Effects of Chokeberries (Aronia spp.) on Cytoprotective and Cardiometabolic Markers and Semen Quality in 109 Mildly Hypercholesterolemic Danish Men: A Prospective, Double-Blinded, Randomized, Crossover Trial.

Background: Chokeberries (Aronia spp.) are known to exhibit both direct and indirect antioxidant properties and have been associated with beneficial effects on human health, including cardiovascular risk factors (inflammation, serum lipids, sugars, blood pressure), oxidative stress, and semen quality. This prospective, double-blinded, randomized, crossover clinical trial was conducted to elucidate the effects of Aronia supplementation on these health targets in mildly hypercholesterolemic men. Methods: The standardized Aronia supplementation comprised three wild Aronia spp. (A. arbutifolia, A prunifolia and A. melanocarpa) and the Aronia hybrid × Sorbaronia mitschurinii (standardized to 150 mg anthocyanins daily). Participants (n = 109) were healthy men with respect to all outcome targets except for the total cholesterol level (5.0−7.0 mM). Participants were randomized to supplementation with either Aronia or placebo for 90 days, followed by a wash-out period and lastly the complementary supplementation. Effects on the health parameters were compared among both the whole group of men and in subgroups according to age, body mass index (BMI), lifestyle, dietary habits, and serum glutathione levels at baseline. The study is registered in ClinicalTrials.gov.: NCT03405753. Results: Glutathione levels were significantly improved after 90 days intake of Aronia supplementation compared to placebo in the subgroup of men with a low level of glutathione at baseline (p = 0.038) and a high coffee intake (p = 0.045). A significant decrease in levels of sperm DNA fragmentation and an increase in the percentage of motile sperm were observed in men aged >40 and in men with BMI > 25. Further, these parameters were significantly improved in the dietary subgroup defined by a high level of coffee intake. Total cholesterol and low-density lipoprotein-cholesterol levels decreased significantly in men <40 years after Aronia supplementation. No statistically significant effects were observed regarding blood pressure, markers of blood sugar regulation, hemoglobin A1c, superoxide dismutase, catalase, isoprostane levels, high sensitivity C reactive protein, or other semen parameters. Conclusions: This study demonstrated a significant increase in glutathione levels and improvement of cytoprotective targets following Aronia supplementation in specific subgroups of men >40 years of age and BMI > 25 but did not demonstrate a significant effect in the overall analysis. The observed concurrent increase in glutathione levels and improvement of cytoprotective targets following Aronia supplementation in subgroups of men, suggests that the endogenous phase II antioxidant glutathione is involved in the modulation of the observed cytoprotective effects. This study is a good foundation for further investigation of these cytoprotective effects in groups with oxidative stress in a dose−response study.

Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study.

BACKGROUND: Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss. METHODS: We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables. RESULTS: No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges. CONCLUSION: No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.

Healthcare Use in the Five Years Before a First Infertility Diagnosis: A Danish Register-Based Case-Control Study in the CROSS-TRACKS Cohort.

Purpose: Infertility may affect somatic and mental health later in life. Nevertheless, health status before diagnosed infertility is sparsely studied in women. We aimed to describe healthcare use in primary and secondary care before a first infertility diagnosis and compare use between cases and controls. Materials and Methods: The case-control study was based on register data and used incidence density sampling. From the CROSS-TRACKS Cohort, we included women residing in the Horsens area in Denmark in 2012-2018 (n = 54,175). Eligible women were aged 18-40 years, nulliparous, and living in heterosexual relationships. Cases were women with a first infertility diagnosis in the Danish National Patient Registry (index date). Five controls were matched on age, birth year, and calendar time. Through linkage to Danish national health registries, we identified general practitioner (GP) attendance, paraclinical examinations, hospital contacts, diagnoses, and redeemed prescriptions. Healthcare use from one year to five years before index date was compared with conditional logistic regression. Results: We identified 711 cases and 3555 controls. At one year before index date, cases consulted their GP (odds ratio (OR) = 5.2, 95% confidence interval (CI): 3.2, 8.3) and visited hospital (OR = 1.2, 95% CI: 1.0, 1.4) and redeemed prescriptions (OR = 2.3 95% CI: 1.9, 2.7) more often compared to controls. Cases more often had blood and hemoglobin tests performed, redeemed more drugs related to genitourinary and hormonal diseases, and were more often diagnosed with endocrine and genitourinary diseases in the year before a first infertility diagnosis compared to controls. Cases and controls had comparable healthcare use from five years to one year before a first infertility diagnosis. Conclusion: Cases and controls had similar healthcare use from five years to one year before a first infertility diagnosis. However, cases had a higher healthcare use in the year preceding a first infertility diagnosis compared to controls.

