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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 60, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 84, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 130, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 160, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 23, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 16)
American J. of Legal History     Full-text available via subscription   (Followers: 5, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 25, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 3, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 26, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 48, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 247, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 143, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 66, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 60, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 34, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 523, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 82, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 58, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 40, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 19, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 59, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 48, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 49, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 153, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 11, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 31, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 9, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 48, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 19, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 26, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 78, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 18, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 59, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 51, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 28)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 135, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 29, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 38, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 40, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 12, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 39, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 18)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 3)
J. of Heredity     Hybrid Journal   (Followers: 4, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Human Reproduction
  [SJR: 2.271]   [H-I: 179]   [78 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
   Published by Oxford University Press Homepage  [370 journals]
  • Who should we trust'
    • Authors: Evers JH; Sharpe RR, Somigliana EE, et al.
      Pages: 1541 - 1542
      PubDate: 2017-07-03
      DOI: 10.1093/humrep/dex211
      Issue No: Vol. 32, No. 8 (2017)
  • Gynaecologists and industry: ain't no sunshine
    • Authors: Farquhar CM; Vercellini P, Marjoribanks J.
      Pages: 1543 - 1548
      Abstract: AbstractThe field of reproductive medicine is known for its innovations, and where there is innovation there is marketing and engagement with the doctors who are potential prescribers and users of those innovations. Financial connections between drug and device manufacturers with doctors have been extensively debated over the past decade. On one hand, relationships between doctors and industry could be considered synergistic by allowing the development of improved treatments. On the other hand, payment (and other benefits) from industry to doctors may subtly shift the main objective of the collaboration from patients’ health to mutual benefits for both doctors and industry. Fertility patients can be considered ‘vulnerable’ as they face the multiple challenges of seeking to be parents, understanding complex and expensive fertility treatments that are by no means universally successful, and at the same time are under pressure because of their ever-increasing age. They are entitled to receive the most cost-effective treatments. We suggest that specialists in the field of reproductive medicine should be transparent about the receipt of financial benefits, including funding from industry, as it may be influencing both research outcomes and treatments that patients are offered. We also recommend that payments arising from industry-sponsored research should be centralized in institutional funds and not paid directly to researchers. And there should be transparency about the source and the purpose of the payment. Industry sponsorship of medical societies and their educational events should be kept to a minimum and declared quantitatively in societies’ websites and scientific programme brochures. Industry sponsorship of scientific meetings should not include the right to host educational symposia or speakers within the programme. All speakers should declare their conflicts of interest (COIs) at their meetings. Guideline groups should require all members to declare their financial COIs before meeting and exclude or limit those members with COI. Governmental authorities should not allow continuing medical education credits to those educational events not complying with the above policies. The crucial role of medical journals as ‘gatekeepers’ for identifying ‘science’ must be reaffirmed.
      PubDate: 2017-07-03
      DOI: 10.1093/humrep/dex228
      Issue No: Vol. 32, No. 8 (2017)
  • Transparent collaboration between industry and academia can serve unmet
           patient need and contribute to reproductive public health
    • Authors: D'Hooghe T.
      Pages: 1549 - 1555
      Abstract: The pharmaceutical and device industry has greatly contributed to diagnostic and therapeutic approaches in reproductive medicine in a very highly regulated environment, ensuring that development and manufacturing follow the highest standards. In spite of these achievements, collaboration between industry and physicians/academia is often presented in a negative context. However, today more than ever, partnership between industry and academia is needed to shorten the timeline between innovation and application, and to achieve faster access to better diagnostics, drugs and devices for the benefit of patients and society, based on complementary knowledge, skills and expertise. Such partnerships can include joined preclinical/clinical and post-marketing research and development, joint intellectual property, and joint revenue. In Europe, the transparency of this collaboration between pharmaceutical industry and medical doctors has been made possible by the Compliance and Disclosure Policy published by the European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents the major pharmaceutical companies operating in Europe, and includes as members some but not all companies active in infertility and women's health. Under the EFPIA Disclosure Code of conduct, companies need to disclose transfers of value including amounts, activity type and the names of the recipient Health Care Professionals and Organizations. EFPIA member companies have also implemented very strict internal quality control processes and procedures in the design, statistical analysis, reporting, publication and communication of clinical research, according to Good Clinical Practice and other regulations, and are regularly inspected by competent authorities such as the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for all trials used in marketing authorization applications. The risk of scientific bias exists not only in the pharmaceutical industry but also in the academic world. When academics believe in a hypothesis, they may build their case by emphasizing the arguments supporting their case, and either refute, refuse, oppose or ignore arguments that challenge their assumptions. A possible solution to reduce this bias is international consensus on study design, data collection, statistical analysis and reporting of outcomes, especially in the area of personalized reproductive medicine, e.g. to demonstrate superiority or non-inferiority of personalized ovarian stimulation using biomarkers. Equally important is that declarations of interest are reported transparently and completely in scientific abstracts and publications, and that ghost authorship is replaced by proactive and clear co-authorship for experts from industry where such co-authorship is required based on the prevailing ICMJE criteria. In that context, however, reviewers should stop believing that publications by industry authors only, or by mixed groups of co-authors from industry and academia, are more prone to bias than papers from academic groups only. Instead, the scientific quality of the work should be the only relevant criterion for acceptance of papers or abstracts, regardless of the environment where the work was done. In the end, neutrality does not exist and different beliefs and biases exist within and between healthcare professionals and organizations and pharmaceutical industries. The challenge is to be transparent about this reality at all times, and to behave in an informed, balanced and ethical way as medical and scientific experts, taking into account compliance and legal regulations of both industry and academic employers, in the best interest of patients and society.
      PubDate: 2017-07-03
      DOI: 10.1093/humrep/dex230
      Issue No: Vol. 32, No. 8 (2017)
  • A prognosis-based approach to infertility: understanding the role of time
    • Authors: .
      Pages: 1556 - 1559
      Abstract: AbstractThe current definition of infertility acknowledges the importance of duration of pregnancy seeking but fails to recognize the prevalent negative impact of female age. In fact, the diagnosis of unexplained infertility increases with women's age because of our incapacity to discern between age-related infertility and real unexplained infertility. Physicians’ response to the pressures of increased female age has been to take prompt refuge in assisted reproduction despite the lack of robust evidence and the inherent risks and costs of these procedures. Moreover, the prioritization of immediate health gains over those in the future, preference for accessing active treatment rapidly and reluctance to wait for spontaneous pregnancy expose patients to additional risks of overtreatment. Solutions are not simple to find but an alternative and innovative vision of infertility based on prognosis may be a valid solution. The availability of validated dynamic models based on real-life data that could predict both natural and ART-mediated conceptions may be of benefit. They could facilitate patients’ counselling and could optimize the chances of success without exposing patients to unnecessary, expensive and demanding treatments.
      PubDate: 2017-06-13
      DOI: 10.1093/humrep/dex214
      Issue No: Vol. 32, No. 8 (2017)
  • Sperm chemorepulsion, a supplementary mechanism to regulate fertilization
    • Authors: Guidobaldi HA; Cubilla MM, Moreno AA, et al.
      Pages: 1560 - 1573
      Abstract: AbstractSTUDY QUESTIONAre human spermatozoa able of chemorepulsive behaviour'SUMMARY ANSWERCapacitated human spermatozoa are able to be chemorepelled by synthetic Progesterone Receptor Ligands (sPRL, known as contraceptives) and zinc (a cation released by the oocyte upon fertilization).WHAT IS KNOWN ALREADYMoving cells can be oriented towards or against a molecular gradient, processes called chemoattraction and chemorepulsion, respectively, which have been described in unicellular organisms such as amoebas and bacteria, to organismic cells such macrophages and developmental cells. In the case of spermatozoa, chemoattraction may help the finding of an oocyte and has been widely studied in various invertebrate and mammalian species; however, chemorepulsion has not yet been verified in spermatozoa.STUDY DESIGN, SIZE, DURATIONThis is an in vitro study involving human, rabbit and mouse spermatozoa which were used to perform 3–30 experiments per treatment.PARTICIPANTS/MATERIALS, SETTING, METHODSHuman sperm samples were obtained by masturbation from healthy donors who gave written consent. Only those samples exhibiting normal semen parameters according to current WHO criteria were included in the study. Rabbit spermatozoa were obtained by artificial vagina whereas mice spermatozoa were obtained from epididymis. The sperm selection assay (SSA), originally designed to evaluate sperm chemoattraction towards progesterone (P), and a video-microscopy and computer motion analysis system were used to test sperm chemorepulsion. Additional kinetic parameters were also determined by video-microscopy and computer motion analysis. In some experiments, the level of induced acrosome-reacted spermatozoa was determined. Rabbit mating manipulation was achieved to perform the sperm–oocyte co-incubation assay.MAIN RESULTS AND THE ROLE OF CHANCESperm accumulation in the well containing 100 pg/ml of sPRL was lower than the culture medium negative control (P < 0.05). The percentage of sperm persistence against the well containing 100 pg/ml ulipristal acetate (UPA) (P = 0.001), and the percentage of sperm showing a repulsive pattern of movement (a linear trajectory followed by a transitional one after turning against the UPA), were higher than the culture medium negative control (P = 0.049). Sperm accumulation was diminished when spermatozoa where exposed to a homogeneous distribution of 100 pg/ml sPRL combined with a chemotactic gradient of progesterone (P), with respect to the culture medium negative control (P < 0.05). These results were reverted when non-capacitated spermatozoa were used to perform the same experimental settings. The accumulation of spermatozoa against 100 pg/ml sPRL was lower than the culture medium negative control also in rabbits and mice (P < 0.05). The relative number of rabbit spermatozoa arriving to the vicinity of the oocyte was diminished under the presence of 100 pg/ml UPA (P = 0.004). Sperm accumulation in the well containing zinc was decreased compared to the culture medium negative control (P < 0.05). A homogeneous distribution of zinc combined with a gradient of 10 pM P, was lower than the culture medium negative control (P = 0.016). The results were quite reproducible with two different methodologies (accumulation assay and video-microscopy combined with computer motion analysis), in three mammalian species.LIMITATIONS REASONS FOR CAUTIONThe experiments were performed in vitro. Even though a quite complete characterization of sperm chemorepulsion was provided, the molecular mechanism that governs sperm repulsion is currently under investigation.WIDER IMPLICATIONS OF THE FINDINGSSince the chemorepelled spermatozoa are those physiologically ready to fertilize the oocyte, these findings may have both biological and clinical implications, preventing either polyspermy under natural conditions or fertilization under pharmacological treatment with sPRL.STUDY FUNDING/COMPETING INTEREST(S)The study was financed by the Universidad Nacional de Cordoba (Argentina). The authors declare that they do not have competing financial interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-06-23
      DOI: 10.1093/humrep/dex232
      Issue No: Vol. 32, No. 8 (2017)
  • Unexplained recurrent miscarriages are associated with an aberrant sperm
           protamine mRNA content
    • Authors: Rogenhofer N; Ott J, Pilatz A, et al.
