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The contribution of sperm to embryogenesis is gaining attention with up to 50% of infertility cases being attributed to a paternal factor. The traditional methods used in assisted reproductive technologies for selecting and assessing sperm quality are mainly based on motility and viability parameters. However, other sperm characteristics, including deoxyribonucleic acid integrity, have major consequences for successful live birth. In natural reproduction, sperm navigate the male and female reproductive tract to reach and fertilize the egg. During transport, sperm encounter many obstacles that dramatically reduce the number arriving at the fertilization site. In humans, the number of sperm is reduced from tens of millions in the ejaculate to hundreds in the Fallopian tube (oviduct). Whether this sperm population has higher fertilization potential is not fully understood, but several studies in animals indicate that many defective sperm do not advance to the site of fertilization. Moreover, the oviduct plays a key role in fertility by modulating sperm transport, viability, and maturation, providing sperm that are ready to fertilize at the appropriate time. Here we present evidence of sperm selection by the oviduct with emphasis on the mechanisms of selection and the sperm characteristics selected. Considering the sperm parameters that are essential for healthy embryonic development, we discuss the use of novel in vitro sperm selection methods that mimic physiological conditions. We propose that insight gained from understanding how the oviduct selects sperm can be translated to assisted reproductive technologies to yield high fertilization, embryonic development, and pregnancy rates.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

To estimate the aneuploidy rates in young women with diminished ovarian reserve (DOR) before treatment and poor ovarian response (POR) postretrieval.Retrospective cohort study.A single academically-affiliated fertility clinic.Autologous frozen embryo transfer cycles from December 2014 to June 2020 were reviewed. Demographic and clinical factors that impact outcomes were used for propensity score matching (PSM) in a ratio of 2:1 and 4:1 for preimplantation genetic testing for aneuploidy pre-cycle DOR and POR after stimulation, respectively.None.Aneuploid rates, defined as the number of aneuploid blastocysts divided by the number of biopsied blastocysts per cycle. No euploid embryos to transfer, defined as all cohorts of embryos being aneuploid.A total of 383 women diagnosed with DOR were compared with matched controls. Aneuploid rates did not differ significantly between the two groups (42.2% vs. 41.7%; RR = 1.06; 95% CI, 0.95-1.06). No differences were identified in live birth rates per transfer between women with and without DOR after euploid single-embryo transfers (56.0% and 60.5%, respectively). An additional PSM analysis to assess aneuploidy rates for patients with POR (5 oocytes) vs. those without it, resulted in similar rates of aneuploidy between the two comparison groups (41.1% vs. 44%, R = 1.02; 95% CI, 0.91-1.14). The prevalence of cycles with "no euploid embryos" in the POR cohort was higher (26% vs. 13%); however, rates of cases with a single embryo available for biopsy were lower in the DOR group, relative to controls (11% vs. 31%).Young women diagnosed with DOR or POR exhibited equivalent aneuploidy rates and live birth rates per euploid embryo transfer in a large matched population, based on age, body mass index, and IVF cycle initiation. The lower percentage of cycles with no euploid embryo available for transfer in DOR and POR patients is because of the decreased total number of oocytes/developing embryos and not because of increased aneuploidy rates in these groups.