Nitrate in Drinking Water and Time to Pregnancy or Medically Assisted Reproduction in Women and Men: A Nationwide Cohort Study in the Danish National Birth Cohort.

Purpose: No studies have investigated if drinking water nitrate affects human fecundity. Experimental studies point at detrimental effects on fetal development and on female and male reproduction. This cohort study aimed to explore if female and male preconception and long-term exposure to nitrate in drinking water was associated with fecundability measured as time to pregnancy (TTP) or use of medically assisted reproduction (MAR) treatment. Methods: The study population consisted of pregnant women recruited in their first trimester in 1996-2002 to the Danish National Birth Cohort. Preconception drinking-water nitrate exposure was estimated for the pregnant women (89,109 pregnancies), and long-term drinking water nitrate exposure was estimated from adolescence to conception for the pregnant women (77,474 pregnancies) and their male partners (62,000 pregnancies) by linkage to the national drinking water quality-monitoring database Jupiter. Difference in risk of TTP >12 months or use of MAR treatment between five exposure categories and log-transformed continuous models of preconception and long-term nitrate in drinking water were estimated. Binominal regression models for risk ratios (RR) were adjusted for age, occupation, education, population density, and lifestyle factors. Results: Nitrate in drinking water (median preconception exposure: 1.9 mg/L; median long-term exposure: 3.3 mg/L) was not associated with TTP >12 months or use of MAR treatment, neither in the categorical nor in the continuous models. Conclusion: We found no association between preconception or long-term exposure to drinking water nitrate and fecundability.

EFFORT study: Comparing impact of operation and assisted reproductive technologies on fertility for women with deep infiltrating endometriosis - study protocol for a multicentre randomised trial.

INTRODUCTION: Deep infiltrating endometriosis (DIE) affecting the rectum or sigmoid colon is associated with infertility, severe pain and decreased quality of life. As most women with DIE are young, many have a pregnancy intention. Treatment possibilities of endometriosis-associated infertility are surgery or assisted reproductive technologies (ART). However, no studies have compared the two interventions directly. Therefore, this study aims to determine the cumulative pregnancy rate (CPR) and the live birth rate (LBR) after first-line surgery compared with first-line ART for women with rectosigmoid DIE and a pregnancy intention. METHODS AND ANALYSIS: Multicentre, parallel-group, randomised trial of women with rectosigmoid DIE and a pregnancy intention for at least 6 months in Aarhus, Denmark and Bordeaux, France. 352 women aged 18-38 years are randomised 1:1 to either surgical management (shaving, disc excision or segmental resection) or ART management (at least two in vitro fertilisation or intracytoplasmic sperm injection procedures if not pregnant after the first cycle). Women in the surgical intervention group will attempt to get pregnant by either spontaneous conception or ART, depending on the endometriosis fertility index score. Primary outcome measures are CPR and LBR at 18 months' follow-up. Secondary outcomes are: Non-viable pregnancies, time to pregnancy, pain score, quality of life, complication rate, bowel and bladder function, endocrine and inflammatory profile, number of oocytes, blastocysts, frozen embryos and blastocyst morphology score within 18 months after either intervention. ETHICS AND DISSEMINATION: Conduct of this study is approved by the Danish National Committee on Health Research Ethics and Comité de Protection des Personnes Ile de France VIII. Study participants must sign an informed consent form. The results will be presented at national and international conferences and published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov (no. NCT04610710). PROTOCOL VERSION: The Danish National Committee on Health Research Ethics: Fifth protocol version approved 7 September 2020 (no. 1-10-72-96-20). Comité de Protection des Personnes Ile de France VIII: Version 1.1 22JAN2021 the 9 March 2021.