      Pages: 1574 - 1582
      Abstract: AbstractSTUDY QUESTIONAre unexplained recurrent miscarriages associated with abnormal protamine-1 and protamine-2 mRNA levels in spermatozoa'SUMMARY ANSWERBoth protamine-1 and protamine-2 mRNA levels as well as the protamine-1 to protamine-2 mRNA ratio in spermatozoa from men whose female partners experienced two or more consecutive miscarriages were significantly different compared to those from both healthy control men and subfertile couples undergoing IVF/ICSI.WHAT IS KNOWN ALREADYAberrant sperm protamine ratios are known to be associated with male-factor infertility. Data from this study suggest that the protamine mRNA ratio may additionally affect early embryo development.STUDY DESIGN, SIZE, DURATIONThe study population was recruited from men whose female partners presented with two or more consecutive unexplained miscarriages in a consultation for recurrent pregnancy loss between 2014 and 2016. At the research laboratory of the Urological Clinic of the University Giessen, spermatozoa from cases and controls were subjected to reverse transcription quantitative PCR (RTqPCR) using specific primer pairs for protamine-1 and protamine-2.PARTICIPANTS/MATERIALS, SETTING, METHODSProtamine-1 and protamine-2 mRNA levels were analysed in semen samples from 25 men whose female partners experienced at least two consecutive idiopathic miscarriages before the 20th week of gestation. The couples were recruited during consultation at the Fertility Center of the LMU Munich, Germany, and at the Clinical Division of Gynecologic Endocrinology and Reproductive Medicine of the Medical University of Vienna, Austria. Results were compared with those from 32 healthy donors (WHO, 2010) recruited at the Department of Urology, Pediatric Urology and Andrology, Giessen, Germany, and 107 men whose partners participated in an IVF/ICSI program at the Fertility Center of the LMU Munich, Germany.MAIN RESULTS AND THE ROLE OF CHANCEProtamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers (P < 0.01). When comparing recurrent miscarriage couples with couples undergoing IVF/ICSI, Ct-values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in RM couples (P < 0.01). When comparing protamine mRNA levels and the protamine mRNA ratio with routine semen parameters, a significant negative correlation was evident between progressive motility and the protamine-2 mRNA level (P = 0.015), as well as between non-progressive motility and the protamine mRNA ratio (P = 0.023).LIMITATIONS REASONS FOR CAUTIONAlthough our data demonstrate significant abnormalities in RM, larger sample sizes will be needed to confirm our results. Larger sample sizes should also balance the fact that we had to focus mainly on median protamine mRNA levels. Finally, men in the healthy control group were younger in age than those in the case group, which might have introduced some bias, at least concerning the classic semen parameters. Moreover, only protamine mRNA instead of protein levels could be measured.WIDER IMPLICATIONS OF THE FINDINGSAlthough the exact mechanism remains to be elucidated, our data suggest that protamine mRNA levels in spermatozoa are not only important for successful fertilization, but also for proper development of the early embryo.STUDY FUNDING/COMPETING INTEREST(S)Grant from the University Clinic Giessen and Marburg (UKGM 29/2015GI). There are no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-06-15
      DOI: 10.1093/humrep/dex224
      Issue No: Vol. 32, No. 8 (2017)
  • Corticotrophin-releasing hormone and corticosterone impair development of
           preimplantation embryos by inducing oviductal cell apoptosis via
           activating the Fas system: an in vitro study
    • Authors: Tan X; Ji C, Zheng L, et al.
      Pages: 1583 - 1597
      Abstract: AbstractSTUDY QUESTIONWhat are the mechanisms by which corticotrophin-releasing hormone (CRH) and corticosterone impair the development of preimplantation embryos in the oviduct.SUMMARY ANSWERCRH and corticosterone do not affect preimplantation embryos directly, but impair their development indirectly by triggering apoptosis of oviductal epithelial cells (OECs) through activation of the Fas system.WHAT IS KNOWN ALREADYStudies report that stress impairs embryo development with facilitated secretion of CRH and glucocorticoids. Although an in vivo study demonstrated that preimplantation stress impaired embryo development in conjunction with oviductal apoptosis and activation of the Fas system, whether CRH or glucocorticoids damage embryos directly or indirectly by way of oviductal cells remains to be clarified.STUDY DESIGN, SIZE, DURATIONMice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in Fas ligand in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female mice were used 8–10 weeks after birth.PARTICIPANTS/MATERIALS, SETTING, METHODSWhile some female mice were killed 48 h after being injected with equine CG to collect oviducts and prepare OECs, others were killed to recover zygotes after mating with males following superovulation with eCG and hCG. The zygotes obtained were cultured with or without CRH or corticosterone (CRH/Cort) either in Chatot–Ziomek–Bavister (CZB) medium with or without OECs or in conditioned medium (CM) conditioned with OECs pretreated or not with CRH/Cort. Preimplantation development, levels of redox potential and apoptosis, and expression of CRH receptor 1 (CRHR1), glucocorticoid receptor (GR), Fas and 11β-hydroxysteroid dehydrogenase (HSD) were observed in embryos recovered at different times of in vitro culture. After culture of OECs with or without CRH/Cort, levels of redox potential and apoptosis, mRNA and protein expression of growth factors, and protein expression of CRHR1, GR and Fas were examined in OECs and the level of FasL was measured in CM. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts.MAIN RESULTS AND THE ROLE OF CHANCEThis study showed that blastocyst development was unaffected when mouse zygotes were cultured in CZB medium containing various concentrations of CRH/Cort but was impaired when embryos were cultured with CRH/Cort plus OECs or in CM conditioned with OECs pretreated with CRH/Cort (treatment CM). Culture in treatment-CM induced oxidative stress and apoptosis in embryos. Preimplantation embryos expressed GR and Fas at all stages and CRHR1 at the blastocyst stage only. Mouse 4-cell embryos and blastocysts expressed HSD2 but not HSD1. Culture of OECs with CRH/Cort increased their oxidative stress, apoptosis, CRHR1, Fas and FasL while decreasing their GR and growth factors. Blastocyst development in treatment-CM conditioned with OECs from gld mice harboring FasL mutations was superior to treatment-CM conditioned with wild-type mouse OECs. The results suggest that CRH/Cort impairs embryo development indirectly by inducing oviductal apoptosis via activating the Fas system. The insensitivity of preimplantation embryos to CRH and corticosterone is due to, respectively, a lack of CRHR and the exclusive expression of HSD2 that inactivate corticosterone.LARGE SCALE DATANot applicable.LIMITATIONS, REASONS FOR CAUTIONAlthough significant, the conclusions were drawn from limited results obtained using mice and thus they need further verification in other species. For example, bovine embryos express both HSD1 and HSD2 at all the preimplantation stages whereas mouse preimplantation embryos express HSD2 exclusively without HSD1.WIDER IMPLICATIONS OF THE FINDINGSThe data are important for our understanding of the mechanisms by which stress affects female reproduction in both human and animals, as early stages of pregnancy are considered more vulnerable to stress than the late stages.STUDY FUNDING AND COMPETING INTEREST(S)This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests.
      PubDate: 2017-06-07
      DOI: 10.1093/humrep/dex217
      Issue No: Vol. 32, No. 8 (2017)
  • A pilot randomized controlled trial of Day 3 single embryo transfer with
           adjunctive time-lapse selection versus Day 5 single embryo transfer with
           or without adjunctive time-lapse selection
    • Authors: Kaser DJ; Bormann CL, Missmer SA, et al.
