The International Glossary on Infertility and Fertility Care, 2017.

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

Can IVF influence human evolution?

IVF, a procedure in which pharmacological and technological manipulation is used to promote pregnancy, offers help to infertile couples by circumventing selection at the most fundamental level. Fertility is clearly one of the key fitness-promoting drivers in all forms of sexually reproducing life, and fertilization and pregnancy are fundamental evolutionary processes that involve a range of pre- and post-zygotic screening mechanisms. Here, we discuss the various selection and screening factors involved in fertilization and pregnancy and assess IVF practices in light of these factors. We then focus on the possible consequences of these differences in selection pressures, mainly at the individual but also at the population level, to evaluate whether changes in the reproducing genotype can affect human evolution. The aim of the article is not to argue for or against IVF, but to address aspects of assisted reproduction in an evolutionary context.

Time to take human embryo culture seriously.

STUDY QUESTION: Is it important that end-users know the composition of human embryo culture media? SUMMARY ANSWER: We argue that there is as strong case for full transparency concerning the composition of embryo culture media intended for human use. WHAT IS KNOWN ALREADY: Published data suggest that the composition of embryo culture media may influence the phenotype of the offspring. STUDY DESIGN, SIZE, DURATION: A review of the literature was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data concerning the potential effects on embryo development of culture media were assessed and recommendations for users made. MAIN RESULTS AND THE ROLE OF CHANCE: The safety of ART procedures, especially with respect to the health of the offspring, is of major importance. There are reports from the literature indicating a possible effect of culture conditions, including culture media, on embryo and fetal development. Since the introduction of commercially available culture media, there has been a rapid development of different formulations, often not fully documented, disclosed or justified. There is now evidence that the environment the early embryo is exposed to can cause reprogramming of embryonic growth leading to alterations in fetal growth trajectory, birthweight, childhood growth and long-term disease including Type II diabetes and cardiovascular problems. The mechanism for this is likely to be epigenetic changes during the preimplantation period of development. In the present paper the ESHRE working group on culture media summarizes the present knowledge of potential effects on embryo development related to culture media, and makes recommendations. LIMITATIONS, REASONS FOR CAUTION: There is still a need for large prospective randomized trials to further elucidate the link between the composition of embryo culture media used and the phenotype of the offspring. We do not presently know if the phenotypic changes induced by in vitro embryo culture represent a problem for long-term health of the offspring. WIDER IMPLICATIONS OF THE FINDINGS: Published data indicate that there is a strong case for demanding full transparency concerning the compositions of and the scientific rationale behind the composition of embryo culture media. STUDY FUNDING/COMPETING INTERESTS: This work was funded by The European Society for Human Reproduction and Embryology. No competing interests to declare.

ESHRE Clinical Embryologist certification: the first 10 years.

