Publisher: Oxford University Press   (Total: 413 journals)

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Showing 1 - 200 of 413 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (Followers: 3, SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 61, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 8, SJR: 1.434, CiteScore: 1)
Aesthetic Surgery J. Open Forum     Open Access   (Followers: 1)
African Affairs     Hybrid Journal   (Followers: 74, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 95, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 21, SJR: 1.376, CiteScore: 3)
American Entomologist     Hybrid Journal   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 216, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 54, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 232, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 228, SJR: 2.713, CiteScore: 3)
American J. of Health-System Pharmacy     Full-text available via subscription   (Followers: 64, SJR: 0.595, CiteScore: 1)
American J. of Hypertension     Hybrid Journal   (Followers: 29, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 11, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 31, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 19, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 25, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 2)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 38, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 62, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 11, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 11, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access   (Followers: 1)
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 66, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 33, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 58, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 396, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Open Access   (Followers: 1)
Biology of Reproduction     Full-text available via subscription   (Followers: 11, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 3, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 234, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 69)
Brain     Hybrid Journal   (Followers: 78, SJR: 5.858, CiteScore: 7)
Brain Communications     Open Access   (Followers: 4)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 53, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 42, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 622, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 99, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 35)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 76, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 13, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 3, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 16, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 56, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 24, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 8, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 24, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 11, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 29, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 79, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 29, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 29, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 28, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 12, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 8, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 5)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 6, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 10, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 15, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 25, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 6, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 17, SJR: 0.139, CiteScore: 0)
Econometrics J.     Hybrid Journal   (Followers: 34, SJR: 2.926, CiteScore: 1)
Economic J.     Hybrid Journal   (Followers: 124, SJR: 5.161, CiteScore: 3)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 27, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 60, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 23, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 12, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental History     Hybrid Journal   (Followers: 28, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 23, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 67, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 10, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access   (Followers: 1)
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 239, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 5, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 23, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 31, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 46, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 19, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 29, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 38, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 26, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 8, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 36, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 17, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 39, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 27, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 6, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 10, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 68, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 19, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 26, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 27, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 33, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 30, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 16, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 11, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 76, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 18, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 66, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 59, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 11)
ILAR J.     Hybrid Journal   (Followers: 3, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 12, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 45, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Innovation in Aging     Open Access   (Followers: 1)
Insect Systematics and Diversity     Hybrid Journal  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 10, SJR: 1.319, CiteScore: 2)
Integrative Biology     Full-text available via subscription   (Followers: 5, SJR: 1.36, CiteScore: 3)
Integrative Organismal Biology     Open Access  
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 72, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 22)
Intl. Health     Hybrid Journal   (Followers: 7, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 4, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 40, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 57, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 291, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 21, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 9, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 14, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 41, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 26, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 55, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 24, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 18, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 55, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 15, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 16, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 46, SJR: 1.226, CiteScore: 2)

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Similar Journals
Journal Cover
Human Reproduction
Journal Prestige (SJR): 2.643
Citation Impact (citeScore): 5
Number of Followers: 76  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0268-1161 - ISSN (Online) 1460-2350
Published by Oxford University Press Homepage  [413 journals]
  • Transiently increased risk of breast cancer after childbirth: implications
           for fertility treatments and surrogacy
    • Authors: Blumenfeld Z; Gleicher N, Adashi E.
      Pages: 1253 - 1255
      Abstract: AbstractWhereas longstanding dogma has purported that pregnancies protect women from breast cancer, a recent meta-analysis now mandates reconsideration since it reported an actual higher breast cancer risk for more than two decades after childbirth before the relative risk turns negative. Moreover, the risk of breast cancer appears higher for women having their first birth at an older age and with a family history and it is not reduced by breastfeeding. The process of obtaining informed consent for all fertility treatments, therefore, must make patients aware of the facts that every pregnancy, to a small degree, will increase the short-term breast cancer risk. This observation may be even more relevant in cases of surrogacy where women agree to conceive without deriving benefits of offspring from assuming the risk, thus creating a substantially different risk-benefit ratio. Consequently, it appears prudent for professional societies in the field to update recommendations regarding consent information for all fertility treatments but especially for treatments involving surrogacy.
      PubDate: Sat, 30 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa102
      Issue No: Vol. 35, No. 6 (2020)
  • Expanded carrier screening should not be mandatory for gamete donors
    • Authors: Pennings G.
      Pages: 1256 - 1261
      Abstract: AbstractMore and more centers are imposing expanded carrier screening (ECS) on their gamete donors. In some clinics and gamete banks, gamete donors are not given this right, contrary to the freedom to decline genetic screening in the general population. The possible social and psychological burdens that are recognized for infertility patients and the general population are downplayed for gamete donors. The procedure of imposing ECS on gamete donors shows that the interests of the recipients are valued higher than those of the donors. The general ethical argument defended here is the principle of proportionality: the burdens imposed on donors have to be balanced against the potential benefits for the offspring and the recipients. The risk reduction of ECS is below 1% and is too small to outweigh the potential dangers and disadvantages for donors. The conclusion is that clinics may ask, but not compel, donors to submit to ECS provided that they offer appropriate genetic and psychological counseling.
      PubDate: Tue, 05 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa088
      Issue No: Vol. 35, No. 6 (2020)
  • The importance of mediation in reproductive health studies
    • Authors: Farland L; Correia K, Dodge L, et al.
      Pages: 1262 - 1266
      Abstract: AbstractA mediator is a factor that occurs after the exposure of interest, precedes the outcome of interest (i.e. between the exposure and the outcome) and is associated with both the exposure and the outcome of interest (i.e. is on the pathway between exposure and outcome). Mediation analyses can be valuable in many reproductive health contexts, as mediation analysis can help researchers to better identify, quantify and understand the underlying pathways of the association they are studying. The purpose of this commentary is to introduce the concept of mediation and provide examples that solidify understanding of mediation for valid discovery and interpretation in the field of reproductive medicine.
      PubDate: Tue, 19 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa064
      Issue No: Vol. 35, No. 6 (2020)
  • Fetal fraction of cell-free DNA in pregnancies after fresh or frozen
           embryo transfer following assisted reproductive technologies
    • Authors: Talbot A; Ambye L, Hartwig T, et al.
      Pages: 1267 - 1275
      Abstract: AbstractSTUDY QUESTIONIs the fetal fraction (FF) of circulating cell-free DNA (cfDNA) affected in pregnancies following ART treatment with either fresh or frozen embryo transfer (ET) compared with natural conception'SUMMARY ANSWERThis study shows a significant reduction in the FF in ART patients compared with naturally conceived pregnancies, which seems to be more pronounced after fresh ET compared with frozen ET.WHAT IS KNOWN ALREADYNon-invasive prenatal testing (NIPT) is based on cfDNA in maternal blood, of which about 10% is of placental origin and thus represents the fetal karyotype. Validation studies have demonstrated a high sensitivity, specificity and positive predictive value of NIPT for the detection of fetal trisomy 21, 18 and 13. Nevertheless, the FF of cfDNA is an important factor for NIPT test accuracy. Several studies have found a reduction in FF for pregnancies following ART in comparison with natural conception. However, knowledge on how the FF is affected in ART pregnancies after fresh ET compared with frozen ET is very limited.STUDY DESIGN, SIZE, DURATIONThe study was designed as a case–control study. A total of 54 women with an ongoing pregnancy following ART treatment were included. After exclusion for different reasons, statistical analyses were based on 23 NIPT samples from pregnant women treated with fresh ET and 26 NIPT samples from pregnant women treated with frozen-thawed ET in a modified natural cycle. Women were included between February 2018 and November 2018. The results were compared with a control group of 238 naturally conceived pregnancies with a high-risk result from the combined first trimester screening (cFTS).PARTICIPANTS/MATERIALS, SETTING, METHODSThe study included women from the Fertility Clinics at Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet. Blood samples for NIPT analysis were drawn between 11 + 0 and 14 + 2 weeks of gestation and were all analyzed at the NIPT Center at Copenhagen University Hospital Hvidovre. The NIPT-test was performed by massive-parallel whole-genome sequencing. The FF was determined using the SeqFF algorithm.MAIN RESULTS AND THE ROLE OF CHANCEWe found a reduction in FF in ART patients compared with naturally conceived pregnancies, and the reduction was more pronounced for ART pregnancies after fresh ET (mean FF = 0.049) compared with frozen ET (mean FF = 0.063) (multivariate analysis adjusted for maternal BMI, P = 0.02). Another multivariate analysis, adjusted for BMI and multiples of median (MoM) values for pregnancy-associated plasma protein-A (PAPP-A), demonstrated a significantly reduced FF for ART pregnancies (mean FF = 0.056) compared with naturally conceived pregnancies (mean FF = 0.072) (P < 0.0001). We found that FF was significantly reduced with increasing maternal BMI (P < 0.0001) and with decreasing MoM values of PAPP-A (P = 0.003).LIMITATIONS, REASONS FOR CAUTIONA limitation of our study design was the relatively small sample size. Another limitation was that the control group was not matched with the ART-treated women. The majority of the women from the control group had a high risk from cFTS, thereby their biochemical markers were diverging. However, the biochemical markers for the ART-treated women with fresh or frozen ET were not divergent within the subgroups.WIDER IMPLICATIONS OF THE FINDINGSConcurrent with other studies demonstrating a reduced FF for singleton pregnancies after ART treatment compared with naturally conceived pregnancies, we found a reduction in FF between the two groups. This is one of the first studies to examine FF in ART pregnancies after fresh ET compared with frozen ET, hence the existing knowledge is limited. We find that FF is even more reduced in pregnancies following fresh ET compared with frozen ET, which might possibly reflect the predisposition of being small for gestational age after fresh ET compared with natural cycle frozen ET.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (the A.P. Møller Foundation for General Purposes). All authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERNA.
