Publications by authors named "Catherine Racowsky"

133 Publications

Extensive analysis of mitochondrial DNA quantity and sequence variation in human cumulus cells and assisted reproduction outcomes.

Hum Reprod 2021 Nov 10. Epub 2021 Nov 10.

Nuffield Department of Women's & Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Study Question: Are relative mitochondrial DNA (mtDNA) content and mitochondrial genome (mtGenome) variants in human cumulus cells (CCs) associated with oocyte reproductive potential and assisted reproductive technology (ART) outcomes?

Summary Answer: Neither the CC mtDNA quantity nor the presence of specific mtDNA genetic variants was associated with ART outcomes, although associations with patient body mass index (BMI) were detected, and the total number of oocytes retrieved differed between major mitochondrial haplogroups.

What Is Known Already: CCs fulfil a vital role in the support of oocyte developmental competence. As with other cell types, appropriate cellular function is likely to rely upon adequate energy production, which in turn depends on the quantity and genetic competence of the mitochondria. mtDNA mutations can be inherited or they can accumulate in somatic cells over time, potentially contributing to aging. Such mutations may be homoplasmic (affecting all mtDNA in a cell) or they may display varying levels of heteroplasmy (affecting a proportion of the mtDNA). Currently, little is known concerning variation in CC mitochondrial genetics and how this might influence the reproductive potential of the associated oocyte.

Study Design, Size, Duration: This was a prospective observational study involving human CCs collected with 541 oocytes from 177 IVF patients. mtDNA quantity was measured in all the samples with a validated quantitative PCR method and the entire mtGenome was sequenced in a subset of 138 samples using a high-depth massively parallel sequencing approach. Associations between relative mtDNA quantity and mtGenome variants in CCs and patient age, BMI (kg/m2), infertility diagnosis and ART outcomes were investigated.

Participants/materials, Setting, Methods: Massively parallel sequencing permitted not only the accurate detection of mutations but also the precise quantification of levels of mutations in cases of heteroplasmy. Sequence variants in the mtDNA were evaluated using Mitomaster and HmtVar to predict their potential impact.

Main Results And The Role Of Chance: The relative mtDNA CC content was significantly associated with BMI. No significant associations were observed between CC mtDNA quantity and patient age, female infertility diagnosis or any ART outcome variable. mtGenome sequencing revealed 4181 genetic variants with respect to a reference genome. The COXI locus contained the least number of coding sequence variants, whereas ATPase8 had the most. The number of variants predicted to affect the ATP production differed significantly between mitochondrial macrohaplogroups. The total number of retrieved oocytes was different between the H-V and J-T as well as the U-K and J-T macrohaplogroups. There was a non-significant increase in mtDNA levels in CCs with heteroplasmic mitochondrial mutations.

Large Scale Data: N/A.

Limitations, Reasons For Caution: Although a large number of samples were analysed in this study, it was not possible to analyse all the CCs from every patient. Also, the results obtained with respect to specific clinical outcomes and macrohaplogroups should be interpreted with caution due to the smaller sample sizes when subdividing the dataset.

Wider Implications Of The Findings: These findings suggest that the analysis of mtDNA in CCs is unlikely to provide an advantage in terms of improved embryo selection during assisted reproduction cycles. Nonetheless, our data raise interesting biological questions, particularly regarding the interplay of metabolism and BMI and the association of mtDNA haplogroup with oocyte yield in ovarian stimulation cycles.

Study Funding/competing Interest(s): This study was funded by National Institutes of Health grant 5R01HD092550-02. D.J.N. and C.R. co-hold patent US20150346100A1 and D.J.N. holds US20170039415A1, both for metabolic imaging methods. D.W. receives support from the NIHR Oxford Biomedical Research Centre. The remaining authors have no conflicts of interest to declare.
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http://dx.doi.org/10.1093/humrep/deab231DOI Listing
November 2021

Inferring simple but precise quantitative models of human oocyte and early embryo development.

J R Soc Interface 2021 09 8;18(182):20210475. Epub 2021 Sep 8.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.

Macroscopic, phenomenological models are useful as concise framings of our understandings in fields from statistical physics to finance to biology. Constructing a phenomenological model for development would provide a framework for understanding the complicated, regulatory nature of oogenesis and embryogenesis. Here, we use a data-driven approach to infer quantitative, precise models of human oocyte maturation and pre-implantation embryo development, by analysing clinical fertilization (IVF) data on 7399 IVF cycles resulting in 57 827 embryos. Surprisingly, we find that both oocyte maturation and early embryo development are quantitatively described by simple models with minimal interactions. This simplicity suggests that oogenesis and embryogenesis are composed of modular processes that are relatively siloed from one another. In particular, our analysis provides strong evidence that (i) pre-antral follicles produce anti-Müllerian hormone independently of effects from other follicles, (ii) oocytes mature to metaphase-II independently of the woman's age, her BMI and other factors, (iii) early embryo development is memoryless for the variables assessed here, in that the probability of an embryo transitioning from its current developmental stage to the next is independent of its previous stage. Our results both provide insight into the fundamentals of oogenesis and embryogenesis and have implications for the clinical IVF.
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http://dx.doi.org/10.1098/rsif.2021.0475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424348PMC
September 2021

Metabolic imaging of human cumulus cells reveals associations among metabolic profiles of cumulus cells, patient clinical factors, and oocyte maturity.

Fertil Steril 2021 Dec 2;116(6):1651-1662. Epub 2021 Sep 2.

Molecular and Cellular Biology and School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; Center for Computational Biology, Flatiron Institute, New York, New York.

Objective: To determine whether fluorescence lifetime imaging microscopy (FLIM) detects differences in metabolic state among cumulus cell samples and whether their metabolic state is associated with patient age, body mass index (BMI), and antimüllerian hormone (AMH) level and maturity of the oocyte.

Design: Prospective observational study.

Setting: Academic laboratory.

Patient(s): Cumulus cell (CC) clusters from cumulus-oocyte complexes were collected from patients undergoing assisted reproductive technology treatment after oocyte retrieval and vitrified.

Intervention(s): Cumulus cell metabolism was assessed using FLIM to measure autofluorescence of nicotinamide adenine (phosphate) dinucleotide and flavine adenine dinucleotide, endogenous coenzymes essential for cellular respiration and glycolysis. Patient age, BMI, and AMH level and the maturity of the corresponding oocytes were recorded.

