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Preview: Human Reproduction - current issue

Human Reproduction Current Issue





Published: Sat, 09 Sep 2017 00:00:00 GMT

Last Build Date: Mon, 18 Sep 2017 20:48:30 GMT

 



Random start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer

2017-09-09

ABSTRACT
STUDY QUESTION
Is random start ovarian stimulation associated with delays in initiation of neoadjuvant chemotherapy for breast cancer?
SUMMARY ANSWER
Among women who complete fertility preservation (FP) consultation, random start ovarian stimulation is unlikely to delay time to initiation of neoadjuvant chemotherapy start.
WHAT IS KNOWN ALREADY
Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and random start ovarian stimulation is an increasingly-utilized modality for FP. While conventional ovarian stimulation does not appear to delay starting adjuvant chemotherapy, the relationship between random start ovarian stimulation and neoadjuvant chemotherapy start is not well-understood.
STUDY DESIGN, SIZE, DURATION
Cross-sectional study of all women seen between from January 2011 to April 2017 for FP consultation prior to starting neoadjuvant chemotherapy for breast cancer.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A chart-review was performed. Study inclusion criteria were female sex; age 18–45; non-metastatic breast cancer diagnosis; underwent FP consultation; underwent neoadjuvant chemotherapy. Referrals for FP evaluation came from a regional referral base of oncology clinics. Various time-points related to cancer diagnosis, FP or chemotherapy were obtained from medical record review. We compared time-points between those who underwent ovarian stimulation for FP versus those who did not using T-tests and linear modeling.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 89 women who had FP consultation prior to neoadjuvant chemotherapy were identified. Sixty-seven percent underwent ovarian stimulation prior to cancer treatment and 33% did not. Women who underwent ovarian stimulation were similar in parity and clinical cancer stage to those who did not. Overall, the average time from cancer diagnosis to chemotherapy start was similar between the group that did undergo ovarian stimulation and those who did not (38.1 ± 11.3 versus 39.4 ± 18.5 days, P = 0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those who did not undergo ovarian stimulation (P < 0.001).
LIMITATIONS REASONS FOR CAUTION
Retrospective study with potential for selection bias among those who underwent ovarian stimulation versus those who did not. Reasons for caution include the possibility of unmeasured differences among those who did and did not undergo ovarian stimulation, including: patients’ and providers’ perceptions of the urgency to start chemotherapy, ongoing oncology work-up and treatment planning, FP decision-making, and the pursuit of second and third opinions. The difference in time from referral to FP consultation may have also influenced patients’ decisions about whether to undergo ovarian stimulation.
WIDER IMPLICATIONS OF THE FINDINGS
In this study, FP with random start ovarian stimulation was not associated with a delay cancer treatment in the neoadjuvant setting, so long as there was a prompt FP referral. Patients undergoing neoadjuvant chemotherapy should be informed of these findings to avoid unnecessary anxiety due to concern for delays.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by departmental research funding within the University of California, San Francisco Department of Obstetrics, Gynecology and Reproductive Sciences. There are no conflicts of interest to declare.



