Publisher: Oxford University Press   (Total: 411 journals)

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Showing 1 - 200 of 411 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (Followers: 3, SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 58, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 7, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access   (Followers: 1)
African Affairs     Hybrid Journal   (Followers: 72, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 94, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 20, SJR: 1.376, CiteScore: 3)
American Entomologist     Hybrid Journal   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 208, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 53, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 221, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 220, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 62, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 28, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 10, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 29, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 18, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 25, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 2)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 61, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 11, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 36, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access  
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 17, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 63, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 22)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 32, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 55, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 386, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal   (Followers: 1)
Biology of Reproduction     Full-text available via subscription   (Followers: 11, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 3, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 18, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 216, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 68)
Brain     Hybrid Journal   (Followers: 75, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 53, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 40, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 620, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 98, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 35)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 73, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 12, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 15, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 54, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 25, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 8, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 24, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 11, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 29, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 77, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 28, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 29, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 28, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 7, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 5)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 4, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 10, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 15, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 24, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 17, SJR: 0.139, CiteScore: 0)
Econometrics J.     Hybrid Journal   (Followers: 34, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 123, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 58, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 21, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 12, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 22, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 67, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 10, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access   (Followers: 1)
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 235, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 5, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 45, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 18, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 37, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 25, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 8, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 36, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 3)
Genome Biology and Evolution     Open Access   (Followers: 17, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 38, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 26, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 6, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 11, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 69, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 19, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 26, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 27, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 30, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 11, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 77, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 66, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 58, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 12)
ILAR J.     Hybrid Journal   (Followers: 3, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 11, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 44, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 45, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access   (Followers: 1)
Insect Systematics and Diversity     Hybrid Journal  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 10, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 5, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 70, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 22)
Intl. Health     Hybrid Journal   (Followers: 7, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 39, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 56, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 286, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 20, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 9, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 39, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 14, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 41, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 25, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 55, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 24, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 18, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 52, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 16, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.226, CiteScore: 2)
J. of Breast Imaging     Full-text available via subscription   (Followers: 2)

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Similar Journals
Journal Cover
Human Reproduction
Journal Prestige (SJR): 2.643
Citation Impact (citeScore): 5
Number of Followers: 77  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
Published by Oxford University Press Homepage  [411 journals]
  • Long, dark, cozy nights'
    • Authors: (Nils Lambalk C.
      Abstract: The human female is not a seasonal breeder. However, some seasonality in birthrates is an acknowledged phenomenon. But good research into a seasonal effect at time of conception is lacking, albeit not absent. For example, Cummings (2010) showed that exposure to light plays a role in the generation of lust in primates such as chimpanzees and baboons. A Swedish study (Carlsen et al., 2004) showed that men ejaculate more often when winter is over.
      PubDate: Sun, 29 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa066
      Issue No: Vol. 35, No. 3 (2020)
  • Identity-by-state analysis: a new method for PGT-M
    • Authors: Brown S.
      Pages: 485 - 487
      PubDate: Sat, 21 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa011
      Issue No: Vol. 35, No. 3 (2020)
  • Fertility, season and a legitimate role for P-values
    • Authors: Weinberg C.
      Pages: 488 - 489
      Abstract: Some mammals are seasonal breeders, with fertility depending on the light–dark cycle, but humans are considered to be continuous breeders. Whether human fecundability nonetheless varies with season has not been well studied. In this journal issue, Wesselink et al. (2019) report intriguing findings based on a large cohort of women attempting to conceive without fertility treatment in North America (the PRESTO study) and Denmark (the Snart Gravid study). Their analysis carefully adjusted for the seasonal patterns of the initiations of attempts to conceive, an important adjustment (Basso et al., 1995), which earlier work had neglected. Based on the extensive data from the two cohorts, they report that fecundability was evidently higher in the fall and lower in the spring. Interestingly, the estimated amplitude of the effect was greater at lower latitudes.
      PubDate: Thu, 13 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa006
      Issue No: Vol. 35, No. 3 (2020)
  • Hidden in plain sight: the overstated benefits and underestimated losses
    • Authors: Paulson R.
      Pages: 490 - 493
      Abstract: AbstractThe utilization of preimplantation genetic testing for aneuploidy (PGT-A) has understandable intuitive appeal in reassuring the clinician that ‘everything possible’ has been done to assure the birth of a healthy baby. Whereas the development of the PGT-A technology is still in a relatively early stage, great strides have nevertheless been made in the understanding of the genetics of the preimplantation human embryo. The problem lies not in the progress that has been achieved, but rather, in the reality that PGT-A is being actively marketed as a mature technology. Those that market the technology overstate its benefits and underestimate the losses of potential implantations that are the consequence of the practice of PGT-A. The implication is that the PGT-A technology is accurate, has minimal errors and is ready to be applied to every case of IVF. This approach is not evidence-based. Substantial losses of potential implantations are even evident in the analysis of the numbers presented by marketing materials themselves. In order to provide accurate, evidence-based counseling for patients undergoing IVF, we need to apply an appropriate level of scientific scrutiny to the data that are available and apply PGT-A selectively to those cases in which the benefits clearly outweigh the costs.
      PubDate: Tue, 25 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez280
      Issue No: Vol. 35, No. 3 (2020)
  • Posttranslational lysine 2-hydroxyisobutyrylation of human sperm tail
           proteins affects motility
    • Authors: Cheng Y; Peng Z, Chen H, et al.
      Pages: 494 - 503
      Abstract: AbstractSTUDY QUESTIONDoes lysine 2-hydroxyisobutyrylation, a newly identified protein posttranslational modification (PTM), occur in human sperm and affect human sperm function'SUMMARY ANSWERLysine 2-hydroxyisobutyrylation mainly occurs in human sperm tail proteins, and excessive lysine 2-hydroxyisobutyrylation affects human sperm motility.WHAT IS KNOWN ALREADYPTM is regarded as an important pathway in regulating sperm function since mature sperm are almost transcriptionally silent. However, only phosphorylation was extensively studied in mature sperm to date. Lysine 2-hydroxyisobutyrylation, a newly characterised PTM, is broadly conserved in both eukaryotic and prokaryotic cells. Although histone lysine 2-hydroxyisobutyrylation has been shown to be associated with active gene expression in spermatogenic cells, the presence, regulatory elements and function of lysine 2-hydroxyisobutyrylation have not been characterised in mature sperm.STUDY DESIGN, SIZE, DURATIONSperm samples were obtained from normozoospermic men and asthenozoospermic men who visited the reproductive medical centre at Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi, China, between May 2017 and November 2018. In total, 58 normozoospermic men and 65 asthenozoospermic men were recruited to participate in this study.PARTICIPANTS/MATERIALS, SETTING, METHODSLysine 2-hydroxyisobutyrylation was examined using immunoblotting and immunofluorescence assays using a previously qualified pan anti-lysine 2-hydroxyisobutyrylation antibody. The immunofluorescence assay was imaged using super-resolution structured illumination microscopy. Sperm viability was examined by using the eosin staining method, and sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm penetration ability was determined by evaluating the ability of the sperm to penetrate a 1% (w/v) methylcellulose solution. The level of intracellular adenosine triphosphate (ATP) was detected using a rapid bioluminescent ATP assay kit.MAIN RESULTS AND THE ROLE OF CHANCELysine 2-hydroxyisobutyrylation was present in several proteins (20–100 kDa) mainly located in the tail of human sperm. Sperm lysine 2-hydroxyisobutyrylation was derived from 2-hydroxyisobutyrate (2-Hib) and was regulated by acyltransferase P300 and nicotinamide adenine dinucleotide-dependent lysine deacylase sirtuins. Elevation of sperm lysine 2-hydroxyisobutyrylation by 2-Hib decreased total motility, progressive motility, penetration ability and ATP level of human sperm. Interestingly, the level of sperm lysine 2-hydroxyisobutyrylation was higher in asthenozoospermic men than that in normozoospermic men and was negatively correlated with the progressive motility of human sperm. Furthermore, high levels of lysine 2-hydroxyisobutyrylation in asthenozoospermic men accompanied decreased ATP levels.LIMITATIONS, REASONS FOR CAUTIONAlthough the present study indicated the involvement of sperm lysine 2-hydroxyisobutyrylation in regulating human sperm motility, the underlying mechanism needs to be further illustrated.WIDER IMPLICATIONS OF THE FINDINGSThe findings of this study provide insight into the novel role of lysine 2-hydroxyisobutyrylation in human sperm and suggest that abnormality of sperm lysine 2-hydroxyisobutyrylation may be one of the causes for asthenozoospermia.STUDY FUNDING/COMPETING INTEREST(S)National Natural Science Foundation of China (81771644 to T.L. and 81871207 to H.C.); Natural Science Foundation of Jiangxi province (20171ACB21006). The authors have no conflicts of interest to declare.
      PubDate: Fri, 06 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez296
      Issue No: Vol. 35, No. 3 (2020)
  • Low anti-MĂĽllerian hormone level is not a risk factor for early pregnancy
           loss in IVF/ICSI treatment
    • Authors: Peuranpää P; Hautamäki H, Halttunen-Nieminen M, et al.