      Pages: 1598 - 1603
      Abstract: AbstractSTUDY QUESTIONCompared to D5 selection with conventional morphology (CM), does adjunctive use of the Eeva™ test on D3 or D5 improve the clinical pregnancy rate (CPR) per transfer'SUMMARY ANSWERThe evidence is insufficient to conclude that adjunctive use of the Eeva™ test on D3 or D5 improves CPR per transfer as compared to D5 selection with CM.WHAT IS KNOWN ALREADYTime-lapse imaging is increasingly used for embryo selection, despite there being no class I data to support its clinical application.STUDY DESIGN, SIZE, DURATIONPilot randomized controlled trial included 163 patients from August 2014 to February 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSPatients up to age 41 years with a planned fresh autologous single embryo transfer (SET), less than four prior oocyte retrievals, and four or more zygotes were blocked according to age (<35, 35–37, 38–40 years) and randomized to one of three study arms: (1) D3 SET + EevaTM, (2) D5 SET + Eeva™ or (3) D5 SET with CM alone. All embryos were cultured in the same time-lapse system under identical conditions. Intention-to-treat (ITT) and as-treated analyses of the primary endpoint (CPR at 7 weeks) and secondary endpoint (ongoing pregnancy rate at 12 weeks) were performed. Multivariate regression analyses adjusted for patient age and ICSI.MAIN RESULTS AND THE ROLE OF CHANCEOf 478 eligible patients, 217 consented and 163 were randomized. Demographic characteristics were similar among the three study arms. There were no statistically significant differences in the clinical pregnancy rate or the ongoing pregnancy rate between the study arms for either the ITT or as-treated analyses (CPR ITT: D3 + Eeva™: 41.1% vs. D5 + Eeva™: 38.9% vs. D5 CM: 49.1%).LIMITATIONS, REASONS FOR CAUTIONThis study was designed as a pilot randomized controlled trial and was not powered to detect a statistically significant difference at α < 0.05. Importantly, the study was terminated prematurely by the sponsor due to a change in funding priorities, so the sample size is limited and the results should be interpreted with caution due to the role of chance. Furthermore, these findings may not be generalizable to other time-lapse systems.WIDER IMPLICATIONS OF THE FINDINGSOur findings do not support the clinical application of these time-lapse markers.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by Progyny, Inc. There are no competing interests.TRIAL REGISTRATION NCT02218255TRIAL REGISTRATION DATE14 August 2014DATE OF FIRST PATIENT'S ENROLLMENT3 September 2014
      PubDate: 2017-06-28
      DOI: 10.1093/humrep/dex231
      Issue No: Vol. 32, No. 8 (2017)
  • Prospective study of automated versus manual annotation of early
           time-lapse markers in the human preimplantation embryo
    • Authors: Kaser DJ; Farland LV, Missmer SA, et al.
      Pages: 1604 - 1611
      Abstract: AbstractSTUDY QUESTIONHow does automated time-lapse annotation (Eeva™) compare to manual annotation of the same video images performed by embryologists certified in measuring durations of the 2-cell (P2; time to the 3-cell minus time to the 2-cell, or t3–t2) and 3-cell (P3; time to 4-cell minus time to the 3-cell, or t4–t3) stages'SUMMARY ANSWERManual annotation was superior to the automated annotation provided by Eeva™ version 2.2, because manual annotation assigned a rating to a higher proportion of embryos and yielded a greater sensitivity for blastocyst prediction than automated annotation.WHAT IS KNOWN ALREADYWhile use of the Eeva™ test has been shown to improve an embryologist's ability to predict blastocyst formation compared to Day 3 morphology alone, the accuracy of the automated image analysis employed by the Eeva™ system has never been compared to manual annotation of the same time-lapse markers by a trained embryologist.STUDY DESIGN, SIZE, DURATIONWe conducted a prospective cohort study of embryos (n = 1477) cultured in the Eeva™ system (n = 8 microscopes) at our institution from August 2014 to February 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSEmbryos were assigned a blastocyst prediction rating of High (H), Medium (M), Low (L), or Not Rated (NR) by Eeva™ version 2.2 according to P2 and P3. An embryologist from a team of 10, then manually annotated each embryo and if the automated and manual ratings differed, a second embryologist independently annotated the embryo. If both embryologists disagreed with the automated Eeva™ rating, then the rating was classified as discordant. If the second embryologist agreed with the automated Eeva™ score, the rating was not considered discordant. Spearman's correlation (ρ), weighted kappa statistics and the intra-class correlation (ICC) coefficients with 95% confidence intervals (CI) between Eeva™ and manual annotation were calculated, as were the proportions of discordant embryos, and the sensitivity, specificity, positive predictive value (PPV) and NPV of each method for blastocyst prediction.MAIN RESULTS AND THE ROLE OF CHANCEThe distribution of H, M and L ratings differed by annotation method (P < 0.0001). The correlation between Eeva™ and manual annotation was higher for P2 (ρ = 0.75; ICC = 0.82; 95% CI 0.82–0.83) than for P3 (ρ = 0.39; ICC = 0.20; 95% CI 0.16–0.26). Eeva™ was more likely than an embryologist to rate an embryo as NR (11.1% vs. 3.0%, P < 0.0001). Discordance occurred in 30.0% (443/1477) of all embryos and was not associated with factors such as Day 3 cell number, fragmentation, symmetry or presence of abnormal cleavage. Rather, discordance was associated with direct cleavage (P2 ≤ 5 h) and short P3 (≤0.25 h), and also factors intrinsic to the Eeva™ system, such as the automated rating (proportion of discordant embryos by rating: H: 9.3%; M: 18.1%; L: 41.3%; NR: 31.4%; P < 0.0001), microwell location (peripheral: 31.2%; central: 23.8%; P = 0.02) and Eeva™ microscope (n = 8; range 22.9–42.6%; P < 0.0001). Manual annotation upgraded 82.6% of all discordant embryos from a lower to a higher rating, and improved the sensitivity for predicting blastocyst formation.LIMITATIONS, REASONS FOR CAUTIONOne team of embryologists performed the manual annotations; however, the study staff was trained and certified by the company sponsor. Only two time-lapse markers were evaluated, so the results are not generalizable to other parameters; likewise, the results are not generalizable to future versions of Eeva™ or other automated image analysis systems.WIDER IMPLICATIONS OF THE FINDINGSBased on the proportion of discordance and the improved performance of manual annotation, clinics using the Eeva™ system should consider manual annotation of P2 and P3 to confirm the automated ratings generated by Eeva™.STUDY FUNDING/COMPETING INTEREST(S)These data were acquired in a study funded by Progyny, Inc. There are no competing interests.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-06-28
      DOI: 10.1093/humrep/dex229
      Issue No: Vol. 32, No. 8 (2017)
  • Comprehensive protocol of traceability during IVF: the result of a
           multicentre failure mode and effect analysis
    • Authors: Rienzi LL; Bariani FF, Dalla Zorza MM, et al.
      Pages: 1612 - 1620
      Abstract: AbstractSTUDY QUESTIONCan traceability of gametes and embryos be ensured during IVF'SUMMARY ANSWERThe use of a simple and comprehensive traceability system that includes the most susceptible phases during the IVF process minimizes the risk of mismatches.WHAT IS KNOWN ALREADYMismatches in IVF are very rare but unfortunately possible with dramatic consequences for both patients and health care professionals. Traceability is thus a fundamental aspect of the treatment. A clear process of patient and cell identification involving witnessing protocols has to be in place in every unit. To identify potential failures in the traceability process and to develop strategies to mitigate the risk of mismatches, previously failure mode and effects analysis (FMEA) has been used effectively. The FMEA approach is however a subjective analysis, strictly related to specific protocols and thus the results are not always widely applicable. To reduce subjectivity and to obtain a widespread comprehensive protocol of traceability, a multicentre centrally coordinated FMEA was performed.STUDY DESIGN, SIZE, DURATIONSeven representative Italian centres (three public and four private) were selected. The study had a duration of 21 months (from April 2015 to December 2016) and was centrally coordinated by a team of experts: a risk analysis specialist, an expert embryologist and a specialist in human factor. Principal investigators of each centre were first instructed about proactive risk assessment and FMEA methodology. A multidisciplinary team to perform the FMEA analysis was then formed in each centre. After mapping the traceability process, each team identified the possible causes of mistakes in their protocol. A risk priority number (RPN) for each identified potential failure mode was calculated. The results of the FMEA analyses were centrally investigated and consistent corrective measures suggested. The teams performed new FMEA analyses after the recommended implementations.PARTICIPANTS/MATERIALS, SETTING, METHODSIn each centre, this study involved: the laboratory director, the Quality Control & Quality Assurance responsible, Embryologist(s), Gynaecologist(s), Nurse(s) and Administration. The FMEA analyses were performed according to the Joint Commission International.MAIN RESULTS AND THE ROLE OF CHANCEThe FMEA teams identified seven main process phases: oocyte collection, sperm collection, gamete processing, insemination, embryo culture, embryo transfer and gamete/embryo cryopreservation. A mean of 19.3 (SD ± 5.8) associated process steps and 41.9 (SD ± 12.4) possible failure modes were recognized per centre. A RPN ≥15 was calculated in a mean of 6.4 steps (range 2–12, SD ± 3.60). A total of 293 failure modes were centrally analysed 45 of which were considered at medium/high risk. After consistent corrective measures implementation and re-evaluation, a significant reduction in the RPNs in all centres (RPN <15 for all steps) was observed. A simple and comprehensive traceability system was designed as the result of the seven FMEA analyses.LIMITATIONS, REASONS FOR CAUTIONThe validity of FMEA is in general questionable due to the subjectivity of the judgments. The design of this study has however minimized this risk by introducing external experts for the analysis of the FMEA results. Specific situations such as sperm/oocyte donation, import/export and pre-implantation genetic testing were not taken into consideration. Finally, this study is only limited to the analysis of failure modes that may lead to mismatches, other possible procedural mistakes are not accounted for.WIDER IMPLICATIONS OF THE FINDINGSEvery single IVF centre should have a clear and reliable protocol for identification of patients and traceability of cells during manipulation. The results of this study can support IVF groups in better recognizing critical steps in their protocols, understanding identification and witnessing process, and in turn enhancing safety by introducing validated corrective measures.STUDY FUNDING/COMPETING INTEREST(S)This study was designed by the Italian Society of Embryology Reproduction and Research (SIERR) and funded by the Italian National Transplant Centre (CNT) of the Italian National Institute of Health (ISS). The authors have no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-05-31
      DOI: 10.1093/humrep/dex144
      Issue No: Vol. 32, No. 8 (2017)
  • Weight reduction intervention for obese infertile women prior to IVF: a
           randomized controlled trial
    • Authors: Einarsson S; Bergh C, Friberg B, et al.