STUDY QUESTION: What has the ESHRE programme 'ESHRE Certification for Clinical Embryologists' achieved after 10 years? SUMMARY ANSWER: The post-exam analysis showed a pass rate of 60% for Clinical and 50% for Senior Clinical Embryologists and a high level of internal consistency of all exams, leading to a total of 773 certified Clinical and 493 Senior Clinical Embryologists over the decade. WHAT IS KNOWN ALREADY: In an ESHRE survey on the educational and professional status of Clinical Embryology in Europe, it was found that education of laboratory personnel working in the field of assisted reproduction is highly variable between countries. In 2008, ESHRE introduced a programme, curriculum and certification in the field of Clinical Embryology. Knowledge gained by postgraduate study of recommended literature, following a clear curriculum, is verified by a written two-level exam for obtaining a certificate for Clinical (basic) or Senior Clinical (advanced) Embryologists. With a total of 1266 certificates awarded over a period of 10 years and recognition by the Union Européenne des Médecins Spécialistes and their Council for European Specialists Medical Assessment, the ESHRE Clinical Embryology exams have become an internationally recognized educational standard in the field of Clinical Embryology. STUDY DESIGN SIZE DURATION: A retrospective analysis of all applications for ESHRE Clinical (2009-2018) and Senior Clinical Embryologist Certification (2008-2018) and exam results of the first decade was carried out by the Steering Committee for Clinical Embryologist Certification. PARTICIPANTS/MATERIALS SETTING METHODS: A total of 2894 applications for ESHRE Certification for Clinical Embryologists and the results of 10 exams for the Clinical (1478 candidates) and 11 exams for Senior Clinical (987 candidates) levels were analysed. A detailed post-exam retrospective analysis was performed regarding difficulty, discrimination and reliability levels of 1600 multiple-choice questions (MCQs) with a single best answer among four options, from eight different curriculum topics (Basic cell biology, Genetics, Developmental biology, Female reproduction, Male reproduction, IVF laboratory, Cryopreservation and Laboratory management), representing the core theoretical knowledge of Clinical Embryology. Difficulty levels of the MCQs were subsequently compared regarding each topic and each yearly exam. The participation and success rates in the ESHRE Clinical Embryology exams were also assessed in terms of the educational and geographic backgrounds of candidates. MAIN RESULTS AND THE ROLE OF CHANCE: Over the 10 years studied, the mean pass rate for the Clinical Embryologist exam was 60% (range 41-86%), and for the Senior Clinical Embryologist exam was 50% (range 34-81%). On average, 63% European candidates and 35% non-European candidates passed the Clinical Embryologist exam, while 52% European candidates and 31% non-European candidates passed the Senior Clinical Embryologist exam. The candidates' educational level impacted on the success of the Clinical Embryologist exam but not of the Senior Clinical Embryologist exam. The mean difficulty indices by study topic showed that in the period of 10 years, there were no statistically significant differences between topics, for either the Clinical or Senior Clinical Embryologist exams. However, the overall exam difficulty varied between years. Reassuringly, the exam MCQ discrimination and reliability indices always showed a high level of internal consistency in all exams. LIMITATIONS REASONS FOR CAUTION: Some data from the initial ESHRE certification programme were not obtained electronically, in particular data for education, implying tables and figures reflect the specified valid data periods. Several countries exhibit different study profiles for those working in ART laboratories, such that laboratory technicians/technologists predominate in some countries, while in others only biologists and medical doctors are allowed to work with human embryos. Such differences could consequently affect the exam performance of candidates from specific countries. WIDER IMPLICATIONS OF THE FINDINGS: The ESHRE exams on Clinical Embryology are the most widely, internationally accepted tests of knowledge in the rapidly growing area of human reproduction. Clinical Embryology is increasingly recognized as a specific discipline for scientific staff who are collaborating closely with clinicians in managing human infertility through medically assisted reproduction. The analysis of the first 10 years of application of a two-level exam for Clinical Embryology shows a consistent high quality and reliability of the exam and MCQs used. These results represent an important follow-up of the quality of the ESHRE Certification programme for Clinical Embryologists, and convincingly position Clinical Embryology in the wider group of health disciplines that are harmonized through professional bodies such as ESHRE and European Board & College of Obstetrics and Gynaecology. The exams provide a clear step towards the increasing professional recognition and establishment of Clinical Embryology within health systems at both European and international level. STUDY FUNDING/COMPETING INTERESTS: No competing interest. All costs of the Steering Committee meetings were covered by ESHRE.

Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study.

BACKGROUND: Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. METHODS: In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. FINDINGS: In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). INTERPRETATION: Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.

Assisted fertilization and breech delivery: risks and obstetric management.

BACKGROUND: Previous studies have suggested that assisted reproduction technology (ART) is associated with increased risk of breech presentation. We investigated whether factors that tend to differ between ART and spontaneously conceived pregnancies may explain the higher risk of breech deliveries associated with ART. MATERIAL AND METHODS: In this population-based cohort study, we included 1 209 151 singleton pregnancies reported to the Medical Birth Registry of Norway between 1984 and 2006 and compared the risk of breech presentation in 8229 ART pregnancies with that in spontaneously conceived pregnancies. Risk ratios (RR), adjusted for maternal age, parity, gestational length and year of birth, were estimated using binominal regression, and we describe differences and time trends in obstetric management for breech and cephalic presentations after ART compared with management of spontaneously conceived pregnancies. RESULTS: Breech presentation occurred nearly 50% more often in ART singleton pregnancies than in spontaneously conceived singletons [crude RR: 1.48, 95% confidence interval (CI): 1.34-1.64], but after adjustment for potentially confounding factors, the difference was fully attenuated (RR: 0.97, 95% CI: 0.88-1.07). The most important contributors to the attenuation were parity and length of gestation. In general, Caesarean sections and induced deliveries were more likely in ART pregnancies, but over the study period, the proportion of Caesarean sections in ART pregnancies gradually approached that of spontaneously conceived pregnancies. CONCLUSION: Increased risk of breech presentation in pregnancies after ART is mediated by lower parity and shorter gestational length. In general, the obstetric management of women with ART pregnancies is gradually approaching the ordinary surveillance of pregnant women.