To identify early follicular phase microribonucleic acids (miRNAs) that are altered in serum of women with endometriosis.Case-control study.Large university-affiliated in vitro fertilization center.Women with (n = 21) and without (n = 24) endometriosis.Serum samples were obtained from laparoscopy-confirmed patients with endometriosis.The differential expression of serum miRNAs relative to controls was measured using the NanoString nCounter technology and validated by quantitative real-time polymerase chain reaction in an independent cohort of 27 patients with endometriosis and controls (n = 24). Microribonucleic acid target signaling pathways and genes were analyzed bioinformatically. A chemically modified stable miR-34-3p oligonucleotide was used to examine the effect on proliferation of VK2E6/E7 endometrial cells in vitro.Eighteen miRNAs were significantly up-regulated, and 1 miRNA (hsa-miR-34c-3p) was significantly down-regulated in the follicular phase of patients with endometriosis. The analysis of target signaling pathways using TargetScan predicted regulation of the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Hippo, adenosine monophosphate-activated protein kinase, transforming growth factor beta, and endometrial cancer pathways, which have been implicated in the pathogenesis of endometriosis, by these miRNAs. The analysis of sequence complementarity identified prostaglandin E2 receptor 4, interleukin 6 signal transducer, and polo-like kinase 4 genes as possible direct targets of hsa-miR-34-3p. DSDI-1, a chemically modified stable miR-34-3p oligonucleotide, reduced cell proliferation in VK2E6/E7 endometrial cells in vitro.The follicular phase miRNA levels are altered in serum of women with endometriosis and may be useful as reproducible detection biomarkers for early diagnosis of endometriosis. hsa-miR-34-3p is significantly down-regulated in endometriosis, targets endometriosis genes, and reduces endometrial cell proliferation in vitro. These results support hsa-miR-34-3p as a potential therapeutic target in endometriosis.

STUDY QUESTION What is the impact of day after rescue ICSI (r-ICSI) on success of fresh and frozen embryo transfers? SUMMARY ANSWER The use of r-ICSI can virtually allay fears of total fertilization failure (TFF) after conventional IVF (C-IVF) and achieve high live birth rates after frozen blastocyst transfer. WHAT IS KNOWN ALREADY More infertility clinics have resorted to the use of ICSI in place of C-IVF in IVF treatment owing to fear of TFF or a low fertilization rate. r-ICSI has been attempted either on the day of IVF or the day after. Day after r-ICSI has proved unsuccessful in the past. STUDY DESIGN, SIZE, DURATION A retrospective data analysis was performed of 16 608 qualifying cases between April 2010 and July 2021 conducted at a single private academically affiliated fertility clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS r-ICSI was performed principally on patients with >4 metaphase II oocytes, showing no signs of fertilization 18 h after C-IVF. C-IVF was performed on patients who had >4 million total motile sperm after preparation. r-ICSI was then performed 18–24 h after insemination, using the sperm sample from the previous day. r-ICSI fertilization rates, cryopreservation of cleavage and blastocysts embryos, and pregnancy rates after fresh or frozen transfer were then assessed. MAIN RESULTS AND THE ROLE OF CHANCE r-ICSI was performed on 377 patients (2.3% of eligible retrieval cycles) who had a mean (±SD) female and male age of 35.9 ± 4.5 and 38.1 ± 9.1 years, respectively. A total of 5459 oocytes were initially retrieved. Of the oocytes undergoing r-ICSI, 2389 (49.5%) fertilized normally, and 205 (54.4%) patients underwent a fresh embryo transfer. The live birth rates were 23/186 (12.3%) for fresh cleavage and 5/19 (26.3%) for fresh blastocyst stage transfers. In 145 cycles a blastocyst was frozen, and 137 transfers were performed with a 64/137 (46.7%) live birth rate. Of the 377 cycles receiving r-ICSI only, 25 of the qualifying cases failed to have any fertilization, reducing TFF to 25/16 608 (0.15%). LIMITATIONS, REASONS FOR CAUTION This was a single-center retrospective study on a specific subset of patients, which may limit its generalizability to other clinics. WIDER IMPLICATIONS OF THE FINDINGS r-ICSI allows a second opportunity to fertilize oocytes despite poor initial outcomes. Patients who had a frozen blastocyst transfer achieved high live birth rates, indicating that a resynchronization of the embryo with the endometrium can optimize r-ICSI cases. r-ICSI allays fears of TFF when using C-IVF, providing evidence that the overuse of ICSI in patients without male factor may not be warranted. STUDY FUNDING/COMPETING INTEREST(S) The study was internally funded by Boston IVF. The authors declare that they have no conflict of interest in relation to the data published in the article. TRIAL REGISTRATION NUMBER N/A.