      Pages: 1621 - 1630
      Abstract: AbstractSTUDY QUESTIONDoes an intensive weight reduction programme prior to IVF increase live birth rates for infertile obese women'SUMMARY ANSWERAn intensive weight reduction programme resulted in a large weight loss but did not substantially affect live birth rates in obese women scheduled for IVF.WHAT IS ALREADY KNOWNAmong obese women, fertility and obstetric outcomes are influenced negatively with increased risk of miscarriage and a higher risk of maternal and neonatal complications. A recent large randomized controlled trial found no effect of lifestyle intervention on live birth in infertile obese women.STUDY DESIGN, SIZE, DURATIONA prospective, multicentre, randomized controlled trial was performed between 2010 and 2016 in the Nordic countries. In total, 962 women were assessed for eligibility and 317 women were randomized. Computerized randomization with concealed allocation was performed in the proportions 1:1 to one of two groups: weight reduction intervention followed by IVF-treatment or IVF-treatment only. One cycle per patient was included.PARTICIPANTS/MATERIALS, SETTING, METHODSNine infertility clinics in Sweden, Denmark and Iceland participated. Women under 38 years of age planning IVF, and having a BMI ≥30 and <35 kg/m2 were randomized to two groups: an intervention group (160 patients) with weight reduction before IVF, starting with 12 weeks of a low calorie liquid formula diet (LCD) of 880 kcal/day and thereafter weight stabilization for 2–5 weeks, or a control group (157 patients) with IVF only.MAIN RESULTS AND ROLE OF CHANCEIn the full analysis set (FAS), the live birth rate was 29.6% (45/152) in the weight reduction and IVF group and 27.5% (42/153) in the IVF only group. The difference was not statistically significant (difference 2.2%, 95% CI: 12.9 to −8.6, P = 0.77). The mean weight change was −9.44 (6.57) kg in the weight reduction and IVF group as compared to +1.19 (1.95) kg in the IVF only group, being highly significant (P < 0.0001). Significantly more live births were achieved through spontaneous pregnancies in the weight reduction and IVF group, 10.5% (16) as compared to the IVF only group 2.6% (4) (P = 0.009). Miscarriage rates and gonadotropin dose used for IVF stimulation did not differ between groups. Two subgroup analyses were performed. The first compared women with PCOS in the two randomized groups, and the second compared women in the weight reduction group reaching BMI ≤ 25 kg/m2 or reaching a weight loss of at least five BMI units to the IVF only group. No statistical differences in live birth rates between the groups in either subgroup analysis were found.LIMITATIONS, REASON FOR CAUTIONThe study was not powered to detect a small increase in live births due to weight reduction and was not blinded for the patients or physician. Further, the intervention group had a longer time to achieve a spontaneous pregnancy, but were therefore slightly older than the control group at IVF. The study only included women with a BMI lower than 35 kg/m2.WIDER IMPLICATIONS OF THE FINDINGSThe study suggests that weight loss for obese women (BMI: 30–34.9 kg/m2) may not rectify the outcome in IVF cycles, although a significant higher number of spontaneous conceptions occurred in the weight loss group. Also, the study suggests that intensive weight reduction with LCD treatment does not negatively affects the results.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB, Solna, Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation and Jane and Dan Olsson Foundation. Dr Thurin-Kjellberg reports grants from Merck, non-financial support from Impolin AB, during the conduct of the study, and personal fees from Merck outside the submitted work. Dr Friberg reports personal fees from Ferring, Merck, MSD, Finox and personal fees from Studentlitteratur, outside the submitted work. Dr Englund reports personal fees from Ferring, and non-financial support from Merck, outside the submitted work. Dr Bergh reports and has been reimbursed for: writing a newsletter twice a year (Ferring), lectures (Ferring, MSD, Merck), and Nordic working group meetings (Finox). Dr Karlström reports lectures (Ferring, Finox, Merck, MSD) and Nordic working group meetings (Ferring). Ms Kluge, Dr Einarsson, Dr Pinborg, Dr Klajnbard, Dr Stenlöf, Dr Larsson, Dr Loft and Dr Wistrand have nothing to disclose.TRIAL REGISTRATION number, NCT01566929.TRIAL REGISTRATION DATE23-03-2012.DATE OF FIRST PATIENT'S ENROLMENT05-10-2010.
      PubDate: 2017-06-29
      DOI: 10.1093/humrep/dex235
      Issue No: Vol. 32, No. 8 (2017)
  • Double-blind randomized controlled trial of letrozole versus clomiphene
           citrate in subfertile women with polycystic ovarian syndrome
    • Authors: Amer SA; Smith JJ, Mahran AA, et al.
      Pages: 1631 - 1638
      Abstract: AbstractSTUDY QUESTIONWould letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)'SUMMARY ANSWERParticipants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%).WHAT IS KNOWN ALREADYAccording to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias.STUDY DESIGN, SIZE, DURATIONThis double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients’ BMI (<30 and 30–35 kg/m2).PARTICIPANTS/MATERIALS, SETTING, METHODSThe trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles.MAIN RESULTS AND THE ROLE OF CHANCEAmongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3–33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3–5] cycles) compared to CC (6[4–7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%).LIMITATIONS, REASONS FOR CAUTIONOne possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks.WIDER IMPLICATIONS OF THE FINDINGSThe results of this trial are consistent with the recent Cochrane systematic review. However, with its robust design, the current RCT provides more valid and compelling evidence for the superiority of letrozole over CC as a primary ovulation induction agent in PCOS women with 40% increase in pregnancy rates and with a shorter time-to-pregnancy. Furthermore, the participants in this RCT are a good representation of subfertile PCOS population receiving fertility treatment in Europe and worldwide. The results are therefore globally generalizable for clinical practice.STUDY FUNDING/COMPETING INTEREST(S)This RCT was mainly funded by the R&D Funding Scheme of Derby Hospitals NHS Foundation Trust. The study also received funds from School of Medicine, University of Nottingham. The Trust R&D department was involved in the development of the protocol and the running of the trial. The trial was sponsored and monitored by the University of Nottingham. The authors have no conflicts of interest.TRIAL REGISTRATION NCT00478504.TRIAL REGISTRATION DATERegistration was verified on 23/05/2007.DATE OF FIRST PATIENT'S ENROLMENT25/04/2007.
      PubDate: 2017-06-29
      DOI: 10.1093/humrep/dex227
      Issue No: Vol. 32, No. 8 (2017)
  • A new fully human recombinant FSH (follitropin epsilon): two phase I
           randomized placebo and comparator-controlled pharmacokinetic and
           pharmacodynamic trials
    • Authors: Abd-Elaziz K; Duijkers I, Stöckl L, et al.
      Pages: 1639 - 1647
      Abstract: AbstractSTUDY QUESTIONWhat are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product'SUMMARY ANSWEROverall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters.WHAT IS KNOWN ALREADYRecombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule.STUDY DESIGN, SIZE, DURATIONBoth studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing.PARTICIPANTS/MATERIALS, SETTING, METHODSIn the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics.MAIN RESULTS AND THE ROLE OF CHANCEThe single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed.LIMITATIONS, REASONS FOR CAUTIONThe studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers.WIDER IMPLICATIONS OF THE FINDINGSThese early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH.STUDY FUNDING/COMPETING INTEREST(S)The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany.K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH.TRIAL REGISTRATION NCT01354886 (single-dose); NCT01477073 (multiple-dose).TRIAL REGISTRATION DATEThe single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011.DATE OF FIRST...
      PubDate: 2017-06-07
      DOI: 10.1093/humrep/dex220
      Issue No: Vol. 32, No. 8 (2017)
  • Implementing targeted expectant management in fertility care using
           prognostic modelling: a cluster randomized trial with a multifaceted
    • Authors: Kersten FM; Nelen WM, van den Boogaard NM, et al.
      Pages: 1648 - 1657
      Abstract: AbstractSTUDY QUESTIONWhat is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility'SUMMARY ANSWERThe multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual.WHAT IS KNOWN ALREADYIntrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations.STUDY DESIGN, SIZE, DURATIONA cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group).MAIN RESULTS AND THE ROLE OF CHANCEGuideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45–4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38–3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67–2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40–1.27).LIMITATIONS REASONS FOR CAUTIONThere is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group.WIDER IMPLICATIONS OF THE FINDINGSGeneralization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples’ exposure to and experiences with the strategy.STUDY FUNDING/COMPETING INTEREST(S)Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests.TRIAL REGISTRATION NUMBERDutch trial Register, NTR3405.TRIAL REGISTRATION DATE19 April 2012.DATE OF FIRST PATIENT'S ENROLMENT10 July 2012.
      PubDate: 2017-06-07
      DOI: 10.1093/humrep/dex213
      Issue No: Vol. 32, No. 8 (2017)
  • Non-publication and publication bias in reproductive medicine: a cohort
    • Authors: Lensen SS; Jordan VV, Showell MM, et al.