      Pages: 504 - 515
      Abstract: AbstractSTUDY QUESTIONIs a low (<1.0 μg/L) or moderately low (1.0–1.9 μg/L) serum anti-Müllerian hormone (AMH) level a risk factor for early pregnancy loss in IVF/ICSI with a fresh or frozen-thawed embryo transfer (ET)'SUMMARY ANSWERA low or moderately low serum AMH level does not associate with miscarriage, non-visualized pregnancy loss or overall early pregnancy loss rate in the IVF/ICSI treatment.WHAT IS KNOWN ALREADYLow AMH predicts poor ovarian response and small oocyte yield in IVF/ICSI treatment, but its value in the evaluation of live birth rate (LBR) is modest. Little is known about the risk of early pregnancy loss in ART among women with low AMH.STUDY DESIGN, SIZE, DURATIONA retrospective cohort study on 1383 women undergoing their first oocyte retrieval for IVF/ICSI in Helsinki University Hospital in Helsinki, Finland, between 2012 and 2016, with all associated fresh (n = 1315) and frozen-thawed (n = 1418) ET cycles finished by August 2018. AMH was measured within 12 months before the IVF/ICSI stimulation.PARTICIPANTS/MATERIALS, SETTING, METHODSOf all the women, 235 (17.0%) had low (<1.0 μg/L), 278 (20.1%) had moderately low (1.0–1.9 μg/L) and 870 (62.9%) had normal (≥2.0 μg/L) AMH. The primary outcomes were miscarriage, non-visualized pregnancy loss and early pregnancy loss (miscarriage and non-visualized pregnancy loss combined) after fresh or frozen-thawed ET. The impact of AMH on these outcomes was calculated in three populations: among all women who became pregnant, among women with AMH ≤6.0 μg/L and in a population weighted by the inverse probability of becoming pregnant (inverse probability weighting, IPW). The impact of AMH was also assessed on the secondary outcomes, cumulative pregnancy rate (cPR) and cumulative live birth rate (cLBR) across all ET cycles in the woman’s first IVF/ICSI. Potential confounders (the woman’s age, overweight, smoking, history of endometriosis and underlying medical conditions) adjusted the final results.MAIN RESULTS AND THE ROLE OF CHANCEOf 1123 pregnancies, 285 (25.4%) ended in non-visualized pregnancy loss and 143 (12.7%) in miscarriage. The LBR was 24.6% per ET (673/2733). Low or moderately low AMH, compared with normal AMH, did not associate with miscarriage or non-visualized pregnancy loss in analyses among all women who became pregnant (adjusted relative risk (RR) for miscarriage vs live birth, 0.70 and 95% CI 0.42–1.17 in low AMH and adjusted RR, 1.00 and 95% CI, 0.68–1.49 in moderately low AMH; adjusted RR for non-visualized pregnancy loss vs live birth, 0.90 and 95% CI, 0.65–1.23 in low AMH and adjusted RR, 1.09 and 95% CI 0.85–1.41 in moderately low AMH), nor did low or moderately low AMH associate with the overall early pregnancy loss rate (adjusted RR for early pregnancy loss vs live birth, 0.86 and 95% CI, 0.68–1.10 in low AMH and adjusted RR, 1.01 and 95% CI, 0.86–1.27 in moderately low AMH). Results remained similar after restricting the analysis to women with AMH ≤6.0 μg/L. Women with low or moderately low AMH had fewer pregnancies and live births than women with normal AMH in their first IVF/ICSI (cPR/cLBR in women with low AMH 50.6/34.0%, moderately low AMH 59.0/36.3% and normal AMH 68.3/49.2%). When the lower probability for pregnancy was considered by using IPW, women with low or moderately low AMH did not have a higher risk for miscarriage, non-visualized pregnancy loss or overall early pregnancy loss compared with women with normal AMH.LIMITATIONS, REASONS FOR CAUTIONThe number of miscarriages in women with low AMH was moderately small, limiting the power of the study. The real-world clinical setting of the study restricted the ability to control for all factors causing selection bias.WIDER IMPLICATIONS OF THE FINDINGSThe cLBR was higher among women with normal AMH than among women with low or moderately low AMH in their first IVF/ICSI treatment because these women had more oocytes and embryos. Women with low or moderately low AMH did not have an increased risk for early pregnancy loss. This information is reassuring for couples and useful in counseling. These results are also valuable when assessing the overall effectiveness of IVF/ICSI treatment.STUDY FUNDING/COMPETING INTEREST(S)Research funds from Helsinki University Hospital (no. TYH2018232), Hyvinkää Hospital (no. M3080TUT18) and the Emil Aaltonen Foundation for P.P. Grants from the Paulo Foundation and the Finnish Medical Foundation for H.H. The authors report no conflicts of interest.TRIAL REGISTRATION NUMBERHUS/138/2017.
      PubDate: Fri, 27 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa008
      Issue No: Vol. 35, No. 3 (2020)
  • Comparison of DNA methylation patterns of parentally imprinted genes in
           placenta derived from IVF conceptions in two different culture media
    • Authors: Mulder C; Wattimury T, Jongejan A, et al.
      Pages: 516 - 528
      Abstract: AbstractStudy questionIs there a difference in DNA methylation status of imprinted genes in placentas derived from IVF conceptions where embryo culture was performed in human tubal fluid (HTF) versus G5 culture medium'Summary answerWe found no statistically significant differences in the mean DNA methylation status of differentially methylated regions (DMRs) associated with parentally imprinted genes in placentas derived from IVF conceptions cultured in HTF versus G5 culture medium.What is known alreadyAnimal studies indicate that the embryo culture environment affects the DNA methylation status of the embryo. In humans, birthweight is known to be affected by the type of embryo culture medium used. The effect of embryo culture media on pregnancy, birth and child development may thus be mediated by differential methylation of parentally imprinted genes in the placenta.Study design, size, durationTo identify differential DNA methylation of imprinted genes in human placenta derived from IVF conceptions exposed to HTF or G5 embryo culture medium, placenta samples (n = 43 for HTF, n = 54 for G5) were collected between 2010 and 2012 s as part of a multi-center randomized controlled trial in the Netherlands comparing these embryo culture media. Placenta samples from 69 naturally conceived (NC) live births were collected during 2008–2013 in the Netherlands as reference material.Participants/materials, setting, methodsTo identify differential DNA methylation of imprinted genes, we opted for an amplicon-based sequencing strategy on an Illumina MiSeq sequencing platform. DNA was isolated and 34 DMRs associated with well-defined parentally imprinted genes were amplified in a two-step PCR before sequencing using MiSeq technology. Sequencing data were analyzed in a multivariate fashion to eliminate possible confounding effects.Main results and the role of chanceWe found no statistically significant differences in the mean DNA methylation status of any of the imprinted DMRs in placentas derived from IVF conceptions cultured in HTF or G5 culture medium. We also did not observe any differences in the mean methylation status per amplicon nor in the variance in methylation per amplicon between the two culture mediumgroups. A separate surrogate variable analysis also demonstrated that the IVF culture medium was not associated with the DNA methylation status of these DMRs. The mean methylation level and variance per CpG was equal between HTF and G5 placenta. Additional comparison of DNA methylation status of NC placenta samples revealed no statistically significant differences in mean amplicon and CpG methylation between G5, HTF and NC placenta; however, the number of placenta samples exhibiting outlier methylation levels was higher in IVF placenta compared to NC (P < 0.00001). Also, we were able to identify 37 CpG sites that uniquely displayed outlier methylation in G5 placentas and 32 CpG sites that uniquely displayed outlier methylation in HTF. In 8/37 (G5) and 4/32 (HTF) unique outliers CpGs, a medium-specific unique outlier could be directly correlated to outlier methylation of the entire amplicon.Limitations, reasons for cautionDue to practical reasons, not all placentas were collected during the trial, and we collected the placentas from natural conceptions from a different cohort, potentially creating bias. We limited ourselves to the DNA methylation status of 34 imprinted DMRs, and we studied only the placenta and no other embryo-derived tissues.Wider implications of the findingsIt has often been postulated, but has yet to be rigorously tested, that imprinting mediates the effects of embryo culture conditions on pregnancy, birth and child development in humans. Since we did not detect any statistically significant effects of embryo culture conditions on methylation status of imprinted genes in the placenta, this suggests that other unexplored mechanisms may underlie these effects. The biological and clinical relevance of detected outliers with respect to methylation levels of CpGs and DMR require additional analysis in a larger sample size as well. Given the importance and the growing number of children born through IVF, research into these molecular mechanisms is urgently needed.Study funding/competing interest(s)This study was funded by the March of Dimes grant number #6-FY13-153. The authors have no conflicts of interest.Trial registration numberPlacental biopsies were obtained under Netherlands Trial Registry number 1979 and 1298.
      PubDate: Mon, 30 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa004
      Issue No: Vol. 35, No. 3 (2020)
  • Female ageing affects the DNA repair capacity of oocytes in IVF using a
           controlled model of sperm DNA damage in mice
    • Authors: Horta F; Catt S, Ramachandran P, et al.
      Pages: 529 - 544
      Abstract: AbstractSTUDY QUESTIONDoes female ageing have a negative effect on the DNA repair capacity of oocytes fertilised by spermatozoa with controlled levels of DNA damage'SUMMARY ANSWERCompared to oocytes from younger females, oocytes from older females have a reduced capacity to repair damaged DNA introduced by spermatozoa.WHAT IS KNOWN ALREADYThe reproductive lifespan in women declines with age predominantly due to poor oocyte quality. This leads to decreased reproductive outcomes for older women undergoing assisted reproductive technology (ART) treatments, compared to young women. Ageing and oocyte quality have been clearly associated with aneuploidy, but the range of factors that influence this change in oocyte quality with age remains unclear. The DNA repair activity prior to embryonic genomic activation is considered to be of maternal origin, with maternal transcripts and proteins controlling DNA integrity. With increasing maternal age, the number of mRNAs stored in oocytes decreases. This could result in diminished efficiency of DNA repair and/or negative effects on embryo development, especially in the presence of DNA damage.STUDY DESIGN, SIZE, DURATIONOocytes from two age groups of 30 super-ovulated female mice (young: 5–8 weeks old, n = 15; old: 42–45 weeks old, n = 15) were inseminated with sperm from five males with three different controlled DNA damage levels; control: ≤10%, 1 Gray (Gy): 11–30%, and 30 Gy: >30%. Inseminated oocytes (young: 125, old: 78) were assessed for the formation of zygotes (per oocyte) and blastocysts (per zygote). Five replicates of five germinal vesicles (GVs) and five MII oocytes from each age group were analysed for gene expression. The DNA damage response (DDR) was assessed in a minimum of three IVF replicates in control and 1 Gy zygotes and two-cell embryos using γH2AX labelling.PARTICIPANTS/MATERIALS, SETTING, METHODSSwim-up sperm samples from the cauda epididymidis of C57BL6 mice were divided into control (no irradiation) and 1- and 30-Gy groups. Treated spermatozoa were irradiated at 1 and 30 Gy, respectively, using a linear accelerator Varian 21iX. Following irradiation, samples were used for DNA damage assessment (Halomax) and for insemination. Presumed zygotes were cultured in a time-lapse incubator (MIRI, ESCO). Gene expression of 91 DNA repair genes was assessed using the Fluidigm Biomark HD system. The DNA damage response in zygotes (6–8 h post-fertilisation) and two-cell embryos (22–24 h post-fertilisation) was assessed by immunocytochemical analysis of γH2AX using confocal microscopy (Olympus FV1200) and 3D volumetric analysis using IMARIS software.MAIN RESULTS AND THE ROLE OF CHANCEThe average sperm DNA damage for the three groups was statistically different (control: 6.1%, 1 Gy: 16.1%, 30 Gy: 53.1%, P < 0.0001), but there were no significant differences in fertilisation rates after IVF within or between the two age groups [(young; control: 86.79%, 1 Gy: 82.75%, 30 Gy: 76.74%) (old; control: 93.1%, 1 Gy: 70.37%, 30 Gy: 68.18%) Fisher’s exact]. However, blastocyst rates were significantly different (P < 0.0001) among the groups [(young; control: 86.95%, 1 Gy: 33.33%, 30 Gy: 0.0%) (old; control: 70.37%, 1 Gy: 0.0%, 30 Gy: 0.0%)]. Between the age groups, 1-Gy samples showed a significant decrease in the blastocyst rate in old females compared to young females (P = 0.0166). Gene expression analysis revealed a decrease in relative expression of 21 DNA repair genes in old GV oocytes compared to young GV oocytes (P < 0.05), and similarly, old MII oocytes showed 23 genes with reduced expression compared to young MII oocytes (P < 0.05). The number of genes with decreased expression in older GV and MII oocytes significantly affected pathways such as double strand break (GV: 5; MII: 6), nucleotide excision repair (GV: 8; MII: 5) and DNA damage response (GV: 4; MII: 8). There was a decreased DDR in zygotes and in two-cell embryos from old females compared to young regardless of sperm treatment (P < 0.05). The decrease in DNA repair gene expression of oocytes and decreased DDR in embryos derived from older females suggests that ageing results in a diminished DNA repair capacity.LARGE-SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONIonising radiation was used only for experimental purposes, aiming at controlled levels of sperm DNA damage; however, it can also damage spermatozoa proteins. The female age groups selected in mice were intended to model effects in young and old women, but clinical studies are required to demonstrate a similar effect.WIDER IMPLICATIONS OF THE FINDINGSFertilisation can occur with sperm populations with medium and high DNA damage, but subsequent embryo growth is affected to a greater extent with aging females, supporting the theory that oocyte DNA repair capacity decreases with age. Assessment of the oocyte DNA repair capacity may be a useful diagnostic tool for infertile couples.STUDY FUNDING/COMPETING INTEREST(S)Funded by the Education Program in Reproduction and Development, Department of Obstetrics and Gynaecology, Monash Un...