Main Outcome Measure(s): Quantitative information from FLIM was obtained regarding metabolite concentrations from fluorescence intensity and metabolite enzyme engagement from fluorescence lifetimes. Associations were investigated between each FLIM parameter and oocyte maturity and patient age, BMI, and AMH. Variance between CC clusters within and between patients was determined.

Result(s): Of 619 CC clusters from 193 patients, 90 were associated with immature oocytes and 505 with metaphase II oocytes. FLIM enabled quantitative measurements of the metabolic state of CC clusters. These parameters were significantly correlated with patient age and AMH independently, but not with BMI. Cumulus cell nicotinamide adenine (phosphate) dinucleotide FLIM parameters and redox ratio were significantly associated with maturity of the enclosed oocyte.

Conclusion(s): FLIM detects variations in the metabolic state of CCs, showing a greater variance among clusters from each patient than between patients. Fluorescence lifetime imaging microscopy can detect CC metabolic associations with patient age and AMH and variations between mature and immature oocytes, suggesting the potential utility of this technique to help identify superior oocytes.
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http://dx.doi.org/10.1016/j.fertnstert.2021.07.1204DOI Listing
December 2021

Validation of the French IVF guidelines during the COVID-19 pandemic.

Reprod Biomed Online 2021 09 13;43(3):491-493. Epub 2021 Jun 13.

Department of Obstetrics, Gynecology and Reproductive Medicine, Hospital Foch, Suresnes, France; Université Paris-Saclay, UVSQ, INRAE, BREED, ENVA, Jouy-en-Josas, France.

Research Question: Is a symptom questionnaire as per the French IVF guidelines adequate for screening patients during the COVID-19 pandemic?

Design: Patients planning IVF from June 2020 to February 2021 were included in the study. In compliance with French IVF guidelines, all patients fever-free on the day of oocyte retrieval were screened for risk of COVID-19 by completing a symptom questionnaire after being counselled regarding the importance of a COVID-19-free medical practice. Patients with IVF planned between June and September 2020 only completed the questionnaire (group 1), while those planning IVF after September 2020 also underwent the RT-PCR test for SARS-CoV-2 RNA (group 2). Cycle cancellation rates between groups were compared. Group 1 patients consented for follicular fluid testing for SARS-CoV-2 and an interview after cycle completion to determine COVID-19 exposure during the 6 months before and after retrieval.

Results: Cycle cancellation rates for groups 1 and 2 were 0% (0/214) versus 1.4% (8/577), respectively, (P = 0.116). All 183 follicular fluid samples from group 1 were negative for SARS-CoV-2 RNA. Of 171 patients interviewed post-IVF, 16 (93.4%) developed COVID-19 symptoms or a positive real-time PCR (RT-PCR) RT-PCR test, but none within 2 months pre- or post-retrieval.

Conclusions: These results provide reassurance that, consistent with the COVID-19 French IVF guidelines, use of a symptom questionnaire is effective in screening patients planning to undergo IVF. Failure to detect viral RNA in any follicular fluid sample does not negate the possibility that follicular fluid is a viral reservoir. However, the findings provide reassurance that the follicular environment in this study's carefully screened population was COVID-free.
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http://dx.doi.org/10.1016/j.rbmo.2021.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200252PMC
September 2021

Utilization of in vitro maturation in cases with a FSH receptor mutation.

J Assist Reprod Genet 2021 Jun 4;38(6):1311-1321. Epub 2021 Jun 4.

Department of Gyneacology, Obstetrics and Reproductive Medicine, Hospital Foch, 92150, Suresnes, France.

Purpose: To identify the FSH receptor (FSHR) variant and efficacy of in vitro maturation (IVM) in a 28-year-old woman with secondary amenorrhea, primary infertility, and ovarian resistance to FSH, and to analyze the genotype-to-phenotype relationship in cases of FSHR mutation for the development of an IVM algorithm for use in patients with gonadotropin resistance syndrome (GRS).

Methods: Oocytes retrieved after menstruation induction with norethisterone, followed by daily estrogen and an ovulatory trigger, underwent IVM, ICSI, and culture in a time-lapse (TL) incubator. Embryo transfers were performed on day 2, and after thawing on day 5. Genes associated with disorders of sex development were sequenced for both the patient and her parents. All reported cases of FSHR mutation were analyzed to investigate genotype/phenotypic relationships.

Results: After ovum pickup, seven of 16 oocytes matured and all fertilized. After unsuccessful day 2 transfer, our patient delivered with a thawed day 5 blastocyst, the sole embryo without abnormal TL phenotypes. Genetic analysis revealed a new composite heterozygous FSHR variant. Analysis of our patient case with published cases of GRS revealed associations among FSHR variant genotype, location on the FSHR, functionality of tested variants, and type of amenorrhea. An algorithm for application of IVM for GRS patients was developed.

Conclusions: We report two novel variants of the FSHR. Although IVM successfully matured some oocytes, only one resulted in an embryo with normal TL phenotypes. We recommend FSHR genetic testing in GRS patients, which will help guide their suitability for IVM.
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http://dx.doi.org/10.1007/s10815-021-02249-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266928PMC
June 2021

Utilization of preimplantation genetic testing in the USA.

J Assist Reprod Genet 2021 May 26;38(5):1045-1053. Epub 2021 Apr 26.

University College London EGA Institute for Women's Health, London, UK.

Purpose: To evaluate the use of preimplantation genetic testing (PGT) and live birth rates (LBR) in the USA from 2014 to 2017 and to understand how PGT is being used at a clinic and state level.

Methods: This study accessed SART data for 2014 to 2017 to determine LBR and the CDC for years 2016 and 2017 to identify PGT usage. Primary cycles included only the first embryo transfer within 1 year of an oocyte retrieval; subsequent cycles included transfers occurring after the first transfer or beyond 1 year of oocyte retrieval.