Impact of frozen thawed embryo transfer in hormone substituted cycles on thrombotic risk markers.

INTRODUCTION: Fertility treatment with frozen thawed embryo transfer (FET) is widely used. Women treated in artificial cycles (AC-FET) receive high doses of estrogen in contrast to natural cycles (NC-FET), where no estrogen is administered. Estrogen substitution may be associated with increased risk of thromboembolism. Our aim is therefore to characterize changes in blood coagulation parameters defined as surrogate thrombotic risk markers in women undergoing estrogen substitution during AC-FET. MATERIALS: In our prospective cohort study, we enrolled 34 women in either: AC-FET (n = 19) or NC-FET (n = 15). Women were recruited at the Department of Obstetrics and Gynaecology, Horsens Fertility Clinic, Denmark, from August 2019 - November 2020. Blood samples were obtained at four timepoints. Thrombin generation, platelet aggregation and fibrinolysis were evaluated as thrombotic risk markers. RESULTS: Within the AC-FET group, we found a significantly shorter lagtime (p < 0.05) and time to peak (TTP) (p < 0.001) after hormone substitution compared to baseline. Furthermore, a significantly higher mean peak (p < 0.0001) and larger endogenous thrombin potential (ETP) (p < 0.0001) was observed. When compared to the NC-FET group, women receiving AC-FET had a significantly shorter mean TTP (p < 0.005), higher mean peak (p < 0.0001) and larger ETP (p < 0.05). Additionally, we demonstrated a significantly prolonged lysis time within the AC-FET group (p < 0.001). CONCLUSION: Our results indicate that women receiving AC-FET have a significantly increased thrombin generation which may increase the thromboembolic risk in women being estrogen substituted.

Effect of dual trigger on reproductive outcome in low responders: a systematic PRISMA review and meta-analysis.

OBJECTIVE: Poor ovarian responders (PORs) pose a great challenge for fertility clinics worldwide. The aim of this study was to examine whether 'dual trigger' consisting of human chorionic gonadotropin (hCG) plus gonadotropin-releasing hormone agonist (GnRHa) is beneficial or not regarding implantation rate, pregnancy rate, and live birth rate for POR. METHODS: This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Risk of bias was evaluated by the Newcastle-Ottawa scale or version 2 (NOS) of the Cochrane risk-of-bias tool for randomized trials (ROB2) independently by two authors. Furthermore, RevMan version 5.4 was used to analyze the extracted data and to create an inverse-weighted summary-odds ratio (OR). RESULTS: A total of 1390 studies were screened. Seven studies containing a total of 2474 POR were included. The pooled meta-analysis revealed a 1.62-fold increase in clinical pregnancy rate (OR = 1.62 [1.00, 2.62], p = .05) and a 2.65-fold increase in live birth rate (OR = 2.65 [1.66, 4.24], p < .0001) in the dual trigger group compared to hCG trigger. The pooled analysis showed no significant difference between the two groups regarding implantation rate (OR = 1.14 [0.93, 1.39], p = .21). CONCLUSIONS: The meta-analysis of this study indicates that dual trigger as finale oocyte maturation is advantageous compared to hCG trigger among POR. However, large-scale, high-quality, randomized controlled trials (RCT) are required to confirm this conclusion and fully address the magnitude of this effect.

Sleep, psychological distress, and clinical pregnancy outcome in women and their partners undergoing in vitro or intracytoplasmic sperm injection fertility treatment.