      PubDate: Fri, 28 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez308
      Issue No: Vol. 35, No. 3 (2020)
  • Follicle size indicates oocyte maturity and blastocyst formation but not
           blastocyst euploidy following controlled ovarian hyperstimulation of
           oocyte donors
    • Authors: McCulloh D; Kutchukhidze N, Charkviani T, et al.
      Pages: 545 - 556
      Abstract: AbstractSTUDY QUESTIONIs there is an association between follicle size and the quality of oocytes retrieved from them as judged by ability to achieve the blastocyst stage, blastocyst grades and blastocyst ploidy'SUMMARY ANSWERAlthough follicle size is a valuable predictor of oocyte maturity and is a significant predictor of the ability of a fertilized oocyte to become a quality blastocyst, the ploidy of each quality blastocyst is not related to the size of the follicle from which its oocyte was retrieved.WHAT IS KNOWN ALREADYIt is unclear whether the oocytes within larger follicles are the best oocytes of the cohort. Although there have been studies examining follicle size in relation to embryo quality, there has been no study relating the incidence of euploidy in embryos to follicle size.STUDY DESIGN, SIZE, DURATIONThe purpose of this study was to examine follicle sizes and the oocytes from those follicles (and the embryos that result from those oocytes) to see if there is an association between follicle size and the quality of oocytes as judged by ability to achieve the blastocyst stage, blastocyst grades and blastocyst ploidy. Follicle sizes for oocytes were assessed both as diameters (mm) and as Z values (expressed as their size relative to the mean and standard deviation of that donor’s follicular cohort). Comparisons were made using cumulative histograms, rolling averages and receiver operator characteristic (ROC) curves and its AUC.PARTICIPANTS/MATERIALS, SETTING, METHODSTwenty-two oocyte donors (ages: 24.5 ± 3.5 years) whose recipients would use ICSI for insemination were enrolled in this study. Follicles were aspirated one-at-a-time to be certain that the aspirated oocyte was from the same follicle measured. The follicle measurement (size) was noted in the embryology records. Oocytes were cultured individually throughout their time in the embryology laboratory so that follicle sizes could be uniquely associated with each oocyte. Oocytes and embryos were analyzed according to the size of the follicle from which the oocyte was retrieved.MAIN RESULTS AND THE ROLE OF CHANCEThree hundred seventeen oocytes (96.1%) had an associated follicle size. Of the oocytes with follicle sizes, 255 (80.4%) had a polar body (MII), and 60 (18.9%) were immature: 31 (9.8%) with a visible germinal vesicle (GV stage) and 29 (9.1%) with neither a polar body nor a visible germinal vesicle (MI). The incidence of MII oocytes was significantly associated with larger follicle size using either mm (ROC’s AUC = 0.87; P < 0.0001) or Z values (ROC’s AUC = 0.86; P < 0.0001). Among MII oocytes there was no association with follicle size for the appearance of 228 oocytes with two pronuclei (2 PN). Among 2 PN’s, the development of 94 quality blastocysts that underwent trophectoderm biopsy (TE Bx) exhibited a significant association with larger follicles using either mm (ROC’s AUC = 0.59; P = 0.01) or Z values (ROC’s AUC = 0.57; P = 0.01). The use of follicle diameter as a feature to distinguish between fertilized oocytes that would ultimately become blastocysts versus those that would not become blastocysts resulted in an enrichment for blastocyst formation from 20 to 40%. Of the 94 quality blastocysts, 51 were determined by next generation sequencing (NGS) to be euploid.Although oocyte maturity and the incidence of blastocyst formation were associated with follicle size, the incidence of euploidy among biopsied blastocysts was not. Follicles measured by two different methods (mm or Z values) led to predominantly the same conclusions.LIMITATIONS, REASONS FOR CAUTIONThis study investigated the relationship between follicle size and measures of oocyte/embryo quality when donors were treated similarly. Therefore, this study does not investigate the effects of triggering and retrieving oocytes when the follicle cohorts are of different sizes or lead follicles are of different sizes. Although no association was found between follicle size and euploid blastocysts, the fact that blastocyst ploidy is not entirely dependent upon oocyte ploidy (e.g. aneuploidies derived from mitotic errors or from the fertilizing sperm) makes it difficult to infer the relationship between follicle diameter and oocyte ploidy.WIDER IMPLICATIONS OF THE FINDINGSIt is confirmed that follicle diameter is predictive of oocyte maturity. However, once oocyte maturity is known, the diameter of the follicle from which the oocyte was retrieved is not instructive. Embryos generated through fertilization and development of the mature oocytes from any observed follicle diameter were equally likely to become euploid blastocysts.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by ReproART: Georgian American Center for Reproductive Medicine. None of the authors declare any actual conflicts of interest. D.H.M. received compensation from ReproART, Biogenetics Corporation and the Sperm and Embryo Bank of New York and honoraria and travel funding from Ferring Pharmaceuticals and from Granata Bio. S.M. received compensation from Cooper Genomics and an honorarium and travel funding from Ferring Pharmaceuticals. L.C. is the founder of LTD Ovamedi, the organization that represent...
      PubDate: Fri, 06 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez291
      Issue No: Vol. 35, No. 3 (2020)
  • Development of automated annotation software for human embryo
    • Authors: Feyeux M; Reignier A, Mocaer M, et al.
      Pages: 557 - 564
      Abstract: AbstractSTUDY QUESTIONIs it possible to develop an automated annotation tool for human embryo development in time-lapse devices based on image analysis'SUMMARY ANSWERWe developed and validated an automated software for the annotation of human embryo morphokinetic parameters, having a good concordance with expert manual annotation on 701 time-lapse videos.WHAT IS KNOWN ALREADYMorphokinetic parameters obtained with time-lapse devices are increasingly used for the assessment of human embryo quality. However, their annotation is time-consuming and can be slightly operator-dependent, highlighting the need to develop fully automated approaches.STUDY DESIGN, SIZE, DURATIONThis monocentric study was conducted on 701 videos originating from 584 couples undergoing IVF with embryo culture in a time-lapse device. The only selection criterion was that the duration of the video must be over 60 h.PARTICIPANTS/MATERIALS, SETTING, METHODSAn automated morphokinetic annotation tool was developed based on gray level coefficient of variation and detection of the thickness of the zona pellucida. The detection of cellular events obtained with the automated tool was compared with those obtained manually by trained experts in clinical settings.MAIN RESULTS AND THE ROLE OF CHANCEAlthough some differences were found when embryos were considered individually, we found an overall concordance between automated and manual annotation of human embryo morphokinetics from fertilization to expanded blastocyst stage (r2 = 0.92).LIMITATIONS, REASONS FOR CAUTIONThese results should undergo multicentric external evaluation in order to test the overall performance of the annotation tool. Getting access to the export of 3D videos would enhance the quality of the correlation with the same algorithm and its extension to the 3D regions of interest. A technical limitation of our work lies within the duration of the video. The more embryo stages the video contains, the more information the script has to identify them correctly.WIDER IMPLICATIONS OF THE FINDINGSOur system paves the way for high-throughput analysis of multicentric morphokinetic databases, providing new insights into the clinical value of morphokinetics as a predictor of embryo quality and implantation.STUDY FUNDING/COMPETING INTEREST(S)This study was partly funded by Finox-Gedeon Richter Forward Grant 2016 and NeXT (ANR-16-IDEX-0007). We have no conflict of interests to declare.TRIAL REGISTRATION NUMBERN/A
      PubDate: Thu, 12 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa001
      Issue No: Vol. 35, No. 3 (2020)
  • Seasonal patterns in fecundability in North America and Denmark: a
           preconception cohort study
    • Authors: Wesselink A; Wise L, Hatch E, et al.