Results: In the SART data, the number of primary PGT cycles showed a significant monotonic annual increase from 18,805 in 2014 to 54,442 in 2017 (P = 0.042) and subsequent PGT cycles in these years increased from 2946 to 14,361 (P = 0.01). There was a significant difference in primary PGT cycle use by age, where younger women had a greater percentage of PGT treatment cycles than older women. In both PGT and non-PGT cycles, the LBR per oocyte retrieval decreased significantly from 2014 to 2017 (P<0001) and younger women had a significantly higher LBR per oocyte retrieval compared to older women (P < 0.001). The CDC data revealed that in 2016, just 53 (11.4%) clinics used PGT for more than 50% of their cycles, which increased to 99 (21.4%) clinics in 2017 (P< 0.001).

Conclusions: A growing number of US clinics are offering PGT to their patients. These findings support re-evaluation of the application for PGT.
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http://dx.doi.org/10.1007/s10815-021-02078-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190209PMC
May 2021

Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression.

Hum Reprod 2021 05;36(6):1590-1599

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Study Question: Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)?

Summary Answer: Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs.

What Is Known Already: Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF.

Study Design, Size, Duration: Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital.

Participants/materials, Setting, Methods: We assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Main Results And The Role Of Chance: Of 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization.

Limitations, Reasons For Caution: The use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes.

Wider Implications Of The Findings: Phthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility.

Study Funding/competing Interests: This work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599830PMC
May 2021

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy.

Fertil Steril 2021 04 17;115(4):841-849. Epub 2021 Mar 17.

Department of Obstetrics and Gynecology, Valencia University and INCLIVA, Valencia, Spain; Department of Obstetrics and Gynecology, BIDMC Harvard University, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.fertnstert.2021.02.045DOI Listing
April 2021

Quality of embryos on day 7 after medium refreshment on day 6: a prospective trial.

Hum Reprod 2021 04;36(5):1253-1259

Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Study Question: Are embryos that fail to meet biopsy or freezing criteria on day 6 (D6) more likely to meet these criteria on day 7 (D7) if cultured in fresh medium from D6 to D7?

Summary Answer: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7, with an adverse effect for women ≥40 years old.

What Is Known Already: Embryo development in continuous single-step medium, from fertilization to the blastocyst stage, is equivalent to that using a sequential media protocol. However, there remains a theoretical benefit of refreshing the culture environment by transitioning slowly developing D6 embryos to a fresh medium droplet of the same composition, with a renewed source of nutrients and a milieu free of metabolic toxins.

Study Design, Size, Duration: This was a prospective trial of culture media exposure in which embryos were randomized on D6 to remain in the same culture medium from D3 to D7 (continuous, n = 620) or be moved to fresh medium (fresh, n = 603) on D6, with re-evaluation on D7. Data were collected from IVF cycles, with or without ICSI, between 29 March 2019 and 17 February 2020.

Participants/materials, Setting, Methods: Embryos from 298 women, aged 18-44 years, from cycles with or without preimplantation genetic testing (PGT) that did not meet criteria for biopsy and/or freeze on D6 were included in the study. Embryos were only included if there was a minimum of two embryos meeting the inclusion criteria in any cohort. Only the first cycle undertaken by each woman in the study period from which embryos were randomized was included.

Main Results And The Role Of Chance: A total of 1254 embryos were randomized from 312 cycles (209 non-PGT and 103 PGT) including 200 women undergoing IVF without PGT and 98 women who underwent PGT. The proportion of usable blastocysts on D7 did not differ between groups: 10.1% (61/603) in fresh versus 9.7% (60/620) in continuous medium (relative risk (RR) 1.05, 95% CI 0.74-1.47)). Embryos from women ≥40 years old had a significantly decreased likelihood of achieving a usable blastocyst on D7 after culture in fresh versus continuous medium: 3.5% versus 12.2%; RR 0.29, 95% CI 0.08-0.98. In total, 9.9% of embryos otherwise discarded on D6 met the criteria for biopsy and/or freeze on D7.

Limitations, Reasons For Caution: Future work investigating implantation, clinical pregnancy and miscarriage rates with D7 embryos is still needed.

Wider Implications Of The Findings: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7 overall. Younger women were more likely to develop D7 embryos after refreshment of medium on D6, while an adverse effect was seen in women ≥40 years old. However, by extending the culture of embryos to D7, additional blastocysts become available for clinical use.

Study Funding/competing Interest(s): Funding was provided through the Department of Obstetrics and Gynecology at Brigham and Women's Hospital. I.G.I. works with Teladoc Health. A.L. has no disclosures. E.S.G. works as a consultant for Teladoc Health, and a writer and editor for UpToDate and BioMed Central. C.R. is a board member of the American Society for Reproductive Medicine and works with UpToDate.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab038DOI Listing
April 2021

The clinical relevance of luteal phase progesterone support in true natural cycle cryopreserved blastocyst stage embryo transfers: a retrospective cohort study.

Fertil Res Pract 2021 Feb 9;7(1). Epub 2021 Feb 9.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.

Background: More than 67% of all embryos transferred in the United States involve frozen-thawed embryos. Progesterone supplementation is necessary in medicated cycles to luteinize the endometrium and prepare it for implantation, but little data is available to show if this is beneficial in true natural cycles. We evaluated the use of luteal phase progesterone supplementation for cryopreserved/warmed blastocyst transfers in true natural cycles not using an ovulatory trigger.

Methods: Retrospective cohort study in a single academic medical center. We studied the use of luteal phase progesterone supplementation in patients undergoing true natural cycle cryopreserved blastocyst embryo transfers. Our primary outcome measure was ongoing pregnancy rate, with other pregnancy outcomes being evaluated (i.e. implantation rate, miscarriage rate, ectopic rate, and multifetal gestation). Categorical data were analyzed utilizing Fisher's exact test and all binary variables were analyzed using log-binomial regression to produce a risk ratio.

Results: Two hundred twenty-nine patients were included in the analysis with 149 receiving luteal phase progesterone supplementation and 80 receiving no luteal phase support. Patient demographic and cycle characteristics, and embryo quality were similar between the two groups. No difference was seen in ongoing pregnancy rate (49.0% vs. 47.5%, p = 0.8738), clinical pregnancy rate (50.3% vs. 47.5%, p = 0.7483), positive HCG rate (62.4% vs. 57.5%, p = 0.5965), miscarriage/abortion rate (5.4% vs. 2.5%, p = 0.2622), ectopic pregnancy rate (0% vs. 1.3%, p = 0.3493), or multifetal gestations (7.4% vs. 3.8%, p = 0.3166).