OBJECTIVES: To explore the prevalence of poor sleep quality in couples undergoing fertility treatment and study possible associations. PARTICIPANTS: 163 women and 132 partners receiving in vitro (IVF) or intracytoplasmic sperm injection (ICSI) fertility treatment. SETTING: Three public Danish fertility clinics. DESIGN AND MEASUREMENTS: Participants completed the Pittsburgh Sleep Quality Index (PSQI) at three time-points as part of a larger RCT. Additional data from patient records and questionnaires were included to evaluate possible associations with treatment protocol type, psychological distress, and pregnancy outcome. RESULTS: Mean PSQI global scores before treatment were 8.1 (standard deviation = 2.3), with 91% of participants having PSQI scores > 5, indicating poor sleep quality. Scores did not differ between women and their partners and did not change during treatment. Statistically significant associations were found between sleep quality and depressive symptoms and state anxiety (p < .001). No difference in PSQI scores was found between protocol types. While there was a trend towards higher clinical pregnancy rates among women with good sleep quality (PSQI ≤ 5 = 72.7%, PSQI 6-10 = 52.6% and PSQI ≥ 11 = 42.3%), the differences did not reach statistical significance (p = .10-.21). CONCLUSIONS: Poor sleep quality is a prevalent problem among couples undergoing fertility treatment and is associated with psychological distress and possibly with pregnancy outcomes. Success rates after fertility treatment remain moderate, and poor sleep quality, a potentially modifiable factor, could be relevant to screen for and treat among couples undergoing fertility treatment. The high prevalence of poor sleep quality calls for further investigation.

Complementary and alternative medicine among women and men prior to and during fertility treatment.

INTRODUCTION The use of complementary and alternative medicine (CAM) is generally increasing. CAM use in relation to fertility treatment is sparsely studied. Thus, the aim of this study was to assess the use prevalence and patterns of CAM among Danish women and men initiating or receiving fertility treatment. Additionally, we aimed to establish whether several fertility treatment attempts influenced CAM use prevalence. METHODS A cross-sectional survey was conducted at the second largest fertility clinic in Denmark in the period from April to June 2018. The CAM use prevalence was reported for two groups of patients. Specifically, CAM use prior to or during fertility treatment was compared between groups, and various general patterns were reported. RESULTS Among the 411 patients approached, 277 responded (67.4%). Among these patients, 142 participants had not previously received fertility treatment, whereas 135 participants had received treatment at least once previously. We found that 52.5% of the patients initiating and undergoing fertility treatment had used CAM. Furthermore, previous fertility treatment was related to a higher CAM use. Surprisingly, only 53.4% of the participating women used folic acid. CONCLUSIONS More than half of the women and men initiating or undergoing fertility treatment had been using the investigated CAM. Of notice, folic acid compliance was low. The frequency of CAM use increased during fertility treatment. FUNDING none. TRIAL REGISTRATION not relevant.

[Oocyt donation].

The number of treatments with donated oocytes has risen markedly in Denmark during the latest decade due to changes in legislation and because female age is increasingly advanced when fertility treatment is warranted. Today, oocyte donation is a standard procedure offering the otherwise untreatable a high chance of achieving a pregnancy. Live birth rates as high as 35% per treatment are being reported. It is, however, important to be aware of increased risks of hypertensive disorders and bleeding complications in these pregnancies. As pointed out in this review, continuous research in the field is therefore highly needed.

Oral melatonin supplementation during in vitro fertilization treatment: a systematic PRISMA review and meta-analysis of randomized controlled trials.

OBJECTIVE: High levels of reactive oxygen species (ROS) have been suspected of reducing the success rate of assisted reproductive technology (ART). Melatonin has anti-oxidative properties and could therefore be of interest as a supplement in in vitro-fertilization (IVF) protocols. The objective of this study was to evaluate if a melatonin supplementation given in vivo to women undergoing IVF-treatment can improve the outcome. METHODS: A systematic literature search was performed on PubMed, Embase and Cochrane. The methodological quality of the included studies was assessed using the version 2 of the Cochrane risk-of-bias tool (RoB2). Primary outcome was clinical pregnancy rate (CPR). Secondary outcomes were total number of oocytes, number of mature oocytes, embryo quality, biochemical pregnancy rate, miscarriage rate and live birth rate (LBR). RESULTS: Seven randomized controlled trials (RCT) were included. The meta-analysis demonstrated a significantly higher mature oocyte count when melatonin was used (Mean Diff. = 1,82; 95% CI 0.37-3.27; p = .01). All seven studies showed a trend for increase in CPR, although not significant. No other measured outcomes showed a significant improvement. Two studies had 'low risk', three 'some concerns' and two studies had 'high risk' of bias. CONCLUSION: This meta-analysis including RCT indicates that an oral melatonin supplement during IVF-treatment can increase the number of mature oocytes, and a trend for increase CPR, albeit not significant. Most of the included studies were small. The methodological quality in three of the seven studies was moderate and two were low. Further investigations are needed to support the positive findings.

In vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI) in patients without severe male factor infertility: study protocol for the randomised, controlled, multicentre trial INVICSI.

INTRODUCTION: Over the last decades, the use of intracytoplasmic sperm injection (ICSI) has increased, even among patients without male factor infertility. The increase has happened even though there is no evidence to support that ICSI results in higher live birth rates compared with conventional in vitro fertilisation (IVF) in cases with nonmale factor infertility. The lack of robust evidence on an advantage of using ICSI over conventional IVF in these patients is problematic since ICSI is more invasive, complex and requires additional resources, time and effort. Therefore, the primary objective of the IVF versus ICSI (INVICSI) study is to determine whether ICSI is superior to standard IVF in patients without severe male factor infertility. The primary outcome measure is first live birth from fresh and frozen-thawed transfers after one stimulated cycle. Secondary outcomes include fertilisation rate, ongoing pregnancy rate, birth weight and congenital anomalies. METHODS AND ANALYSIS: This is a two-armed, multicentre, randomised, controlled trial. In total, 824 couples/women with infertility without severe male factor will be recruited and allocated randomly into two groups (IVF or ICSI) in a 1:1 ratio. Participants will be randomised in variable block sizes and stratified by trial site and age. The main inclusion criteria are (1) no prior IVF/ICSI treatment, (2) male partner sperm with an expected count of minimum 2 million progressive motile spermatozoa following density gradient purification on the day of oocyte pick up and (3) age of the woman between 18 and 42 years. ETHICS AND DISSEMINATION: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committee of the Capital Region of Denmark. Study findings will be presented, irrespectively of results at international conferences and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04128904. Pre-results.

Long-term growth in offspring of infertile parents: A 20-year follow-up study.

INTRODUCTION: Long-term growth has been poorly investigated in boys and girls born to parents receiving fertility treatment. This study aimed to investigate the growth of children born following fertility treatment up to adulthood hypothesizing comparable growth in children born to parents receiving fertility treatment or to subfertile parents conceiving spontaneously to that in children spontaneously conceived by fertile parents. MATERIAL AND METHODS: In this historical long-term follow-up study the study population consisted of 4151 singletons born at term in the Aarhus Birth Cohort between 1990 and 1992. Parental lifestyle and sociodemographic characteristics together with multiple measurements of weight and height were collected up to 20 years of age (6.1% of children contributed with at least one measurement for height or weight at age 20 years). The main outcome was difference in z-score for height (m) and weight (kg) between children conceived spontaneously (reference) and children conceived following fertility treatment, children conceived spontaneously by subfertile parents, or unplanned. Results were adjusted for pre-pregnancy maternal and paternal body mass index, maternal educational level, smoking during pregnancy, maternal age, and parity. RESULTS: Singletons conceived following fertility treatment (n = 164; 4.0%) or by subfertile parents (n = 271; 6.5%) had comparable magnitude of weight estimates to children conceived spontaneously (difference in z-score per year 0.0148 [95% CI 0.0026-0.0270] and 0.0069 [95% CI -0.0028 to 0.0165], respectively). Height estimates were also comparable between groups of children conceived following fertility treatment or by subfertile parents (difference in z-score per year 0.0022 [95% CI -0.0075 to 0.0119]) compared with children conceived spontaneously (difference in z-score per year -0.0026 (95% CI -0.0103 to 0.0052). From the beginning of adolescence, we found lower weight for children born to subfertile parents and to parents receiving fertility treatment compared with spontaneously conceived children. CONCLUSIONS: The main finding was equal long-term growth for children born at term by parents who received fertility treatment or parents waiting more than 12 months to conceive compared with spontaneously conceived children.