      Pages: 565 - 572
      Abstract: AbstractSTUDY QUESTIONTo what extent does fecundability vary across seasons'SUMMARY ANSWERAfter accounting for seasonal patterns in pregnancy planning, we observed higher fecundability in the fall and lower fecundability in the spring, particularly at lower latitudes.WHAT IS KNOWN ALREADYIn human populations, there are strong seasonal patterns of births that vary across geographic regions and time periods. However, previous studies of seasonality and fecundity are limited because they examine season of birth rather than season of conception and therefore neglect to account for seasonal variation in initiating attempts to conceive or pregnancy loss or differences in gestational length.STUDY DESIGN, SIZE, DURATIONWe conducted a preconception cohort study of 14 331 women residing in North America (June 2013–May 2018: n = 5827) and Denmark (June 2007–May 2018: n = 8504). Participants were attempting to conceive without fertility treatment and had been attempting pregnancy for ≤6 menstrual cycles at enrolment.PARTICIPANTS/MATERIAL, SETTING, METHODSWe collected information on season of each pregnancy attempt using last menstrual period dates over the study period. Pregnancy was reported on female bi-monthly follow-up questionnaires. We fit log-binomial models with trigonometric regression to examine periodic variation in fecundability. We accounted for seasonal variation in initiation of pregnancy attempts by including indicator variables for menstrual cycle of attempt in the regression models.MAIN RESULTS AND THE ROLE OF CHANCEInitiation of pregnancy attempts peaked in September, with stronger seasonality in North America than in Denmark (48 vs. 16% higher probability initiating attempts in September compared with March). After accounting for seasonal variation in initiation of pregnancy attempts, we observed modest seasonal variation in fecundability, with a peak in the late fall and early winter in both cohorts, but stronger peak/low ratios in North America (1.16; 95% confidence interval [CI]: 1.05, 1.28) than in Denmark (1.08; 95% CI: 1.00, 1.16). When we stratified the North American data by latitude, we observed the strongest seasonal variation in the southern USA (peak/low ratio of 1.45 [95% CI: 1.14, 1.84]), with peak fecundability in late November.LIMITATIONS, REASONS FOR CAUTIONWe estimated menstrual cycle dates between follow-up questionnaires, which may have introduced exposure misclassification, particularly when women skipped follow-up questionnaires. We were unable to measure seasonally varying factors that may have influenced fecundability, including ambient temperature, vitamin D levels or infectious disease.WIDER IMPLICATIONS OF THE FINDINGSAn understanding of how fecundability varies across seasons could help identify factors that can impair reproductive function. Neglecting to account for seasonal variation in initiation of pregnancy attempts could bias estimates of seasonal patterns in fecundability. This is the first preconception cohort study to examine seasonal variation in fecundability after accounting for seasonality in initiation of pregnancy attempts. Fecundability was highest in the fall and lowest in the spring, with stronger effects in southern latitudes of North America, suggesting that seasonal exposures may affect fecundity.STUDY FUNDING/COMPETING INTEREST(S)This research was funded by the Eunice K. Shriver National Institute of Child Health and Human Development (R21-050264, R01-HD060680, R21-HD072326 and R01-HD086742) and the Danish Medical Research Council (271-07-0338). The authors declare no conflicts of interest.
      PubDate: Fri, 31 Jan 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez265
      Issue No: Vol. 35, No. 3 (2020)
  • Decisional conflict among couples seeking specialty treatment for
           infertility in the USA: a longitudinal exploratory study
    • Authors: Anguzu R; Cusatis R, Fergestrom N, et al.
      Pages: 573 - 582
      Abstract: AbstractSTUDY QUESTIONWhat are couples’ decisional conflicts around family-building approaches before and after seeking a specialty consultation for infertility'SUMMARY ANSWERDecisional conflict is high among couples before an initial specialty consultation for infertility; on average, women resolved decisional conflict more quickly than men.WHAT IS KNOWN ALREADYCouples have multiple options for addressing infertility, and decisional conflict may arise due to lack of information, uncertainty about options and potential risks or challenges to personal values.STUDY DESIGN, SIZE, DURATIONWe conducted a total of 385 interviews and 405 surveys for this longitudinal, mixed-methods cohort study of 34 opposite-sex couples who sought a new reproductive specialty consultation (n = 68), who enrolled before the initial consultation and were followed over 12 months.PARTICIPANTS/MATERIALS, SETTING, METHODSThe in-depth, semi-structured interviews included questions about information gathering, deliberation and decision-making, and self-administered surveys included the Decisional Conflict Scale (DCS), at six time points over 12 months. A DCS total score of 25 is associated with implementing a decision, and higher scores indicate more decisional conflict. A systematic content analysis of interview transcripts identified major themes. Paired t tests identified differences in DCS between women and men within couples. Linear mixed models predicted changes in DCS over time, adjusting for sociodemographic and fertility-related factors.MAIN RESULTS AND THE ROLE OF CHANCEThe major qualitative themes were communication with partners, feeling supported and/or pressured in decision (s), changing decisions over time and ability to execute a desired decision. Average DCS scores were highest before the initial consultation. Within couples, men had significantly higher decisional conflict than women pre-consultation (48.9 versus 40.2, P = 0.037) and at 2 months (28.9 versus 22.1, P = 0.015), but differences at other time points were not significant. In adjusted models, predicted DCS scores declined over time, with women, on average, reaching the DCS threshold for implementing a decision at 2 months while for men it was not until 4 months.LIMITATIONS, REASONS FOR CAUTIONThis is a convenience sample from a single center, and generalizability may be limited.WIDER IMPLICATIONS OF THE FINDINGSUnderstanding how couples discuss and make decisions regarding family-building could improve the delivery of patient-centered infertility care. Our findings are the first to prospectively explore decisional conflict at multiple time points in both men and women; the observed gender differences underlie the importance of supporting both partners in clinical decision-making for infertility.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the National Institute of Child Health and Human Development under Grant [R21HD071332], the Research and Education Program Fund, of the Advancing a Healthier Wisconsin endowment at Medical College of Wisconsin, the National Research Service Award under Grant [T32 HP10030] and the use of REDCap for data collection from the National Center for Advancing Translational Sciences, National Institutes of Health under Grant through [8UL1TR000055]. The authors have no competing interests.
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez292
      Issue No: Vol. 35, No. 3 (2020)
  • ICSI does not improve reproductive outcomes in autologous ovarian response
           cycles with non-male factor subfertility
    • Authors: Supramaniam P; Granne I, Ohuma E, et al.
      Pages: 583 - 594
      Abstract: AbstractSTUDY QUESTIONDoes the method of fertilisation improve reproductive outcomes in poor ovarian response (POR) cycles when compared to all other ovarian response categories in the absence of male factor subfertility'SUMMARY ANSWERICSI does not confer any benefit in improving the clinical pregnancy or live birth (LB) outcome in autologous ovarian response cycles in the absence of male factor subfertility when compared to IVF.WHAT IS KNOWN ALREADYICSI is associated with an improved outcome when compared to IVF in patients with severe male factor subfertility.STUDY DESIGN, SIZE, DURATIONA retrospective study involving 1 376 454 ART cycles, of which 569 605 (41.4%) cycles fulfilled the inclusion and exclusion criteria for all autologous ovarian response categories: 272 433 (47.8%) IVF cycles and 297 172 (52.2%) ICSI cycles. Of these, the POR cohort represented 62 641 stimulated fresh cycles (11.0%): 33 436 (53.4%) IVF cycles and 29 205 (46.6%) ICSI cycles.PARTICIPANTS/MATERIALS, SETTING, METHODAll cycles recorded on the anonymised Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All fresh cycles with normal sperm parameters, performed after 1998 were included: frozen cycles, donor oocyte and sperm usage, intrauterine insemination cycles, preimplantation genetic testing (PGT) for aneuploidies (PGT-A), PGT for monogenic/single gene defects (PGT-M), PGT for chromosomal structural arrangements (PGT-SR) cycles, where the reason for stimulation was for storage and unstimulated cycles were excluded.MAIN RESULTS AND THE ROLE OF CHANCEICSI did not confer any benefit in improving the LB outcome when compared to conventional IVF per treatment cycle (PTC), when adjusted for female age, number of previous ART treatment cycles, number of previous live births through ART, oocyte yield, stage of transfer, method of fertilisation and number of embryos transferred in the POR cohort (adjusted odds ratio [a OR] 1.03, 99.5% confidence interval [CI] 0.96–1.11, P = 0.261) and all autologous ovarian response categories (aOR 1.00, 99.5% CI 0.98–1.02, P = 0.900). The mean fertilisation rate was statistically lower for IVF treatment cycles (64.7%) when compared to ICSI treatment cycles (67.2%) in the POR cohort (mean difference −2.5%, 99.5% CI −3.3 to −1.6, P < 0.001). The failed fertilisation rate was marginally higher in IVF treatment cycles (17.3%, 95% binomial exact 16.9 to 17.7%) when compared to ICSI treatment cycles (17.0%, 95% binomial exact 16.6 to 17.4%); however, this did not reach statistical significance (P = 0.199). The results followed a similar trend when analysed for all autologous ovarian response categories with a higher rate of failed fertilisation in IVF treatment cycles (4.8%, 95% binomial exact 4.7 to 4.9%) when compared to ICSI treatment cycles (3.2%, 95% binomial exact 3.1 to 3.3%) (P < 0.001).LIMITATIONS, REASONS FOR CAUTIONThe quality of data is reliant on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst-stage embryo transfers. The inability to link the treatment cycle to the individual patient meant that we were unable to calculate the cumulative LB outcome per patient.WIDER IMPLICATIONS OF THE FINDINGSThis is the largest study to date which evaluates the impact of method of fertilisation in the POR patient and compares this to all autologous ovarian response categories. The results demonstrate that ICSI does not confer any benefit in improving reproductive outcomes in the absence of male factor subfertility, with no improvement seen in the clinical pregnancy or LB outcomes following a fresh treatment cycle.STUDY FUNDING/COMPETING INTEREST(S)The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Bayer AG, Wellbeing of Women, the European Union and Finox.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Wed, 11 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez301
      Issue No: Vol. 35, No. 3 (2020)
  • Reduced pregnancy and live birth rates after in vitro fertilization in
           women with previous Caesarean section: a retrospective cohort study
    • Authors: Vissers J; Sluckin T, van Driel-Delprat C, et al.