Conclusion(s): The addition of luteal phase progesterone support in true natural cycle cryopreserved blastocyst embryo transfers did not improve pregnancy outcomes and therefore the routine use in practice cannot be recommended based on this study, but the utilization should not be discouraged without further studies.

Capsule: Progesterone supplementation as luteal phase support in true natural cycle cryopreserved blastocyst transfers does not improve ongoing pregnancies.
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http://dx.doi.org/10.1186/s40738-021-00096-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871584PMC
February 2021

Electronic whiteboard implementation as a quality management tool optimizes IVF laboratory standardization and improves clinical outcomes.

J Assist Reprod Genet 2021 Jan 11;38(1):203-210. Epub 2020 Nov 11.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham & Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Purpose: To test whether an electronic whiteboard in the IVF laboratory increases the likelihood that critical evaluation procedures are performed within optimum pre-set time ranges.

Methods: A retrospective cohort study of oocyte retrievals in our IVF clinic between 06/01/2012 and 05/31/2018 was included. The electronic whiteboard was introduced on 04/06/2014. Prior to implementation, embryologists strived to adhere to the set evaluation times without a formal guide. The primary outcomes were the proportion of embryologist evaluations performed in optimum time ranges and the proportion of usable embryos per patient.

Results: A total of 4645 retrievals met inclusion criteria. Implementation of the whiteboard was associated with (1) an increase in the proportion of fertilization checks performed within the optimum time range for ICSI cycles (+ 5.1%, RR = 1.06, CI = 1.02-1.10); (2) an increase in the proportion of day 3 evaluations performed within the optimum time range, whether assisted hatching was performed (+ 23.6%, RR = 1.48, CI = 1.36-1.60) or not (+ 13.8%, RR = 1.23, CI = 1.12-1.35); and (3) an increase in the proportion of day 5 evaluations within the optimum time range (+ 15.5%, RR = 1.23, CI = 1.12-1.35). Additionally, the mean number of usable embryos per patient increased from 2.8 to 4.5 after the whiteboard was implemented (RR = 1.25, CI = 1.19-1.31).

Conclusion: The use of an electronic whiteboard that posts optimum times for performing critical procedures significantly increases the proportion of evaluations that occur within these ranges. Such improved standardization led to positive downstream effects on the number of usable embryos per patient. We suggest that electronic whiteboard implementation driven by real-time data collection should be considered in all IVF laboratories.
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http://dx.doi.org/10.1007/s10815-020-02007-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822993PMC
January 2021

Letter to editor.

J Assist Reprod Genet 2020 Nov 22;37(11):2653-2655. Epub 2020 Oct 22.

Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA.

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http://dx.doi.org/10.1007/s10815-020-01968-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577779PMC
November 2020

Seasonal variation, temperature, day length, and IVF outcomes from fresh cycles.

J Assist Reprod Genet 2020 Oct 13;37(10):2427-2433. Epub 2020 Aug 13.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: It is known that delivery rates from spontaneous conception vary according to season which may be due to cultural or environmental factors; however, conflicting data exist regarding whether outcomes from IVF are also seasonally dependent. The present study was designed to test the hypothesis that the season at oocyte retrieval is associated with livebirth after fresh transfer.

Methods: Dates of oocyte retrieval for all autologous cycles in our IVF program between January 2012 and December 2017 were categorized by season. Dates were linked to local temperature (min, max, average) and day length obtained from meteorological records. Average maximum temperature and day length were categorized into tertiles. Multivariable logistic regression, adjusted for age and quadratic age, were used to model odds (aOR) of implantation, clinical pregnancy, spontaneous abortion, and livebirth.

Results: Patient characteristics were similar across seasons. As expected, temperature and day length varied by season. When compared with cycles started during winter, there was no difference in the age-adjusted odds of livebirth for the other three seasons (spring: aOR: 0.97, 95% CI: 0.82-1.13; summer: aOR: 1.05, 0.90-1.23; fall: aOR: 0.98, 0.84-1.15). There was a positive linear trend between temperature and odds of implantation, and clinical pregnancy (p value, test for linear trend (implantation, p = 0.02; clinical pregnancy, p = 0.01)) but no association with livebirth for temperature or day length.

Conclusions: We found that season at oocyte retrieval was not associated with livebirth, contrary to patterns seen in naturally conceived populations. However, our data did suggest modestly higher odds of clinical pregnancy for retrievals in June and July, and that higher temperature at time of retrieval was associated with higher odds of clinical pregnancy but not livebirth.
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http://dx.doi.org/10.1007/s10815-020-01915-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550498PMC
October 2020

Machine learning vs. classic statistics for the prediction of IVF outcomes.

J Assist Reprod Genet 2020 Oct 11;37(10):2405-2412. Epub 2020 Aug 11.

Department of Obstetrics and Gynecology, Sheba Medical Center, 52561, Ramat Gan, Israel.

Purpose: To assess whether machine learning methods provide advantage over classic statistical modeling for the prediction of IVF outcomes.

Methods: The study population consisted of 136 women undergoing a fresh IVF cycle from January 2014 to August 2016 at a tertiary, university-affiliated medical center. We tested the ability of two machine learning algorithms, support vector machine (SVM) and artificial neural network (NN), vs. classic statistics (logistic regression) to predict IVF outcomes (number of oocytes retrieved, mature oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births) based on age and BMI, with or without clinical data.

Results: Machine learning algorithms (SVM and NN) based on age, BMI, and clinical features yielded better performances in predicting number of oocytes retrieved, mature oocytes, fertilized oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births, compared with logistic regression models. While accuracies were 0.69 to 0.9 and 0.45 to 0.77 for NN and SVM, respectively, they were 0.34 to 0.74 using logistic regression models.

Conclusions: Our findings suggest that machine learning algorithms based on age, BMI, and clinical data have an advantage over logistic regression for the prediction of IVF outcomes and therefore can assist fertility specialists' counselling and their patients in adjusting the appropriate treatment strategy.
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http://dx.doi.org/10.1007/s10815-020-01908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550518PMC
October 2020

Trophectoderm biopsy-perhaps not such a benign intervention.