      Pages: 1658 - 1666
      Abstract: STUDY QUESTIONDoes publication bias or non-publication exist in fertility trials presented as conference abstracts'SUMMARY ANSWERThis study did not detect any publication bias; however, it did identify a high level of non-publication, with only 49% of abstracts reaching full-text publication four or more years after abstract presentation.WHAT IS KNOWN ALREADYSystematic reviews of randomized controlled trials (RCTs) are the foundation of evidence based medicine. Non-publication or publication deficit refer to the failure to publish trial results. A publication bias exists when there is any tendency on the parts of the investigators or editors to fail to publish study results on the basis or strength of the study findings. Both present a serious problem for researchers, clinicians and policymakers alike, and ultimately impact on patient care.STUDY DESIGN, SIZE, DURATIONA retrospective cohort study identified 337 fertility RCTs presented as conference abstracts between 2007 and 2010, as captured by an electronic search of the Cochrane Gynaecology and Fertility Database. After excluding ineligible trials and duplicates, 224 abstracts remained.PARTICIPANTS/MATERIALS, SETTING, METHODSA search for the full-text papers of each abstract was undertaken in Pubmed, MEDLINE, Embase, CINAHL and Google in May 2015 using a probabilistic approach. Trial authors were contacted to query the publication status of abstracts when no full-text was identified. The association between individual variables and the probability of publication, and time to publication, was assessed using logistic regression and Cox regression, respectively.MAIN RESULTS AND THE ROLE OF CHANCEOf the 224 included abstracts, only 110 (49%; 95% CI: 42.6, 55.6) were found to be published as full-text articles. Publication bias was not identified in this cohort; studies with positive results had a similar probability of reaching full-text publication 52/113 (46%; 95% CI: 37.0, 55.3) as studies with non-positive (negative or null) results 58/111 (52%; 95% CI: 17.8, 33.9) (adjusted odds ratio (AOR): 1.02; 95% CI: 0.53, 1.97). Similarly, the time from abstract presentation to full-text publication was similar in studies with positive and non-positive results. Oral presentations were more likely to be published, and to be published sooner, than poster presentations (poster presentation AOR: 0.31; 95% CI: 0.15, 0.61 and adjusted hazard ratio (AHR): 0.57; 95% CI: 0.38, 0.86). Studies that were not registered were less likely to be published and to have delayed publication, than studies which were registered either prospectively or retrospectively (AOR: 0.14; 95% CI: 0.04, 0.44 and AHR: 0.43; 95% CI: 0.25, 0.72). s which were presented a longer time ago also had a higher probability of reaching full-text publication (P  = 0.01).LIMITATIONS, REASONS FOR CAUTIONCommencing with a cohort of RCTs from ethics committee registers may provide a better picture of the extent of non-publication and publication bias, as not all trials reach the stage of abstract presentation. It is also possible that the search did not identify all published trials, as some may have been published after the follow-up period.WIDER IMPLICATIONS OF THE FINDINGSThis study did not identify any publication bias. However, only half of the abstracts in this cohort have been published as full-text articles, four or more years after their presentation at a conference. This is similar to publication rates reported previously for fertility trials, and is despite increasing awareness of the importance of publishing trial results, and subsequent requirements for all RCTs to be registered prior to trial initiation. A better understanding of the reasons for non-publication should assist in facilitating the prompt full-text publication of RCTs in the future.STUDY FUNDING/COMPETING INTEREST(S)Funding provided from the University of Auckland. All authors declare they have no conflicts of interest in relation to this article.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-06-29
      DOI: 10.1093/humrep/dex236
      Issue No: Vol. 32, No. 8 (2017)
  • A qualitative study of the impact of endometriosis on male partners
    • Authors: Culley LL; Law CC, Hudson NN, et al.
      Pages: 1667 - 1673
      Abstract: AbstractSTUDY QUESTIONWhat is the impact of endometriosis on male partners of women with the condition'SUMMARY ANSWEREndometriosis significantly impacts men across several life domains and can negatively impact emotional well-being.WHAT IS KNOWN ALREADYEndometriosis has been shown to negatively impact women's quality of life and may strain intimate relationships. Little is known about the impact on male partners.STUDY DESIGN, SIZE, DURATIONThe ENDOPART study was a cross-sectional, qualitative study of 22 women with endometriosis and their male partners (n = 44) in the UK (2012–2013).PARTICIPANTS/MATERIALS, SETTING, METHODSInclusion criteria: laparoscopic diagnosis of endometriosis; the presence of symptoms for at least a year; partners living together. Data were collected via face to face, semi structured interviews with partners interviewed separately. Data were analysed thematically, assisted by NVivo 10.MAIN RESULTS AND THE ROLE OF CHANCEMen reported that endometriosis affected many life domains including sex and intimacy, planning for and having children, working lives and household income. It also required them to take on additional support tasks and roles. Endometriosis also had an impact on men's emotions, with responses including helplessness, frustration, worry and anger. The absence of professional or wider societal recognition of the impact on male partners, and a lack of support available to men, results in male partners having a marginalized status in endometriosis care.LIMITATIONS REASONS FOR CAUTIONSelf-selection of participants may have resulted in a sample representing those with more severe symptoms. Couples included are in effect ‘survivors’ in relationship terms, therefore, findings may underestimate the contribution of endometriosis to relationship breakdown.WIDER IMPLICATIONS OF THE FINDINGSThe study extends knowledge about the impact of endometriosis on relationships, which thus far has been drawn largely from studies with women, by providing new insights about how this condition affects male partners. Healthcare practitioners need to take a more couple-centred, biopsychosocial approach toward the treatment of endometriosis, inclusive of partners and relationship issues. The findings demonstrate a need for information and support resources aimed at partners and couples.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by the Economic and Social Research Council (reference ES/J003662/1). The authors have no conflicts of interest.
      PubDate: 2017-06-29
      DOI: 10.1093/humrep/dex221
      Issue No: Vol. 32, No. 8 (2017)
  • Factors influencing women's preferences for subsequent management in the
           event of incomplete evacuation of the uterus after misoprostol treatment
           for miscarriage
    • Authors: Hentzen JR; Verschoor MA, Lemmers M, et al.
      Pages: 1674 - 1683
      Abstract: AbstractSTUDY QUESTIONWhat affects women's treatment preferences in the management of an incomplete evacuation of the uterus after misoprostol treatment for a first-trimester miscarriage'SUMMARY ANSWERWomen's treatment preferences in the management of an incomplete evacuation of the uterus after misoprostol treatment for miscarriage are most strongly influenced by ‘the risk of a reduced fertility’ followed by ‘the probability of success’.WHAT IS KNOWN ALREADYAvailable treatment options in miscarriage are surgical, medical or expectant management. Treatment with misoprostol leads to an incomplete evacuation of the uterus and additional surgical treatment in 20–50% of women. To our knowledge, women's preferences for subsequent treatment of an incomplete evacuation of the uterus after misoprostol treatment for miscarriage have not been studied yet.STUDY DESIGN, SIZE, DURATIONBetween April 2014 and January 2015, we conducted a prospective nationwide multicentre discrete-choice experiment (DCE). DCEs have become the most frequently applied approach for studying patient preferences in health care. In our DCE, which considerers five attributes, a target sample size was calculated including 20 patients per attribute for the main analysis. We intended to include 25% more patients, i.e. a total of 125 thus enabling us to assess heterogeneity of treatment choices.PARTICIPANTS/MATERIALS, SETTING, METHODSAll women visiting the outpatient clinic with first-trimester miscarriage or incomplete miscarriage were invited to participate in the study. Women under 18 years of age, women who were unable to understand the Dutch questionnaire or women who already had received a treatment for the current miscarriage were excluded. Women's preferences were assessed using a DCE. A literature review, expert opinions and interviews with women from the general population were used to define relevant treatment characteristics. Five attributes were selected: (i) certainty about the duration of convalescence; (ii) number of days of bleeding after treatment; (iii) probability of success (empty uterus after treatment); (iv) risk of reduced fertility and (v) risk of complications requiring more time or readmission to hospital. Fourteen scenarios using these attributes were selected in the DCE. Each of these scenarios presented two treatment options, while treatment characteristics varied between the 14 scenarios. For each scenario, respondents were asked to choose the preferred treatment option. The importance of each attribute was analysed, and preference heterogeneity was investigated through latent-class analysis.MAIN RESULTS AND THE ROLE OF CHANCEOne hundred and eighty-six women were included of whom 128 completed the DCE (69% response rate). The two attributes with the greatest effect on their preference were, probability of success and risk of reduced fertility. The latent-class analysis revealed two subgroups of patients with different preference patterns. Forty per cent of women were more influenced by treatment success and 59% were more influenced by risk.LIMITATIONS, REASONS FOR CAUTIONMost women were highly educated and were of Dutch origin, which limits the generalizability of our findings. Women with lower education levels, other cultural backgrounds and/or different previous experiences may differ from our findings.WIDER IMPLICATIONS OF THE FINDINGSPatients preferences should be addressed when counselling patients with an incomplete miscarriage after misoprostol treatment.STUDY FUNDING/COMPETING INTEREST(S)This study was embedded in the MisoREST trial, and funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97-12066. There were no conflicts of interests.TRIAL REGISTRATION NUMBERDutch Trial Register NTR3310, http://www.trialregister.nlTRIAL REGISTRATION DATE27 February 2012.DATE OF FIRST PATIENT'S ENROLMENT12 June 2012.
      PubDate: 2017-05-31
      DOI: 10.1093/humrep/dex216
      Issue No: Vol. 32, No. 8 (2017)
  • Dormancy and activation of human oocytes from primordial and primary
           follicles: molecular clues to oocyte regulation
    • Authors: Ernst EH; Grøndahl ML, Grund SS, et al.