Assisted reproductive technologies and the risk of stillbirth in singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: To identify the risk of stillbirth from in vitro types of assisted reproductive technologies compared with spontaneous conception (SC), limited to singleton births. DESIGN: Systematic literature search and search chaining on online databases: PubMed, Embase, and Scopus. SETTING: Not applicable. PATIENT(S): Singleton pregnancies from in vitro fertilization (IVF) or fertilization by IVF and intracytoplasmic sperm injection (IVF-ICSI). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Adjusted odds ratio for stillbirth or prevalence of stillbirth in case-control groups of IVF/IVF-ICSI singletons and SCs, respectively, in matched studies. RESULT(S): A total of 19 studies were included, and study quality was mixed. Ten studies qualified for inclusion to the meta-analysis, which revealed a significantly increased risk of stillbirth in IVF/IVF-ICSI compared with that in SC (odds ratio [95% confidence interval]: 1.82 [1.37-2.42]), and there was no evidence of publication bias. CONCLUSION(S): In vitro fertilization and IVF-ICSI treatment increases the risk of stillbirth compared with natural conception. CLINICAL TRIAL REGISTRATION NUMBER: PROSPERO 216768.

Embryo Culture Media Influence on Live Birth Rate and Birthweight after IVF/ICSI: A Systematic Review Comparing Vitrolife G5 Media to Other Common Culture Media.

Previous studies have indicated that culture media vary in efficiency and outcomes, such as live birth rate, birthweight and embryo quality. Does Vitrolife G5 series culture media result in higher live birth rates and birthweight compared to other common culture media? This study is a systematic review based on the PRISMA criteria. Relevant search terms, mesh terms (PubMed and Cochrane) and Emtree terms (Embase) were identified. We searched the literature using PubMed, Embase and Cochrane, on November 10, 2019. The inclusion criteria involved published articles in English comparing Vitrolife G5 to other common culture media. We included randomized controlled trials (RCTs) and cohort studies. The quality of the studies was assessed using the Cochrane Risk of Bias tool 2.0 and the Newcastle-Ottawa Scale. Primary outcomes were live birth rate and birthweight. Secondary outcomes were fertilization rate, implantation rate, biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate, multiple pregnancies and congenital malformations. Of 187 articles screened, 11 studies fulfilled the inclusion criteria: Five RCTs and six retrospective cohort studies. Only one study reported live birth rate, showing a non-significantly higher live birth rate for Vitrolife G5 media. Birthweight had equivocal results with three of six studies, showing significantly lower (2)/higher (1) birthweights, whereas the others were non-significant. Overall, there were no significant differences concerning secondary outcomes. The results are equivocal, and we need more studies to evaluate culture media and their effect on short- and long-term health.

The association between psychosocial interventions and fertility treatment outcome: A systematic review and meta-analysis.

OBJECTIVE: Does psychosocial intervention affect pregnancy outcomes in women and couples undergoing assisted reproductive technology (ART) treatment?. DESIGN: A systematic review and meta-analysis of Randomized Controlled Trials (RCTs) evaluating the efficacy of psychosocial intervention on pregnancy outcomes in women and couples undergoing ART treatment. The primary outcome was Pregnancy Rates. Secondary outcomes were Live Birth Rate (LBR) and Abortion Rate (AR). MATERIALS AND METHODS: Databases searched were Pubmed, PsycINFO, Embase, CINAHL and The Cochrane Library. 1439 records were screened, 15 were eligible and included in the meta-analyses (N = 2434). Data was extracted using the Covidence software. Effect sizes were reported as relative risks with 95% confidence-intervals and p-values. RESULTS: A positive association was found between psychosocial intervention and pregnancy rates (RR = 1.12 CI=(1.01;1.24), p = 0.033). Long-duration interventions and mind-body intervention types were found to be associated with increased pregnancy rates (RR 1.21, CI= (1.04;1.43), p = 0.017) and (RR = 1.25, CI= (1.00;1.55), p = 0.046) respectively. Q and I2tests suggested no to low heterogeneity. Funnel plots, Trim and Fill analyses and Fail-safe numbers were applied to adjust for possible publication bias. CONCLUSIONS: Our findings suggest a positive association between psychosocial interventions, particularly long-duration interventions, and pregnancy rate in infertile women and couples in ART treatment. The findings are in line with findings from other reviews and meta-analyses exploring the same topic. More good quality RCTs need to be performed to increase the quality of guidance for infertile women and couples. The effect of psychosocial interventions on LBR and AR remain to be examined.