Significant reduction of twins with single embryo transfer in IVF.

Multiple pregnancies in assisted reproduction can be regarded as iatrogenic and avoidable, given that the phenomenon is related to the number of embryos replaced. Prospective studies have shown that transferring one fresh embryo and subsequently one frozen embryo gives similar cumulative pregnancy rates to transferring two fresh embryos. However, the multiple pregnancy rates differ significantly between the two strategies. In Trondheim, elective double embryo transfer (eDET) was introduced in September 1991. Prior to that, multiple pregnancy rates were nearly 35% and the triplet rate was 7%. The triplet rate dropped to below 1%, but the twin rate still remained high. In 2002, it was decided to start elective single embryo transfer (eSET) and currently SET is performed in more than 90% of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. The inclusion criteria are nearly as simple as: 'If you have two good embryos, you get only one embryo at a time'. Multiple pregnancy rates are well below 10% and there are no triplets. In conclusion, triplet rates can be reduced to zero and twin rates to below 10% by eSET. The cumulative pregnancy rate per oocyte recovery is not reduced, including replacement of frozen- thawed embryos.

The International Glossary on Infertility and Fertility Care, 2017.

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

[Elective single embryo transfer in assisted reproduction]. / Tilbakeføring av ett embryo ved assistert befruktning.

BACKGROUND: More than one embryo is normally transferred per cycle to increase the probability for pregnancy after assisted reproduction. This has led to a high rate of multiple pregnancies, which increases the risk of complications for the mother and child. MATERIAL AND METHODS: 2765 assisted reproduction cycles were performed in the Fertility Unit at St. Olav's Hospital, Trondheim from 2002 to 2005. During this period we changed our cryopreservation programme and introduced elective single embryo transfer in an increasing number of women. RESULTS AND INTERPRETATION: From 2002 to 2005 the multiple pregnancy rate following transfer of fresh embryos decreased from 36 to 8 %. 75 % of all women who received hormone stimulated treatment with transfer of fresh embryos in 2005, had one embryo transferred. The proportion of cycles with surplus embryos available for cryopreservation increased from 27 % in 2002 to 69 % in 2005. Despite a slight reduction in the number of pregnancies during this period the pregnancy rate per oocyte recovery has remained stable. The improvement of our freezing/thawing routines has been crucial for improving treatment at the same time as we have reduced the fraction of multiple pregnancies. This implies less constraint on the couple and reduced costs for society. Lack of refund and valuation of freezing/thawing of embryos renders a continued optimal medical practice difficult.

The assisted reproductive technology laboratory: toward evidence-based practice?

In the past decades, the efficiency of human assisted reproductive technologies (ART) has improved. We have witnessed important new developments such as intracytoplasmic sperm injection, blastocyst culture, vitrification, and methods for genetic analysis of human embryos. Despite these improvements, current ART laboratories are to a large extent composed of general laboratory equipment that is not designed and manufactured especially for human ART. Human reproductive cells have different physiochemical requirements than somatic cells. We encourage the development of laboratory equipment, utensils, and consumables that are designed specifically for human ART. In addition, the quality and consistency of commercially available culture media have improved, but the composition of commercially available ART culture media varies considerably. It is difficult to see the scientific rationale for this variation. Currently it is not known which of these formulations gives the best clinical results. Finally, selection of embryos in routine ART should be done with the use of variables that have been shown to have statistically independent selection power. With the advent of automatic and objective methods for recording morphology and growth kinetics of human embryos, there is a possibility to pool data sets from many different clinics. This may enable the construction of selection algorithms based on objectively recorded embryo parameters. New methods for the genetic analysis of chromosomal status of embryos may prove to be useful, but they should be tested in controlled randomized trials before being introduced for routine use in ART.

Possible metformin effect on adrenal androgens during pretreatment and IVF cycle in women with polycystic ovary syndrome.

