Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis.

BACKGROUND: In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed. OBJECTIVE AND RATIONALE: This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis. SEARCH METHODS: A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET. OUTCOMES: Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo transfers, treatment type, or infertility cause. WIDER IMPLICATIONS: This is the first meta-analysis based on IPD of more than 4000 participants, and it demonstrates that endometrial scratching may improve LB rates in women undergoing IVF/ICSI. Subgroup analysis for age, number of previous failed embryo transfers, treatment type, and infertility cause could not identify subgroups in which endometrial scratching performed better or worse. The timing of endometrial scratching may play a role in its effectiveness. The use of endometrial scratching in clinical practice should be considered with caution, meaning that patients should be properly counseled on the level of evidence and the uncertainties.

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.

A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities.

BACKGROUND: In the decade following the introduction of ICSI, a higher prevalence of de novo chromosome abnormalities, in particular sex chromosome and autosomal structural abnormalities, as well as inherited abnormalities was described in children conceived by ICSI compared to both naturally conceived (NC) children and children conceived by standard IVF. The explanation for the observed increase in prevalence is not clear and has been suggested to reflect parental factors (e.g. age or sperm quality) or to be a result of the ICSI procedure itself. Over the years, the procedure, as well as the patient group, and indications for ICSI treatment have changed. OBJECTIVE AND RATIONALE: The objective of this systematic review and meta-analysis was to assess the prevalence of chromosome abnormalities in ICSI pregnancies and children and to examine any potentially increased risk compared to standard IVF and NC. SEARCH METHODS: Pubmed, Embase, Cochrane Libraries and Web of Science up to October 2020 were searched. Primary outcome measures were overall chromosome abnormalities and de novo abnormalities (including sex chromosome abnormalities and autosomal abnormalities). The secondary outcome was inherited abnormalities. We followed the PRISMA guidelines and relevant meta-analyses were performed. OUTCOMES: The search included 4648 articles, out of which 27 met the inclusion criteria, and 19 were included in quantitative synthesis (meta-analyses). The prevalence of chromosome abnormalities varied considerably between studies, possibly explained by large differences in sample size and patient demographics. Only five studies were eligible for pooled analyses on adjusted data. All studies had a critical risk of bias. Results from pooled adjusted data showed no evidence of an increased risk of overall chromosome abnormalities when comparing ICSI to either standard IVF (aOR 0.75 (95% CI 0.41-1.38)) or NC (aOR 1.29 (95% CI 0.69-2.43)). In contrast, meta-analyses on unadjusted data showed an increased risk of overall chromosome abnormalities in ICSI compared to both standard IVF (OR 1.42 (95% CI 1.09-1.85)) and NC (OR 2.46 (95% CI 1.52-3.99)) and an increased risk of de novo abnormalities in ICSI compared to NC (OR 2.62 (95% CI 2.07-3.31)). Yet, based on a very low certainty of evidence, the conclusion remains, that no indication of an increased risk of chromosome abnormalities in ICSI offspring could be found. If an increased risk of chromosome abnormalities in selected ICSI offspring should exist, the absolute risk continues to be small. WIDER IMPLICATIONS: This review provides an extensive overview of the existing evidence on the relationship between ICSI and chromosome abnormalities in the offspring. We highlight the need for well-designed large, prospective, controlled studies with systematic cytogenetic testing. Existing data are limited and, in many cases, marred by critical levels of bias.

Pregnancy outcomes following oocyte donation.

The use of oocyte donation (OD) has increased continuously over the last three decades, and it is now an indispensable part of assisted reproductive technology (ART). With OD, it has become possible to overcome the biological barrier of ovarian follicle pool depletion and the general age-related decline in fertility. This review contains a thorough appraisal of the safety of OD with an analysis of short-term pregnancy outcomes. Salient up-to-date evidence was evaluated, which revealed that in comparison with both IVF with autologous oocytes, and naturally conceived pregnancies, there is: (i) an increased risk of hypertensive disorders of pregnancy and preeclampsia; (ii) an increased risk of low birth weight and preterm birth and (iii) an increased risks of obstetric emergencies, following OD treatment. As a precaution, it is therefore highly encouraged to perform only single embryo transfer (SET) and to prescribe prophylactic low-dose aspirin during OD pregnancies.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns.

OBJECTIVE: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes. METHODS: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available. RESULTS: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies. CONCLUSION: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.

Endometrial scratch injury with office hysteroscopy before IVF/ICSI: A randomised controlled trial.