Fertil Steril 2020 10 16;114(4):748-749. Epub 2020 Jul 16.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.fertnstert.2020.06.027DOI Listing
October 2020

Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved single embryo transfer: a retrospective cohort study.

Fertil Res Pract 2020 1;6:10. Epub 2020 Jul 1.

Department of Obstetrics & Gynecology, Brigham & Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 USA.

Background: The optimal route of progesterone administration for luteal support in cryopreserved embryo transfer (CET) has been the subject of much debate. While most published research has pertained to day 3 transfers, recent data on blastocyst CET has suggested that intramuscular progesterone (IMP) is superior to twice daily vaginal Endometrin suppositories for luteal phase support, resulting in significantly higher ongoing pregnancy rates. This study aimed to determine whether IMP is similarly superior to 8% Crinone vaginal gel for luteal phase support following blastocyst CET.

Methods: Autologous and donor oocyte blastocyst cryopreserved single embryo transfer (SET) cycles from January 2014-January 2019 utilizing either 50 mg IMP daily or 90 mg 8% Crinone gel twice daily for luteal support were included. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, spontaneous abortion, and clinical pregnancy. All analyses were adjusted a priori for oocyte age. Log-binomial regression analysis was performed with differences in outcomes reported as relative risk (RR) with 95% confidence intervals (CI).

Results: A total of 1710 cycles were included, of which 1594 utilized IMP and 116 utilized 8% Crinone gel. Demographic and cycles characteristics were similar between the two groups. Compared to cycles utilizing IMP, cycles utilizing Crinone gel resulted in similar rates of live birth (RR 0.91; 95% CI 0.73-1.13), biochemical pregnancy (RR 1.12, 95% CI 0.65-1.92), spontaneous abortion (RR 1.41, 95% CI 0.90-2.20), and clinical pregnancy (RR 1.00, 95% CI 0.86-1.17).

Conclusions: Compared to cryopreserved blastocyst SET cycles utilizing IMP for luteal support, cycles utilizing 8% Crinone gel resulted in similar likelihood of live birth.
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http://dx.doi.org/10.1186/s40738-020-00079-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329474PMC
July 2020

Endometrioma, the follicular fluid inflammatory network and its association with oocyte and embryo characteristics.

Reprod Biomed Online 2020 Mar 23;40(3):399-408. Epub 2019 Dec 23.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA; Boston Center for Endometriosis, Boston Children's and Brigham and Women's Hospitals, Boston MA, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, 400 Monroe Avenue NW, Grand Rapids MI, 49503, USA.

Research Question: What is the association between endometrioma-affected ovaries, their follicular fluid inflammatory microenvironment, and ovary-specific oocyte and embryo yield and quality?

Design: Exposure-matched prospective cohort study conducted at a university-affiliated infertility clinic. Thirty-four women presenting for oocyte retrieval were enrolled between 2012 and 2013: women with unilateral endometrioma and no other observed peritoneal or deep lesions (n = 10) and women with no signs or symptoms of endometriosis (n = 24). Follicular fluid was aspirated at the time of oocyte retrieval. Samples from each ovary were analysed using a 27-plex immunoassay panel. The associations were evaluated by ovary-specific endometrioma exposure status (affected, unaffected, unexposed) with cytokine levels, oocyte yield and embryo quality.

Results: Levels of interleukin (IL)-8 and monocyte chemoattractant protein-1 were higher in fluid obtained from endometrioma-affected ovaries compared with the unexposed ovaries from women without endometriosis, with intermediate levels observed in the contralateral unaffected ovaries. More modest differences were observed for IL-1β and IL-6. The affected ovaries of women with endometriosis yielded fewer oocytes (mean ± SD = 4.6 ± 2.3) compared with both the unaffected (6.0 ± 3.8) and unexposed (7.9 ± 5.6) ovaries. After adjusting for potential confounders and variables generated in a cytokine principal components analysis, oocyte yield remained slightly lower for the endometrioma-affected ovaries compared with unexposed ovaries. No informative differences among ovary groups for embryo quality parameters were observed.

Conclusions: The results suggest that the inflammatory milieu of ovarian endometriosis is strongly localized and has a more modestly systemic effect. The effect of endometriomas on infertility, however, cannot be entirely explained by increased inflammation.
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http://dx.doi.org/10.1016/j.rbmo.2019.12.005DOI Listing
March 2020

Reply to Gleicher and Barad: Noninvasive preimplantation genetic testing may provide the solution to the problem of embryo mosaicism.

Proc Natl Acad Sci U S A 2019 10 1;116(44):21978-21979. Epub 2019 Oct 1.

Beijing Advanced Innovation Center for Genomics, Peking University, Beijing 100871, China;

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http://dx.doi.org/10.1073/pnas.1912042116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825306PMC
October 2019

Association between blastocyst morphology and pregnancy and perinatal outcomes following fresh and cryopreserved embryo transfer.

J Assist Reprod Genet 2019 Nov 12;36(11):2315-2324. Epub 2019 Sep 12.

Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham & Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Purpose: To assess the importance of each blastocyst morphological criteria with pregnancy and perinatal outcomes.

Methods: This single-center retrospective cohort study included blastocyst single embryo transfers (SET) performed between 1/2012-2/2018. Poisson regression was used to evaluate pregnancy outcomes following fresh and cryopreserved embryo transfer (CET) for association with blastocyst expansion, inner cell mass (ICM) quality, and trophectoderm (TE) quality. Among cycles resulting in live birth, associations with preterm birth, small for gestational age (SGA) and large for gestational age (LGA), were evaluated using logistic regression.

Results: A total of 1023 fresh and 1222 CET cycles were included, of which 465 (45.1%) fresh and 600 (48.5%) CET cycles resulted in singleton live birth. Clinical pregnancy rates increased with increasing expansion among fresh transfers (p for trend = 0.001) but not CET (p = 0.221), and with TE quality for both fresh and CET cycles (p = 0.005 and < 0.0001, respectively). Live birth rates increased with increasing expansion (fresh p = 0.005, CET p = 0.018) and TE quality (fresh p = 0.028, CET p = 0.023). ICM grade was not associated with pregnancy outcomes; however, higher ICM quality among CET cycles was associated with increased chance of preterm birth (p = 0.005).