      Pages: 595 - 604
      Abstract: AbstractSTUDY QUESTIONDoes a previous Caesarean section affect reproductive outcomes, including live birth, in women after IVF or ICSI'SUMMARY ANSWERA previous Caesarean section impairs live birth rates after IVF or ICSI compared to a previous vaginal delivery.WHAT IS KNOWN ALREADYRates of Caesarean sections are rising worldwide. Late sequelae of a Caesarean section related to a niche (Caesarean scar defect) include gynaecological symptoms and obstetric complications. A systematic review reported a lower pregnancy rate after a previous Caesarean section (RR 0.91 CI 0.87–0.95) compared to a previous vaginal delivery. So far, studies have been unable to causally differentiate between problems with fertilisation, and the transportation or implantation of an embryo. Studying an IVF population allows us to identify the effect of a previous Caesarean section on the implantation of embryos in relation to a previous vaginal delivery.STUDY DESIGN, SIZE, DURATIONWe retrospectively studied the live birth rate in women who had an IVF or ICSI treatment at the IVF Centre, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands, between 2006 and 2016 with one previous delivery. In total, 1317 women were included, of whom 334 had a previous caesarean section and 983 had previously delivered vaginally.PARTICIPANTS/MATERIALS, SETTING, METHODSAll secondary infertile women, with only one previous delivery either by caesarean section or vaginal delivery, were included. If applicable, only the first fresh embryo transfer was included in the analyses. Patients who did not intend to undergo embryo transfer were excluded. The primary outcome was live birth. Multivariate logistic regression analyses were used with adjustment for possible confounders ((i) age; (ii) pre-pregnancy BMI; (iii) pre-pregnancy smoking; (iv) previous fertility treatment; (v) indication for current fertility treatment: (a) tubal, (b) male factor and (c) endometriosis; (vi) embryo quality; and (vii) endometrial thickness), if applicable. Analysis was by intention to treat (ITT).MAIN RESULTS AND THE ROLE OF CHANCEBaseline characteristics of both groups were comparable. Live birth rates were significantly lower in women with a previous caesarean section than in women with a previous vaginal delivery, 15.9% (51/320) versus 23.3% (219/941) (OR 0.63 95% CI 0.45–0.87) in the ITT analyses. The rates were also lower for ongoing pregnancy (20.1 versus 28.1% (OR 0.64 95% CI 0.48–0.87)), clinical pregnancy (25.7 versus 33.8% (OR 0.68 95% CI 0.52–0.90)) and biochemical test (36.2 versus 45.5% (OR 0.68 95% CI 0.53–0.88)). The per protocol analyses showed the same differences (live birth rate OR 0.66 95% CI 0.47–0.93 and clinical pregnancy rate OR 0.72 95% CI 0.54–0.96).LIMITATIONS, REASONS FOR CAUTIONThis study is limited by its retrospective design. Furthermore, 56 (16.3%) cases lacked data regarding delivery outcomes, but these were equally distributed between the two groups.WIDER IMPLICATIONS OF THE FINDINGSThe lower clinical pregnancy rates per embryo transfer indicate that implantation is hampered after a caesarean section. Its relation with a possible niche (caesarean scar defect) in the uterine caesarean scar needs further study. Our results should be discussed with clinicians and patients who consider an elective caesarean section.STUDY FUNDING/COMPETING INTEREST(S)Not applicable.TRIAL REGISTRATION NUMBERThis study has been registered in the Dutch Trial Register (Ref. No. NL7631
      PubDate: Fri, 06 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez295
      Issue No: Vol. 35, No. 3 (2020)
  • Is infertility resolution associated with a change in women’s
    • Authors: Shreffler K; Greil A, Tiemeyer S, et al.
      Pages: 605 - 616
      Abstract: AbstractSTUDY QUESTIONIs giving birth associated with improved subjective well-being among involuntarily childless women'SUMMARY ANSWERResolution of infertility is associated with increased life satisfaction and self-esteem, but not with a decrease in depressive symptoms.WHAT IS KNOWN ALREADYCross-sectional data and studies of treatment-seekers show that infertility is associated with lower subjective well-being. Childless women with infertility tend to report lower subjective well-being than women who experience secondary infertility, but a prospective study using a random sample of involuntarily childless women over time has not previously been conducted.STUDY DESIGN, SIZE, DURATIONThe sample for the current study includes all women without children who met medical criteria for infertility or perceived a fertility problem (N = 283) at baseline and who were interviewed in both waves (3 years apart) of the National Survey of Fertility Barriers (NSFB), in a random-digit dialing telephone survey. It is therefore possible to explore here whether there are differences in the association of infertility resolution and subjective well-being among women who do and do not perceive themselves as having a fertility problem.PARTICIPANTS/MATERIALS, SETTING, METHODSDepressive symptoms (as measured by the Center for Epidemiologic Studies—Depression Scale), self-esteem (as measured by a modified version of the Rosenberg Self-esteem Scale) and life satisfaction (as measured by a modified version of the Satisfaction with Life Scale) were assessed for all 283 participants at both waves. For all three variables, change scores of 47 involuntarily childless women who resolved their infertility through a live birth were compared to the scores for the 236 women who remained childless. A number of variables shown to be associated with subjective well-being among infertile women were included as controls.MAIN RESULTS AND THE ROLE OF CHANCENo relationship between infertility resolution and change in depressive symptoms was observed (b = −0.04; P > 0.05). Involuntarily childless women who resolved their infertility improved in self-esteem (b = 0.74; P < 0.01) and life satisfaction (b = 1.06; P < 0.01).LIMITATIONS, REASONS FOR CAUTIONWomen were measured at only two time points. Only 47 women had a live birth between waves. While it is common practice to make causal interpretations based on panel data, such interpretations should be made with caution. In addition, the NSFB was conducted in the USA where medical expenditures are high and most fertility treatment expenses are not covered by insurance. Thus it may not be possible to generalize the findings to other modern industrialized societies.WIDER IMPLICATIONS OF THE FINDINGSKnowing that resolution of infertility is associated with improved subjective well-being is important for infertile couples and infertility professionals alike.STUDY FUNDING/COMPETING INTEREST(S)This research was supported in part by NICHD grant R01-HD044144 and NIGMS grant P20-GM109097 from the National Institutes of Health. The authors have no competing interests.
      PubDate: Sat, 29 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez297
      Issue No: Vol. 35, No. 3 (2020)
  • Seminal plasma promotes decidualization of endometrial stromal fibroblasts
           in vitro from women with and without inflammatory disorders in a manner
           dependent on interleukin-11 signaling
    • Authors: George A; Jang K, Nyegaard M, et al.
      Pages: 617 - 640
      Abstract: AbstractSTUDY QUESTIONDo seminal plasma (SP) and its constituents affect the decidualization capacity and transcriptome of human primary endometrial stromal fibroblasts (eSFs)'SUMMARY ANSWERSP promotes decidualization of eSFs from women with and without inflammatory disorders (polycystic ovary syndrome (PCOS), endometriosis) in a manner that is not mediated through semen amyloids and that is associated with a potent transcriptional response, including the induction of interleukin (IL)-11, a cytokine important for SP-induced decidualization.WHAT IS KNOWN ALREADYClinical studies have suggested that SP can promote implantation, and studies in vitro have demonstrated that SP can promote decidualization, a steroid hormone-driven program of eSF differentiation that is essential for embryo implantation and that is compromised in women with the inflammatory disorders PCOS and endometriosis.STUDY DESIGN, SIZE, DURATIONThis is a cross-sectional study involving samples treated with vehicle alone versus treatment with SP or SP constituents. SP was tested for the ability to promote decidualization in vitro in eSFs from women with or without PCOS or endometriosis (n = 9). The role of semen amyloids and fractionated SP in mediating this effect and in eliciting transcriptional changes in eSFs was then studied. Finally, the role of IL-11, a cytokine with a key role in implantation and decidualization, was assessed as a mediator of the SP-facilitated decidualization.PARTICIPANTS/MATERIALS, SETTING, METHODSeSFs and endometrial epithelial cells (eECs) were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. Assays were conducted to assess whether the treatment of eSFs with SP or SP constituents affects the rate and extent of decidualization in women with and without inflammatory disorders. To characterize the response of the endometrium to SP and SP constituents, RNA was isolated from treated eSFs or eECs and analyzed by RNA sequencing (RNAseq). Secreted factors in conditioned media from treated cells were analyzed by Luminex and ELISA. The role of IL-11 in SP-induced decidualization was assessed through Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-9-mediated knockout experiments in primary eSFs.MAIN RESULTS AND THE ROLE OF CHANCESP promoted decidualization both in the absence and presence of steroid hormones (P < 0.05 versus vehicle) in a manner that required seminal proteins. Semen amyloids did not promote decidualization and induced weak transcriptomic and secretomic responses in eSFs. In contrast, fractionated SP enriched for seminal microvesicles (MVs) promoted decidualization. IL-11 was one of the most potently SP-induced genes in eSFs and was important for SP-facilitated decidualization.LARGE SCALE DATARNAseq data were deposited in the Gene Expression Omnibus repository under series accession number GSE135640.LIMITATIONS, REASONS FOR CAUTIONThis study is limited to in vitro analyses.WIDER IMPLICATIONS OF THE FINDINGSOur results support the notion that SP promotes decidualization, including within eSFs from women with inflammatory disorders. Despite the general ability of amyloids to induce cytokines known to be important for implantation, semen amyloids poorly signaled to eSFs and did not promote their decidualization. In contrast, fractionated SP enriched for MVs promoted decidualization and induced a transcriptional response in eSFs that overlapped with that of SP. Our results suggest that SP constituents, possibly those associated with MVs, can promote decidualization of eSFs in an IL-11-dependent manner in preparation for implantation.STUDY FUNDING/COMPETING INTEREST(S)This project was supported by NIH (R21AI116252, R21AI122821 and R01AI127219) to N.R.R. and (P50HD055764) to L.C.G. The authors declare no conflict of interest.
      PubDate: Fri, 27 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa015
      Issue No: Vol. 35, No. 3 (2020)
  • Profiling the expression and function of oestrogen receptor isoform ER46
           in human endometrial tissues and uterine natural killer cells
    • Authors: Gibson D; Esnal-Zufiaurre A, Bajo-Santos C, et al.