      PubDate: Mon, 15 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa110
      Issue No: Vol. 35, No. 6 (2020)
  • Effects of MTHFR C677T polymorphism on vitamin D, homocysteine and natural
           killer cell cytotoxicity in women with recurrent pregnancy losses
    • Authors: Ota K; Takahashi T, Han A, et al.
      Pages: 1276 - 1287
      Abstract: AbstractSTUDY QUESTIONIs there any relationship between vitamin D [25 (OH) vitamin D], total plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with recurrent pregnancy losses (RPL)'SUMMARY ANSWERWomen with MTHFR 677TT (homozygous mutation, TT) genotype have significantly lower vitamin D levels, higher homocysteine and natural killer (NK) cell cytotoxicities than those of women with MTHFR 677CC (wild type, CC) and 677CT (heterozygous mutation, CT) genotypes.WHAT IS KNOWN ALREADYVitamin D insufficiency, MTHFR C677T polymorphism and hyperhomocysteinemia have been reported as risk factors for RPL. However, the relationship between these risk factors is not known in this population.STUDY DESIGN, SIZE, DURATIONThis is a retrospective cross-sectional study, including 837 women with RPL, who were enrolled in Reproductive Medicine and Immunology, Chicago Medical School, between 2012 and 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with two or more RPL prior to 20 weeks of gestation were included. To investigate whether the MTHFR C677T polymorphism affects the levels of homocysteine and vitamin D as well as immune parameters in women with RPL, biochemical data, such as plasma total homocysteine and serum vitamin D levels, and immune parameters, including NK cell cytotoxicity, were analyzed by MTHFR C677T genotype (CC, CT and TT).MAIN RESULTS AND THE ROLE OF CHANCEThe serum level of vitamin D in TT was significantly lower when compared with those of CT (P = 0.001) and CC (P = 0.003), while the level of homocysteine in TT was significantly higher than those in CT (P = 0.01) and CC (P = 0.01). NK cytotoxicity in TT was significantly higher than that of CC (P = 0.04) but not CT (P = 0.09). There was a significant negative correlation between the levels of vitamin D and homocysteine in TT (r = −0.357, P < 0.01). In multivariate analysis, vitamin D insufficiency (<30 ng/ml) was an independent risk factor for hyperhomocysteinemia (adjusted odds ratio 1.89, 95% CI 1.41–2.52).LIMITATIONS, REASONS FOR CAUTIONThe study was retrospective and included only women with RPL but not healthy fertile controls. In addition, folic acid, vitamin B6 and B12 intake, which could modify the level of homocysteine and vitamin D, were not investigated. Thus, a considerable part of women might have folic acid and vitamin D supplementation and prenatal vitamin pills, and there are probable confounders in this study associated with unrestricted vitamin supplementation. Therefore, the findings should be carefully interpreted and applied to RPL women with MTHFR gene polymorphism.WIDER IMPLICATIONS OF THE FINDINGSThe findings attained in this analysis regarding the MTHFR polymorphism and its relationship with vitamin D, homocysteine and NK cytotoxicity may aid in uncovering the underlying etiology and mechanism for RPL. The study highlights an interplay between nutrition and immune responses in RPL.STUDY FUNDING/COMPETING INTEREST(S)No external funding was received for this study. None of the authors have any conflict of interest to declare.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Mon, 01 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa095
      Issue No: Vol. 35, No. 6 (2020)
  • Relationship between natural and intrauterine insemination-assisted live
           births and the degree of sperm autoimmunisation
    • Authors: Barbonetti A; Castellini C, D’Andrea S, et al.
      Pages: 1288 - 1295
      Abstract: AbstractSTUDY QUESTIONWhat is the relationship between the degree of sperm autoimmunisation, as assessed by IgG-mixed antiglobulin reaction (MAR) test, and natural and intrauterine insemination (IUI)-assisted live births'SUMMARY ANSWERCompared with a lower degree of positivity (50–99%), a 100%-positive MAR test was associated with a much lower occurrence of natural live births in infertile couples, who could be successfully treated with IUI, as first-line treatment.WHAT IS KNOWN ALREADYThe World Health Organization (WHO) has recommended screening for antisperm antibodies, through either the IgG-MAR test or an immunobead-binding test, as an integral part of semen analysis, with 50% antibody-coated motile spermatozoa considered to be the clinically relevant threshold. However, the predictive value of the degree of positivity of the MAR test above such a cut-off on the occurrence of natural pregnancies remains largely undetermined. Furthermore, the effectiveness of IUI in cases of strong sperm autoimmunisation is not yet well-established.STUDY DESIGN, SIZE, DURATIONThis was a retrospective cohort study on 108 men with a ≥50%-positive MAR test, where the couple had attended a university/hospital andrology/infertility clinic for the management of infertility from March 1994 to September 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSThe IgG-MAR test was carried out as an integral part of semen analysis. The patients were divided into two groups: 100% and 50%–99%-positive MAR test. The post-coital test (PCT) was performed in all the couples, and IUI was offered as the first-line treatment. Laboratory and other clinical data were retrieved from a computerised database. Data on subsequent pregnancies were obtained by contacting patients over the telephone.MAIN RESULTS AND THE ROLE OF CHANGEA total of 84 men (77.8%) were successfully contacted by telephone, and they agreed to participate. Of these, 44 men belonged to the group with a 100%-positive MAR test, while 40 showed lower MAR test positivity. The couples with a 100%-positive MAR test showed a natural live birth rate per couple (LBR) that was considerably lower than that observed with a lower degree of positivity (4.5% vs. 30.0%; P = 0.00001). Among the clinical variables, a significant difference between the two groups was observed only for the PCT outcome, which was poor in the 100%-positive MAR test group. Better PCT outcomes (categorised as negative, subnormal and good) were positively associated with the occurrence of natural live births (6.3, 21.7 and 46.2%, respectively; P = 0.0005 for trend), for which the sole independent negative predictor was the degree of sperm autoimmunisation. IUI was performed as the first-line treatment in 38 out of 44 couples with a 100%-positive MAR test, yielding 14 live births (36.8%). In couples with lower MAR test positivity, the LBR after IUI (26.9%) was similar to the natural LBR in this group (30.0%).LIMITATIONS, REASONS FOR CAUTIONGiven the retrospective nature of the study, we cannot exclude uncontrolled variables that may have affected natural pregnancies during the follow up or a selection bias from the comparison of natural live births with those after IUI.WIDER IMPLICATIONS OF THE FINDINGSThe routine use of the IgG-MAR test in the basic fertility workup is justified as it influences decision making. A 100%-positive IgG-MAR test can represent the sole cause of a couple’s infertility, which could be successfully treated with IUI. On the other hand, a lower degree of positivity may only represent a contributing factor to a couple’s infertility, and so the decision to treat or wait also depends on the evaluation of conventional prognostic factors including the PCT outcome.STUDY FUNDING, COMPETING INTEREST(S)This study was supported by PRIN 2017, Ministero dell’Università e della Ricerca Scientifica (MIUR), Italy. On behalf of all authors, the corresponding author states that there is no conflict of interest.TRIAL REGISTRATION NUMBERN/A
      PubDate: Sat, 02 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa070
      Issue No: Vol. 35, No. 6 (2020)
  • Intrauterine insemination performance characteristics and post-processing
           total motile sperm count in relation to live birth for couples with
           unexplained infertility in a randomised, multicentre clinical trial
    • Authors: Hansen K; , Peck J, et al.