New permeable cryoprotectant-free vitrification method for native human sperm

2017-08-31

ABSTRACT
STUDY QUESTION
Is permeable cryoprotectant-free vitrification of native sperm samples a good alternative to conventional slow freezing?
SUMMARY ANSWER
The permeable cryoprotectant-free sperm vitrification protocol tested in this study renders considerably better recovery rates of good quality sperm compared to slow freezing.
WHAT IS KNOWN ALREADY
Slow freezing is currently the most commonly used technique for sperm cryopreservation, though this method has been repeatedly shown to have negative effects on both structural and functional sperm features. New alternative methods such as vitrification have been established as a successful alternative in other reproductive cell types, but vitrification of spermatozoa is still a rather unexplored methodology, with limited studies showing its efficacy in male gametes.
STUDY DESIGN SIZE, DURATION
This study included 18 normozoospermic sperm samples from patients seeking ART treatment between 2014 and 2015. The effects of a new vitrification protocol on functional and structural sperm quality parameters in comparison to fresh and slow-frozen samples were assessed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All samples were divided into three aliquots: fresh (F), slow freezing–thawing (S) and vitrification-warming (V). Sperm concentration, motility, morphology, vitality, DNA fragmentation, cytoskeleton integrity and spontaneous acrosome reaction were assessed and compared between the groups.
MAIN RESULTS AND THE ROLE OF CHANCE
Results showed improved preservation of sperm features after vitrification compared to conventional freezing. Permeable cryoprotectant-free vitrification presented a significantly higher percentage of live spermatozoa, than slow freezing, better preservation of acrosomes was achieved in vitrified samples and DNA fragmentation was reduced approximately one-third on average compared to slow freezing. Regarding tubulin assay, three different labelling patterns were observed. The frequency of these labelling patterns was similar in F and V groups but this was not the case of the S group. The multivariate analysis of all sperm quality parameters studied revealed that the V group presented features that are closer to the F group than the S group, indicating that samples are better preserved through vitrification than slow freezing.
LIMITATIONS REASONS FOR CAUTION
This validation has been undertaken only on normozoospermic sperm samples. It would be necessary to compare these results in pathological samples and also to evaluate the influence of the application of this methodology on clinical outcomes.
WIDER IMPLICATIONS OF THE FINDINGS
The sperm vitrification protocol here described warrants better maintenance of sperm quality parameters than traditional freezing methods and may be a good alternative to preserve sperm samples from patients seeking IVF treatment.
STUDY FUNDING/COMPETING INTEREST(S)
This study was funded by IVF-Spain Foundation. The authors have no conflicts of interest to declare.



Allowable warm ischemic time and morphological and biochemical changes in uterine ischemia/reperfusion injury in cynomolgus macaque: a basic study for uterus transplantation

2017-08-31

Abstract
STUDY QUESTION
How long is the allowable warm ischemic time of the uterus and what morphological and biochemical changes are caused by uterine ischemia/reperfusion injury in cynomolgus macaques?
SUMMARY ANSWER
Warm ischemia in the uterus of cynomolgus macaques is tolerated for up to 4 h and reperfusion after uterine ischemia caused no further morphological and biochemical changes.
WHAT IS KNOWN ALREADY
Uterus transplantation is a potential option for women with uterine factor infertility. The allowable warm ischemic time and ischemia/reperfusion injury of the uterus in humans and non-human primates is unknown.
STUDY DESIGN, SIZE, DURATION
This experimental study included 18 female cynomolgus macaques with periodic menstruation.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Animals were divided into six groups of three monkeys each: a control group and groups with uterine ischemia for 0.5, 1, 2, 4 and 8 h. Biopsies of uterine tissues were performed before blood flow blockage, after each blockage time, and after reperfusion for 3 h. Blood sampling was performed after each blockage time, and after reperfusion for 5, 15 and 30 min for measurement of biochemical data. Resumption of menstruation was monitored after the surgical procedure. Morphological, physiological and biochemical changes after ischemia and reperfusion were evaluated.
MAIN RESULTS AND THE ROLE OF CHANCE
Mild muscle degeneration and zonal degeneration were observed in all animals subjected to warm ischemia for 4 or 8 h, but there were no marked differences in the appearance of specimens immediately after ischemia and after reperfusion for 3 h in animals subjected to 4 or 8 h of warm ischemia. There were no significant changes in any biochemical parameters at any time point in each group. Periodical menstruation resumed in all animals with warm ischemia up to 4 h, but did not recover in animals with warm ischemia for 8 h with atrophic uteri.
LIMITATIONS, REASON FOR CAUTION
Warm ischemia in actual transplantation was not exactly mimicked in this study because uteri were not perfused, cooled, transplanted or reanastomosed with vessels. Results in non-human primates cannot always be extrapolated to humans.
WIDER IMPLICATIONS OF THE FINDINGS
The findings suggest that the tolerable warm ischemia time in the uterus is expected to be longer than that in other vital organs.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 26713050. None of the authors has a conflict of interest to declare.