      Pages: 641 - 651
      Abstract: AbstractSTUDY QUESTIONDoes the oestrogen receptor isoform, ER46, contribute to regulation of endometrial function'SUMMARY ANSWERER46 is expressed in endometrial tissues, is the predominant ER isoform in first trimester decidua and is localised to the cell membrane of uterine natural killer (uNK) cells where activation of ER46 increases cell motility.WHAT IS KNOWN ALREADYOestrogens acting via their cognate receptors are essential regulators of endometrial function and play key roles in establishment of pregnancy. ER46 is a 46-kDa truncated isoform of full length ERα (ER66, encoded by ESR1) that contains both ligand- and DNA-binding domains. Expression of ER46 in the human endometrium has not been investigated previously. ER46 is located at the cell membrane of peripheral blood leukocytes and mediates rapid responses to oestrogens. uNK cells are a phenotypically distinct (CD56brightCD16−) population of tissue-resident immune cells that regulate vascular remodelling within the endometrium and decidua. We have shown that oestrogens stimulate rapid increases in uNK cell motility. Previous characterisation of uNK cells suggests they are ER66-negative, but expression of ER46 has not been characterised. We hypothesise that uNK cells express ER46 and that rapid responses to oestrogens are mediated via this receptor.STUDY DESIGN, SIZE, DURATIONThis laboratory-based study used primary human endometrial (n = 24) and decidual tissue biopsies (n = 30) as well as uNK cells which were freshly isolated from first trimester human decidua (n = 18).PARTICIPANTS/MATERIALS, SETTING, METHODSPrimary human endometrial and first trimester decidual tissue biopsies were collected using methods approved by the local institutional ethics committee (LREC/05/51104/12 and LREC/10/51402/59). The expression of ERs (ER66, ER46 and ERβ) was assessed by quantitative PCR, western blot and immunohistochemistry. uNK cells were isolated from first-trimester human decidua by magnetic bead sorting. Cell motility of uNK cells was measured by live cell imaging: cells were treated with 17β-oestradiol conjugated to bovine serum albumin (E2-BSA, 10 nM equivalent), the ERβ-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nM) or dimethylsulphoxide vehicle control.MAIN RESULTS AND THE ROLE OF CHANCEER46 was detected in proliferative and secretory phase tissues by western blot and was the predominant ER isoform in first-trimester decidua samples. Immunohistochemistry revealed that ER46 was co-localised with ER66 in cell nuclei during the proliferative phase but detected in both the cytoplasm and cell membrane of stromal cells in the secretory phase and in decidua. Triple immunofluorescence staining of decidua tissues identified expression of ER46 in the cell membrane of CD56-positive uNK cells which were otherwise ER66-negative. Profiling of isolated uNK cells confirmed expression of ER46 by quantitative PCR and western blot and localised ER46 protein to the cell membrane by immunocytochemistry. Functional analysis of isolated uNK cells using live cell imaging demonstrated that activation of ER46 with E2-BSA significantly increased uNK cell motility.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONExpression pattern in endometrial tissue was only determined using samples from proliferative and secretory phases. Assessment of first trimester decidua samples was from a range of gestational ages, which may have precluded insights into gestation-specific changes in these tissues. Our results are based on in vitro responses of primary human cells and we cannot be certain that similar mechanisms occur in situ.WIDER IMPLICATIONS OF THE FINDINGSE2 is an essential regulator of reproductive competence. This study provides the first evidence for expression of ER46 in the human endometrium and decidua of early pregnancy. We describe a mechanism for regulating the function of human uNK cells via expression of ER46 and demonstrate that selective targeting with E2-BSA regulates uNK cell motility. These novel findings identify a role for ER46 in the human endometrium and provide unique insight into the importance of membrane-initiated signalling in modulating the impact of E2 on uNK cell function in women. Given the importance of uNK cells to regulating vascular remodelling in early pregnancy and the potential for selective targeting of ER46, this may be an attractive future therapeutic target in the treatment of reproductive disorders.STUDY FUNDING/COMPETING INTEREST(S)These studies were supported by Medical Research Council (MRC) Programme Grants G1100356/1 and MR/N024524/1 to PTKS. H.O.D.C. was supported by MRC grant G1002033. The authors declare no competing interests related to the published work.
      PubDate: Fri, 28 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez306
      Issue No: Vol. 35, No. 3 (2020)
  • Impact of the newly recommended antral follicle count cutoff for
           polycystic ovary in adult women with polycystic ovary syndrome
    • Authors: Kim J; Hwang K, Chae S, et al.
      Pages: 652 - 659
      Abstract: AbstractSTUDY QUESTIONWhat is the impact of the newly recommended antral follicle count (AFC) cutoff for polycystic ovary (PCO) on the diagnostic status of polycystic ovary syndrome (PCOS)'SUMMARY ANSWERAmong patients with phenotypes requiring the presence of PCO for diagnosis, approximately half (48.2%) were excluded from having PCOS based on the new AFC cutoff, although these excluded women had worse metabolic and hormonal profiles than the controls and were indistinguishable from the remaining patients with regard to major hormonal and metabolic parameters.WHAT IS KNOWN ALREADYIn the Rotterdam criteria, PCO is defined as either 12 or more follicles measuring 2–9 mm in diameter or an increased ovarian volume >10 cm3. Recently, an international PCOS guideline development group recommended an AFC threshold for PCO of ≥20 in adult women when using transducers with a high-resolution frequency, including 8 MHz.STUDY DESIGN, SIZE, DURATIONThe current study used a case control design.PARTICIPANTS/MATERIALS, SETTING, METHODSPCOS was diagnosed according to the Rotterdam criteria. Ultrasonography examinations were conducted with wide band frequency (5–9 MHz) transvaginal transducers and the centre frequency was 8 MHz. In patients who show both irregular menstruation and hyperandrogenism (HA), a diagnosis of PCOS can be made irrespective of the ovarian criteria change. Patients who were diagnosed according to HA and PCO (n = 86) or irregular menstruation and PCO (n = 443) were initially included among a total of 1390 adult women with PCOS (aged 20–40 years). Regardless of the AFC, if the ovarian volume is ≥10 cm3, a diagnosis of PCO can still be made. Thus, only patients who had an ovarian volume of <10 cm3 were analysed. Subjects who had an AFC of 12–19 and an ovarian volume <10 cm3 were designated as the ‘low AFC group’ (n = 255) and were the main focus of the study because they were excluded from having PCOS based on the new cutoff. Subjects with an AFC ≥20 and an ovarian volume <10 cm3 were designated as the ‘high AFC group’ (n = 101). A total of 562 premenopausal women without PCOS were enrolled as controls.MAIN RESULTS AND THE ROLE OF CHANCEAmong patients with irregular menstruation and PCO or HA and PCO phenotypes, approximately half (48.2%, 255/529) were excluded from having PCOS, which corresponded to one-fifth (18.3%, 255/1390) of the total adult patients. However, compared to the control group, these excluded women had worse metabolic profiles and were more androgenised. Notably, they were indistinguishable from the ‘high AFC group’ with regard to major hormonal and metabolic parameters (BMI and diabetic classification status, and the prevalence of insulin resistance, metabolic syndrome and HA).LIMITATIONS, REASONS FOR CAUTIONWe cannot exclude the possibility of inter- and intraobserver variation in the evaluation of AFC.WIDER IMPLICATIONS OF THE FINDINGSWith the newly recommended follicle count cutoff, a substantial proportion of women with PCOS might be classified as not having PCOS despite visiting a hospital due to irregular menstruation or hyperandrogenic symptoms. A practical approach to them would involve controlling the menstrual or hyperandrogenic symptoms in hand and regularly evaluating them regarding newly developed or worsening PCOS-related symptoms or metabolic abnormalities.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by a grant from the Seoul National University Hospital Research Fund (No. 2520140090), Republic of Korea. The authors have no conflicts of interest to disclose.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Wed, 25 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa012
      Issue No: Vol. 35, No. 3 (2020)
  • Clinicians’ perspectives on diagnosing polycystic ovary syndrome in
           Australia: a qualitative study
    • Authors: Copp T; Muscat D, Hersch J, et al.
      Pages: 660 - 668
      Abstract: AbstractSTUDY QUESTIONWhat are clinicians’ views about the diagnosis of polycystic ovary syndrome (PCOS), and how do they handle any complexities and uncertainties in practice'SUMMARY ANSWERClinicians have to navigate many areas of complexity and uncertainty regarding the diagnosis of PCOS, related to the diagnostic criteria, limitations in current evidence and misconceptions surrounding diagnosis, and expressed concern about the risk and consequences of both under- and overdiagnosis.WHAT IS KNOWN ALREADYPCOS is a complex, heterogeneous condition with many areas of uncertainty, raising concerns about both underdiagnosis and overdiagnosis. Quantitative studies with clinicians have found considerable variation in diagnostic criteria used and care provided, as well as a lack of awareness around the breadth of PCOS features and poor uptake of recommended screening for metabolic complications. Clinicians’ views about the uncertainties and complexities of diagnosing PCOS have not been explored.STUDY DESIGN, SIZE, DURATIONSemi-structured telephone interviews were conducted with clinicians from September 2017 to July 2018 to explore their perceptions about the diagnosis of PCOS, including how they handle any complexities and uncertainties in practice.PARTICIPANTS/MATERIALS, SETTING, METHODSA group of 36 clinicians (15 general practitioners, 10 gynaecologists and 11 endocrinologists) currently practicing in Australia, were recruited through advertising via professional organisations, contacting a random sample of endocrine and gynaecology teams across Australia and snowballing. Transcribed audio-recordings were analysed thematically using Framework analysis.MAIN RESULTS AND THE ROLE OF CHANCEClinicians expressed a range of uncertainties and complexities regarding the diagnosis of PCOS, which were organised into three areas: (i) establishing diagnosis (e.g. lack of standardisation regarding diagnostic cut-offs, risk of misdiagnosis), (ii) factors influencing the diagnostic process (e.g. awareness of limitations in evidence and consideration of the benefits and harms) and (iii) strategies for handling challenges and uncertainties (e.g. using caution and communication of uncertainties). Clinicians also varied in their concerns regarding under- and overdiagnosis. Overall, most felt the diagnosis was beneficial for women provided that it was the correct diagnosis and time was taken to assess patient expectations and dispel misconceptions, particularly concerning fertility.LIMITATIONS, REASONS FOR CAUTIONThere is possible selection bias, as clinicians who are more knowledgeable about PCOS may have been more likely to participate. Clinicians’ views may also differ in other countries.WIDER IMPLICATIONS OF THE FINDINGSThese findings underscore the vital need to first consider PCOS a diagnosis of exclusion and use caution before giving a diagnosis in order to reduce misdiagnosis, as suggested by clinicians in our study. Until there is greater standardisation of diagnostic criteria, more transparent conversations with women may help them understand the uncertainties surrounding the criteria and limitations in the evidence. Additionally, clinicians emphasised the importance of education and reassurance to minimise the potential harmful impact of the diagnosis and improve patient-centred outcomes.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by the University of Sydney Lifespan Research Network and an NHMRC Program Grant (APP1113532). T.C. is supported by an Australian Government Research Training Program (RTP) Scholarship and a Sydney Medical School Foundation Scholarship, from the The University of Sydney, Australia. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA and Guerbet. No further competing interests exist.TRIAL REGISTRATION NUMBERN/A
      PubDate: Wed, 26 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa005
      Issue No: Vol. 35, No. 3 (2020)
  • Parental comorbidity and medication use in the USA: a panel study of
           785 000 live births
    • Authors: Sun A; Li S, Zhang C, et al.