Conclusions: In blastocyst SET, blastocyst expansion and TE quality were each associated with clinical pregnancy and live birth. While higher ICM quality was associated with increased chance of preterm birth among CET, no other associations with perinatal outcomes were identified. Clinicians can be reassured that pregnancies from blastocysts with lower expansion, ICM, or TE qualities are not more likely to result in adverse perinatal outcomes.
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http://dx.doi.org/10.1007/s10815-019-01580-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885471PMC
November 2019

Hyperglycosylated human chorionic gonadotropin as a predictor of ongoing pregnancy.

Am J Obstet Gynecol 2020 01 8;222(1):68.e1-68.e12. Epub 2019 Aug 8.

Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Hyperglycosylated human chorionic gonadotropin, the predominant human chorionic gonadotropin variant secreted following implantation, is associated with trophoblast invasion.

Objective: To determine whether the initial serum hyperglycosylated human chorionic gonadotropin differs between ongoing and failed pregnancies, and to compare it to total serum human chorionic gonadotropin as a predictor of ongoing pregnancy.

Materials And Methods: Women undergoing fresh/frozen in vitro fertilization cycles at a university-based infertility clinic with an autologous day 5 single embryo transfer resulting in serum human chorionic gonadotropin >3 mIU/mL (n = 115) were included. Human chorionic gonadotropin was measured 11 days after embryo transfer in a single laboratory (coefficient of variation <6%). Surplus frozen serum (-80C) was shipped to Quest Laboratories for measurement of hyperglycosylated human chorionic gonadotropin (coefficient of variation <9.1%). Linear regression analyses adjusted for oocyte age a priori were used to compare human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin in ongoing pregnancies (>8 weeks of gestation) and failed pregnancies (clinical pregnancy loss, biochemical and ectopic pregnancies).

Results: A total of 85 pregnancies (73.9%) were ongoing. Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated (Pearson correlation coefficient 92.14, P < .0001), and mean values of both were positively correlated with blastocyst expansion score (P value test for trend < .0004). Mean human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin were significantly higher in ongoing vs failed pregnancies. Among ongoing pregnancies vs clinical losses, mean hyperglycosylated human chorionic gonadotropin, but not human chorionic gonadotropin, was significantly higher (19.0 vs 12.2 ng/mL, β -8.1, 95% confidence interval -13.0 to -3.2), and hyperglycosylated human chorionic gonadotropin comprised a higher proportion of total human chorionic gonadotropin (4.6% vs 4.1%; risk ratio, 0.79; 95% confidence interval, 0.66-0.94).

Conclusion: Measured 11 days after single blastocyst transfer, hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated, but only mean hyperglycosylated human chorionic gonadotropin and its ratio to total human chorionic gonadotropin were significantly higher in ongoing pregnancies vs clinical pregnancy losses. Further evaluation of hyperglycosylated human chorionic gonadotropin, including in multiple embryo transfers and multiple pregnancy, and using serial measurements, is required.
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http://dx.doi.org/10.1016/j.ajog.2019.08.004DOI Listing
January 2020

Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy.

Proc Natl Acad Sci U S A 2019 07 24;116(28):14105-14112. Epub 2019 Jun 24.

Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

Preimplantation genetic testing for aneuploidy (PGT-A) with trophectoderm (TE) biopsy is widely applied in in vitro fertilization (IVF) to identify aneuploid embryos. However, potential safety concerns regarding biopsy and restrictions to only those embryos suitable for biopsy pose limitations. In addition, embryo mosaicism gives rise to false positives and false negatives in PGT-A because the inner cell mass (ICM) cells, which give rise to the fetus, are not tested. Here, we report a critical examination of the efficacy of noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) in the spent culture media of human blastocysts by analyzing the cell-free DNA, which reflects ploidy of both the TE and ICM. Fifty-two frozen donated blastocysts with TE biopsy results were thawed; each of their spent culture medium was collected after 24-h culture and analyzed by next-generation sequencing (NGS). niPGT-A and TE-biopsy PGT-A results were compared with the sequencing results of the corresponding embryos, which were taken as true results for aneuploidy reporting. With removal of all corona-cumulus cells, the false-negative rate (FNR) for niPGT-A was found to be zero. By applying an appropriate threshold for mosaicism, both the positive predictive value (PPV) and specificity for niPGT-A were much higher than TE-biopsy PGT-A. Furthermore, the concordance rates for both embryo ploidy and chromosome copy numbers were higher for niPGT-A than TE-biopsy PGT-A. These results suggest that niPGT-A is less prone to errors associated with embryo mosaicism and is more reliable than TE-biopsy PGT-A.
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http://dx.doi.org/10.1073/pnas.1907472116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628824PMC
July 2019

Body mass index in relation to extracellular vesicle-linked microRNAs in human follicular fluid.

Fertil Steril 2019 08 27;112(2):387-396.e3. Epub 2019 May 27.

Department of Obstetrics and Gynecology, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel. Electronic address:

Objective: To study whether increased body mass index is associated with altered expression of extracellular vesicle microRNAs (EV-linked miRNAs) in human follicular fluid.

Design: Cross-sectional study.

Setting: Tertiary-care university-affiliated center.

Patient(s): One hundred thirty-three women undergoing in vitro fertilization (IVF) were recruited from January 2014 to August 2016.

Interventions(s): None.

Main Outcome Measure(s): EV-linked miRNAs were isolated from follicular fluid and their expression profiles were measured with the use of the Taqman Open Array Human miRNA panel. EV-linked miRNAs were globally normalized and inverse-normal transformed. Associations between body mass index (BMI) and EV-linked miRNA outcomes were analyzed by means of multivariate linear regression and principal component analysis.

Result(s): Eighteen EV-linked miRNAs were associated with an increase in BMI after adjusting for age, ethnicity, smoking status, and batch effects. Hsa-miR-328 remained significant after false discovery rate adjustments. Principal component analyses identified the first principal component to account for 40% of the variation in our EV-linked miRNA dataset, and adjusted linear regression found that the first principal component was significantly associated with BMI after multiple testing adjustments. Using Kyoto Encyclopedia of Genes and Genomes enrichment analyses, we predicted gene targets of EV-linked miRNA in silico and identified PI3K-Akt signaling, ECM-receptor interaction, focal adhesion, FoxO signaling, and oocyte meiosis pathways.

