Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study.

STUDY QUESTION: Does the transfer of single low-grade blastocysts result in acceptable reproductive and perinatal outcomes compared to the transfer of single good-grade blastocysts? SUMMARY ANSWER: The transfer of single low-grade blastocysts resulted in a reduced live birth rate of around 30% (14% for very low-grade blastocysts) compared to 44% for single good-grade blastocysts, but does not lead to more adverse perinatal outcomes. WHAT IS KNOWN ALREADY: It is known that low-grade blastocysts can result in live births. However, the current studies are limited by relatively small sample sizes and single-centre designs. Furthermore, evidence on perinatal outcomes after transferring low-grade blastocysts is limited. STUDY DESIGN, SIZE, DURATION: We conducted a multi-centre, multi-national retrospective cohort study of 10 018 women undergoing 10 964 single blastocyst transfer cycles between 2009 and 2020 from 14 clinics across Australia, China, and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blastocysts were graded individually based on assessment of the morphology and development of the inner cell mass (ICM) and trophectoderm (TE), and were grouped into three quality categories: good- (AB, AB, or BA), moderate- (BB), and low-grade (grade C for ICM or TE) blastocysts. CC blastocysts were individually grouped as very low-grade blastocysts. Logistic regression with generalized estimating equation was used to analyse the association between blastocyst quality and live birth as well as other reproductive outcomes. Binomial, multinomial logistic, or linear regression was used to investigate the association between blastocyst quality and perinatal outcomes. Odds ratio (OR), adjusted OR (aOR), adjusted regression coefficient, and their 95% CIs are presented. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: There were 4386 good-grade blastocysts, 3735 moderate-grade blastocysts, and 2843 low-grade blastocysts were included in the analysis, for which the live birth rates were 44.4%, 38.6%, and 30.2%, respectively. Compared to good-grade blastocysts, the live birth rate of low-grade blastocysts was significantly lower (aOR of 0.48 (0.41-0.55)). Very low-grade blastocysts were associated with an even lower live birth rate (aOR 0.30 (0.18-0.52)) and their absolute live birth rate was 13.7%. There were 4132 singleton live births included in the analysis of perinatal outcomes. Compared with good-grade blastocysts, low-grade blastocysts had comparable preterm birth rates (<37 weeks, aOR 1.00 (0.65-1.54)), birthweight Z-scores (adjusted regression coefficient 0.02 (0.09-0.14)), and rates of very low birth weight (<1500 g, aOR 0.84 (0.22-3.25)), low birth weight (1500-2500 g, aOR 0.96 (0.56-1.65)), high birth weight (>4500 g, aOR 0.93 (0.37-2.32)), small for gestational age (aOR 1.63 (0.91-2.93)), and large for gestational age (aOR 1.28 (0.97-1.70)). LIMITATIONS, REASONS FOR CAUTION: Due to the nature of the retrospective design, residual confounding could not be excluded. In addition, the number of events for some perinatal outcomes was small. Between-operator and between-laboratory variations in blastocyst assessment were difficult to control. WIDER IMPLICATIONS OF THE FINDINGS: Patients undergoing IVF should be informed that low-grade blastocysts result in a lower live birth rate, however they do not increase the risk of adverse perinatal outcomes. Further research should focus on the criteria for embryos that should not be transferred and on the follow-up of long-term outcomes of offspring. STUDY FUNDING/COMPETING INTEREST(S): H.Z. is supported by a Monash Research Scholarship. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). R.W. is supported by an NHMRC Emerging Leadership Investigator grant (2009767). B.W.J.M. reports consultancy, travel support, and research funding from Merck. The other authors do not have competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

What happens to abnormally fertilized embryos? A scoping review.