Association between women's age and stage, morphology, and implantation of the competent blastocyst: a multicenter cohort study.

OBJECTIVE: To study if the age of women undergoing assisted reproductive technology treatment associates with stage, morphology, and implantation of the competent blastocyst. DESIGN: Multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial human chorionic gonadotrophin [hCG] rise) from women undergoing single blastocyst transfer resulting in singleton pregnancy/birth. SETTING: Sixteen private and university-based facilities. PATIENT(S): In this study, 7,246 women who, between 2014 and 2018, underwent controlled ovarian stimulation (COS) or frozen-thawed embryo transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. Linking data to the Danish Medical Birth Registry resulted in a total of 4,842 women with a live birth being included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The competent blastocyst development stage (1-6), inner cell mass (A, B, C), trophectoderm (A, B, C), and initial serum hCG value. RESULT(S): Adjusted analysis of age and stage in COS treatments showed that for every 1-year increase in age there was a 5% reduced probability of the competent blastocyst assessed as being in a high stage at transfer. Comparison between hCG values in women 18-24 years and 25-29 years in both COS and FET showed significantly lower levels in the youngest women. CONCLUSION(S): The initial hCG rise was influenced by the age of the woman, with an identical pattern for hCG values in COS and FET treatments. In COS, the competent blastocyst had a reduced stage with increasing women's age.

Comprehensive analysis of soluble RNAs in human embryo culture media and blastocoel fluid.

PURPOSE: miRNAs have been suggested as biomarkers of embryo viability; however, findings from preliminary studies are divergent. Furthermore, the presence of other types of small RNA molecules remains to be investigated. The purpose of this study was to perform a comprehensive analysis of small non-coding RNA levels in spent and unconditioned embryo culture media, along with miRNA levels in blastocoelic fluid samples from human embryos. METHODS: miRNAs in unconditioned culture medium from 3 different manufacturers, along with miRNA from day 5 conditioned culture medium, control medium, and corresponding blastocoel fluid from 10 human blastocysts were analyzed with array-based q-PCR analysis. Subsequently, deep sequencing of total and small RNA in day 5 spent culture medium from 5 human blastocysts and corresponding controls was performed. RESULTS: In spite of using state-of-the-art sensitive detection methods, no miRNAs were found to be reliably present in the spent culture medium or the blastocoel fluid. Ct values were above the recommended limit for detection in the array-based analysis, a finding that was confirmed by deep sequencing. The majority of miRNAs identified by deep sequencing were expressed in all samples including control media and seem to originate from sources other than conditioned IVF media. CONCLUSIONS: Our findings question the use of miRNAs as a reliable biomarker and highlight the need for a critical methodological approach in miRNA studies. Interestingly, tiRNA fragments appear to be overexpressed in conditioned IVF media samples and could potentially be a novel biomarker worthy of investigation.

Associations of bedtime, sleep duration, and sleep quality with semen quality in males seeking fertility treatment: a preliminary study.