      Pages: 1296 - 1305
      Abstract: AbstractSTUDY QUESTIONAre intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility'SUMMARY ANSWERPatient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success.WHAT IS ALREADY KNOWNWe previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome.STUDY DESIGN, SIZE, DURATIONThis was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSAMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate.MAIN RESULTS AND THE ROLE OF CHANCEAfter adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16–0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1–20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31–3.33)). However, live births did occur with TMC ≤ 1 million (5.1%).LIMITATIONS, REASONS FOR CAUTIONThis investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI.WIDER IMPLICATIONS OF THE FINDINGSMost factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI.STUDY FUNDING/COMPETING INTEREST(S)Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work.TRIAL REGISTRATION NUMBERn/a
      PubDate: Wed, 20 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa027
      Issue No: Vol. 35, No. 6 (2020)
  • The depot GnRH agonist protocol improves the live birth rate per fresh
           embryo transfer cycle, but not the cumulative live birth rate in normal
           responders: a randomized controlled trial and molecular mechanism study
    • Authors: Xu B; Geerts D, Hu S, et al.
      Pages: 1306 - 1318
      Abstract: AbstractSTUDY QUESTIONDo cumulative live birth rates (CLBRs) after one complete ART cycle differ between the three commonly used controlled ovarian stimulation (COS) protocols (GnRH antagonist, depot GnRHa (GnRH agonist) and long GnRHa) in normal responders undergoing IVF/ICSI'SUMMARY ANSWERThere were similar CLBRs between the GnRH antagonist, depot GnRHa and long GnRHa protocols.WHAT IS KNOWN ALREADYThere is no consensus on which COS protocol is the most optimal in women with normal ovarian response. The CLBR provides the final success rate after one complete ART cycle, including the fresh and all subsequent frozen–thawed embryo transfer (ET) cycles. We suggest that the CLBR measure would allow for better comparisons between the different treatment protocols.STUDY DESIGN, SIZE, DURATIONA prospective controlled, randomized, open label trial was performed between May 2016 and May 2017. A total of 819 patients were allocated to the GnRH antagonist, depot GnRHa or long GnRHa protocol in a 1:1:1 ratio. The minimum follow-up time from the first IVF cycle was 2 years. To further investigate the potential effect of COS with the GnRH antagonist, depot GnRHa or long GnRHa protocol on endometrial receptivity, the expression of homeobox A10 (HOXA10), myeloid ecotropic viral integration site 1 (MEIS1) and leukemia inhibitory factor (LIF) endometrial receptivity markers was evaluated in endometrial tissue from patients treated with the different COS protocols.PARTICIPANTS/MATERIALS, SETTING, METHODSInfertile women with normal ovarian response (n = 819) undergoing IVF/ICSI treatment were randomized to the GnRH antagonist, depot GnRHa or long GnRHa protocol. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen partner ejaculates or frozen donor ejaculates. The primary outcome was the live birth rate (LBR) per fresh ET cycle, and the CLBR after one complete ART cycle, until the birth of a first child (after 28 weeks) or until all frozen embryos were used, whichever occurred first. Pipelle endometrial biopsies from 34 female patients were obtained on Days 7–8 after oocyte retrieval or spontaneous ovulation in natural cycles, respectively, and HOXA10, MEIS1 and LIF mRNA and protein expression levels in the human endometrium was determined by quantitative real-time PCR and western blot, respectively.MAIN RESULTS AND THE ROLE OF CHANCEThere were no significant differences in CLBRs between the GnRH antagonist, depot GnRHa or long GnRHa protocol (71.4 versus 75.5 versus 72.2%, respectively). However, there was a significantly higher LBR per fresh ET cycle in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (62.6 versus 52.1% versus 45.6%, P < 0.05). Furthermore, HOXA10, MEIS1 and LIF mRNA and protein expression in endometrium all showed significantly higher in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (P < 0.05).LIMITATIONS, REASONS FOR CAUTIONA limitation of our study was that both our clinicians and patients were not blinded to the randomization for the randomized controlled trial (RCT). An inclusion criterion for the current retrospective cohort study was based on the ‘actual ovarian response’ during COS treatment, while the included population for the RCT was ‘expected normal responders’ based on maternal age and ovarian reserve test. In addition, the analysis was restricted to patients under 40 years of age undergoing their first IVF cycle. Furthermore, the endometrial tissue was collected from patients who cancelled the fresh ET, which may include some patients at risk for ovarian hyperstimulation syndrome, however only patients with 4–19 oocytes retrieved were included in the molecular study.WIDER IMPLICATIONS OF THE FINDINGSThe depot GnRH agonist protocol improves the live birth rate per fresh ET cycle, but not the cumulative live birth rate in normal responders. A possible explanation for the improved LBR after fresh ET in the depot GnRHa protocol could be molecular signalling at the level of endometrial receptivity.STUDY FUNDING/COMPETING INTEREST(S)This project was funded by Grant 81571439 from the National Natural Sciences Foundation of China and Grant 2016YFC1000206-5 from the National Key Research & Development Program of China. The authors declare no conflict of interest.TRIAL REGISTRATION NUMBERThe RCT trial was registered at the Chinese Clinical Trial Registry, Study Number: ChiCTR-INR-16008220.TRIAL REGISTRATION DATE5 April 2016.DATE OF FIRST PATIENT’S ENROLLMENT12 May 2016
      PubDate: Mon, 01 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa086
      Issue No: Vol. 35, No. 6 (2020)
  • Gonadotrophins or clomiphene citrate in women with normogonadotropic
           anovulation and CC failure: does the endometrium matter'
    • Authors: Bordewijk E; Weiss N, Nahuis M, et al.
      Pages: 1319 - 1324
      Abstract: AbstractSTUDY QUESTIONIs endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles'SUMMARY ANSWERUsing a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles.WHAT IS ALREADY KNOWNFor women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins.STUDY DESIGN, SIZE, DURATIONBetween 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC.PARTICIPANTS/MATERIALS, SETTING, METHODSEMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER).MAIN RESULTS AND THE ROLE OF CHANCEMid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13–2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75–1.29).LIMITATIONS, REASONS FOR CAUTIONThis was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women.WIDER IMPLICATIONS OF THE FINDINGSIn women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs.STUDY FUNDING/COMPETING INTEREST(S)The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare.TRIAL REGISTRATION NUMBERNetherlands Trial Register, number NTR1449
      PubDate: Tue, 02 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa052
      Issue No: Vol. 35, No. 6 (2020)
  • Comparison of euploidy rates of blastocysts in women treated with
           progestins or GnRH antagonist to prevent the luteinizing hormone surge
           during ovarian stimulation
    • Authors: La Marca A; Capuzzo M, Sacchi S, et al.