OBJECTIVE: Endometrial scratch injury (ESI) has been proposed to improve endometrial receptivity and thereby increase implantation rates in assisted reproductive technology (ART) treatment. ESI has been widely incorporated into clinical practice despite inconclusive evidence of its effect on reproductive outcomes. We aimed to assess pregnancy and live birth rates in subfertile women receiving ESI before IVF treatment in comparison to controls. STUDY DESIGN: This was a randomised controlled trial (RCT) with no blinding of participants, investigators or health care personnel. Women in ART treatment were allocated to either office hysteroscopy with ESI (ESI group) or no intervention (control group). In total 184 women in IVF/ICSI treatment with minimum one previous failed IVF/ICSI cycle, were included in the final analysis. The primary outcome was positive serum hCG (s-hCG). Secondary outcomes were ongoing pregnancy and live birth rate. Only per-protocol analyses were performed as all patients included at one centre had to be excluded. The trial is registered at ClinicalTrials.gov, NCT01743391. RESULTS: Our results showed a non-significant increase in positive s-hCG (OR 1.23, 95 % CI (0.65-2.33)), ongoing pregnancy (OR 1.52, 95 % CI (0.73-3.17)), and live birth rates (OR 1.69, 95 % CI (0.78-3.64)) per randomised woman between the ESI and the control group. CONCLUSION: We observed no significant differences in positive s-hCG or other reproductive outcomes in the ESI vs. the control group. While the crude estimates of positive reproductive outcomes were higher in the ESI group, statistical significance was not reached, and the study was not powered to show smaller differences. However, data from this study will be re-evaluated in the context of an individual participant data meta-analysis (IPD-MA) of RCTs on ESI.

Susceptibility patterns in Neisseria gonorrhoeae in Nuuk, Greenland, 2015-2018: a short communication.

Antimicrobial resistance in Neisseria gonorrhoeae (GC) has made gonorrhoea control and treatment more complex globally. In Greenland, the incidence of gonorrhoea is high and there is a need for continued surveillance of antimicrobial susceptibility.This study investigated gonococcal isolates obtained in Greenland's capital Nuuk between January 2015 and June 2018. Subsequent to collection, isolates were tested for ciprofloxacin and ceftriaxone susceptibility in order to monitor the resistance pattern among GC strains. 150 GC strains were isolated in Nuuk during the observation period (139 males, 93%; 11 females, 7%). All strains were fully susceptible to ceftriaxone. 49% of the GC strains were susceptible to ciprofloxacin. The median minimal inhibitory concentration (MIC) for ceftriaxone among GC strains resistant to ciprofloxacin was higher than among GC strains susceptible to ciprofloxacin. No differences in ciprofloxacin susceptibility and median MICs for ceftriaxone were observed by collection year. In conclusion no ceftriaxone resistance has been found in Nuuk to date. Continued easy access to diagnostics and treatment combined with increased and more systematic surveillance of antimicrobial susceptibility in Nuuk is recommended. Further, it is advisable to investigate the possibilities for intermittent sampling in Greenland outside of Nuuk, if obstacles in relation to sending sampling material to Nuuk can be bypassed.

The health of children conceived by ART: 'the chicken or the egg?'

Worldwide, more than 7 million children have now been born after ART: these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and overall improved health for the ART progeny. In this review we summarize the risks for short- and long-term health in ART singletons and discuss if the increased health risks are associated with intrinsic maternal or paternal factors related to subfertility or to the ART treatments per se. Although the risks are modest, singletons born after ART are more likely to have adverse perinatal outcomes compared to spontaneously conceived (SC) singletons dependent on the ART method. Fresh embryo transfer is associated with a higher risk of small for gestational age babies (SGA), low birthweight and preterm birth (PTB), while frozen embryo transfer is associated with large-for-gestational age babies and pre-eclampsia. ICSI may be associated with a higher risk of birth defects and transferral of the poor semen quality to male progeny, while oocyte donation is associated with increased risk of SGA and pre-eclampsia. Concerning long-term health risks, the current evidence is limited but suggests an increased risk of altered blood pressure and cardiovascular function in ART children. The data that are available for malignancies seem reassuring, while results on neurodevelopmental health are more equivocal with a possible association between ART and cerebral palsy. The laboratory techniques used in ART may also play a role, as different embryo culture media give rise to different birthweights and growth patterns in children, while culture to blastocyst stage is associated with PTB. In addition, children born after ART have altered epigenetic profiles, and these alterations may be one of the key areas to explore to improve our understanding of adverse child outcomes after ART. A major challenge for research into adverse perinatal outcomes is the difficulty in separating the contribution of infertility per se from the ART treatment (i.e. 'the chicken or the egg'?). Choosing and having access to the appropriate control groups for the ART children in order to eliminate the influence of subfertility per se (thereby exploring the pure association between ART and child outcomes) is in itself challenging. However, studies including children of subfertile couples or of couples treated with milder fertility treatments, such as IUI, as controls show that perinatal risks in these cohorts are lower than for ART children but still higher than for SC indicating that both subfertility and ART influence the future outcome. Sibling studies, where a mother gave birth to both an ART and a SC child, support this theory as ART singletons had slightly poorer outcomes. The conclusion we can reach from the well designed studies aimed at disentangling the influence on child health of parental and ART factors is that both the chicken and the egg matter.

Large for gestational age and macrosomia in singletons born after frozen/thawed embryo transfer (FET) in assisted reproductive technology (ART).