ESHRE PGD Consortium data collection XIV–XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013

2017-08-30

Abstract
STUDY QUESTION
How does the data collection XIV–XV of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium compare with the cumulative data for data collections I–XIII?
SUMMARY ANSWER
The 14th and 15th retrospective collection represents valuable data on PGD/PGS cycles, pregnancies and children: the main trend observed is the increased application of array technology at the cost of FISH testing in PGS cycles and in PGD cycles for chromosomal abnormalities.
WHAT IS KNOWN ALREADY
Since 1999, the PGD Consortium has collected, analysed and published 13 previous data sets and an overview of the first 10 years of data collections.
STUDY DESIGN, SIZE, DURATION
Data were collected from each participating centre using a FileMaker Pro database (versions 5–12). Separate predesigned FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar years 2011 and 2012 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2013).
PARTICIPANTS/MATERIALS, SETTINGS, METHOD
Data were submitted by 71 centres (full PGD Consortium members). Records with incomplete or inconsistent data were excluded from the calculations. Corrections, calculations and tables were made by expert co-authors.
MAIN RESULTS AND THE ROLE OF CHANCE
For data collection XIV–XV, 71 centres reported data for 11 637 cycles with oocyte retrieval (OR), along with details of the follow-up on 2147 pregnancies and 1755 babies born. A total of 1953 cycles to OR were reported for chromosomal abnormalities, 144 cycles to OR for sexing for X-linked diseases, 3445 cycles to OR for monogenic diseases, 6095 cycles to OR for PGS and 38 cycles to OR for social sexing. From 2010 until 2012, the use of arrays for genetic testing increased from 4% to 20% in PGS and from 6% to 13% in PGD cycles for chromosomal abnormalities; the uptake of biopsy at the blastocyst stage (from <1% up to 7%) was only observed in cycles for structural chromosomal abnormalities, alongside the application of array comparative genomic hybridization.
LIMITATIONS, REASONS FOR CAUTION
The findings apply to the 71 participating centres and may not represent worldwide trends in PGD.
WIDER IMPLICATIONS OF THE FINDINGS
The annual data collections provide an important resource for data mining and for following trends in PGD/PGS practice.
STUDY FUNDING/COMPETING INTEREST(S)
None.



An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield

2017-08-30

AbstractSTUDY QUESTIONAre meiotic and developmental competence of human oocytes from small (2–8 mm) antral follicles improved by applying an optimized IVM method involving a prematuration step in presence of C-Type Natriuretic Peptide (CNP) followed by a maturation step in presence of FSH and Amphiregulin (AREG)?SUMMARY ANSWERA strategy involving prematuration culture (PMC) in the presence of CNP followed by IVM using FSH + AREG increases oocyte maturation potential leading to a higher availability of Day 3 embryos and good-quality blastocysts for single embryo transfer.WHAT IS KNOWN ALREADYIVM is a minimal-stimulation ART with reduced hormone-related side effects and risks for the patients, but the approach is not widely used because of an efficiency gap compared to conventional ART. In vitro systems that enhance synchronization of nuclear and cytoplasmic maturation before the meiotic trigger are crucial to optimize human IVM systems. However, previous PMC attempts have failed in sustaining cumulus-oocyte connections throughout the culture period, which prohibited a normal cumulus-oocyte communication and precluded an adequate response by the cumulus-oocyte complex (COC) to the meiotic trigger.STUDY DESIGN, SIZE, DURATIONA first prospective study involved sibling oocytes from a group of 15 patients with polycystic ovary syndrome (PCOS) to evaluate effects of a new IVM culture method on oocyte nuclear maturation and their downstream developmental competence. A second prospective study in an additional series of 15 women with polycystic ovaries characterized and fine-tuned the culture conditions.PARTICIPANTS/MATERIALS, SETTING, METHODSFifteen women with PCOS (according to Rotterdam criteria) underwent IVM treatment after 3–5 days of highly purified human menopausal gonadotropin (HP-hMG) stimulation and no human chorionic gonadotropin (hCG) trigger before oocyte retrieval. A first study was designed with sibling oocytes to prospectively evaluate the impact of an IVM culture method: 24 h PMC with CNP + 30 h IVM with FSH and AREG, on embryo yield, in comparison to the standard (30 h) IVM clinical protocol (Group I, n = 15).A second prospective study was performed in 15 women with polycystic ovaries, to characterize and optimize the PMC conditions (Group II, n = 15). The latter study involved the evaluation of oocyte meiotic arrest, the preservation of cumulus-oocyte transzonal projections (TZPs), the patterns of oocyte chromatin configuration and cumulus cells apoptosis following the 24 and 46 h PMC. Furthermore, oocyte developmental potential following PMC (24 and 46 h) + IVM was also evaluated. The first 20 good-quality blastocysts from PMC followed by IVM were analysed by next generation sequencing to evaluate their aneuploidy rate.MAIN RESULTS AND THE ROLE OF CHANCEPMC in presence of CNP followed by IVM using FSH and AREG increased the meiotic maturation rate per COC to 70%, which is significantly higher than routine standard IVM (49%; P ≤ 0.001). Hence, with the new system the proportion of COCs yielding transferable Day 3 embryos and good-quality blastocysts increased compared to routine standard IVM (from 23 to 43%; P ≤ 0.001 and from 8 to 18%; P ≤ 0.01, respectively). CNP was able to prevent meiosis resumption for up to 46 h. After PMC, COCs had preserved cumulus-oocyte TZPs. The blastocysts obtained after PMC + IVM did not show increased aneuploidy rates as compared to blastocysts from conventional ART.LIMITATIONS REASONS FOR CAUTIONThe novel IVM approach in PCOS patients was tested in oocytes derived from small antral follicles which have an intrinsically low developmental potential. Validation of the system would be required for COCs from different (larger) follicular sizes, which may involve further adjustment of PMC conditions. Furthermore, considering that this is a novel strategy in human IVM treatment, its global efficiency needs to be confirmed in large prospective randomized controlled tri[...]