STUDY QUESTION Is there a relationship between endometrial compaction and live birth in euploid frozen embryo transfer (FET) cycles? SUMMARY ANSWER Live birth rates (LBRs) were similar in both patients that demonstrated endometrial compaction or no compaction in single euploid FETs. WHAT IS KNOWN ALREADY There has been increasing interest in the correlation between endometrial compaction and clinical outcomes but there has been conflicting evidence from prior investigations. STUDY DESIGN, SIZE, DURATION This was a prospective observational study from 1 September 2020 to 9 April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was performed at a single, academically affiliated fertility center in which patients who had an autologous single euploid FET using a programmed or modified natural cycle protocol were included. All embryos had trophectoderm biopsy for preimplantation genetic testing for aneuploidy followed by vitrification at the blastocyst stage. Two ultrasound measurements of endometrial thickness (EMT) were obtained. The first measurement (T1) was measured transvaginally within 1 day of initiation of progesterone or ovulation trigger injection, and a second EMT (T2) was measured transabdominally at the time of embryo transfer (ET). The primary outcome (LBR) was based on the presence and proportion of compaction (percentage difference in EMT between T1 and T2). MAIN RESULTS AND THE ROLE OF CHANCE Of the 186 participants included, 54%, 45%, 35%, 28% and 21% of women exhibited >0%, ≥5%, ≥10%, ≥15% and ≥20% endometrial compaction, respectively. Endometrial compaction was not predictive of live birth at any of the defined cutoffs. A sub-analysis stratified by FET protocol type (n = 89 programmed; n = 97 modified natural) showed similar results. LIMITATIONS, REASONS FOR CAUTION There was the potential for measurement error in the recorded EMTs. The T2 measurement was performed transabdominally, which may cause potential measurement error, as it is generally accepted that transvaginal measurements of EMT are more accurate, though, any bias is expected to be non-differential. The sub-analysis performed looking at FET protocol type was underpowered and should be interpreted with caution. Our study, however, represents a pragmatic approach, as it allowed patients to avoid having to come in for an extra transvaginal ultrasound the day before or on the day of ET. WIDER IMPLICATIONS OF THE FINDINGS Assessing endometrial compaction may lead to unnecessary cycle cancellation. However, further studies are needed to determine if routine screening for endometrial compaction would improve clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S) No authors report conflicts of interest or disclosures. There was no study funding. TRIAL REGISTRATION NUMBER NCT04330066.