      Pages: 1325 - 1331
      Abstract: AbstractSTUDY QUESTIONDoes the prevalence of euploid blastocysts differ between patients treated with progestin primed ovarian stimulation (PPOS) and those treated with conventional ovarian stimulation'SUMMARY ANSWERThe numbers of blastocysts and euploid blastocysts per patient and the number of euploid embryos per injected oocyte are similar for patients undergoing progestin-primed ovarian stimulation and for those undergoing conventional ovarian stimulation with GnRH antagonist.WHAT IS KNOWN ALREADYNew approaches to ovarian stimulation have been developed based on the use of drugs administrable by mouth instead of via injections. Attention has been dedicated to progestins to block the LH surge. Previous data regarding the number of oocytes retrieved and the number of good-quality embryos generated in PPOS have demonstrated similar outcomes when compared to conventional ovarian stimulation, even if some concerns regarding the quality of embryos have been advanced.STUDY DESIGN, SIZE, DURATIONThis is a prospective non-inferiority age-matched case–control study. In a period of 6 months, a total of 785 blastocysts from 1867 injected oocytes obtained from 192 patients were available for analysis.PARTICIPANTS/MATERIALS, SETTING, METHODSInfertile women undergoing IVF and preimplanation genetic testing (PGT) cycles were included. Forty-eight patients were treated with PPOS, and for each of them three age-matched historical controls (n = 144) treated with a GnRH antagonist protocol were selected. PGT was performed according to next-generation sequencing technology.MAIN RESULTS AND THE ROLE OF CHANCEBasal characteristics were similar in the two groups; a substantial similarity of the main outcome measures in the two treatment groups has also been found. The rate of formation of euploid blastocysts per oocyte was 21% in both the two treatment groups. The percentage of patients with euploid embryos and the total number of euploid blastocysts per patient (median and interquartile range, IQR) in the PPOS group were 38.7 (25.5–52.9) and 2 (1.3–3.1), respectively. These figures were not significantly different in women treated with the GnRH antagonist protocol i.e. 42 (28–53.8) and 2.1 (1.3–2.9), respectively.LIMITATIONS, REASONS FOR CAUTIONThis was a case–control study which may limit the reliability of the main findings.WIDER IMPLICATIONS OF THE FINDINGSOur results encourage the use of PPOS, especially for oocyte donation, for fertility preservation and for patients in which total freezing of embryos is foreseen, for those expected to be high responders or candidates for preimplantation genetic testing. However, studies aiming to investigate the effect of PPOS on the live birth rate are warranted.STUDY FUNDING/COMPETING INTEREST(S)None.
      PubDate: Tue, 12 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa068
      Issue No: Vol. 35, No. 6 (2020)
  • A distinctive epigenetic ageing profile in human granulosa cells
    • Authors: Olsen K; Castillo-Fernandez J, Zedeler A, et al.
      Pages: 1332 - 1345
      Abstract: AbstractSTUDY QUESTIONDoes women’s age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells'SUMMARY ANSWERAccumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile.WHAT IS KNOWN ALREADYThe mechanisms underlying the decline in women’s fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa).STUDY DESIGN, SIZE, DURATIONThis study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden.PARTICIPANTS/MATERIALS, SETTING, METHODSBlood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package.MAIN RESULTS AND ROLE OF CHANCEUsing established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson’s correlation coefficient = −0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10−08) and gene expression (152 genes, P = 2.3 × 10−06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONNo gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found.WIDER IMPLICATIONS OF THE FINDINGSOur findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age.STUDY FUNDING/COMPETING INTEREST(S)This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.
      PubDate: Sat, 30 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa071
      Issue No: Vol. 35, No. 6 (2020)
  • Granulosa cells provide elimination of apoptotic oocytes through
           unconventional autophagy-assisted phagocytosis
    • Authors: Yefimova M; Lefevre C, Bashamboo A, et al.
      Pages: 1346 - 1362
      Abstract: AbstractSTUDY QUESTIONDo human granulosa cells (GCs) ingest and destroy apoptotic oocytes'SUMMARY ANSWERSomatic GCs ingest and destroy apoptotic oocytes and other apoptotic substrates through unconventional autophagy-assisted phagocytosis.WHAT IS KNOWN ALREADYMost (99%) ovarian germ cells undergo apoptosis through follicular atresia. The mode of cleaning of atretic follicles from the ovary is unclear. Ovarian GCs share striking similarities with testicular Sertoli cells with respect to their origin and function. Somatic Sertoli cells are responsible for the elimination of apoptotic spermatogenic cells through unconventional autophagy-assisted phagocytosis.STUDY DESIGN, SIZE, DURATIONHuman GCs were tested for the ability to ingest and destroy the apoptotic oocytes and other apoptotic substrates. A systemic study of the main phagocytosis steps has been performed at different time points after loading of apoptotic substrates into the GC.PARTICIPANTS/MATERIALS, SETTING, METHODSPrimary cultures of GC retrieved following controlled ovarian stimulation of five women for IVF/ICSI and a human granulosa KGN cell line were incubated with different apoptotic substrates: oocytes which underwent spontaneous apoptosis during the cultivation of immature germ cells for IVF/ICSI; apoptotic KGN cells; and apoptotic membranes from rat retinas. Cultured GC were analyzed for the presence of specific molecular markers characteristic of different steps of phagocytic and autophagy machineries by immunocytochemistry, confocal microscopy, transmission electron microscopy and western blotting, before and after loading with apoptotic substrates.MAIN RESULTS AND THE ROLE OF CHANCEIncubation of human GC with apoptotic substrates resulted in their translocation in cell cytoplasm, concomitant with activation of the phagocytosis receptor c-mer proto-oncogene tyrosine kinase MERTK (P < 0.001), clumping of motor molecule myosin II, recruitment of autophagy proteins: autophagy-related protein 5 (ATG5), autophagy-related protein 6 (Beclin1) and the rise of a membrane form of microtubule-associated protein 1 light chain 3 (LC3-II) protein. Ingestion of apoptotic substrates was accompanied by increased expression of the lysosomal protease Cathepsin D (P < 0.001), and a rise of lysosomes in the GCs, as assessed by different techniques. The level of autophagy adaptor, sequestosome 1/p62 (p62) protein remained unchanged.LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONThe number of patients described here is limited. Also the dependence of phagocytosis on reproductive hormone status of patients should be analyzed.WIDER IMPLICATIONS OF THE FINDINGSRemoval of apoptotic oocytes by surrounding GC seems likely to be a physiological mechanism involved in follicular atresia. Proper functioning of this mechanism may be a new strategy for the treatment of ovarian dysfunctions associated with an imbalance in content of germ cells in the ovaries, such as premature ovarian failure and polycystic ovary syndrome.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by Rennes Metropole (AIS 2015) and Agence de BioMédecine. This work was supported by funding from Université de Rennes1, Institut National de la Santé et de la Recherche Médicale (INSERM) and CHU de Rennes. A.B. is funded in part by the program Actions Concertées Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. This work is supported by the Agence Nationale de la Recherche Grants ANR-17-CE14-0038 and ANR-10-LABX-73. The authors declare no competing interests.
      PubDate: Fri, 12 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa097
      Issue No: Vol. 35, No. 6 (2020)
  • Endometrial inflammasome activation accompanies menstruation and may have
           implications for systemic inflammatory events of the menstrual cycle
    • Authors: Azlan A; Salamonsen L, Hutchison J, et al.