Women's career priority is associated with attitudes towards family planning and ethical acceptance of reproductive technologies

2017-08-30

ABSTRACT
STUDY QUESTION
Do women who place high importance on career success have different perceptions of pregnancy planning, delayed reproduction, and the ethical acceptability of ART than women with less emphasis on their career?
SUMMARY ANSWER
Career-focused women place more importance on pregnancy planning, have greater confidence in delayed childbearing, and are more ethically accepting of donor gamete ART than women who do not place as much importance on career success.
WHAT IS KNOWN ALREADY
Women in high-professional careers are more likely to delay childbearing while simultaneously possessing a stronger desire for motherhood. The underlying values which enable these competing desires have not been elucidated.
STUDY DESIGN, SIZE, DURATION
This cross-sectional study utilized data from the National Survey of Fertility Barriers (NSFB), a nationally representative telephone survey of US women aged 25–45. Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NSFB surveyed 4712 women from 2004 to 2007.
PARTICIPANTS/MATERIALS, SETTING, METHODS
In addition to demographic data, the NSFB obtained information about the reproductive history and personal values of participants. Weighted multivariate regression analysis was used to assess reproductive values in career-focused women.
MAIN RESULTS AND THE ROLE OF CHANCE
In total, 48.8% of women considered success in work very important, while 17.3% considered it somewhat or not important. Women who placed less value on career success were less likely to consider pregnancy planning important and were less optimistic about the success of delayed childbearing than their work-centric counterparts. Women less focused on their careers were also more likely to have serious ethical concerns about donor gametes, but less likely to have ethical concerns about IUI or IVF, when compared to career-focused women.
LIMITATIONS, REASONS FOR CAUTION
Intention to bear children could not be evaluated in the setting of career intentions due to a lack of data on when the participant intended on pursuing motherhood. Political preferences on reproductive health were also not evaluated. The validity of the career priority questions has not been assessed. Additionally, respondents’ value statements were not matched to subsequent actions, so it remains possible that these values do not directly impact reproductive behaviors.
WIDER IMPLICATIONS OF THE FINDINGS
Our results suggest that reproductive counseling for career-focused women should focus on effective contraception when attempting to delay pregnancy, improved knowledge about age-related fertility decline, and the scope and limitations of current reproductive technologies. In addition, the unique reproductive views of career-focused women suggest that they may benefit from increased employer/insurer support for strategies to enable delayed childbearing, such as fertility preservation and third-party reproduction.
STUDY FUNDING/COMPETING INTEREST(S)
None.