Conclusion(s): These results show that a 1-unit increase in BMI is associated with altered follicular fluid expression of EV-linked miRNAs that may influence follicular and oocyte developmental pathways. Our findings provide potential insight into a mechanistic explanation for the reduced fertility rates associated with increased BMI.
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http://dx.doi.org/10.1016/j.fertnstert.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663626PMC
August 2019

The Implications of Reproductive Aging for the Health, Vitality and Economic Welfare of Human Societies.

J Clin Endocrinol Metab 2019 Apr 16. Epub 2019 Apr 16.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Context: Powerful demographic transitions towards aging of human populations, older age at first childbirth, and lower birth-rates will profoundly influence the health, vitality, and economies of human societies, and deserve greater attention in health policy and research.

Evidence Acquisition: Information on birth-rates, fertility rates, and outcomes of assisted reproductive technologies were obtained from databases of government agencies (census data, Centers for Disease Control).

Evidence Synthesis: Fecundity declines with advancing age, especially in women >35 and in men >50. Advanced parental age adversely affects pregnancy outcomes for the mother and the offspring, and increases the offspring's risk of chromosomal disorders, neurodegenerative diseases and birth defects. Because of increased life expectancy, today, men and women can expect to spend a major portion of their life during a period of reproductive senescence; diseases associated with reproductive senescence will influence the health and wellbeing of middle-aged and older adults. Inversion of the population age pyramid would affect healthcare costs, retirement age, generational distribution of wealth, and the vitality of human societies.Several actions can be taken to mitigate the societal consequences of these trends. An educational campaign to inform young people about the trade-offs associated with postponement of childbirth will enable them to make informed choices. Some repositioning of research agenda and healthcare policy is needed to address the public health threat posed by reproductive aging.

Conclusion: The societal consequences of low fertility rates and delayed parenthood on nation's health, vitality, and economic growth should be considered in crafting research, health and economic policy.
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http://dx.doi.org/10.1210/jc.2019-00315DOI Listing
April 2019

Maternal-biased H3K27me3 correlates with paternal-specific gene expression in the human morula.

Genes Dev 2019 04 26;33(7-8):382-387. Epub 2019 Feb 26.

Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin-dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased toward the maternal allele with some associated with DNA methylation-independent paternally expressed genes (PEGs) in human morulae. The H3K27me3 domains largely overlap with DNA partially methylated domains (PMDs) and occupy developmental gene promoters. Thus, our study not only reveals the H3K27me3 landscape but also establishes a correlation between maternal-biased H3K27me3 and PEGs in human morulae.
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http://dx.doi.org/10.1101/gad.323105.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446541PMC
April 2019

Supraphysiological Concentrations of Bisphenol A Alter the Expression of Extracellular Vesicle-Enriched miRNAs From Human Primary Granulosa Cells.

Toxicol Sci 2019 05;169(1):5-13

Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Bisphenol A (BPA) is a widely used chemical that has been detected in follicular fluid and associated with adverse reproductive effects. Granulosa cells have an important role in follicular growth and oocyte maturation, however, little is known about the biological mechanisms of BPA toxicity on human granulosa cells. In this study, we exposed primary granulosa cells to different concentrations of BPA (0, 20, 200, 2000, and 20 000 ng/ml) and used quantitative polymerase chain reaction to measure the expression levels of miRNAs enriched in extracellular vesicles (EV-enriched miRNAs), and cellular levels of selected target genes of differentially expressed EV-enriched miRNAs. We found that exposure to 20 000 ng/ml BPA was associated with decreased levels of EV-miR-27b-3p (FC = 0.58, p = .04) and increased levels of its biologically relevant target genes FADD (FC = 1.22, p = .01), IGF1 (FC = 1.59, p = .06), and PPARG (FC = 1.73, p = .001) as compared with the control. In addition, we observed that under the same exposure conditions, the expression levels of miR-27b-3p in granulosa cells were also downregulated (FC = 0.65, p = .03) as compared with the control. Our findings suggest that both cellular and extracellular changes in gene expression may mediate BPA toxicity in granulosa cells.
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http://dx.doi.org/10.1093/toxsci/kfz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804414PMC
May 2019

Making evidence-based decisions in reproductive medicine.

Fertil Steril 2018 12;110(7):1227-1230

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.fertnstert.2018.08.010DOI Listing
December 2018

Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

Environ Int 2019 02 24;123:20-28. Epub 2018 Nov 24.

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan 52561 and, Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

Background: Phenols and phthalates are potential endocrine disrupting chemicals (EDCs) that are associated with adverse health outcomes. These EDCs dysregulate a number of biomolecules and pathways, including microRNAs. MicroRNAs can be carried in transport systems called extracellular vesicles (EVs) that are present in most biofluids. EVs in the follicular fluid, which fills the ovarian follicle and influences oocyte developmental competency, carry microRNAs (EV-miRNAs) that have been associated with In Vitro Fertilization (IVF) outcomes. However, it remains unclear whether EDCs affect EV-miRNAs in follicular fluid.

Objectives: This study sought to determine whether urinary concentrations of phenols and phthalates biomarkers are associated with EV-miRNAs expression in follicular fluid collected from women undergoing IVF treatment.

Methods: This cross-sectional study included 130 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. Participants provided urine samples during ovarian stimulation and on the day of oocyte retrieval. We assessed urinary concentrations of five phenols, eight phthalate metabolites, and one phthalate alternative metabolite. EV-miRNAs were isolated from follicular fluid and their expression profiles were measured using the TaqMan Open Array® Human microRNA panel. We fitted multivariable linear regression models and principal component analysis to examine associations between individual and molar sums of exposure biomarkers and EV-miRNAs.

Results: Of 754 miRNAs tested, we detected 133 EV-miRNAs in the microRNA array which expressed in at least 50% of the follicular fluid samples. After adjusting for multiple testing, we identified eight EV-miRNAs associated with individual phenols and phthalate metabolites, as well as molar ΣDEHP that met a q < 0.10 false-discovery rate (FDR) threshold. Hsa-miR-125b, hsa-miR-106b, hsa-miR-374a, and hsa-miR15b was associated with mono(2-ethylhexyl) phthalate concentrations, hsa-let-7c with concentrations mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of metabolites of di(2-ethylhexyl) phthalate, hsa-miR-24 with mono-n-butyl phthalate concentrations, hsa-miR-19a with cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), and hsa-miR-375 with ethyl paraben concentrations. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, gene targets and pathways of these EV-miRNAs were predicted in silico and 17 KEGG FDR-significant pathways related to follicular development and oocyte competence were identified.