      Pages: 1684 - 1700
      Abstract: AbstractSTUDY QUESTIONDo specific transcriptome dynamics in human oocytes from primordial and primary follicles identify novel pathways in oocyte activation'SUMMARY ANSWERThe transcriptomic profiles in oocytes from primordial and primary follicles, respectively, revealed several new canonical pathways as putative mediators of oocyte dormancy and activation.WHAT IS KNOWN ALREADYCellular signaling pathways including PI3K/AKT and AKT/mTOR as well as TGF-β and IGF signaling are known to regulate the primordial-to-primary transition in mammalian follicle development.STUDY DESIGN, SIZE, DURATIONWe performed a class comparison study on human oocytes from primordial (n = 436) and primary (n = 182) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy.PARTICIPANTS/MATERIALS, SETTING, METHODSRNA was extracted from oocytes from primordial and primary follicles isolated by Laser Capture Microdissection, and submitted to the HiSeq Illumina platform. Data mapping, quality control, filtering and expression analysis were performed using Tophat (2.0.4), Cufflinks (2.0.2), BWA (0.6.2) and software R. Modeling of complex biological systems was performed using the IPA® software. Finally, qPCR and immunohistochemistry were employed to explore expression and localization of selected genes and products in human ovarian tissueMAIN RESULTS AND THE ROLE OF CHANCEWe found 223 and 268 genes down-regulated and up-regulated, respectively, in the oocytes during the human primordial-to-primary follicle transition (P < 0.05 and/or FPKM fold-change >2). IPA® enrichment analysis revealed known pathways (‘mTOR Signaling’, ‘PI3K/AKT Signaling’ and ‘PTEN Signaling’) as well as enriched canonical pathways not previously associated with human ovarian follicle development such as ‘ErB Signaling’ and ‘NGF Signaling’ in the down-regulated category and ‘Regulation of eIF4 and P70S6K Signaling’ and ‘HER-2 Signaling in Breast Cancer’ in the up-regulated group. Additionally, immunohistochemistry on human ovarian tissue explored the intraovarian localization of VASA, FOXO1 and eIF4E.LARGE SCALE DATA, REASONS FOR CAUTIONThis is a descriptive analysis and no functional studies were performed. The study was based on a limited number of patients and the experimental design could not take into account the natural biological variance in human samples. Therefore, qPCR was used to confirm selected genes alongside immunohistochemical stainings.WIDER IMPLICATIONS OF THE FINDINGSThis study shows, for the first time, a detailed molecular description of global gene transcription activities in oocytes from primordial and primary follicles, respectively. Knowing the global transcription profiles of human oocyte dormancy and activation are important in developing new clinical applications.STUDY FUNDING/COMPETING INTEREST(S)E.H.E. was supported by Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.H. and S.F. were supported by an MRC (UK) project grant MR/M012638/1. K.L.H. was supported by grants from Fonden til Lægevidenskabens Fremme, Kong Christian Den Tiendes Fond. K.L.H. and L.S. were supported by the IDEAS grant from Aarhus University Research Foundation (AUFF). There are no conflicts of interest.
      PubDate: 2017-07-04
      DOI: 10.1093/humrep/dex238
      Issue No: Vol. 32, No. 8 (2017)
  • Ovarian response to controlled ovarian hyperstimulation: what does serum
           FSH say'
    • Authors: Oudshoorn SC; van Tilborg TC, Hamdine O, et al.
      Pages: 1701 - 1709
      Abstract: AbstractSTUDY QUESTIONDo serum FSH levels on day of hCG trigger differ between women with a poor, normal or hyper response to a fixed daily dose of 150 IU recombinant FSH (rFSH)'SUMMARY ANSWERThere is no consistent relationship between ovarian response and serum FSH levels on day of hCG trigger in a 150 IU fixed dose treatment protocol.WHAT IS KNOWN ALREADYWhen ovarian response to stimulation for IVF/ICSI is suboptimal, the FSH dose is often adjusted in a subsequent cycle, thereby assuming that serum FSH levels were inadequate for optimal stimulation.STUDY DESIGN, SIZE, DURATIONNested cohort study within a randomized controlled trial conducted at the University Medical Centre Utrecht between March 2009 and July 2011. Blood was drawn from 124 women on cycle Day 2 and on day of hCG triggering. Serum FSH level was determined by the Beckman-Coulter Unicel DXi800 chemiluminescence assay. In order to detect a difference of 2 IU/L between poor, normal and hyper responders, a total of 64 participants (16 poor, 32 normal and 16 hyper responders) would provide 80% power, assuming a standard deviation of 2 and an alpha of 0.05.PARTICIPANTS, SETTING, METHODSWomen aged ≤39 years with a regular cycle and fixed FSH dose of 150 IU. Exclusion criteria: BMI > 32 kg/m2 and >2 previous unsuccessful IVF/ICSI cycles. The primary outcome measure was serum FSH level on day of triggering.MAIN RESULTS AND THE ROLE OF CHANCEMedian [range] body weight was 70.0 kg [55.0–85.6], 68.0 kg [52.0–94] and 60.6 kg [51.0–78.0] for poor (n = 16), normal (n = 94) and hyper (n = 17) responders, respectively. Mean (SD) serum FSH levels on day of triggering were 9.5 IU/L (2.4) in poor, 10.4 IU/L (2.3) in normal and 11.5 IU/L (2.2) in hyper responders. Serum FSH levels on day of hCG in poor responders differed significantly as compared to those in hyper responders (P = 0.03).LIMITATIONS, REASONS FOR CAUTIONThe number of retrieved oocytes is only minimally determined by serum FSH level on the day of hCG trigger. After correction for age, body weight, basal serum FSH and basal anti-Mullerian hormone the correlation between serum FSH level on the day of hCG and ovarian response regarding the number of retrieved oocytes disappeared.WIDER IMPLICATIONS OF THE FINDINGSThe current study shows that a poor response is not related to inadequate serum FSH levels per se. One could therefore question whether increasing the rFSH dose in women with a suboptimal response is meaningful. In women with a hyper response, however, lowering the dose of rFSH in a subsequent IVF cycle may lead to lower serum FSH levels and thereby mitigate ovarian response and improve safety of the IVF treatment. As this was not a dose–response study, future research should assess whether dose adjustments benefit the poor and hyper responder.STUDY FUNDING/COMPETING INTEREST(S)No external funds were obtained for this study. S.C.O, T.C.v.T., O.H., H.L.T., E.G.W.M.L., C.B.L. and M.J.C.E. have nothing to disclose. F.J.M.B. receives monetary compensation: member of the external advisory board for Merck Serono and Ferring, the Netherlands; educational activities for Ferring BV, the Netherlands; consultancy work for Gedeon Richter, Belgium; strategic cooperation with Roche on automated AMH assay development and research cooperation with Ansh Labs.
      PubDate: 2017-06-15
      DOI: 10.1093/humrep/dex222
      Issue No: Vol. 32, No. 8 (2017)
  • Non-equivalence of anti-Müllerian hormone automated assays—clinical
           implications for use as a companion diagnostic for individualised
           gonadotrophin dosing
    • Authors: Iliodromiti S; Salje B, Dewailly D, et al.
      Pages: 1710 - 1715
      Abstract: AbstractSTUDY QUESTIONCan anti-Müllerian hormone (AMH) automated immunoassays (Elecsys® and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing'SUMMARY ANSWERThe Access assay gives systematically higher AMH values than the Elecsys® assay which results in over 29% of women being misclassified to a different follitropin delta dose.WHAT IS KNOWN ALREADYFollitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys® AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required.STUDY DESIGN, SIZE, DURATIONWe systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data.PARTICIPANTS/MATERIALS, SETTING, METHODSWe identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing–Bablok regression and Bland–Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta.MAIN RESULTS AND THE ROLE OF CHANCEThe Passing–Bablok regression shows a linear relationship (Access = −0.05 + 1.10 × Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were −11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay.LIMITATIONS REASONS FOR CAUTIONWe compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination.WIDER IMPLICATIONS OF THE FINDINGSAn international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm.STUDY FUNDING/COMPETING INTEREST(S)No formal funding has been received for this study. SI is funded by a UK Medical Research Council skills development fellowship (MR/N015177/1). SMN has received speakers fees, travel to meetings and participated in advisory Boards for Beckman Coulter, IBSA, Ferring Pharmaecuticals, Finox, Merck Serono, Merck and Roche Diagnostics. SMN has received research support from Ansh laboratories, Beckman Coulter, Ferring Pharmaceuticals and Roche Diagnostics.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-06-22
      DOI: 10.1093/humrep/dex219
      Issue No: Vol. 32, No. 8 (2017)
  • Use of the serum anti-Müllerian hormone assay as a surrogate for
           polycystic ovarian morphology: impact on diagnosis and phenotypic
           classification of polycystic ovary syndrome
    • Authors: Fraissinet A; Robin G, Pigny P, et al.
      Pages: 1716 - 1722
      Abstract: AbstractSTUDY QUESTIONDoes the use of the serum anti-Müllerian hormone (AMH) assay to replace or complement ultrasound (U/S) affect the diagnosis or phenotypic distribution of polycystic ovary syndrome (PCOS)'SUMMARY ANSWERCombining U/S and the serum AMH assay to define polycystic ovarian morphology (PCOM) diagnoses PCOS (according to the Rotterdam classification) in more patients than definitions using one or the other of these indicators exclusively.WHAT IS KNOWN ALREADYSince 2003, PCOM, as defined by U/S, is one of the three diagnostic criteria for PCOS. As it is closely correlated with follicle excess seen at U/S, an excessive serum AMH level could be used as a surrogate for PCOM.STUDY DESIGN, SIZE, DURATIONSingle-center retrospective study from a database of prospectively collected clinical, laboratory and ultrasound data from patients referred for oligo-anovulation (OA) and/or hyperandrogenism (HA) between January 2009 and January 2016.PARTICIPANTS/MATERIALS, SETTING, METHODThe standard Rotterdam classification for PCOS was tested against two modified versions that defined PCOM by either excessive serum AMH level alone (AMH-only) or a combination (i.e. ‘and/or’) of the latter and U/S. The PCOS phenotypes were defined as A (full phenotype, OA+HA+PCOM), B (OA+HA), C (HA+PCOM) and D (OA+PCOM).MAIN RESULTS AND THE ROLE OF CHANCEPCOS was more frequently diagnosed when PCOM was defined as the combination ‘positive U/S’ and/or ‘positive AMH’ (n = 639) than by either only U/S-only (standard definition, n = 612) or by AMH-only (n = 601). With this combination, PCOM was recognized in 637 of the 639 cases that met the Rotterdam classification, and phenotype B practically disappeared. In this population, U/S and AMH markers were discordant for PCOM in 103 (16.1%) cases (9% U/S-only, 7.1% AMH-only, P = 0.159). The markers used had no other significant impact on the phenotypic distribution (except for phenotype B). However, the percentage of cases positive by U/S-only was significantly higher in phenotype D than in phenotype A (14.1% vs. 5.8%, P < 0.05). Furthermore, in the discordant cases, plasma LH levels were significantly higher in the AMH-only group than in the concordant cases, and fasting insulin serum levels tended to be higher in the U/S-only group.LIMITATIONS, REASONS FOR CAUTIONThis is a retrospective study. A referral bias explains the relatively high proportion of patients with phenotype D (28%). PCOM was defined by in-house thresholds. The AMH assay used is no longer commercially available.WIDER IMPLICATIONS OF THE FINDINGSOur results suggest that ideally both U/S data and serum AMH level should be integrated to define PCOM in the Rotterdam classification. In a cost-effectiveness approach, the choice of one or the other has little impact on the diagnosis and the phenotyping of PCOS.STUDY FUNDING/COMPETING INTEREST(S)No external funding. The authors have no conflict of interest to declare.