The testicular transcriptome associated with spermatogonia differentiation initiated by gonadotrophin stimulation in the juvenile rhesus monkey ( Macaca mulatta )

2017-08-30

AbstractSTUDY QUESTIONWhat is the genetic landscape within the testis of the juvenile rhesus monkey (Macaca mulatta) that underlies the decision of undifferentiated spermatogonia to commit to a pathway of differentiation when puberty is induced prematurely by exogenous LH and FSH stimulation?SUMMARY ANSWERForty-eight hours of gonadotrophin stimulation of the juvenile monkey testis resulted in the appearance of differentiating B spermatogonia and the emergence of 1362 up-regulated and 225 down-regulated testicular mRNAs encoding a complex network of proteins ranging from enzymes regulating Leydig cell steroidogenesis to membrane receptors, and from juxtacrine and paracrine factors to transcriptional factors governing spermatogonial stem cell fate.WHAT IS KNOWN ALREADYOur understanding of the cell and molecular biology underlying the fate of undifferentiated spermatogonia is based largely on studies of rodents, particularly of mice, but in the case of primates very little is known. The present study represents the first attempt to comprehensively address this question in a highly evolved primate.STUDY DESIGN, SIZE, DURATIONGlobal gene expression in the testis from juvenile rhesus monkeys that had been stimulated with recombinant monkey LH and FSH for 48 h (N = 3) or 96 h (N = 4) was compared to that from vehicle treated animals (N = 3). Testicular cell types and testosterone secretion were also monitored.PARTICIPANTS/MATERIALS, SETTING, METHODSPrecocious testicular puberty was initiated in juvenile rhesus monkeys, 14–24 months of age, using a physiologic mode of intermittent stimulation with i.v. recombinant monkey LH and FSH that within 48 h produced ‘adult’ levels of circulating LH, FSH and testosterone. Mitotic activity was monitored by immunohistochemical assays of 5-bromo-2′-deoxyuridine and 5-ethynyl-2′-deoxyuridine incorporation. Animals were bilaterally castrated and RNA was extracted from the right testis. Global gene expression was determined using RNA-Seq. Differentially expressed genes (DEGs) were identified and evaluated by pathway analysis. mRNAs of particular interest were also quantitated using quantitative RT-PCR. Fractions of the left testis were used for histochemistry or immunoflouresence.MAIN RESULTS AND THE ROLE OF CHANCEDifferentiating type B spematogonia were observed after both 48 and 96 h of gonadotrophin stimulation. Pathway analysis identified five super categories of over-represented DEGs. Repression of GFRA1 (glial cell line-derived neurotrophic factor family receptor alpha 1) and NANOS2 (nanos C2HC-type zinc finger 2) that favor spermatogonial stem cell renewal was noted after 48 and 96 h of LH and FSH stimulation. Additionally, changes in expression of numerous genes involved in regulating the Notch pathway, cell adhesion, structural plasticity and modulating the immune system were observed. Induction of genes associated with the differentiation of spermatogonia stem cells (SOHLH1(spermatogenesis- and oogenesis-specific basic helix-loop-helix 1), SOHLH2 and KIT (V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)) was not observed. Expression of the gene encoding STRA8 (stimulated by retinoic acid 8), a protein generally considered to mark activation of retinoic acid signaling, was below our limit of detection.LARGE SCALE DATAThe entire mRNA data set for vehicle and gonadotrophin treated animals (N = 10) has been deposited in the GEO-NCBI repository (GSE97786).LIMITATIONS REASONS FOR CAUTIONThe limited number of monkeys per group and the dilution of low abundance germ cell transcripts by mRNAs contributed from somatic cells likely resulted in an underestimation of the number of differentially expressed germ cell genes.WIDER IMPLICATIONS OF THE FINDINGSThe findings that expression of GDNF (a major promoter of spermatogonial stem cell renewal) was not detected in the control juvenile testes, expression of SOHLH1[...]