Conclusions: Our results show that urinary concentrations of select phenol and phthalate metabolites are correlated with altered EV-miRNAs expression in follicular fluid. These findings may provide insight regarding the molecular mechanisms underlying adverse effects of phenol and phthalate exposure on female fertility.
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http://dx.doi.org/10.1016/j.envint.2018.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343661PMC
February 2019

Extracellular microRNAs profile in human follicular fluid and IVF outcomes.

Sci Rep 2018 11 19;8(1):17036. Epub 2018 Nov 19.

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan, 52561, Israel.

Encapsulated microRNAs (i.e., miRNAs within the extracellular vesicles, i.e., EV-miRNAs) have been detected in follicular fluid in both animal and human studies and different profiles have been associated with IVF cycle characteristics. However, limited studies to date have investigated other IVF outcomes, including fertilization status and embryo quality on day three". In this cohort, we performed a cross-sectional analysis on 126 women who contributed follicular fluid from a single follicle during a single IVF cycle. One hundred and ninety-two EV-miRNAs were assessed by univariable fold-change and multivariable logistic regression analyses. Hsa-miR-92a and hsa-miR-130b, were over-expressed in follicular fluid samples from oocytes that failed to fertilize compared to those that were normally fertilized. Additionally, hsa-miR-888 was over-expressed and hsa-miR-214 and hsa-miR-454 were under-expressed in samples that resulted in impaired day-3 embryo quality compared to top-quality day-3 embryos. After adjusting for confounders as BMI, smoking and total motile sperm, associations of these EV-miRNAs remained significant. In-silico KEGG pathway analyses assigned the identified EV-miRNAs to pathways of follicular growth and development, cellular signaling, oocyte meiosis, and ovarian function. Our findings suggest that EV-miRNAs may play a role in pathways of ovarian function and follicle development, which could be essential for understanding the molecular mechanisms that could lead to a successful pregnancy and birth.
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http://dx.doi.org/10.1038/s41598-018-35379-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242846PMC
November 2018

The cost of a euploid embryo identified from preimplantation genetic testing for aneuploidy (PGT-A): a counseling tool.

J Assist Reprod Genet 2018 Sep 31;35(9):1641-1650. Epub 2018 Jul 31.

Center for Infertility and Reproductive Surgery, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Purpose: To determine the expected out-of-pocket costs of IVF with preimplantation genetic testing for aneuploidy (PGT-A) to attain a 50%, 75%, or 90% likelihood of a euploid blastocyst based on individual age and AMH, and develop a personalized counseling tool.

Methods: A cost analysis was performed and a counseling tool was developed using retrospective data from IVF cycles intended for PGT or blastocyst freeze-all between January 1, 2014 and August 31, 2017 (n = 330) and aggregate statistics on euploidy rates of > 149,000 embryos from CooperGenomics. Poisson regression was used to determine the number of biopsiable blastocysts obtained per cycle, based on age and AMH. The expected costs of attaining a 50%, 75%, and 90% likelihood of a euploid blastocyst were determined via 10,000 Monte Carlo simulations for each age and AMH combination, incorporating age-based euploidy rates and IVF/PGT-A cost assumptions.

Results: The cost to attain a 50% likelihood of a euploid blastocyst ranges from approximately $15,000 U.S. dollars (USD) for younger women with higher AMH values (≥ 2 ng/mL) to > $150,000 for the oldest women (44 years) with the lowest AMH values (< 0.1 ng/mL) in this cohort. The cost to attain a 75% versus 90% likelihood of a euploid blastocyst is similar (~ $16,000) for younger women with higher AMH values, but varies for the oldest women with low AMH values (~ $280,000 and > $450,000, respectively). A typical patient (36-37 years, AMH 2.5 ng/mL) should expect to spend ~ $30,000 for a 90% likelihood of attaining a euploid embryo.

Conclusions: This tool can serve as a counseling adjunct by providing individualized cost information for patients regarding PGT-A.
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http://dx.doi.org/10.1007/s10815-018-1275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133815PMC
September 2018

The association between quality of supernumerary embryos in a cohort and implantation potential of the transferred blastocyst.

J Assist Reprod Genet 2018 Sep 5;35(9):1651-1656. Epub 2018 Jul 5.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA.

Purpose: Despite studies focused on the association between embryo morphology and implantation potential, it is unknown how the collective quality of the supernumerary embryos in a cohort is associated with the implantation rate (IR) of the transferred embryo. This study tested the hypothesis that a relationship exists between the quality of the supernumerary cohort and IR.

Methods: A retrospective cohort study of first fresh autologous IVF cycles from 05/2012 to 09/2016, with ≥ 3 blastocysts, resulting in a single blastocyst transfer (n = 819) was performed. Cohorts were grouped in two ways: by mean priority score (PS; 1 being best) of supernumerary embryos and by percent supernumerary embryos with low implantation potential. The relationship between cohort quality and IR was assessed using logistic regression.

Results: As mean cohort PS increased, IR of the transferred embryo decreased (test for linear trend, p = 0.05). When ≥ 75% of the supernumerary cohort was predicted to have low implantation potential, IR of the transferred embryo was significantly lower compared to when < 75% of the cohort was predicted to have low implantation potential (OR 0.71; 95% CI (0.53-0.94)). All associations were attenuated when adjusting for PS of the transferred embryo.

Conclusions: Our findings suggest that quality of supernumerary embryos is associated with IR of the transferred embryo, among patients with ≥ 3 blastocysts available on day 5. As cohort quality declines and the proportion of low implantation potential embryos increases, the IR of the transferred embryo declines. These associations are attenuated when controlling for quality of the transferred embryo, suggesting that the relationship between embryo cohort quality and implantation is not independent of the transferred embryo quality.
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http://dx.doi.org/10.1007/s10815-018-1254-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133805PMC
September 2018
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