STUDY QUESTION Can non-invasive imaging with fluorescence lifetime imaging microscopy (FLIM) detect metabolic differences in euploid versus aneuploid human blastocysts? SUMMARY ANSWER FLIM has identified significant metabolic differences between euploid and aneuploid blastocysts. WHAT IS KNOWN ALREADY Prior studies have demonstrated that FLIM can detect metabolic differences in mouse oocytes and embryos and in discarded human blastocysts. STUDY DESIGN, SIZE, DURATION This was a prospective observational study from August 2019 to February 2020. Embryo metabolic state was assessed using FLIM to measure the autofluorescence metabolic factors nicotinamide adenine dinucleotide dehydrogenase together with nicotinamide adenine phosphate dinucleotide dehydrogenase (NAD(P)H) and flavin adenine dinucleotide (FAD). Eight metabolic FLIM parameters were obtained from each blastocyst (four for NAD(P)H and four for FAD): short (T1) and long (T2) fluorescence lifetime, fluorescence intensity (I) and fraction of the molecules engaged with enzymes (F). The redox ratio (NAD(P)H-I)/(FAD-I) was also calculated for each image. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was performed at a single academically affiliated centre where there were 156 discarded frozen blastocysts (n = 17 euploids; 139 aneuploids) included. Ploidy status was determined by pre-implantation genetic testing for aneuploidy (PGT-A). Discarded human blastocysts were compared using single FLIM parameters. Additionally, inner cell mass (ICM) and trophectoderm (TE) were also evaluated. Multilevel models were used for analysis. A post-hoc correction used Benjamini–Hochberg’s false discovery rate, at a q-value of 0.05. MAIN RESULTS AND THE ROLE OF CHANCE Comparing euploid (n = 17) versus aneuploid (n = 139) embryos, a significant difference was seen in NAD(P)H-F (P < 0.04), FAD-I (P < 0.04) and redox ratio (P < 0.05). Euploid ICM (n = 15) versus aneuploid ICM (n = 119) also demonstrated significantly different signatures in NAD(P)H-F (P < 0.009), FAD-I (P < 0.03) and redox ratio (P < 0.03). Similarly, euploid TE (n = 15) versus aneuploid TE (n = 119) had significant differences in NAD(P)H-F (P < 0.0001) and FAD-I (P < 0.04). LIMITATIONS, REASONS FOR CAUTION This study utilized discarded human blastocysts, and these embryos may differ metabolically from non-discarded human embryos. The blastocysts analysed were vitrified after PGT-A biopsy and it is unclear how the vitrification process may affect the metabolic profile of blastocysts. Our study was also limited by the small number of rare donated euploid embryos available for analysis. Euploid embryos are very rarely discarded due to their value to patients trying to conceive, which limits their use for research purposes. However, we controlled for the imbalance with the bootstrap resampling analysis. WIDER IMPLICATIONS OF THE FINDINGS These findings provide preliminary evidence that FLIM may be a useful non-invasive clinical tool to assist in identifying the ploidy status of embryos. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

STUDY QUESTION Can non-invasive metabolic imaging via fluorescence lifetime imaging microscopy (FLIM) detect variations in metabolic profiles between discarded human blastocysts? SUMMARY ANSWER FLIM revealed extensive variations in the metabolic state of discarded human blastocysts associated with blastocyst development over 36 h, the day after fertilization and blastocyst developmental stage, as well as metabolic heterogeneity within individual blastocysts. WHAT IS KNOWN ALREADY Mammalian embryos undergo large changes in metabolism over the course of preimplantation development. Embryo metabolism has long been linked to embryo viability, suggesting its potential utility in ART to aid in selecting high quality embryos. However, the metabolism of human embryos remains poorly characterized due to a lack of non-invasive methods to measure their metabolic state. STUDY DESIGN, SIZE, DURATION We conducted a prospective observational study. We used 215 morphologically normal human embryos from 137 patients that were discarded and donated for research under an approved institutional review board protocol. These embryos were imaged using metabolic imaging via FLIM to measure the autofluorescence of two central coenzymes, nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) and flavine adenine dinucleotide (FAD+), which are essential for cellular respiration and glycolysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Here, we used non-invasive FLIM to measure the metabolic state of human blastocysts. We first studied spatial patterns in the metabolic state within human blastocysts and the association of the metabolic state of the whole blastocysts with stage of expansion, day of development since fertilization and morphology. We explored the sensitivity of this technique in detecting metabolic variations between blastocysts from the same patient and between patients. Next, we explored whether FLIM can quantitatively measure metabolic changes through human blastocyst expansion and hatching via time-lapse imaging. For all test conditions, the level of significance was set at P MAIN RESULTS AND THE ROLE OF CHANCE We found that FLIM is sensitive enough to detect significant metabolic differences between blastocysts. We found that metabolic variations between blastocyst are partially explained by both the time since fertilization and their developmental expansion stage (P LIMITATIONS, REASONS FOR CAUTION Although we observed significant variations in metabolic parameters, our data are taken from human blastocysts that were discarded and donated for research and we do not know their clinical outcome. Moreover, the embryos used in this study are a mixture of aneuploid, euploid and embryos of unknown ploidy. WIDER IMPLICATIONS OF THE FINDINGS This work reveals novel aspects of the metabolism of human blastocysts and suggests that FLIM is a promising approach to assess embryo viability through non-invasive, quantitative measurements of their metabolism. These results further demonstrate that FLIM can provide biologically relevant information that may be valuable for the assessment of embryo quality. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. TRIAL REGISTRATION NUMBER N/A.

