryos, high-quality embryos, CPR, IR and LBR were similar in women with and without endometrioma. ConclusionEven though women with endometriomas had a reduced number of oocytes and MII oocytes retrieved when compared to women without, no other differences in reproductive outcomes were identified. This implies that IVF/ICSI is a beneficial ART approach for women with endometrioma.