      Pages: 1363 - 1376
      Abstract: AbstractSTUDY QUESTIONDoes NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation within decidualized endometrial stromal cells accompany menstruation and is this reflected systemically'SUMMARY ANSWERComponents of the NLRP3 inflammasome immunolocalize to decidualized endometrial stromal cells immediately prior to menstruation, and are activated in an in vitro model of menstruation, as evidenced by downstream interleukin (IL)-1beta and IL-18 release, this being reflected systemically in vivo.WHAT IS KNOWN ALREADYMenstruation is a highly inflammatory event associated with activation of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), local release of chemokines and cytokines and inflammatory leukocyte influx. Systemically, chemokines and cytokines fluctuate across the menstrual cycle.STUDY DESIGN, SIZE, DURATIONThis study examined the NLRP3 inflammasome and activation of downstream IL-1beta and IL-18 in endometrial tissues from women of known fertility (≥1 previous parous pregnancy) across the menstrual cycle (n ≥ 8 per cycle phase), serum from women during the proliferative, secretory and menstrual phases (≥9 per cycle phase) of the cycle and menstrual fluid collected on Day 2 of menses (n = 18). Endometrial stromal cells isolated from endometrial tissue biopsies (n = 10 in total) were used for an in vitro model of pre-menstrual hormone withdrawal.PARTICIPANTS/MATERIALS, SETTING, METHODSExpression and localization of components of the NLRP3 inflammasome (NLRP3 & apoptosis-associated speck–caspase recruit domain [ASC]) in endometrial tissues was performed by immunohistochemistry. Unbiased digital quantification of immunohistochemical staining allowed determination of different patterns of expression across the menstrual cycle. Serum from women across the menstrual cycle was examined for IL-1beta and IL-18 concentrations by ELISA. An in vitro model of hormone withdrawal from estrogen/progestin decidualized endometrial stromal cells was used to more carefully examine activation of the NLRP3 inflammasome. Endometrial stromal cells isolated from endometrial tissue biopsies (n = 10) were treated with estrogen/medroxyprogesterone acetate for 12 days to induce decidualization (assessed by release of prolactin) followed by withdrawal of steroid hormone support. Activation of NLRP3, & ASC in these cells was examined on Days 0–3 after hormone withdrawal by Western immunoblotting. Release of IL-1beta and IL-18 examined during decidualization and across the same time course of hormone withdrawal by ELISA. Specific involvement of NLRP3 inflammasome activation in IL-1beta and IL-18 release after hormone withdrawal was investigated via application of the NLRP3 inflammasome inhibitor MCC950 at the time of hormone withdrawal.MAIN RESULTS AND THE ROLE OF CHANCECritical components of the NLRP3 inflammasome (NLRP3, ASC) were increased in menstrual phase endometrial tissues versus early secretory phase tissues (P < 0.05, n/s, respectively). NLRP3 and ASC were also elevated in the proliferative versus secretory phase of the cycle (P < 0.01, n/s, respectively) with ASC also significantly increased in the late-secretory versus early-secretory phase (P < 0.05). The pattern of activation was reflected in systemic levels of the inflammasome mediators, with IL-1beta and IL-18 elevated in peripheral blood serum during menstruation (Day 2 of menses) versus secretory phase (P = 0.026, P = 0.0042, respectively) and significantly elevated in menstrual fluid (Day 2 of menses) versus systemic levels across all cycle phases, suggesting that local inflammasome activation within the endometrium during menses is reflected by systemic inflammation. NLRP3 and ASC localized to decidualized cells adjacent to the spiral arterioles in the late secretory phase of the menstrual cycle, where the menstrual cascade is thought to be initiated, and to endometrial leukocytes during the menstrual phase. NLRP3 also localized to glandular epithelial cells during the late-secretory/menstrual phases. Localization of both NLRP3 and ASC switched from predominant epithelial localization during the early-secretory phase to stromal localization during the late-secretory/menstrual phase. Using an in vitro model of hormone withdrawal from decidualized human endometrial stromal cells, we demonstrated progressive activation of NLRP3 and ASC after hormone withdrawal increasing from Day 0 of withdrawal/Day 12 of decidualization to Day 3 of withdrawal. Downstream release of IL-1beta and IL-18 from decidualized stromal cells after hormone withdrawal followed the same pattern with the role of NLRP3 inflammasome activation confirmed via the inhibition of IL-1beta and IL-18 release upon application of MCC950.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis study uses descriptive and semi-quantitative measures of NLRP3 inflammasome activation within endometrial tissues. Further, the
      PubDate: Wed, 03 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa065
      Issue No: Vol. 35, No. 6 (2020)
  • TIPE2 inhibits the migration and invasion of endometrial cells by
           targeting β-catenin to reverse epithelial–mesenchymal transition
    • Authors: Liu Y; Wang X, Wan L, et al.
      Pages: 1377 - 1390
      Abstract: AbstractSTUDY QUESTIONDo changes in tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) levels in endometrium of patients with adenomyosis alter the proliferation, migration and invasion ability of endometrial cells'SUMMARY ANSWERTIPE2 expression levels were low in eutopic and ectopic endometrium of adenomyosis patients, and TIPE2 inhibited the migration and invasion of endometrial cells, mainly by targeting β-catenin, to reverse the epithelial-mesenchymal transition (EMT).WHAT IS KNOWN ALREADYAdenomyosis is a benign disease, but it has some pathophysiological characteristics similar to the malignant tumor. TIPE2 is a novel negative immune regulatory molecule, and it also participates in the development of malignant tumors.STUDY DESIGN, SIZE, DURATIONControl endometrium (n = 48 women with non-endometrial diseases) and eutopic/ectopic endometrium from patients with adenomyosis (n = 50), human endometrial cancer cell lines, and primary endometrial cells from the eutopic endometrium of adenomyosis patients were used in the study.PARTICIPANTS/MATERIALS, SETTING, METHODSThe expression level of TIPE2 mRNA and protein in the eutopic/ectopic endometrial tissues of adenomyosis patients and control endometrium was determined by quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of endometrial cell lines and primary adenomyotic endometrial cells were determined using a cell counting kit-8, 5-ethynyl-2′-deoxyuridine assay, colony-forming assay, transwell migration assay and matrigel invasion assay. The expression of EMT-related markers and signal molecules was detected by western blot. The interaction between TIPE2 and β-catenin was detected by co-immunoprecipitation and laser confocal microscopy.MAIN RESULTS AND THE ROLE OF CHANCEThe mRNA and protein expression levels of TIPE2 in the eutopic and ectopic endometrial tissues of adenomyosis patients were significantly downregulated compared with the control endometrium (P ˂ 0.01). TIPE2 could bind to β-catenin and inhibit the nuclear translocation of β-catenin, downregulate the expression of stromal cell markers, upregulate the expression of glandular epithelial cell markers, decrease the occurrence of epithelial-mesenchymal transition (EMT) and suppress the migration and invasion of endometrial cells (P ˂ 0.01).LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONIn this study, the experiments were performed only in eutopic and ectopic endometrial tissues, endometrial cancer cell lines and primary adenomyotic endometrial cells. A mouse model of adenomyosis will be constructed to detect the effects of TIPE2 in vivo.WIDER IMPLICATIONS OF THE FINDINGSThese results suggest that TIPE2 is involved in the development of adenomyosis, which provides a potential new diagnostic and therapeutic strategy for the treatment of adenomyosis.STUDY FUNDINGS/COMPETING INTEREST(S)This present study was supported by grants from the National Natural Science Foundation of China (81471437, 81771554), Natural Science Foundation of Shandong (ZR2018MH013), Science and technology development plan provided by Health and Family Planning Committee in Shandong (2014-25). The authors declare that they have no conflicts of interest.
      PubDate: Fri, 29 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa062
      Issue No: Vol. 35, No. 6 (2020)
  • Spatiotemporal changes in mechanical matrisome components of the human
           ovary from prepuberty to menopause
    • Authors: Ouni E; Bouzin C, Dolmans M, et al.