Research question What is the clinical experience of patients who have undergone planned oocyte cryopreservation and oocyte thawing and warming? Design Retrospective observational cohort study. All women who completed planned oocyte cryopreservation at a single large university-affiliated fertility centre between June 2006 and October 2020 were identified, including the subset who returned to use their oocytes. Patients who underwent oocyte cryopreservation for medical reasons were excluded. Baseline demographics, oocyte cryopreservation and thawing–warming cycle parameters, and clinical outcomes, were extracted from the electronic medical record. The primary outcome was cumulative live birth rate (LBR), and secondary outcomes were cumulative clinical pregnancy rate (CPR), and CPR and LBR per transfer. Results were stratified by age at time of cryopreservation ( Results Of 921 patients who underwent planned oocyte cryopreservation, 68 (7.4%) returned to use their oocytes. Forty-six patients (67.6%) completed at least one embryo transfer. The CPR per transfer was 47.5% and LBR was 39.3%. The cumulative LBR per patient who initiated thawing–warming was 32.4%. Cycle outcomes were not significantly different in patients aged younger than 38 years and those aged 38 years or over. No patient aged 40 years or older (n = 6) was successful with their cryopreserved oocytes. Ten patients (14.7%) who were unsuccessful with their cryopreserved oocytes achieved a live birth using donor oocytes, with most (7/10) of these patients aged 38 years and older. Conclusion Only a small percentage of patients returned to use their oocytes, and 32% of those were able to achieve a live birth.

Over the past four decades our ability to maintain a viable human embryo in vitro has improved dramatically, leading to higher implantation rates. This has led to a notable shift to single blastocyst transfer and the ensuing elimination of high order multiple gestations. Future improvements to embryo culture systems will not only come from new improved innovative media formulations (such as the inclusion the addition of antioxidants), but plausibly by moving away from static culture to more dynamic perfusion-based systems now made a reality due to breakthroughs in 3D printing technology and micro fabrication. Such an approach has already made it feasible to create high resolution devices for ICSI, culture and cryopreservation, paving the way not only for improvements in outcomes but also automation of ART. While improvements in culture systems can lead to further increases in pregnancy outcomes, the ability to quantitate biomarkers of embryo health and viability will reduce time to pregnancy and decrease pregnancy loss. Currently artificial intelligence is being used to assess embryo development through image analysis, but we predict its power will be realised through the creation of selection algorithms based on the integration of information related to metabolic functions, cell free DNA, morphokinetics, thereby using vast amounts of different data types obtained for each embryo to predict outcomes. All of this will not only make ART more effective, but it will also make it more cost effective, thereby increasing patient access to infertility treatment worldwide.

PURPOSE: The precise timing of insemination after oocyte retrieval is sometimes challenging. In this study, we have assessed the effect of the variation in insemination timing on reproductive outcome for both conventional insemination (CI) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: A single-center retrospective cohort data analysis was performed on 6559 patients (9575 oocyte retrievals) from January 2017 to July 2019. The main outcome measured was live birth rates. Secondary outcomes included fertilization rate per all oocytes retrieved, blastocyst utilization, clinical pregnancy, and miscarriage rates. The time interval between oocyte retrieval and insemination was analyzed in eight categories: 0 (0– 6.5 h, any detrimental effects are moderate on fertilization but do not affect blastocyst usage and birth rates. TRIAL REGISTRATION: Institutional Review Board Approval from the Beth Israel Deaconess Medical Centre [IRB Protocol #: 2015P000122]. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02299-7.