A dearth of evidence exists on embryos derived from oocytes without two pronuclei (2PN) or 'normal fertilization', i.e. embryos arising from non-pronuclear oocytes (0PN), mono-pronuclear oocytes (1PN) and tri-pronuclear oocytes (3PN). We searched the published literature on non-2PN oocytes and their clinical outcomes using a two-part collection strategy of relevant articles. A total of 33 articles were deemed eligible for the scoping review. A significant difference exists between potential development of oocytes with an abnormal number of pronuclei and those with 2PN in most studies; the abnormal pronuclei oocytes occur rarely and significant attrition occurs between day 1 and day 6, with corresponding reduction in chromosome integrity and clinical utility. Most recent studies describe outcomes of blastocysts derived from non-2PN oocytes, rather than cleavage stage embryo transfers. Compared with 2PN oocytes, blastocyst rates are lower in 1PN oocytes (68.3 versus 32.2%), with larger 1PN oocytes having better developmental potential compared with their smaller counterparts. Blastocysts from 1PN oocytes seem to have a slightly reduced implantation potential compared with those from 2PN blastocysts (33.3% versus 35.9%), with a reduced ongoing pregnancy rate (27.3% versus 28.1%). Live birth rates were only reported in 13 of the included studies. The comparators varied between studies, with live birth rates provided ranging from 0-66.7%, with two case reports (100%); this is a clear indication of the variability in practices and the significant heterogeneity of studies. A distinct lack of evidence exists on non-2PN oocytes; however, it seems that most abnormally fertilized oocytes that are non-viable will developmentally arrest in culture, and those that are viable can form viable pregnancies. Concerns remain about the outcome of pregnancies arising from the use of abnormally fertilized oocytes. Coupled with appropriate outcome measures, abnormally fertilized oocytes hold the potential to increase the pool of embryos eligible for transfer.

A protocol for developing a core outcome set for ectopic pregnancy.

BACKGROUND: Randomised controlled trials (RCTs) evaluating ectopic pregnancy have reported many different outcomes, which are themselves often defined and measured in distinct ways. This level of variation results in an inability to compare results of individual RCTs. The development of a core outcome set to ensure outcomes important to key stakeholders are collected consistently will guide future research in ectopic pregnancy. STUDY AIM: To develop and implement a core outcome set to guide future research in ectopic pregnancy. METHODS AND ANALYSIS: We have established an international steering group of key stakeholders, including healthcare professionals, researchers, and individuals with lived experience of ectopic pregnancy. We will identify potential outcomes from ectopic pregnancy from a comprehensive literature review of published randomised controlled trials. We will then utilise a modified Delphi method to prioritise outcomes. Subsequently, key stakeholders will be invited to score potential core outcomes on a nine-point Likert scale, ranging from 1 (not important) to 9 (critical). Repeated reflection and rescoring should promote whole and individual stakeholder group convergence towards consensus 'core' outcomes. We will also establish standardised definitions and recommend high-quality measurements for individual core outcomes. TRIAL REGISTRATION: COMET 1492 . Registered in November 2019.

Should we look for a low-grade threshold for blastocyst transfer? A scoping review.

Embryo quality is a key determinant of the success of IVF. Although the focus has been on selecting the best embryo for transfer, the classification of low-grade blastocysts (LGB) in existing scoring systems has received less attention. This is worrisome; embryo freezing allows optimal use of all created embryos, thus maximizing the cumulative live birth rate, which is arguably the most important outcome for infertile couples. A PubMed search was conducted in August 2020, using '((('poor-quality' OR 'poor quality') OR ('low-grade' OR 'low grade')) AND ('embryo' OR 'blastocyst')) AND ('pregnancy' OR 'live birth')'. This scoping review shows that LGB have similar euploidy and pregnancy success rates after implantation and have no adverse effects on pregnancy or perinatal outcomes. Evidence for pregnancy outcomes is lacking for different grades of LGB, with most studies clustering all LQB as one to compare with optimal blastocysts.

Vehicle Exhaust Remote Sensing Device Method to Screen Vehicles for Evaporative Running Loss Emissions.

Vehicle hydrocarbon (HC) emissions can be emitted from either tailpipe or nontailpipe locations, and understanding their fleet apportionment is important for a successful air pollution policy. Vehicles initially misidentified as having elevated tailpipe HC emissions first indicated that roadside exhaust sensors could detect the presence of evaporative HC emissions as increased noise in the HC/carbon dioxide (CO2) correlation measurement. The 90th percentile of the largest residual of the HC/CO2 correlation is defined as a running loss index (RLI) for each measurement. An RLI that is three standard deviations or greater above the instrument noise indicates possible evaporative running loss emissions with the probability increasing with larger RLI values. Two databases of vehicle emission measurements previously collected in West Los Angeles in 2013 and 2015 were screened using this method. The screening estimated that 0.09% (31/33,806) and 0.18% (49/27,413) of the attempted measurements indicated evaporative running loss emissions from a 9-year-old fleet. California LEV I certified vehicles (1994-2003 model years) accounted for the largest age group for both. The minimum detection limits for the instrument used were estimated at 2.8 and 1.6 g/mile on a propane basis for the 2013 and 2015 data, respectively, or 32-56 times the Federal Tier 2 and Tier 3 standards of 0.05 g/mile.

Preimplantation genetic testing for aneuploidy: are we examining the correct outcomes?