      PubDate: 2017-06-29
      DOI: 10.1093/humrep/dex239
      Issue No: Vol. 32, No. 8 (2017)
  • Polycystic ovarian morphology and the diagnosis of polycystic ovary
           syndrome: redefining threshold levels for follicle count and serum
           anti-Müllerian hormone using cluster analysis
    • Authors: Lie Fong SS; Laven JE, Duhamel AA, et al.
      Pages: 1723 - 1731
      Abstract: AbstractSTUDY QUESTIONCan cluster analysis be used to differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with polycystic ovarian morphology (PCOM) in a non-subjective manner'SUMMARY ANSWERCluster analysis can be used to accurately and non-subjectively differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with PCOM.WHAT IS KNOWN ALREADYCurrently, PCOM is diagnosed using a fixed threshold level, i.e. 12 or more follicles per ovary, and is one of the diagnostic criteria of polycystic ovary syndrome (PCOS). However, PCOM is also encountered in normo-ovulatory women, suggesting that it could just represent a normal variant. On the other hand, recent studies have shown subtle endocrine abnormalities in women with isolated PCOM that resemble those found in women with PCOS. Because of the strong correlation between anti-Müllerian hormone (AMH) and follicle number, a high serum AMH level has been proposed as a surrogate marker for PCOM and could, therefore, be integrated in the diagnostic classifications for PCOS.STUDY DESIGN, SIZE, DURATIONThis was a retrospective observational cohort study. Original cohorts had been recruited for previous studies between 1998 and 2010. Two hundred ninety-seven regularly cycling women and 700 women with PCOS were eligible for inclusion.PARTICIPANTS/MATERIALS, SETTING, METHODSCluster analysis was performed in 297 regularly cycling women. After exclusion of ‘PCOM’ clusters, each ‘non-PCOM’ cluster (young, n = 118 and old, n = 100) was included in the construction of a receiver operating characteristics curve to test the diagnostic performance of follicle number per ovary (FNPO) and serum AMH in discriminating similarly aged full-blown PCOS patients (n = 411 and 237, respectively) from normal regularly cycling non-PCOM women.MAIN RESULTS AND ROLE OF CHANCEThe optimal number of clusters was four; age was the most important classifying variable, followed by the FNPO and serum AMH. Two distinct clusters of normo-ovulatory women with PCOM were isolated and differed solely by age, i.e. ‘young’ and ‘old’. Both ‘PCOM’ clusters had their similarly aged counterpart of ‘non-PCOM’ clusters. Likewise, two clusters comprised women younger than 30 years, with (n = 28, ‘PCOM regularly cycling women’) or without (n = 118, ‘normal regularly cycling women’) features of PCOM (increased FNPO and/or serum AMH). The two other clusters in older women could be labelled ‘normal regularly cycling women’ or ‘PCOM regularly cycling women’ (n = 100 and 51, respectively). The prevalence of PCOM was significantly greater in old than in young regularly cycling women controls. In the young population, after exclusion of the ‘PCOM regularly cycling women’, the diagnostic performance of AMH, expressed by area under the curve (AUC) (AUC = 0.903; CI (0.876–0.930)) to differentiate PCOS women from normal regularly cycling women was similar to that using the FNPO (AUC = 0.915, CI (0.891–0.940)) (P = 0.25), confirming results from earlier studies. In the old population, the diagnostic performance of AMH was greater than that of FNPO (AUCs = 0.948 (0.927–0.970) vs 0.874 (0.836–0.912), respectively, P = 0.00035). Cut-off levels of AMH and antral follicle count distinguishing regularly cycling non-PCOM women from PCOS women were higher in young women than in older women.LIMITATIONS, REASONS FOR CAUTIONData of normal women were obtained from earlier studies, aiming to measure normal endocrine values. Apparently, the strong effect of age in cluster analysis revealed a dichotomy in the age distribution among the cohort of regularly cycling women included. This was involuntary since in none of the original studies, eligibility was limited by age and there was considerable overlap in age ranges of the cohorts. Transvaginal ultrasound was performed using a 6.5–8 mHz probe and our data confirm that this threshold level for FNPO is still valid if using such probe frequencies, although the use of devices with a maximum frequency lower than 8 mHz has become obsolete. Obviously, newer ultrasound scanner using higher transducer frequency will facilitate the detection of more follicles.WIDER IMPLICATIONS OF THE FINDINGSOur data support the use of AMH as a surrogate for ultrasound to define PCOM, which is one of the three items of the Rotterdam classification. They also show that age should be taken into account to define the optimal threshold. The fact that the prevalence of PCOM was increased in the older regularly cycling women, may be due to ‘attenuated’ PCOS, a phenomenon that has been described in ageing women with PCOS. These women might have had anovulatory cycles in the past and have become ovulatory with increasing age, and were, therefore, eligible for this study. However, since most women included at older age have had spontaneous pregnancies in the past, PCOM at older age may be associated with a subclinical form of PCOS, which may also be present in young regularly cycling women.STUDY FUNDING/COMPETING INTEREST(S)No funding was received for this study. J.S.E.L. has received grants and support from Ferring, MSD, Organon, Mer...
      PubDate: 2017-06-22
      DOI: 10.1093/humrep/dex226
      Issue No: Vol. 32, No. 8 (2017)
  • Associations among body size across the life course, adult height and
    • Authors: Farland LV; Missmer SA, Bijon AA, et al.
      Pages: 1732 - 1742
      Abstract: AbstractSTUDY QUESTIONAre body size across the life course and adult height associated with endometriosis'SUMMARY ANSWEREndometriosis is associated with lean body size during childhood, adolescence and adulthood; tall total adult height; and tall sitting height.WHAT IS KNOWN ALREADYThe literature suggests that both adult body size and height are associated with endometriosis risk, but few studies have investigated the role of body size across the life course. Additionally, no study has investigated the relationships between components of height and endometriosis.STUDY DESIGN, SIZE, DURATIONWe used a nested case-control design within E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale), a prospective cohort of French women. Data were updated every 2–3 years through self-administered questionnaires. Odds ratios (ORs) and 95% CIs were computed using logistic regression models adjusted for a priori confounding factors.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 2416 endometriosis cases were reported as surgically ascertained among the 61 208 included women.MAIN RESULTS AND THE ROLE OF CHANCEThe odds of endometriosis were lower among women who reported having a large versus lean body size at 8 years (P for trend = 0.003), at menarche (P for trend < 0.0001) and at ages 20–25 years (P for trend < 0.0001). Women in the highest quartiles of height had statistically significantly increased odds of endometriosis compared to those in the lowest (<158 cm) (162–164 cm: OR = 1.28, 95% CI = 1.12–1.46; ≥165 cm: OR = 1.33, 95% CI = 1.18–1.49, P for trend < 0.0001). Statistically significantly increased odds were also observed among women with a taller sitting height (OR = 1.24, 95% CI = 1.05–1.47, P for trend = 0.01). Leg length was not statistically significantly associated with endometriosis.LIMITATIONS REASONS FOR CAUTIONEndometriosis cases may be prone to misclassification; however, we restricted our case definition to surgically-confirmed cases, which showed a high validation rate. Body size is based on retrospective self-report, which may be subject to recall bias.WIDER IMPLICATIONS OF THE FINDINGSThe results of this study suggest that endometriosis is positively associated with lean body size across the life course and total adult height. They also suggest that components of height are associated with endometriosis, which should be investigated further.STUDY FUNDING/COMPETING INTEREST(S)The Mutuelle Générale de l'Education Nationale (MGEN); the European Community; the French League against Cancer (LNCC); Gustave Roussy; the French Institute of Health and Medical Research (Inserm). L.V.F. was supported by a T32 grant (#HD060454) in reproductive, perinatal and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (3R25CA057711) National Institutes of Health. M.K. was supported by a Marie Curie Fellowship within the seventh European Community Framework Programme (#PIOF-GA-2011–302078). The authors have no conflicts of interest to declare.
      PubDate: 2017-06-07
      DOI: 10.1093/humrep/dex207
      Issue No: Vol. 32, No. 8 (2017)
  • Folate, homocysteine and the ovarian cycle among healthy regularly
           menstruating women
    • Authors: Michels KA; Wactawski-Wende J, Mills JL, et al.