Objective To study the impact of routine ketorolac administration during oocyte retrieval on the proportion of patients who require postoperative narcotics for analgesia. Design Retrospective cohort study. Setting Single, university-affiliated infertility clinic. Patient(s) All women undergoing oocyte retrieval between July and November 2016 (non-ketorolac group [NKG]; n = 826) and April-August 2017 (ketorolac group, KG; n = 1780). Intervention(s) A single 30 mg intravenous dose of ketorolac was administered after the oocyte retrieval procedure. Main outcome measure(s) The number of patients who required postoperative narcotic analgesia, postoperative complication rate, and fresh embryo transfer pregnancy outcomes were examined. Result(s) In the KG, we found a significant decrease in the patients who required narcotics after oocyte retrieval compared with the NKG (12% KG vs. 25.5% NKG). We found no significant change in the clinical pregnancy rate (CPR) resulting from fresh embryo transfer after our intervention (NKG CPR 32.6%, KG CPR 32.4%). Furthermore, there was no increase in postoperative bleeding complications in the KG. Conclusion(s) Routine use of ketorolac at the time of oocyte retrieval may decrease the rate of postoperative opioid use without adversely impacting pregnancy and complication rates.

PURPOSE: To explore how the assisted reproductive technology (ART) laboratories can be optimized and standardized to enhance embryo culture and selection, to bridge the gap between standard practice and the new concept of shortening time to healthy singleton birth. METHODS: A Delphi consensus was conducted (January to July 2018) to assess how the ART laboratory could be optimized, in conjunction with existing guidelines, to reduce the time to a healthy singleton birth. Eight experts plus the coordinator discussed and refined statements proposed by the coordinator. The statements were distributed via an online survey to 29 participants (including the eight experts from step 1), who voted on their agreement/disagreement with each statement. Consensus was reached if ≥ 66% of participants agreed/disagreed with a statement. If consensus was not achieved for any statement, that statement was revised and the process repeated until consensus was achieved. Details of statements achieving consensus were communicated to the participants. RESULTS: Consensus was achieved for all 13 statements, which underlined the need for professional guidelines and standardization of lab processes to increase laboratory competency and quality. The most important points identified were the improvement of embryo culture and embryo assessment to shorten time to live birth through the availability of more high-quality embryos, priority selection of the most viable embryos and improved cryosurvival. CONCLUSION: The efficiency of the ART laboratory can be improved through professional guidelines on standardized practices and optimized embryo culture environment, assessment, selection and cryopreservation methodologies, thereby reducing the time to a healthy singleton delivery.

Research question Ovarian stimulation during IVF cycles involves close monitoring of oestradiol, progesterone and ultrasound measurements of follicle growth. In contrast to blood draws, sampling saliva is less invasive. Here, a blind validation is presented of a novel saliva-based oestradiol and progesterone assay carried out in samples collected in independent IVF clinics. Design Concurrent serum and saliva samples were collected from 324 patients at six large independent IVF laboratories. Saliva samples were frozen and run blinded. A further 18 patients had samples collected more frequently around the time of HCG trigger. Saliva samples were analysed using an immunoassay developed with Salimetrics LLC. Results In total, 652 pairs of saliva and serum oestradiol were evaluated, with correlation coefficients ranging from 0.68 to 0.91. In the European clinics, a further 237 of saliva and serum progesterone samples were evaluated; however, the correlations were generally poorer, ranging from –0.02 to 0.22. In the patients collected more frequently, five out of 18 patients (27.8%) showed an immediate decrease in oestradiol after trigger. When progesterone samples were assessed after trigger, eight out of 18 (44.4%) showed a continued rise. Conclusions Salivary oestradiol hormone testing correlates well to serum-based assessment, whereas progesterone values, around the time of trigger, are not consistent from patient to patient.