BACKGROUND: Poor sleep has been linked to a number of adverse health outcomes. Recent studies suggest that late bedtimes, short or long sleep durations, and poor sleep quality may impair semen quality. No study has previously explored all three factors in relation to semen quality. RESULTS: One hundred and four men and their partners treated at three fertility clinics in Denmark between 2010 and 2012 completed an online-version of the Pittsburgh Sleep Quality Index (PSQI). The results of the semen analyses conducted at the fertility clinics were self-reported and categorised as normal or reduced.Early bedtime (< 10:30 PM) was more often associated with normal semen quality compared with both regular (10:30 PM-11:29 PM) and late (≥11:30 PM) bedtime (OR: 2.75, 95%CI: 1.1-7.1, p = 0.04 and OR: 3.97, 95%CI: 1.2-13.5, p = 0.03). Conventional sleep duration (7.5-7.99 h) was more often associated with normal semen quality than both short (7.0-7.49 h) and very short (< 7.0 h) sleep duration (OR: 1.36, 95% CI: 1.2-12.9, p = 0.03 and OR: 6.18, 95%CI: 1.6-24.2, p = 0.01). Although poor sleep quality was associated with reduced semen quality in the descriptive statistics (p = 0.04), no differences were found between optimal (PSQI ≤6) and either borderline (PSQI 7-8) or poor (PSQI ≥9) sleep quality (OR: 1.19, 95%CI: 0.4-3.4, p = 0.75 and OR: 2.43, 95%CI: 0.8-7.1, p = 0.11) in multivariate regression models. CONCLUSION: Early bedtimes (< 10:30 PM) and conventional sleep duration (7.5-7.99 h) were associated with self-reported normal semen quality. The role of subjective sleep quality remains uncertain.

CONTEXTE: Un mauvais sommeil a été associé à plusieurs issues néfastes pour la santé. De récentes études suggèrent que les heures de coucher tardives, des durées de sommeil courtes ou longues, et une mauvaise qualité de sommeil altèrent la qualité du sperme. Aucune étude n'a à ce jour exploré les trois facteurs en relation avec la qualité du sperme. RÉSULTATS: Cent quatre hommes et leurs partenaires traités dans trois cliniques de fertilité au Danemark entre 2010 et 2012 ont rempli un questionnaire correspondant à une version en ligne de l'Indice de Qualité du Sommeil de Pittsburg (IQSP). Les résultats des analyses de sperme réalisées dans les cliniques de fertilité ont été autodéclarés et classés comme normaux ou réduits.Une heure de coucher précoce (< 22 h30) était plus souvent associée à une qualité normale du sperme comparativement à la fois à une heure régulière (22 h30-23 h29) et à une heure tardive (≥23 h30) de coucher (OR: 2.75, 95% CI: 1.1­7.1, p = 0.04 et OR: 3.97, 95% CI: 1.2­13.5, p = 0.03). Une durée conventionnelle de sommeil (7.5­7.99 heures) était plus souvent associée à une qualité normale du sperme qu'une courte (7.0­7.49 heures) et qu'une très courte (< 7.0 heures) durée de sommeil (OR: 1.36, 95% CI: 1.2­12.9, p = 0.03 et OR: 6.18, 95% CI: 1.6­24.2, p = 0.01). Bien qu'une mauvaise qualité du sommeil ait été associée à une qualité réduite du sperme dans les statistiques descriptives (p = 0.04), aucune différence n'a été retrouvée entre une qualité du sommeil optimale (IQSP ≤6) et une qualité soit limite (IQSP 7­8) ou soit pauvre (IQSP ≥9) du sommeil (OR: 1.19, 95% CI: 0.4­3.4, p = 0.75 et OR: 2.43, 95% CI: 0.8­7.1, p = 0.11) dans les modèles de régression multivariée. CONCLUSIONS: Des heures de coucher précoces (< 22 h30) et une durée conventionnelle de sommeil (7.5­7.99 heures) ont été associées à une qualité normale autodéclarée du sperme. Un éventuel rôle de la qualité suggestive du sommeil reste incertain.

Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial.

INTRODUCTION: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome. METHODS AND ANALYSIS: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed. ETHICS AND DISSEMINATION: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated. TRIAL REGISTRATION NUMBER: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.