      Pages: 1743 - 1750
      Abstract: AbstractSTUDY QUESTIONHow are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women'SUMMARY ANSWERHigher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone.WHAT IS KNOWN ALREADYHigher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics.STUDY DESIGN, SIZE, DURATIONThe BioCycle Study (2005–2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSSerum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake.MAIN RESULTS AND THE ROLE OF CHANCEHigher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] −2.3%, 95% CI: −4.2, −0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC −6.5%, 95% CI: −11.1, −1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation.LIMITATIONS, REASONS FOR CAUTIONOur results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation.WIDER IMPLICATIONS OF THE FINDINGSIf these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women.Study FUNDING/COMPETING INTEREST(S)This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
      PubDate: 2017-06-23
      DOI: 10.1093/humrep/dex233
      Issue No: Vol. 32, No. 8 (2017)
  • Incidence, prevalence, diagnostic delay, morbidity, mortality and
           socioeconomic status in males with 46,XX disorders of sex development: a
           nationwide study
    • Authors: Berglund AA; Johannsen TH, Stochholm KK, et al.
      Pages: 1751 - 1760
      Abstract: AbstractSTUDY QUESTIONWhat is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)'SUMMARY ANSWER46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income.WHAT IS KNOWN ALREADY46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males.STUDY DESIGN, SIZE, DURATIONIn this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908–2012 and follow-up started at birth or at start of registration and ended in 2014.PARTICIPANTS/MATERIALS, SETTING, METHODSPotential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark.MAIN RESULTS AND THE ROLE OF CHANCEAmong newborn males the prevalence of diagnosed 46,XX DSD males was 3.5–4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0–62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8–3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8–1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2–2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0–0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2–0.7) than male controls, and their income was reduced for the following age groups; 45–49 years: odds ratio [OR] = 0.4 (95% CI: 0.2–0.7); 50–54 years: OR = 0.1 (95% CI: 0.0–0.6).LIMITATIONS, REASONS FOR CAUTIONThe study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males.WIDER IMPLICATIONS OF THE FINDINGSThis study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Møller Foundation ‘Fonden til Laegevidenskabens Fremme’, the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare.TRIAL REGISTRATION NUMBERN/A.
      PubDate: 2017-06-22
      DOI: 10.1093/humrep/dex210
      Issue No: Vol. 32, No. 8 (2017)
  • DNA methylation signatures in cord blood of ICSI children
    • Authors: El Hajj N; Haertle L, Dittrich M, et al.
      Pages: 1761 - 1769
      Abstract: AbstractSTUDY QUESTIONDoes ICSI induce specific DNA methylation changes in the resulting offspring'SUMMARY ANSWERAlthough several thousand analyzed CpG sites (throughout the genome) displayed significant between-group methylation differences, both ICSI and spontaneously conceived children varied within the normal range of methylation variation.WHAT IS KNOWN ALREADYChildren conceived by ART have increased risks for medical problems at birth and to the extent of present knowledge also in later life (i.e. impaired metabolic and cardiovascular functions). One plausible mechanism mediating these ART effects are epigenetic changes originating in the germ cells and/or early embryos and persisting during further development.STUDY DESIGN, SIZE, DURATIONWe compared the cord blood methylomes and candidate gene methylation patterns of newborns conceived through ICSI or spontaneously.PARTICIPANTS/MATERIALS, SETTING, METHODSUmbilical cord bloods were obtained from healthy newborn singletons conceived spontaneously (53 samples), through ICSI (89) or IVF (34). Bisulfite-converted DNA samples of 48 ICSI and 46 control pregnancies were used for genome-wide analyses with Illumina's 450K methylation arrays. Candidate genes from the methylation screen were analyzed in all three groups by bisulfite pyrosequencing.MAIN RESULTS AND THE ROLE OF CHANCEAltogether, 4730 (0.11%) of 428 227 analyzed CpG sites exhibited significant between-group methylation differences, but all with small (β < 10%) or very small (β < 1%) effect size. ICSI children showed a significantly decreased DNA methylation age at birth, lagging approximately half a week behind the controls. ART-susceptible CpGs were enriched in CpG islands with low methylation values (0–20%) and in imprinting control regions (ICRs). Eighteen promoter regions (six in microRNA and SNORD RNA genes), four CpG islands (three in genes including one long non-coding RNA), and two ICRs contained multiple significant sites. Three differentially methylated regions were studied in more detail by bisulfite pyrosequencing. ATG4C and SNORD114-9 could be validated in an independent ICSI group, following adjustment for maternal age and other confounding factors. ATG4C was also significant in the IVF group.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThe observed epigenetic effects are small and there are numerous potential confounding factors such as parental age and infertility. Although our study meets current standards for epigenetic screens, sample size is still two orders of magnitude below that of genome-wide association studies.WIDER IMPLICATIONS OF THE FINDINGSOur study suggests an impact of ICSI on the offspring's epigenome(s), which may contribute to phenotypic variation and disease susceptibility in ART children. Epigenetic regulation of gene expression by different classes of non-coding RNAs may be a key mechanism for developmental programming through ART.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by a research grant (no. 692185) from the European Union (ERA of ART). There are no competing interests.
      PubDate: 2017-05-31
      DOI: 10.1093/humrep/dex209
      Issue No: Vol. 32, No. 8 (2017)
  • Genetic diseases and aneuploidies can be detected with a single blastocyst
           biopsy: a successful clinical approach
    • Authors: Minasi M; Fiorentino F, Ruberti A, et al.
      Pages: 1770 - 1777
      Abstract: AbstractSTUDY QUESTIONCan simultaneous detection of aneuploidies and genetic diseases or chromosomal aberrations in blastocysts reduce the chance of transferring embryos with low implantation potential, guaranteeing good clinical outcomes'SUMMARY ANSWERThe screening for chromosomal aneuploidies revealed that 50.6% of blastocysts diagnosed free of genetic disease or balanced, were aneuploid, therefore avoiding the transfer of blastocysts potentially resulting in implantation failures, miscarriages, or in some cases, in health affected live births.WHAT IS KNOWN ALREADYPGD is applied in patients at risk of transmitting genetically inheritable diseases to their offspring. It has been demonstrated that aneuploidies can involve chromosomes other than those investigated with PGD, affecting embryo implantation competence. Performing the biopsy at blastocyst level produces higher clinical outcomes allowing a more accurate diagnosis, compared to blastomere biopsy.STUDY DESIGN, SIZE, DURATIONThis consecutive case series study was performed from October 2011 to May 2016. Clinical and biological outcomes from 1122 blastocysts obtained in 304 PGD cycles for monogenic diseases (N = 163) or chromosomal rearrangements (N = 141) were analyzed. When the blastocyst resulted transferable after the PGD analysis or chromosomal rearrangement analysis, its ploidy status by mean of preimplantation genetic screening (PGS) was also detected using the same biopsy sample. Mean female age was 35.4 ± 4.2 years old. All biopsies were performed at blastocyst stage and analyzed by Whole Genome Amplification (WGA) followed by PCR for monogenic diseases, and by array-comparative genotype hybridization (array-CGH) for all cycles.PARTICIPANTS/MATERIALS, SETTING, METHODAll mature oocytes retrieved were injected and cultured individually until the blastocyst stage at 37°C, 6% CO2, 5% O2. When the blastocyst was formed, it was biopsied and vitrified, awaiting the genetic results. The frozen–thawed embryo transfer was performed in a subsequent cycle. In some cases, when the blastocyst was obtained within the morning of Day 5 of culture, it had been maintained in culture and transferred on Day 6, after receiving the genetic report.MAIN RESULTS AND THE ROLE OF CHANCEA total of 2809 (2718 fresh and 91 frozen–thawed) mature oocytes were injected with a fertilization rate of 75.5% (N = 2120), leading to the development of 2102 embryos. A further 24 frozen embryos, previously vitrified without any genetic testing, were successfully warmed for genetic screening. A total of 2126 embryos were cultured with a blastocyst formation rate of 52.8% (N = 1122); all of them were biopsied from Day 4 to Day 7 of culture. After the genetic analysis, 309 (27.5%) blastocysts resulted transferable, both for monogenic disease or translocation and for their ploidy status, 42 were diploid/aneuploid mosaic, 55 were no result and 716 were not transferable, due to genetic disease or chromosomal rearrangement and/or for their ploidy status. Of note, 316 (50.6% of transferable blastocysts after PGD and 28.2% of total number of biopsied blastocysts) of the blastocysts resulted healthy for the genetic disease or chromosomal rearrangement were aneuploid. Out of 304 PGD/PGS cycles performed, 28.6% (N = 87) resulted in no-transferable blastocysts after only PGD analysis; this percentage increased to 39.8% (N = 121) when also PGS was carried out (Mc Nemar test P < 0.001). A total of 202 embryo-transfers were performed, 53 fresh and 149 cryopreserved, in which 218 healthy or carrier euploid blastocysts were transferred. Clinical pregnancy, implantation and miscarriage rates were 49.0, 47.7 and 9.9%, respectively. To date, 66 deliveries occurred with 70 healthy babies born and 13 pregnancies are still ongoing. Finally, 91 euploid healthy blastocysts are still cryopreserved waiting to be transferred.LIMITATIONS, REASONS FOR CAUTIONA higher than expected cycle cancellation rate could be found due to the double genetic analysis performed. For this reason, particular care should be taken in drafting and explaining informed consent, in order to avoid patient drop out.WIDER IMPLICATIONS OF THE FINDINGSWhen the biopsy has to be performed in order to prevent the transmission of an inheritable disease, it should be mandatory to analyze also the genetic status of the blastocyst, avoiding useless embryo-transfers in this particular category of patients. In our study, 316 aneuploid healthy blastocysts could have been transferred without performing PGS, leading to implantation failures, miscarriages, or in some cases, to live births affected by different syndromes.STUDY FUNDING/COMPETING INTEREST(S)No specific funding was obtained for this study. None of the authors have any competing interests to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: 2017-06-12
      DOI: 10.1093/humrep/dex215
      Issue No: Vol. 32, No. 8 (2017)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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