Can we develop an interpretable machine learning model that optimizes starting gonadotrophin dose selection in terms of mature oocytes (metaphase II [MII]), fertilized oocytes (2 pronuclear [2PN]) and usable blastocysts?This was a retrospective study of patients undergoing autologous IVF cycles from 2014 to 2020 (n = 18,591) in three assisted reproductive technology centres in the USA. For each patient cycle, an individual dose-response curve was generated from the 100 most similar patients identified using a K-nearest neighbours model. Patients were labelled as dose-responsive if their dose-response curve showed a region that maximized MII oocytes, and flat-responsive otherwise.Analysis of the dose-response curves showed that 30% of cycles were dose-responsive and 64% were flat-responsive. After propensity score matching, patients in the dose-responsive group who received an optimal starting dose of FSH had on average 1.5 more MII oocytes, 1.2 more 2PN embryos and 0.6 more usable blastocysts using 10 IU less of starting FSH and 195 IU less of total FSH compared with patients given non-optimal doses. In the flat-responsive group, patients who received a low starting dose of FSH had on average 0.3 more MII oocytes, 0.3 more 2PN embryos and 0.2 more usable blastocysts using 149 IU less of starting FSH and 1375 IU less of total FSH compared with patients with a high starting dose.This study demonstrates retrospectively that using a machine learning model for selecting starting FSH can achieve optimal laboratory outcomes while reducing the amount of starting and total FSH used.

Objective To investigate clinic-specific risk factors for monozygotic twinning (MZT) using a large, electronic database. Design Retrospective case-control study. Setting Infertility clinics. Patient(s) Using an electronic medical record system, viable clinical pregnancy (confirmation of a gestational sac(s) and presence of at least one fetal pole with a heartbeat on first trimester ultrasound), data were obtained from homologous in vitro fertilization (IVF) cycles after single ET from June 1, 2004, to December 31, 2016. Monozygotic twinning was defined as a pregnancy with two fetal heartbeats on ultrasound with sex concordance at birth. Intervention(s) None. Main Outcome Measure(s) Risk factors for MZT including cycle type, method of insemination, and method of cryopreservation. Result(s) Of the 28,265 IVF cycles that met inclusion criteria over the study period, 8,749 (31.0%) resulted in a viable intrauterine clinical pregnancy. There were 102 (2.7%) MZT in the fresh cycle cohort and 133 (2.7%) in the frozen cycle cohort. Neither cryopreservation nor the method of cryopreservation was a significant risk factor for MZT. However, the use of sequential media was an independent risk factor for MZT in fresh, but not frozen, ETs (odds ratio = 1.72, 95% confidence interval, 1.10–2.68). Significant differences were seen in the incidence of MZT between clinics, and this difference persisted after controlling for known risk factors (clinic 0, reference; clinic 2, odds ratio = 2.22; 95% confidence interval, 1.48–3.32; clinic 3, odds ratio = 1.93; 95% confidence interval, 1.30–2.87). Conclusion(s) Differences in MZT rates exist between individual IVF clinics, suggesting that variations in practice patterns may contribute to this event. The present study noted the use of sequential media was an independent risk factor for fresh but not frozen cycles.

To develop an interpretable machine learning model for optimizing the day of trigger in terms of mature oocytes (MII), fertilized oocytes (2PNs), and usable blastocysts.Retrospective study.A group of three assisted reproductive technology centers in the United States.Patients undergoing autologous in vitro fertilization cycles from 2014 to 2020 (n = 30,278).None.Average number of MII oocytes, 2PNs, and usable blastocysts.A set of interpretable machine learning models were developed using linear regression with follicle counts and estradiol levels. When using the model to make day-by-day predictions of trigger or continuing stimulation, possible early and late triggers were identified in 48.7% and 13.8% of cycles, respectively. After propensity score matching, patients with early triggers had on average 2.3 fewer MII oocytes, 1.8 fewer 2PNs, and 1.0 fewer usable blastocysts compared with matched patients with on-time triggers, and patients with late triggers had on average 2.7 fewer MII oocytes, 2.0 fewer 2PNs, and 0.7 fewer usable blastocysts compared with matched patients with on-time triggers.This study demonstrates that it is possible to develop an interpretable machine learning model for optimizing the day of trigger. Using our model has the potential to improve outcomes for many in vitro fertilization patients.