Increase in success rates with frozen embryo transfer (FET) and reduced risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies has lead to a steady rise in FET. Further, FET is associated with lower risk of prematurity and low birth weight in singletons, when compared with fresh transfer. However, there is a growing concern of increased risk of large for gestational (LGA) and/or macrosomic children after FET. Macrosomic/LGA births have a higher risk of cesarean section, fetal hypoxia and stillbirth. Improvements in cryopreservation techniques indicate that FET is a trend expected to continue and a freeze-all policy has lately been introduced. With this review, we wished to evaluate the association between FET and LGA and/or macrosomia. We searched electronic databases on January 12, 2018. Ten studies on LGA and six studies on macrosomia were eligible for meta-analysis. We found that the risk of LGA in FET was increased 1.5-fold (AOR = 1.50 95% CI 1.44-1.57 p < 0.001) compared to fresh cycles and 1.3-fold (AOR = 1.31 95% CI 1.20-1.43 p < 0.001) compared to natural conception (NC). Similarly we found a 1.7-fold increased risk of macrosomia in FET compared to fresh transfer (AOR = 1.71 95% CI 1.59-1.83 p < 0.001) and a 1.4-fold increased risk compared to NC (AOR = 1.42 95% CI 1.17-1.71 p < 0.001). Whether the increased risk of LGA and macrosomia is associated with higher long-term health risks remains unknown. Future studies should explore epigenetics modifications in children born after FET and predictors of long-term diseases need to be examined further with longitudinal studies.

Gonorrhoea in Greenland: geographic differences in diagnostic activity and incidence of gonorrhoea in 2015.

For decades the spread of sexually transmitted infections (STIs) has been a health concern in Greenland, especially within the age group of 15-34 year olds. However, no overview exists of the potential differences in regional incidence and management of STIs. This study investigates the age, gender and region specific diagnostic activity and incidence of gonorrhoea in Greenland in 2015. The study design was an observational cross sectional register study with inclusion of patients tested for gonorrhoea in 2015. Patients above 15 years of age were included. Data was obtained from the laboratory system used at The Central Laboratory at Queen Ingrid's Hospital in Nuuk. We found, in 2015, a total of 17,911 tests for gonorrhoea were performed on both men and women. Women accounted for 68% of the tests, while men accounted for 32%. The positivity rate was 7,878 pr. 100,000 of which 56% were women and 44% were men. The regional distribution showed a disparity of the testing rate and the rate of positive gonorrhoea tests.. Thus, we have documented a high diagnostic activity and high incidence of gonorrhoea in Greenland in 2015 among both women and men. We also found significant regional differences in both diagnostic activity and gonorrhoea incidence.

Gonorrhoea in Greenland, incidence and previous preventive measures: a review to improve future strategies.

Gonorrhoea continues to be a significant health challenge in Greenland. The aim of this study was to describe the development of gonorrhoea in Greenland through time including incidence rates and previous measures taken to address the challenge. A systematic literature search in PubMed, Embase and The Cochrane Library was conducted. Furthermore, local archives were searched in the Health Clinic in Nuuk for relevant literature. From the 1940s the incidence of gonorrhoea increased steadily with a steep incline around 1970, possibly as a consequence of changes in living conditions and urbanisation. Significant declines in the incidence were seen the late 1970s and again in the late 1980s, most likely in the wake of an outbreak of ulcus molle/chancroid in the 1970s and as a result of focused education in venereology for Greenlandic nurses in the late 1980s combined with the stop-AIDS campaign. Since the early 1990s the incidence of gonorrhoea in Greenland has not risen to previously high levels. However, the incidence remains high and with a gradually increasing trend. Prevention intervention strategies such as peer-to-peer sexual education, storytelling and involvement of parent/guardian in sexual education of the youth could be appropriate approaches to improve sexual health in Greenland.

Alcohol consumption and mortality in patients with mild Alzheimer's disease: a prospective cohort study.

OBJECTIVE: To investigate the association between alcohol consumption and mortality in patients recently diagnosed with mild Alzheimer's disease (AD). DESIGN: A post hoc analysis study based on a clinical trial population. SETTING: The data reported were collected as part of the Danish Alzheimer's Intervention Study (DAISY), a longitudinal multicentre randomised controlled study on the efficacy of psychosocial intervention in patients with mild AD across five county districts in Denmark. PARTICIPANTS: 321 patients with mild AD (Mini-Mental State Examination ≥ 20) were included. Data regarding current daily alcohol consumption were obtained from the patient's primary caregivers at inclusion. MAIN OUTCOME: All-cause mortality retrieved from The Danish Civil Registration System over a period of 36 months after baseline. RESULTS: Information about alcohol consumption was obtained from all 321 study participants: 8% were abstinent, 71% only had alcohol occasionally (1 or <1 unit/day), 17% had 2-3 units/day and 4% had more than 3 units/day. An analysis adjusted for a range of potential confounders demonstrated a reduced mortality for patients with moderate alcohol consumption (2-3 units/day): HR 0.23 (95% CI (0.08 to 0.69)) compared with patients who had 1 or <1 unit/day. Mortality was not significantly different in abstinent patients or in patients with an alcohol consumption of more than 3 units/day, compared with patients drinking 1 or <1 unit/day. CONCLUSIONS: In this cohort of patients with mild AD, moderate alcohol consumption (2-3 units/day) was associated with a significantly lower mortality over a period of 36 months. Further studies are needed in this area. These may especially focus on the association between alcohol consumption and cognitive decline in patients with AD.