      Pages: 669 - 675
      Abstract: AbstractSTUDY QUESTIONHow prevalent is paternal medication use and comorbidity, and are rates of these rising'SUMMARY ANSWERPaternal medication use and comorbidity is common and rising, similar to trends previously described in mothers.WHAT IS KNOWN ALREADYMaternal medication use and comorbidity has been rising for the past few decades. These trends have been linked to potential teratogenicity, maternal morbidity and mortality and poorer fetal outcomes.STUDY DESIGN, SIZE, DURATIONThis is a Panel (trend) study of 785 809 live births from 2008 to 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSWe used the IBM© Marketscan®™ database to gather data on demographic information and International Classification of Diseases codes and Charlson comorbidity index (CCI) during the 12 months prior to the estimated date of conception for mothers and fathers. We similarly examined claims of prescriptions in the 3 months prior to conception. We performed companion analyses of medications used for >90 days in the 12 months prior to conception and of any medication use in the 12 months prior to conception.MAIN RESULTS AND THE ROLE OF CHANCEWe confirmed that both maternal medication use and comorbidity (e.g. hypertension, diabetes, hyperlipidemia) rose over the study period, consistent with prior studies. We found a concurrent rise in both paternal medication use 3 months prior to conception (overall use, 31.5–34.9% during the study period; P < 0.0001) and comorbidity (CCI of ≥1 and 10.6–18.0% over study period; P < 0.0001). The most common conditions seen in the CCI were chronic obstructive pulmonary disease for mothers (6.6–11.6%) and hyperlipidemia for fathers (8.6–13.7%). Similar trends for individual medication classes and specific comorbidities such as hypertension, diabetes and hyperlipidemia were also seen. All primary result trends were statistically significant, making the role of chance minimal.LIMITATIONS, REASONS FOR CAUTIONAs this is a descriptive study, the clinical impact is uncertain and no causal associations may be made. Though the study uses a large and curated database that includes patients from across the USA, our study population is an insured population and our findings may not be generalizable. Mean parental age was seen to slightly increase over the course of the study (<1 year) and may be associated with increased comorbidity and medication use.WIDER IMPLICATIONS OF THE FINDINGSAs parental comorbidity and certain medication use may impact fecundability, temporal declines in parental health may impact conception, pregnancy and fetal outcomes.STUDY FUNDING/COMPETING INTEREST(S)None.TRIAL REGISTRATION NUMBERN/A
      PubDate: Wed, 18 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa022
      Issue No: Vol. 35, No. 3 (2020)
  • Do physical activity, sitting time and body mass index affect fertility
           over a 15-year period in women' Data from a large population-based
           cohort study
    • Authors: Mena G; Mielke G, Brown W.
      Pages: 676 - 683
      Abstract: AbstractSTUDY QUESTIONDo physical activity (PA), sitting time (ST) and body mass index (BMI) affect fertility over a 15-year period in Australian women'SUMMARY ANSWERModerate and high levels of PA confer advantages for fertility in women with normal BMI, but increased risk of infertility was observed in obese women.WHAT IS KNOWN ALREADYHigher BMI is positively associated with higher rates of problems with fertility, but the effects of physical activity and sitting time on fertility are less well understood.STUDY DESIGN, SIZE, DURATIONParticipants in The Australian Longitudinal Study of Women’s Health (ALSWH) completed mailed surveys in 2000, with follow-ups in 2003, 2006, 2009, 2012 and 2015 (N = 6130).PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants were aged 22 to 27 in 2000. They were asked to report their physical activity levels, sitting time and fertility problems in each survey from 2000 to 2015. BMI was calculated from self-reported weight and height. Cumulative incidence of fertility problems was calculated from 2000 to 2015 and hazard ratios (HR) and 95% CIs were calculated using survival analysis.MAIN RESULTS AND THE ROLE OF CHANCEFrom 2000 to 2015, the cumulative incidence of fertility problems was 15.4% (95% CI: 14.5–16.4). High levels of PA were associated with reduced risk of problems with fertility [HR 0.82 (95% CI: 0.69–0.98)], and higher BMI was positively associated with fertility problems [overweight: HR 1.18, (95% CI 0.99–1.39); obese: HR 1.36, (95% CI 1.14–1.63)]. In survival analyses, incidence rates were highest in every survey interval in women who reported low PA levels and in women who were obese. Overall, ST was not associated with fertility problems. In stratified models, high levels of PA attenuated the risk of problems with fertility in women who were in the normal BMI category [HR 0.64, (95% CI 0.49–0.82)].LIMITATIONS, REASONS FOR CAUTIONThe ALSWH relies on self-reported data, which may be subject to recall bias.WIDER IMPLICATIONS OF THE FINDINGSThe study provides estimates of problems with fertility in a cohort of young adult Australian women, and the results indicate that these are inversely associated with physical activity levels and positively associated with BMI. However, the high infertility risk in obese women was not attenuated by high levels of PA. The protective effects of PA were only observed in women with normal BMI. As rates of developing problems with fertility were highest in every survey interval among women who reported low levels of physical activity and in women who were obese, these findings suggest that improving physical activity levels could be an affordable strategy to reduce problems with fertility in women who are trying to conceive. These findings should be considered by clinical and public health practitioners.STUDY FUNDING/COMPETING INTEREST(S)The ALSWH is funded by the Australian Government. Funding for these analyses was provided by a University of Queensland (UQ) International Postgraduate Research Scholarship and a UQ International Development Fellowship. The authors declare no conflicts of interest.
      PubDate: Mon, 16 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez300
      Issue No: Vol. 35, No. 3 (2020)
  • Infertility treatment and autism risk using the Modified Checklist for
           Autism in Toddlers (M-CHAT)
    • Authors: Robinson S; Parikh T, Lin T, et al.
      Pages: 684 - 693
      Abstract: AbstractSTUDY QUESTIONAre toddlers conceived by fertility treatment at higher risk of failing a screening tool for autism spectrum disorders (ASD) than toddlers not conceived by treatment'SUMMARY ANSWERCompared with children not conceived by infertility treatment, children conceived by any infertility treatment, ovulation induction with or without intrauterine insemination (OI/IUI), or assisted reproductive technologies (ART) appeared to have had higher odds of failing an ASD screening; however, results were inconclusive and need replication.WHAT IS KNOWN ALREADYAlthough most of the studies which have examined risk of ASD after ART show no association, the results are mixed. Thus, further studies are needed to clarify this association.STUDY DESIGN SIZE, DURATIONThe Upstate KIDS Study is a population-based, prospective cohort study of children born in New York State between 2008 and 2010. Children were screened for ASD using the Modified Checklist for Autism in Toddlers (M-CHAT) at ages 18 and 24 months.PARTICIPANTS/MATERIALS, SETTING, AND METHODSThe New York State live-birth registry was used to identify newborns conceived with and without fertility treatment with a 1:3 ratio, frequency matched on region of birth. At 18 and 24 months, 3183 and 3063 mothers, respectively, completed the M-CHAT questionnaire. The current analysis included 2586 singletons and 1296 twins with M-CHAT information at 18 and/or 24 months. Multivariable logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (aOR) and 95% confidence intervals (CI) after adjustment for covariates such as maternal age, education and plurality.MAIN RESULTS AND THE ROLE OF CHANCEWe found that 200 (5.2%) and 115 (3.0%) children failed the M-CHAT at 18 and 24 months, respectively. The associations between use of infertility treatment and failing the M-CHAT at 18 and/or 24 months were positive but inconclusive as they failed to exclude no association (18 months aOR 1.71, 95% CI: 0.81–3.61; 24 months aOR 1.78, 95% CI: 0.66–4.81; and both 18 and 24 months aOR 1.53, 95% CI: 0.78–2.99). The relationships between OI/IUI and ART with M-CHAT failure at 18 and/or 24 months were similar to those of using any fertility treatment. In vitro fertilization with intracytoplasmic sperm injection was not consistently positively or inversely associated with M-CHAT failure at each time point (18 months aOR 1.20, 95% CI: 0.51–2.83; 24 months aOR 0.93, 95% CI: 0.37–2.31; and both 18 and 24 months aOR 1.09, 95% CI: 0.50–2.60).LIMITATIONS REASONS FOR CAUTIONThe M-CHAT is a screening tool used for ASD risk assessment, and therefore, M-CHAT failure does not indicate ASD diagnosis. In addition, we did not have power to detect associations of small magnitude. Finally, non-response to follow-up may bias the results.WIDER IMPLICATIONS OF THE FINDINGSDespite lack of precision, the positive associations between ART and M-CHAT failure suggest that larger population-based studies with longer follow-up are needed.STUDY FUNDING/COMPETING INTEREST(S)Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, HHSN267200700019C). The sponsor played no role in the study design, data collection, data analysis or interpretation, writing of the manuscript or decision to submit the article for publication. There are no conflicts of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Thu, 12 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez298
      Issue No: Vol. 35, No. 3 (2020)
  • A minimum estimate of the prevalence of 22q11 deletion syndrome and other
           chromosome abnormalities in a combined prenatal and postnatal cohort
    • Authors: Hui L; Poulton A, Kluckow E, et al.
      Pages: 694 - 704
      Abstract: AbstractSTUDY QUESTIONWhat is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births'SUMMARY ANSWERThe overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively.WHAT IS KNOWN ALREADYOver the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics.STUDY DESIGN, SIZE, DURATIONA population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included.PARTICIPANTS/MATERIALS, SETTING, METHODSA research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation.MAIN RESULTS AND THE ROLE OF CHANCEDuring the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births.LIMITATIONS, REASONS FOR CAUTIONClinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected.WIDER IMPLICATIONS OF THE FINDINGSOur study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS.STUDY FUNDING/COMPETING INTEREST(S)L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children’s Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work.TRIAL REGISTRATION NUMBERNA
      PubDate: Tue, 24 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez286
      Issue No: Vol. 35, No. 3 (2020)
  • Variation in the HLA-F gene locus with functional impact is associated
           with pregnancy success and time-to-pregnancy after fertility treatment
    • Authors: Langkilde C; Nilsson L, Jørgensen N, et al.