Questions continue to be raised regarding the benefit of genetic assessment of embryos prior to transfer in IVF, specifically with regards to preimplantation genetic testing for aneuploidy (PGT-A). To evaluate and quantify these concerns, we appraised the most recent (2012-2019) randomized controlled trials on the topic. Only two of these six studies listed cumulative live birth rates per started cycle, with both eliciting a statistically non-significant result. This article describes the concern that a focus on results from the first embryo transfer compared to cumulative outcomes falsely construes PGT-A as having superior outcomes, whilst its true benefit is not confirmed, and it cannot actually improve the true pregnancy outcome of an embryo pool.

Reproducible research practices and transparency in reproductive endocrinology and infertility articles.

OBJECTIVE: To analyse the published literature in reproductive endocrinology and infertility (REI) to examine the transparency and the use of reproducible research practices of the scientific literature and to identify possible avenues for improvement. DESIGN: Meta-epidemiologic study. We examined the first 20 consecutive full-text original articles presenting primary data from five REI-specific journals for 2013 and for 2018, and eligible REI articles published in 2013-2018 in five high-impact general journals. Eligible articles were required to be full-text original articles, presenting primary data. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Each article was assessed for study type, trial registration, protocol and raw data availability, funding and conflict of interest declarations, inclusion in subsequent systematic reviews and/or meta-analyses, sample size, and whether the work claimed to be novel or replication. Sample sizes and citation counts also were obtained. RESULT(S): A total of 222 articles were deemed eligible; 98 from REI journals published in 2013, 90 from REI journals published in 2018, and 34 from high-impact journals. There were 37 studies registered, 15 contained a protocol, and two stated actively that they were willing to share data. Most studies provided a statement about funding and conflicts of interest. Two articles explicitly described themselves as replications. All randomized controlled trial published in REI journals were registered prospectively; many meta-analyses were not registered. High-impact journal articles had a greater median sample size and more citations and were more likely to be registered, to have a protocol, and to claim novelty explicitly when compared with REI 2013 and 2018 articles. CONCLUSION(S): Research in REI can be improved in prospective registration, routine availability of protocols, wider sharing of raw data whenever feasible, and more emphasis on replication.

The quality and utility of research in ectopic pregnancy in the last three decades: An analysis of the published literature.

OBJECTIVE: Ectopic pregnancy is a potentially life-threatening health problem that affects fertility and generates a significant economic burden. Optimal management, including when to choose methotrexate, and whether to do salpingectomy or salpingostomy, is still unclear. This study aimed to assess the quality and utility of research on ectopic pregnancy in the last three decades. STUDY DESIGN: We analyzed the quantity, quality and utility of the published literature, including 6,309 articles published over a 30-year period. We searched PubMed for studies on ectopic pregnancy, with subsequent analysis utilizing bibliometric network maps. Consolidated Standards of Reporting Trials (CONSORT) guidelines and a newly adapted checklist for usefulness of research were applied to assess randomized controlled trial (RCT) quality. RESULTS: The initial search returned 14,727 articles, of which, after filters of publication date (1987/01/01 to 2017/12/31), species (Human) and language (English) were applied, 6,309 articles remained. The number of publications each year remained relatively stable, with a mean number of 280 articles published three decades ago versus 248 articles published on average in the last decade. The 7,733 human species articles published between 1987-2017 were written in 27 different languages, with 82 % in English. Publications in 14 selected high-impact journals accounted for 26.5 % (1,673/6,309) of all articles, with on average 54 publications per year across three decades. An increase in systematic reviews and meta-analyses (+1000 %), and case reports (+53 %) was seen between 1987-2017, while the percentage of RCTs (-25 %) decreased. The analyzed RCTs were of moderate quality, and few addressed the most important clinical questions. CONCLUSION: In the last three decades, both the number of articles on ectopic pregnancy and the number of articles in high-impact journals have remained stable. Despite these constant numbers, the quality of RCTs was suboptimal and there was a decrease in the annual number of published RCTs, while the use of meta-analysis significantly amplified. This study suggests continued review of research practices and provides suggestions on how the quality of the published literature can be improved.

Preimplantation Genetic Testing for Aneuploidy: A Review.