      Pages: 1391 - 1410
      Abstract: AbstractSTUDY QUESTIONHow do elastic matrisome components change during the lifetime of the human ovary'SUMMARY ANSWERThe deposition and remodeling of mechanical matrisome components (collagen, elastin, elastin microfibril interface-located protein 1 (EMILIN-1), fibrillin-1 and glycosaminoglycans (GAGs)) that play key roles in signaling pathways related to follicle activation and development evolve in an age- and follicle stage-related manner.WHAT IS KNOWN ALREADYThe mechanobiology of the human ovary and dynamic reciprocity that exists between ovarian cells and their microenvironment is of high importance. Indeed, while the localization of primordial follicles in the collagen-rich ovarian cortex offers a rigid physical environment that supports follicle architecture and probably plays a role in their survival, ovarian extracellular matrix (ECM) stiffness limits follicle expansion and hence oocyte maturation, maintaining follicles in their quiescent state. As growing follicles migrate to the medulla of the ovary, they encounter a softer, more pliant ECM, allowing expansion and development. Thus, changes in the rigidity of the ovarian ECM have a direct effect on follicle behavior. Evidence supporting a role for the physical environment in follicle activation was provided in clinical practice by ovarian tissue fragmentation, which promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth and generation of mature oocytes.STUDY DESIGN, SIZE, DURATIONWe investigated quantitative spatiotemporal changes in collagen, elastin, EMILIN-1, fibrillin-1 and GAGs from prepuberty to menopause, before conducting a closer analysis of the ECM surrounding follicles, from primordial to secondary stages, in both prepubertal and tissue from women of reproductive age. The study included ovarian tissue (cortex) from 68 patients of different ages: prepubertal (n = 16; mean age [±SD]=8 ± 2 years); reproductive (n = 21; mean age [±SD]=27 ± 4 years); menopausal with estrogen-based HRT (n = 7; mean age [±SD]=58 ± 4 years); and menopausal without HRT (n = 24; mean age [±SD]=61 ± 5 years).PARTICIPANTS/MATERIALS, SETTING, METHODSQuantitative investigations of collagen and GAG deposition in ovarian tissue throughout a woman’s lifetime were conducted by analyzing brightfield images. Characteristic features of collagen fiber content were based on polarized light microscopy, since polarized light changes with fiber thickness. To evaluate the deposition and distribution of elastin, fibrillin-1 and EMILIN-1, multiplex immunofluorescence was used on at least three sections from each patient. Image processing and tailored bioinformatic analysis were applied to enable spatiotemporal quantitative evaluation of elastic system component deposition in the human ovary over its lifetime.MAIN RESULTS AND THE ROLE OF CHANCEWhile collagen levels increased with age, fibrillin-1 and EMILIN-1 declined. Interestingly, collagen and elastin reached their peak in reproductive-age women compared to prepubertal (P < 0.01; P = 0.262) and menopausal subjects with (P = 0.706; P < 0.01) and without (P = 0.987; P = 0.610) HRT, indicating a positive impact of secreted estrogen and hormone treatment on collagen and elastin preservation. Interestingly, HRT appears to affect elastin presence in ovarian tissue, since a significantly higher (P < 0.05) proportion of elastin was detected in biopsies from menopausal women taking HRT compared to those not. Higher GAG levels were found in adult ovaries compared to prepubertal ovaries (P < 0.05), suggesting changes in tissue ultrastructure and elasticity with age. In this context, elevated GAG values are suspected to participate in hampering formation of the fibrillin-1 network (r = −0.2475; P = 0.04687), which explains its decline over time. This decline partially accounts for the decrease in EMILIN-1 (r = 0.4149; P = 0.00059). Closer examination of the ECM surrounding follicles from the primordial to the secondary stage, both before and after puberty, points to high levels of mechanical stress placed on prepubertal follicles compared to the more compliant ECM around reproductive-age follicles, as suggested by the higher collagen levels and lower elastin content detected mainly around primordial (P < 0.0001; P < 0.0001, respectively) and primary (P < 0.0001; P < 0.001, respectively) follicles. Such a stiff niche is nonpermissive to prepubertal follicle activation and growth, and is more inclined to quiescence.LARGE SCALE DATA
      PubDate: Mon, 15 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa100
      Issue No: Vol. 35, No. 6 (2020)
  • Does an FSH surge at the time of hCG trigger improve IVF/ICSI
           outcomes' A randomized, double-blinded, placebo-controlled study
    • Authors: Qiu Q; Huang J, Li Y, et al.
      Pages: 1411 - 1420
      Abstract: AbstractSTUDY QUESTIONDoes an artificially induced FSH surge at the time of hCG trigger improve IVF/ICSI outcomes'SUMMARY ANSWERAn additional FSH bolus administered at the time of hCG trigger has no effect on clinical pregnancy rate, embryo quality, fertilization rate, implantation rate and live birth rate in women undergoing the long GnRH agonist (GnRHa) protocol for IVF/ICSI.WHAT IS KNOWN ALREADYNormal ovulation is preceded by a surge in both LH and FSH. Few randomized clinical trials have specifically investigated the role of the FSH surge. Some studies indicated that FSH given at hCG ovulation trigger boosts fertilization rate and even prevents ovarian hyperstimulation syndrome (OHSS).STUDY DESIGN, SIZE, DURATIONThis was a randomized, double-blinded, placebo-controlled trial conducted at a single IVF center, from June 2012 to November 2013. A sample size calculation indicated that 347 women per group would be adequate. A total of 732 women undergoing IVF/ICSI were randomized, using electronically randomized tables, to the intervention or placebo groups. Participants and clinical doctors were blinded to the treatment allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSPatients aged ≤42 years who were treated with IVF/ICSI owing to tubal factor, male factor, unexplained, endometriosis and multiple factors were enrolled in this trial. Subjects all received a standard long GnRHa protocol for IVF/ICSI and hCG 6000–10 000 IU to trigger oocyte maturation. A total of 364 and 368 patients were randomized to receive a urinary FSH (uFSH) bolus (6 ampules, 450 IU) and placebo, respectively, at the time of the hCG trigger. The primary outcome measure was clinical pregnancy rate. The secondary outcome measures were FSH level on the day of oocyte retrieval, number of oocytes retrieved, good-quality embryo rate, live birth rate and rate of OHSS.MAIN RESULTS AND THE ROLE OF CHANCEThere were no significant differences in the baseline demographic characteristics between the two study groups. There were also no significant differences between groups in cycle characteristics, such as the mean number of stimulation days, total gonadotrophin dose and peak estradiol. The clinical pregnancy rate was 51.6% in the placebo group and 52.7% in the FSH co-trigger group, with an absolute rate difference of 1.1% (95% CI −6.1% to 8.3%). The number of oocytes retrieved was 10.47 ± 4.52 and 10.74 ± 5.01 (P = 0.44), the rate of good-quality embryos was 37% and 33.9% (P = 0.093) and the implantation rate was 35% and 36% (P = 0.7) in the placebo group and the FSH co-trigger group, respectively.LIMITATIONS, REASONS FOR CAUTIONThis was a single-center study, which may limit its effectiveness. The use of uFSH is a limitation, as this is not the same as the natural FSH. We did not collect follicular fluid for further study of molecular changes after the use of uFSH as a co-trigger.WIDER IMPLICATIONS OF THE FINDINGSBased on previous data and our results, an additional FSH bolus administered at the time of hCG trigger has no benefit on clinical pregnancy rates in women undergoing the long GnRHa protocol in IVF/ICSI: a single hCG trigger is sufficient.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the National Key Research and Development Program of China (2016YFC1000205); Sun Yat-Sen University Clinical Research 5010 Program (2016004); the Science and Technology Project of Guangdong Province (2016A020216011 and 2017A020213028); and Science Technology Research Project of Guangdong Province (S2011010004662). There are no conflicts of interest to declare.TRIAL REGISTRATION NUMBERThe trial was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-12002246).TRIAL REGISTRATION DATE20 May 2012.DATE OF FIRST PATIENT’S ENROLMENT10 June 2012.
      PubDate: Fri, 08 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa087
      Issue No: Vol. 35, No. 6 (2020)
  • Kisspeptin and neurokinin B interactions in modulating gonadotropin
           secretion in women with polycystic ovary syndrome
    • Authors: Skorupskaite K; George J, Veldhuis J, et al.
      Pages: 1421 - 1431
      Abstract: AbstractSTUDY QUESTIONWhat is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)'SUMMARY ANSWERAdministration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.WHAT IS KNOWN ALREADYPCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.STUDY DESIGN, SIZE, DURATIONThe NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.MAIN RESULTS AND THE ROLE OF CHANCENK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.LIMITATIONS, REASONS FOR CAUTIONThe study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.WIDER IMPLICATIONS OF THE FINDINGSThese data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.STUDY FUNDING/COMPETING INTEREST(S)Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.TRIAL REGISTRATION NUMBERN/A.
      PubDate: Mon, 08 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa104
      Issue No: Vol. 35, No. 6 (2020)
  • Cumulative live birth rates for women returning to ART treatment for a
           second ART-conceived child
    • Authors: Paul R; Fitzgerald O, Lieberman D, et al.