      Pages: 705 - 717
      Abstract: AbstractSTUDY QUESTIONThe aim of this study was to investigate a possible influence of three single nucleotide polymorphisms (SNPs) in the HLA-F gene locus on time-to-pregnancy and pregnancy success after fertility treatment.SUMMARY ANSWERHLA-F SNP genotypes and HLA-F diplotypes are associated with the number of fertility treatment cycles needed to achieve pregnancy and live birth.WHAT IS KNOWN ALREADYHLA class Ib molecules, including HLA-F, which are known to be expressed by extra-villous trophoblast cells have immunomodulatory properties and play a role at the feto-maternal interface. However, a few recent studies suggest that HLA-F expressed in the mid-luteal endometrium may play a part in the establishment of pregnancy as well. Three genetic polymorphisms in the HLA-F gene locus influence the expression of HLA-F in the mid-luteal endometrium and are associated with time-to-pregnancy in healthy women.STUDY DESIGN, SIZE, DURATIONThe current study included 102 female patients and 91 male patients attending for ART treatment and recruited between 2009 and 2014 at fertility clinics in a University Hospital setting, and 78 fertile female controls recruited in 2017 and 2018 at a department of Obstetrics and Gynaecology in a University Hospital. All women in the control group conceived naturally, and no other clinical data for the controls were retrieved.PARTICIPANTS/MATERIALS, SETTING, METHODSGenotyping of genomic DNA from blood samples was performed with Sanger sequencing for the three SNPs of interest in the HLA-F gene locus: rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G). Furthermore, clinical data were collected for the couples in fertility treatment.MAIN RESULTS AND THE ROLE OF CHANCEThere were no significant differences in the distributions of the three HLA-F SNP genotypes and alleles between the female fertile control group and the female infertility group. We considered if the number of treatment cycles was related to the HLA-F SNP genotypes and HLA-F diplotypes in a discrete time to event analyses. A significant association with longer time-to-pregnancy, measured as number of fertility treatment cycles, was observed for women in the ART group who carried the HLA-F genotypes that are associated with a lower amount of HLA-F mRNA expressed in mid-luteal endometrium. For the rs1362126 AA genotype relative to the GG genotype, the odds ratio (OR) was 0.30 (95% CI = 0.10–0.87, P = 0.02); for the rs2523405 GG genotype relative to the TT genotype, the OR was 0.40 (95% CI = 0.15–1.04, P = 0.06); and for the rs2523393 GG genotype relative to the AA genotype, the OR was 0.27 (95% CI = 0.09–0.78, P = 0.01). In addition to comparing the HLA-F genotypes by a standard likelihood-ratio test, a trend test based on the number of G or A alleles were also performed. The HLA-F genotypes associated with longer time-to-pregnancy in these tests were as follows: number of A alleles at rs1362126 (P = 0.01), the OR was 0.56 per A allele (95% CI = 0.35–0.89); number of G alleles at rs2523405 (P = 0.05), OR was 0.65 per G allele (95% CI = 0.42–1.00); and number of G alleles at rs2523393 (P = 0.01), OR was 0.56 per G allele (95% CI = 0.36–0.86). On average, for the rs1362126 SNP, 2.1 more treatment cycles for a woman who carried the AA genotype were needed to achieve pregnancy within the first eight treatment cycles compared with a woman who carried the GG genotype. Likewise, for the rs2523405 SNP, 1.8 more cycles for the GG genotype compared with the TT genotype were needed, and for the rs2523393 SNP, 2.2 more treatment cycles for a woman who carried the GG genotype compared with a woman who carried the AA genotype were needed. Adjustments for the covariates BMI, female age, IVF (yes/no for each cycle), ICSI (yes/no for each cycle), female factor (yes/no) and male factor (yes/no), were also performed modeling the cycle-specific probabilities and the genotypes remained significant and almost unchanged.LIMITATIONS, REASONS FOR CAUTIONSpecific types of ART will be chosen from the start of treatment, which means that the chances of achieving pregnancy could differ between the women solely due to their first line of treatment. However, multivariate analyses are performed to adjust for type of ART treatment.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first study that shows associations between, and implications of, HLA-F gene locus variation and time-to-pregnancy and pregnancy success in a clinical setting for fertility treatment/ART.STUDY FUNDING/COMPETING INTEREST(S)Supported by the Region Zealand Health Sciences Research foundation and by Zealand University Hospital through the ReproHealth Research Consortium ZUH. The authors declare no conflict of interest.
      PubDate: Tue, 04 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez276
      Issue No: Vol. 35, No. 3 (2020)
  • Identity-by-state-based haplotyping expands the application of
           comprehensive preimplantation genetic testing
    • Authors: Ding J; Dimitriadou E, Tšuiko O, et al.
      Pages: 718 - 726
      Abstract: AbstractSTUDY QUESTIONIs it possible to haplotype parents using parental siblings to leverage preimplantation genetic testing (PGT) for monogenic diseases and aneuploidy (comprehensive PGT) by genome-wide haplotyping'SUMMARY ANSWERWe imputed identity-by-state (IBS) sharing of parental siblings to phase parental genotypes.WHAT IS KNOWN ALREADYGenome-wide haplotyping of preimplantation embryos is being implemented as a generic approach for genetic diagnosis of inherited single-gene disorders. To enable the phasing of genotypes into haplotypes, genotyping the direct family members of the prospective parent carrying the mutation is required. Current approaches require genotypes of either (i) both or one of the parents of the affected prospective parent or (ii) an affected or an unaffected child of the couple. However, this approach cannot be used when parents or children are not attainable, prompting an investigation into alternative phasing options.STUDY DESIGN, SIZE, DURATIONThis is a retrospective validation study, which applied IBS-based phasing of parental haplotypes in 56 embryos derived from 12 PGT families. Genome-wide haplotypes and copy number profiles generated for each embryo using the new phasing approach were compared with the reference PGT method to evaluate the diagnostic concordance.PARTICIPANTS/MATERIALS, SETTING, METHODSThis study included 12 couples with a known hereditary genetic disorder, participating in the comprehensive PGT program and with at least one parental sibling available (e.g. brother and/or sister). Genotyping data from both prospective parents and the parental sibling(s) were used to perform IBS-based phasing and to trace the disease-associated alleles. The outcome of the IBS-based PGT was compared with the results of the clinically implemented reference haplotyping-based PGT method.MAIN RESULTS AND THE ROLE OF CHANCEIBS-based haplotyping was performed for 12 PGT families. In accordance with the theoretical prediction of allele sharing between sibling pairs, 6 out of 12 (50%) couples or 23 out of 56 embryos could be phased using parental siblings. In families where phasing was possible, haplotype calling in the locus of interest was 100% concordant between the reference PGT method and IBS-based approach using parental siblings.LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONPhasing of parental haplotypes will only be possible when the disease locus lies in an informative region (categorized as IBS1). Phasing prospective parents using relatives with reduced genetic relatedness as a reference (e.g. siblings) decreases the size and the occurrence of informative IBS1 regions, necessary for haplotype calling. By including more than one extended family member, the chance of obtaining IBS1 coverage in the interrogated locus can be increased. A pre-PGT work-up can define whether the carrier couple could benefit from this approach.WIDER IMPLICATIONS OF THE FINDINGSPhasing by relatives extends the potential of comprehensive PGT, since it allows the inclusion of couples who do not have access to the standard phasing references, such as parents or offspring.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by the KU Leuven grant (C14/18/092), Research Foundation Flanders (FWO; GA09311N), Horizon 2020 innovation programme (WIDENLIFE, 692065) and Agilent Technologies. J.R.V., T.V. and M.Z.E. are co-inventors of a patent ZL910050-PCT/EP2011/060211-WO/2011/157846 ‘Methods for haplotyping single-cells’ and ZL913096-PCT/EP2014/068315-WO/2015/028576 ‘Haplotyping and copy number typing using polymorphic variant allelic frequencies’ licensed to Agilent Technologies. The other authors have no conflict of interest to declare.
      PubDate: Sat, 21 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez285
      Issue No: Vol. 35, No. 3 (2020)
  • The birth of a baby with mosaicism resulting from a known mosaic embryo
           transfer: a case report
    • Authors: Kahraman S; Cetinkaya M, Yuksel B, et al.
      Pages: 727 - 733
      Abstract: AbstractMosaic embryos have the potential to implant and develop into healthy babies. The transfer of mosaic embryos is now considered to be a possible option for women undergoing ART with preimplantation genetic testing for aneuploidies and in the absence of euploid embryos, particularly those with diminished ovarian reserve and/or advanced maternal age. It can aid in avoiding the discard of potentially viable embryos, which might otherwise result in healthy babies. In over 500 studies on mosaicism, there have been no reports of mosaicism in babies born following the transfer of mosaic embryos. Here, we present a case report of a 39-year-old woman with diminished ovarian reserve with only one blastocyst available for trophectoderm biopsy. The transfer of the embryo, which showed 35% mosaicism of monosomy 2, resulted in pregnancy. Amniocentesis revealed a mosaic trisomic mos46,XX(98)/47,XX,+2(2) karyotype. There were no pathological findings in detailed ultrasonography, and the fetus showed a normal fetal growth with no evidence of intrauterine growth retardation. A healthy female baby was born at Week 37. The peripheral blood chromosome analysis validated with fluorescence in situ hybridization showed 2% mosaic monosomy 2 [mos45,XX,-2(2)/46,XX(98)]. This is the first reported case of true fetal mosaicism resulting in a live birth following the transfer of a known mosaic embryo. Worldwide, prenatal diagnosis has shown the depletion of mosaicism in embryos transferred after they have been reported as mosaics. Our case demonstrates the need for close prenatal monitoring and diagnosis by early amniocentesis, preferably at >14 weeks gestation.
      PubDate: Tue, 10 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez309
      Issue No: Vol. 35, No. 3 (2020)
  • Reply: Open and closed carriers and the ‘sex of angels’
    • Authors: Pujol A; Zamora M, Obradors A, et al.
      Pages: 734 - 735
      Abstract: Sir,
      PubDate: Fri, 13 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez304
      Issue No: Vol. 35, No. 3 (2020)
  • Open and closed carriers and the ‘sex of angels’
    • Authors: Parmegiani L.
      Pages: 734 - 734
      Abstract: Sir,
      PubDate: Fri, 13 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/dez303
      Issue No: Vol. 35, No. 3 (2020)
  • Corrigendum. Excision versus colorectal resection in deep endometriosis
           infiltrating the rectum: 5-year follow-up of patients enrolled in a
           randomized controlled trial
    • Authors: Roman H; Tuech J, Huet E, et al.
      Pages: 736 - 736
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa019
      Issue No: Vol. 35, No. 3 (2020)
  • Corrigendum: Variation in the HLA-F gene locus with functional impact is
           associated with pregnancy success and time-to-pregnancy after fertility
    • Authors: Langkilde C; Nilsson L, Jørgensen N, et al.
      Pages: 737 - 738
      Abstract: Hum Reprod 2020;35:705–717
      PubDate: Sat, 21 Mar 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa046
      Issue No: Vol. 35, No. 3 (2020)
  • Corrigendum to P-434 (Effect of microgravity on frozen human sperm
           samples. Can they be sent to space')
    • Authors: Boada M; Perez -Poch A, Ballester M, et al.
      Pages: 739 - 739
      Abstract: The originally published version of the s of the 35th Annual Meeting of the European Society of Human Reproduction and Embryology, did not include the abstract, `P-434' (Effect of microgravity on frozen human sperm samples. Can they be sent to space'). This has since been added and can be found on p.i511.
      PubDate: Thu, 05 Sep 2019 00:00:00 GMT
      DOI: 10.1093/humrep/dez183
      Issue No: Vol. 35, No. 3 (2019)
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