Objective To compare the impact of the COVID-19 pandemic on the psychological health of infertility patients who have become pregnant to women who have not. Design Prospective cohort study from April to June 2020. Participants completed three questionnaires over this period. Setting A single large, university-affiliated infertility practice. Patient(s) 443 pregnant women and 1476 women still experiencing infertility who completed all three questionnaires. Intervention(s) None. Main Outcome Measure(s) Patient-reported primary stressor over three months of the first major COVID-19 surge. Further data on self-reported sadness, anxiety, loneliness and the use of personal use of coping strategies. Results Pregnant participants were significantly less likely to report taking an antidepressant (p, Women pregnant after infertility treatment were more concerned about COVID-19 than patients continuing with infertility treatment but overall were less distressed.

To determine the association of interpregnancy interval on perinatal outcomes and whether this was influenced by mode of conception.Retrospective cohort.Centers for Disease Control and Prevention's natality national database.Patients who had an index singleton live birth with a preceding live birth. Index pregnancies from 2016 to 2019 were conceived with in vitro fertilization (IVF) (n = 32,829) or ovulation induction/intrauterine insemination (OI/IUI) (n = 23,016) or without assistance (n = 7,564,042).None.The primary outcomes evaluated were preterm birth (37 weeks) and low birth weight (2,500 g). Multivariable logistic regression was performed to evaluate the association of interpregnancy intervals with perinatal outcomes stratified by mode of conception. Adjusted odds ratios and 95% confidence intervals (CIs) were presented.Compared with the interpregnancy interval reference group of 12 to18 months, a12 month interpregnancy interval was associated with an increase in preterm birth (37 weeks) for pregnancies conceived with OI/IUI or without assistance (aOR, 1.42; 95% CI, 1.16-1.74, and aOR, 1.14; 95% CI, 1.13-1.15, respectively), whereas IVF was not associated with an increase (aOR, 0.90; 95% CI, 0.77-1.04). A12 month interpregnancy interval was associated with an increase in low birth weight for pregnancies conceived with IVF or OI/IUI or without assistance (aOR, 1.34; 95% CI, 1.09-1.64; aOR, 1.33; 95% CI, 1.01-1.76; and aOR, 1.26; 95% CI, 1.24-1.27, respectively).An interpregnancy interval of at least 12 months reduces adverse perinatal outcomes for pregnancies conceived with and without infertility treatment.

To perform a series of analyses characterizing an artificial intelligence (AI) model for ranking blastocyst-stage embryos. The primary objective was to evaluate the benefit of the model for predicting clinical pregnancy, whereas the secondary objective was to identify limitations that may impact clinical use.Retrospective study.Consortium of 11 assisted reproductive technology centers in the United States.Static images of 5,923 transferred blastocysts and 2,614 nontransferred aneuploid blastocysts.None.Prediction of clinical pregnancy (fetal heartbeat).The area under the curve of the AI model ranged from 0.6 to 0.7 and outperformed manual morphology grading overall and on a per-site basis. A bootstrapped study predicted improved pregnancy rates between +5% and +12% per site using AI compared with manual grading using an inverted microscope. One site that used a low-magnification stereo zoom microscope did not show predicted improvement with the AI. Visualization techniques and attribution algorithms revealed that the features learned by the AI model largely overlap with the features of manual grading systems. Two sources of bias relating to the type of microscope and presence of embryo holding micropipettes were identified and mitigated. The analysis of AI scores in relation to pregnancy rates showed that score differences of ≥0.1 (10%) correspond with improved pregnancy rates, whereas score differences of0.1 may not be clinically meaningful.This study demonstrates the potential of AI for ranking blastocyst stage embryos and highlights potential limitations related to image quality, bias, and granularity of scores.