      Pages: 1432 - 1440
      Abstract: AbstractSTUDY QUESTIONWhat are the success rates for women returning to ART treatment in the hope of having a second ART-conceived child.SUMMARY ANSWERThe cumulative live birth rate (LBR) for women returning to ART treatment was between 50.5% and 88.1% after six cycles depending on whether women commenced with a previously frozen embryo or a new ovarian stimulation cycle and the assumptions made regarding the success rates for women who dropped-out of treatment.WHAT IS KNOWN ALREADYPrevious studies have reported the cumulative LBR for the first ART-conceived child to inform patients about their chances of success. However, most couples plan to have more than one child to complete their family and, for that reason, patients commonly return to ART treatment after the birth of their first ART-conceived child. To our knowledge, there are no published data to facilitate patient counseling and clinical decision-making regarding the success rates for these patients.STUDY DESIGN, SIZE, DURATIONA population-based cohort study with 35 290 women who commenced autologous (using their own oocytes) ART treatment between January 2009 and December 2013 and achieved their first treatment-dependent live birth from treatment performed during this period. These women were then followed up for a further 2 years of treatment to December 2015, providing a minimum of 2 years and a maximum of 7 years of treatment follow-up.PARTICIPANTS/MATERIALS, SETTING, METHODSCycle-specific LBR and cumulative LBR were calculated for up to six complete ART cycles (one ovarian stimulation and all associated transfers). Three cumulative LBR were calculated based on the likelihood of success in women who dropped-out of treatment (conservative, optimal and inverse probability-weighted (IPW)). A multivariable logistic regression model was used to predict the chance of returning to ART treatment for a second ART-conceived child, and a discrete time logistic regression model was used to predict the chance of achieving a second ART-conceived child up to a maximum of six complete cycles. The models were adjusted for patient characteristics and previous and current treatment characteristics.MAIN RESULTS AND THE ROLE OF CHANCEAmong the women who had their first ART-conceived live birth, 15 325 (43%) returned to treatment by December 2015. LBRs were consistently better in women who recommenced treatment with a previously frozen embryo, compared to women who underwent a new ovarian stimulation cycle. After six complete cycles, plus any surplus frozen embryos, the cumulative LBR was between 60.9% (95% CI: 60.0–61.8%) (conservative) and 88.1% (95% CI: 86.7–89.5%) (optimal) [IPW 87.2% (95% CI: 86.2–88.2%)] for women who recommenced treatment with a frozen embryo, compared to between 50.5% (95% CI: 49.0–52.0%) and 69.8% (95% CI: 67.5–72.2%) [IPW 68.1% (95% CI: 67.3–68.9%)] for those who underwent a new ovarian stimulation cycle. The adjusted odds of a second ART-conceived live birth decreased for women ≥35 years, who waited at least 3 years before returning to treatment, or who required a higher number of ovarian stimulation cycles or double embryo transfer to achieve their first child.LIMITATIONS, REASONS FOR CAUTIONOur estimates do not fully account for a number of individual prognostic factors, including duration of infertility, BMI and ovarian reserve.WIDER IMPLICATIONS OF THE FINDINGSThis is the first study to report success rates for women returning to ART treatment to have second ART-conceived child. These age-specific success rates can facilitate individualized counseling for the large number of patients hoping to have a second child using ART treatment.STUDY FUNDING/COMPETING INTEREST(S)No funding was received to undertake this study. R. Paul and O. Fitzgerald have nothing to declare. D. Lieberman reports being a fertility specialist and receiving non-financial support from MSD and Merck outside the submitted work. C. Venetis reports being a fertility specialist and receiving personal fees and non-financial support from MSD, personal fees and non-financial support from Merck Serono and Beisins and non-financial support from Ferring outside the submitted work. G.M. Chambers reports being a paid employee of the University of New South Wales, Sydney (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The Fertility Society of Australia (FSA) contracts UNSW to prepare the Australian and New Zealand Assisted Reproductive Technology Database (ANZARD) annual report series and benchmarking reports.TRIAL REGISTRATION NUMBERNA.
      PubDate: Fri, 08 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa030
      Issue No: Vol. 35, No. 6 (2020)
  • The demographics of assisted reproductive technology births in a Nordic
    • Authors: Goisis A; Håberg S, Hanevik H, et al.
      Pages: 1441 - 1450
      Abstract: AbstractSTUDY QUESTIONWhat are the socio-demographic characteristics of families in Norway who have children after assisted reproductive technology (ART), and have these characteristics changed over time'SUMMARY ANSWERParents who conceive through ART in Norway tend to be advantaged families, and their socio-demographic profile has not changed considerably over the period 1985–2014.WHAT IS KNOWN ALREADYA small number of studies show that couples who conceive through ART tend to be socio-economically advantaged.STUDY DESIGN, SIZE, DURATIONNorwegian Population Register, the Medical Birth Register and the national data bases were linked to study all live births in Norway between 1985 and 2014.PARTICIPANTS/MATERIALS, SETTING, METHODSThe sample consisted of 1 757 768 live births. Simple bivariate analyses were performed to describe the socio-demographic characteristics of parents who conceived through ART and changes in these characteristics over the time period 1985–2014. We used linear probability models to estimate the association between parental income and giving birth after ART from 2000 to 2014, before and after adjustment for maternal age at delivery, education and area of residence.MAIN RESULTS AND THE ROLE OF CHANCEParents conceiving through ART were more likely to be older, with the highest levels of income and education, and married. Their socio-demographic profiles did not change considerably during the period 1985–2014. In the unadjusted model, parents belonging to the top income quartile were 4.2 percentage points more likely (95% CI: 4.1 to 4.3) to have conceived through ART than parents who belonged to the bottom income quartile. Adjustment for maternal age only partially reduced the income disparities (for the top income quartile by 35% (β = 2.7 with 95% CI: 2.5 to 2.8)). Additional adjustment for maternal education, marital status and area of residence did not further attenuate the associations.LIMITATIONS, REASONS FOR CAUTIONThe data does not enable us to tell whether the lower numbers of children conceived through ART amongst more disadvantaged individuals is caused by lower success rates with ART treatment, lower demand of ART services or barriers faced in access to ART. The study focuses on Norway, a context characterised by high subsidisation of ART services.WIDER IMPLICATIONS OF THE FINDINGSEven though in Norway access to ART services is highly subsidised, the results highlight important and persisting social inequities in use of ART. The results also indicate that children born after ART grow up in resourceful environments, which will benefit their development and well-being.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by European Research Council agreement n. 803959 (to A.G.), by Economic and Social Research Council grant ES/M001660/1 and by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The authors have no conflict of interest to declare.TRIAL REGISTRATION NUMBERNot applicable.
      PubDate: Thu, 28 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa055
      Issue No: Vol. 35, No. 6 (2020)
  • Adverse childhood experiences are associated with increased risk of
           miscarriage in a national population-based cohort study in England
    • Authors: Demakakos P; Linara-Demakakou E, Mishra G.