IMPORTANCE: Preimplantation genetic testing for aneuploidy (PGT-A) has undergone many technical developments over recent years, including changes in biopsy timings, methodology, and genetic analysis techniques. The evidence surrounding the efficaciousness of PGT-A is sporadic and inconsistent; as such, significant doubt and concern remain regarding its widespread implementation. OBJECTIVE: This review seeks to describe the historical development of PGT-A and to analyze and summarize the current published literature. CONCLUSIONS: At times during its infancy, PGT-A failed to display conclusive improvements in results; with newer technologies, PGT-A appears to yield superior outcomes, including reductions in miscarriages and multiple gestations. Clinicians and patients should assess the use of PGT-A on a case-by-case basis, with laboratories encouraged to utilize blastocyst biopsy and next-generation sequencing when conducting PGT-A. Further studies providing cumulative live birth rates and time to live birth are required if PGT-A is to be proven as producing superior outcomes. RELEVANCE: PGT-A has the potential ability to impact in vitro fertilization success rates, and as it is increasingly adopted worldwide, it is crucial that clinicians are aware of the evidence for its continued use.

Quality of evidence on pre-eclampsia in the last three decades: An analysis of published literature.

OBJECTIVES: In recent years, there has been an increasing amount of information published on pre-eclampsia. We analyzed trends in pre-eclampsia literature between 1997 and 2016 and reported on the quality and utility of randomized controlled trials (RCTs) between 1987 and 2016. METHODS: We searched PubMed for all articles containing "pre-eclampsia" or "hypertensive disorders of pregnancy" in the title between 1997 and 2016 for the general literature and between 1987 and 2016 for RCTs. An analysis was performed based on study type, languages and publications from high-impact journals. Specific to RCTs, a quality and utility analysis based on the CONSORT guidelines and a usefulness checklist was adapted. An analysis by continents and proportion of RCTs published was also performed. Bibliometric network maps were created to determine trends in pre-eclampsia literature. RESULTS: In total, 9654 articles were identified, with a doubling in the number of annual average publications from 310 to 655 between 1997 and 2016. This increase occurred in both English and non-English publications. There was a decline in the proportion of publications from selected high-impact journals from 22% in 1997-2001 to 8% in 2012-2016. Out of the available 130 RCTs that we analyzed, the number of RCTs published in 5-yearly periods remained relatively stable between 1987 and 2016, with quality and utility scores increasing from 24.6 and 11.6 to 31.9 and 13.3, respectively. A geographical search by continents showed that North America produced the majority of RCTs, followed by Asia and Europe. For completed pre-eclampsia trials that were registered between 2005 and 2014, only 68% resulted in peer-reviewed publications. CONCLUSION: The yearly number of publications on pre-eclampsia has substantially increased, with a stable number of high-level study types and publications from high-impact journals. The reporting quality and usefulness of RCTs relating to pre-eclampsia have improved over time.

Subsidizing PGD: The Moral Case for Funding Genetic Selection.

Preimplantation genetic diagnosis (PGD) allows the detection of genetic abnormalities in embryos produced through in vitro fertilization (IVF). Current funding models in Australia provide governmental subsidies for couples undergoing IVF, but do not extend to PGD. There are strong reasons for publicly funding PGD that follow from the moral principles of autonomy, beneficence and justice for both parents and children. We examine the objections to our proposal, specifically concerns regarding designer babies and the harm of disabled individuals, and show why these are substantially outweighed by arguments for subsidizing PGD. We argue that an acceptance of PGD is aligned with present attitudes towards procreative decision making and IVF use, and that it should therefore receive government funding.

Impact of adaptation on flex-fuel vehicle emissions when fueled with E40.

Nine flex-fuel vehicles meeting Tier 1, light duty vehicle-low emission vehicle (LDV-LEV), light duty truck 2-LEV (LDT2-LEV), and Tier 2 emission standards were tested over hot-start and cold-start three-phase LA92 cycles for nonmethane organic gases, ethanol, acetaldehyde, formaldehyde, acetone, nitrous oxide, nitrogen oxides (NO(x)), carbon monoxide (CO), and carbon dioxide (CO(2)), as well as fuel economy. Emissions were measured immediately after refueling with E40. The vehicles had previously been adapted to either E10 or E76. An overall comparison of emissions and fuel economy behavior of vehicles running on E40 showed results generally consistent with adaptation to the blend after the length of the three-phase hot-start LA92 test procedure (1735 s, 11 miles). However, the single LDT2-LEV vehicle, a Dodge Caravan, continued to exhibit statistically significant differences in emissions for most pollutants when tested on E40 depending on whether the vehicle had been previously adapted to E10 or E76. The results were consistent with an overestimate of the amount of ethanol in the fuel when E40 was added immediately after the use of E76. Increasing ethanol concentration in fuel led to reductions in fuel economy, NO(x), CO, CO(2), and acetone emissions as well as increases in emissions of ethanol, acetaldehyde, and formaldehyde.