OBJECTIVE: To determine the effects of metformin treatment on serum androgen levels ahead of and during the IVF cycle in infertile polycystic ovary syndrome (PCOS) women. DESIGN: A prospective, double-blind, placebo-controlled study. SETTING: Single-center, university IVF clinic. PATIENTS: Sixty-three PCOS women. INTERVENTION(S): Treatment with metformin 2,000 mg/day or identical placebo tablets for at least 14 weeks before and then during IVF treatment, ending on the day of hCG injection. MAIN OUTCOME MEASURE(S): Serum levels of dehydroepiandrosterone, dehydroepiandrosterone sulphate (DHEAS), androstenedione, free testosterone index (FTI), dihydrotestosterone, and the androgen metabolite 5alpha-androstane-3alpha, 17beta-diol-glucuronide were measured at five time points ending on the day of ovum collection. RESULT(S): During metformin pretreatment DHEAS increased, wheres other androgens were unaffected. During the IVF procedure androgens were unaffected by metformin treatment. Within 36 hours after the study medication was withdrawn the levels of androstenedione and FTI increased in the metformin group, whereas DHEAS decreased. CONCLUSION(S): In infertile PCOS women metformin treatment increased DHEAS levels. During the IVF cycle androgen levels were unaffected by metformin, whereas there was a "rebound" effect when stopping metformin treatment.

C-reactive protein levels are unaffected by metformin during pretreatment and an IVF cycle in women with polycystic ovary syndrome.

OBJECTIVE: Low-grade chronic inflammation, evaluated by serum C-reactive protein (CRP) levels, has been connected with the polycystic ovary syndrome (PCOS). Effects of metformin on CRP before and during IVF treatment in women with PCOS are unknown. DESIGN: A prospective double-blind placebo-controlled study. SETTING: Single-center IVF clinic. PATIENT(S): Sixty-three PCOS women. INTERVENTION(S): Treatment with 2000 mg/day metformin or identical placebo tablets for at least 14 weeks before and then during IVF treatment, ending on the day of hCG injection. MAIN OUTCOME MEASURE(S): The CRP levels at five time points ending on the day of ovum collection. RESULT(S): At inclusion of infertile untreated PCOS women, body mass index associated with CRP in multivariable regression analysis (r = 0.18). Androgen levels did not associate with CRP levels. Metformin did not influence CRP levels during pretreatment or IVF cycle. After hCG injection, CRP increased in both the metformin and the placebo groups with no significant difference between the groups. CONCLUSION(S): In infertile PCOS women, CRP levels are unaffected by metformin treatment. The CRP level increases during IVF treatment, and this increase is unaffected by concomitant metformin. We observed an association between CRP levels and body mass index.

Increased risk of placenta previa in pregnancies following IVF/ICSI; a comparison of ART and non-ART pregnancies in the same mother.

BACKGROUND: The risk of placenta previa may be increased in pregnancies conceived by assisted reproduction technology (ART). Whether the increased risk is due to factors related to the reproductive technology, or associated with maternal factors, is not known. METHODS: In a nationwide population-based study, we included 845,384 pregnancies reported to the Medical Birth Registry of Norway between 1988 and 2002 and compared the risk of placenta previa in 7568 pregnancies conceived after assisted fertilization, with the risk in naturally conceived pregnancies. To study the influence of ART more directly, we compared the risk of placenta previa between consecutive pregnancies among 1349 women who had conceived both naturally and after assisted fertilization. Odds ratios (OR), adjusted for maternal age, parity, previous Caesarean section and time interval between pregnancies were estimated using logistic regression. RESULTS: There was a six-fold higher risk of placenta previa in singleton pregnancies conceived by assisted fertilization compared with naturally conceived pregnancies [adjusted OR 5.6, 95% confidence interval (CI) 4.4-7.0]. Among mothers who had conceived both naturally and after assisted fertilization, the risk of placenta previa was nearly three-fold higher in the pregnancy following assisted fertilization (adjusted OR 2.9, 95% CI 1.4-6.1), compared with that in the naturally conceived pregnancy. CONCLUSIONS: The use of ART is associated with an increased risk of placenta previa. Our findings suggest that the increased risk may be caused by factors related to the reproductive technology.