      Pages: 1451 - 1460
      Abstract: AbstractSTUDY QUESTIONIs there an association between adverse childhood experiences (ACE) and the risk of miscarriage in the general population'SUMMARY ANSWERSpecific ACE as well as the summary ACE score were associated with an increased risk of single and recurrent miscarriages.WHAT IS KNOWN ALREADYThere is scarce evidence on the association between ACE and miscarriage risk.STUDY DESIGN, SIZE, DURATIONWe conducted a retrospective national cohort study. The sample consisted of 2795 women aged 55–89 years from the English Longitudinal Study of Ageing (ELSA).PARTICIPANTS/MATERIALS, SETTING, METHODSOur study was population-based and included women who participated in the ELSA Life History Interview in 2007. We estimated multinomial logistic regression models of the associations of the summary ACE score and eight individual ACE variables (pertaining to physical and sexual abuse, family dysfunction and experiences of living in residential care or with foster parents) with self-reported miscarriage (0, 1, ≥2 miscarriages).MAIN RESULTS AND THE ROLE OF CHANCEFive hundred and fifty-three women (19.8% of our sample) had experienced at least one miscarriage in their lifetime. Compared with women with no ACE, women with ≥3 ACE were two times more likely to experience a single miscarriage in their lifetime (relative risk ratio 2.00, 95% CI 1.25–3.22) and more than three times more likely to experience recurrent miscarriages (≥2 miscarriages) (relative risk ratio 3.10, 95% CI 1.63, 5.89) after adjustment for birth cohort, age at menarche and childhood socioeconomic position. Childhood experiences of physical and sexual abuse were individually associated with increased risk of miscarriage.LIMITATIONS, REASONS FOR CAUTIONGiven the magnitude of the observed associations, their biological plausibility, temporal order and consistency with evidence suggesting a positive association between ACE and adverse reproductive outcomes, it is unlikely that our findings are spurious. Nevertheless, the observed associations should not be interpreted as causal as our study was observational and potentially susceptible to bias arising from unaccounted confounders. Non-response and ensuing selection bias may have also biased our findings. Retrospectively measured ACE are known to be susceptible to underreporting. Our study may have misclassified cases of ACE and possibly underestimated the magnitude of the association between ACE and the risk of miscarriage.WIDER IMPLICATIONS OF THE FINDINGSOur study highlights experiences of psychosocial adversity in childhood as a potential risk factor for single and recurrent miscarriages. Our findings contribute to a better understanding of the role of childhood trauma in miscarriage and add an important life course dimension to the study of miscarriage.STUDY FUNDING/COMPETING INTEREST(S)ELSA is currently funded by the National Institute on Aging in USA (R01AG017644) and a consortium of UK government departments coordinated by the National Institute for Health Research. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the article. The authors have no actual or potential competing financial interests to disclose.
      PubDate: Mon, 08 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa113
      Issue No: Vol. 35, No. 6 (2020)
  • Fathers of children conceived using ART have higher cognitive ability
           scores than fathers of naturally conceived children
    • Authors: Bratsberg B; Rogeberg O, Skirbekk V.
      Pages: 1461 - 1468
      Abstract: STUDY QUESTIONDoes paternal cognitive ability differ for children conceived with and without assisted reproductive technology (ART)'SUMMARY ANSWERYoung fathers of ART conceived children tend to score cognitively below their same-age natural conception (NC) counterparts and older (above 35) fathers of ART conceived children tend to score above.WHAT IS KNOWN ALREADYCognitive ability is a genetically and socially transmitted trait, and If ART and NC children have parents with different levels of this trait, then this would in itself predict systematic differences in child cognitive outcomes. Research comparing cognitive outcomes of children with different modes of conception finds conflicting results, and studies may be influenced by selection and confounding.STUDY DESIGN, SIZE, DURATIONThis is a population-based study based on Norwegian data, combining information from the Medical Birth Registry (births through 2012), military conscription tests (birth cohorts 1955–1977) and the population registry. These data allow us to compare the cognitive ability scores of men registered as the father of an ART-conceived child to the cognitive abilities of other fathers and to average scores in the paternal birth cohorts.PARTICIPANTS/MATERIALS, SETTINGS, METHODSThe population level study included 18 566 births after ART (5810 after ICSI, 12 756 after IVF), and 1 048 138 NC births. It included all Norwegian men who received a cognitive ability score after attending military conscription between 1973 and 1995. This constituted 614 827 men (89.4% of the male birth cohorts involved). An additional 77 650 unscored males were included in sensitivity analyses.MAIN RESULTS AND THE ROLE OF CHANCEPaternal cognitive level was assessed using intelligence quotients (IQ) converted from stanine scores on a three-part cognitive ability test with items measuring numeracy, vocabulary and abstract thought (Raven-like matrices). ART fathers averaged 1.95 IQ points above the average of their own birth cohort (P-value < 0.0005) and 1.83 IQ points above NC fathers in their own birth cohort (P < 0.0005). Comparisons of the IQ of ART fathers to those of NC fathers of similar age and whose children were born in the same year, however, found average scores to be more similar (point estimate 0.24, P = 0.023). These low average differences were found to differ substantially by age of fatherhood, with young ART fathers scoring below their NC counterparts and older ART fathers scoring above their NC counterparts.LIMITATIONS, REASONS FOR CAUTIONWe do not have information on maternal cognition. We also lack information on unsuccessful infertility treatments that did not result in a live birth.WIDER IMPLICATIONS OF THE FINDINGSPaternal cognitive ability of ART children differs from that of NC children, and this difference varies systematically with paternal age at child birth. Selection effects into ART may help explain differences between ART and NC children and need to be adequately controlled for when assessing causal effects of ART treatment on child outcomes.STUDY FUNDING/COMPETING INTEREST(S)This research has also been supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700 (Centre for Fertility and Health). It has also been supported by the Research Council of Norway’s Project 236992 (Egalitarianism under pressure' New perspectives on inequality and social cohesion). There are no competing interests.TRIAL REGISTRATION NUMBERN/A
      PubDate: Wed, 10 Jun 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa119
      Issue No: Vol. 35, No. 6 (2020)
  • G-CSFin RPL: what’s new'
    • Authors: Sbracia M; Scarpellini F, Stamenov G.
      Pages: 1469 - 1474
      Abstract: Sir,
      PubDate: Tue, 19 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa078
      Issue No: Vol. 35, No. 6 (2020)
  • G-CSF and repeated spontaneous abortions: comparability of inclusion and
           exclusion criteria in existing RCT-studies
    • Authors: Santjohanser C; Wagner A, Hirv K.
      Pages: 1470 - 1470
      Abstract: Sir,
      PubDate: Tue, 19 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa079
      Issue No: Vol. 35, No. 6 (2020)
  • G-CSF and repeated spontaneous abortions: deficiency is an indication,
           previous live births and ‘unexplained’ situations are not
    • Authors: Würfel W; Santjohanser C.
      Pages: 1471 - 1471
      Abstract: Sir,
      PubDate: Tue, 19 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa080
      Issue No: Vol. 35, No. 6 (2020)
  • Reply: G-CSF and repeated spontaneous abortions: what’s new;
           comparability of inclusion and exclusion criteria in existing RCT-studies;
           deficiency is an indication, previous live births and ‘unexplained’
           situations are not
    • Authors: Eapen A; , Lissauer D, et al.
      Pages: 1472 - 1473
      Abstract: Sir,
      PubDate: Tue, 19 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa081
      Issue No: Vol. 35, No. 6 (2020)
  • Can deep learning automatically predict fetal heart pregnancy with almost
           perfect accuracy'
    • Authors: Kan-Tor Y; Ben-Meir A, Buxboim A.
      Pages: 1473 - 1473
      Abstract: Sir,
      PubDate: Wed, 27 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa083
      Issue No: Vol. 35, No. 6 (2020)
  • Reply: Can deep learning automatically predict fetal heart pregnancy with
           almost perfect accuracy'
    • Authors: Tran D; Cooke S, Illingworth P, et al.
      Pages: 1474 - 1474
      Abstract: Sir,
      PubDate: Wed, 27 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa084
      Issue No: Vol. 35, No. 6 (2020)
  • Erratum. Ethics beyond ethics
    • Authors: Lambalk C; Van Wely M, Kirkegaard K, et al.
      Pages: 1475 - 1475
      Abstract: Hum Reprod 2020;35:1-2
      PubDate: Sat, 30 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa059
      Issue No: Vol. 35, No. 6 (2020)
  • Oxygen concentration alters mitochondrial structure and function in in
           vitro fertilized preimplantation mouse embryos
    • Authors: Belli M; Zhang L, Liu X, et al.
      Pages: 1476 - 1476
      Abstract: Hum Reprod 2019;34:601–611
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa047
      Issue No: Vol. 35, No. 6 (2020)
  • Erratum: Assisted reproductive technology service availability, efficacy
           and safety in mainland China: 2016
    • Authors: Bai F; Wang D, Fan Y, et al.
      Pages: 1477 - 1477
      Abstract: Hum Reprod 2020;35:446–452
      PubDate: Thu, 21 May 2020 00:00:00 GMT
      DOI: 10.1093/humrep/deaa076
      Issue No: Vol. 35, No. 6 (2020)
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