The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015

2017-08-30

ABSTRACT
STUDY QUESTION
How has the mean paternal age in the USA changed over the past 4 decades?
SUMMARY ANSWER
The age at which men are fathering children in the USA has been increasing over time, although it varies by race, geographic region and paternal education level.
WHAT IS KNOWN ALREADY
While the rise in mean maternal age and its implications for fertility, birth outcomes and public health have been well documented, little is known about paternal characteristics of births within the USA.
STUDY DESIGN, SIZE, DURATION
A retrospective data analysis of paternal age and reporting patterns for 168 867 480 live births within the USA since 1972 was conducted.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All live births within the USA collected through the National Vital Statistics System (NVSS) of the Centers for Disease Control and Prevention (CDC) were evaluated. Inverse probability weighting (IPW) was used to reduce bias due to missing paternal records.
MAIN RESULTS AND THE ROLE OF CHANCE
Mean paternal age has increased over the past 44 years from 27.4 to 30.9 years. College education and Northeastern birth states were associated with higher paternal age. Racial/ethnic differences were also identified, whereby Asian fathers were the oldest and Black fathers were the youngest. The parental age difference (paternal age minus maternal age) has decreased over the past 44 years. Births to Black and Native American mothers were most often lacking paternal data, implying low paternal reporting. Paternal reporting was higher for older and more educated women.
LIMITATIONS, REASONS FOR CAUTION
Although we utilized IPW to reduce the impact of paternal reporting bias, our estimates may still be influenced by the missing data in the NVSS.
WIDER IMPLICATIONS OF THE FINDINGS
Paternal age is rising within the USA among all regions, races and education levels. Given the implications for offspring health and demographic patterns, further research on this trend is warranted.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received for this study and there are no competing interests.
TRIAL REGISTRATION NUMBER
N/A.



Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

2017-08-30

Abstract
STUDY QUESTION
What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)?
SUMMARY ANSWER
An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases.
WHAT IS KNOWN ALREADY
Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear.
STUDY, DESIGN, SIZE, DURATION
This study was a retrospective review of investigations performed on 122 boys.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records.
MAIN RESULTS AND THE ROLE OF CHANCE
An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations.
LIMITATIONS, REASONS FOR CAUTION
A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel.
WIDER IMPLICATIONS OF THE FINDINGS
The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD.
STUDY FUNDING/COMPETING INTEREST(S)
RN was supported by the James Paterson Bursary and the Glasgow Children's Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest.
TRIAL REGISTRATION NUMBER
None.



A closer look at expanded carrier screening from a PGD perspective

2017-08-30

Abstract
Conventionally, the search for carrier status was based on ethnicity and/or family history and targeted to a restricted number of genetic conditions and mutations. This is now being replaced by extended panels testing for hundreds of genetic disorders with a broad range of phenotypes, in what is called ‘expanded carrier screening’. While the ultimate aim of these panels is to increase the reproductive autonomy of the individuals and couples by providing preconception knowledge that could lead to the broadest range of available options, including PGD, we argue that: (i) Given the number and heterogeneity of the conditions included in panels, it cannot be guaranteed that a couple who tests positive for one of those conditions will be eligible for PGD; patients should be informed of this potential limitation before undertaking screening. (ii) Family history is typically lacking in couples identified through panels as being at high-risk for certain disorders. This should promote a reflection on the inclusion of personal experience with a condition as a consideration for PGD in disorders with incomplete penetrance or for which treatment options are available. (iii) With the advent of next-generation sequencing panels, cases of couples in which one member carries a disease-causing variant and the other has a variant of uncertain significance found in the same gene are likely to become more common and need to be discussed from the PGD perspective. (iv) With comprehensive panels where healthy individuals are likely to be identified as carriers for several conditions, testing of carrier status for embryos and prioritisation of the embryos to transfer needs reassessing. We believe that these points should be included in the discussion on expanded carrier screening and that all stakeholders, patients included, must be aware of the challenges and limitations that may come with a positive result.












Resolution of infertility and number of children: 1386 couples followed for a median of 13 years

2017-08-29

Abstract
STUDY QUESTION
How common were children among infertile couples?
SUMMARY ANSWER
A total of 61.7% of infertile couples presenting for care subsequently had live born children 13.1 years after first being clinically assessed, with a mean of 1.7 children among those who had at least one.
WHAT IS KNOWN ALREADY
While the prognoses for infertile couples undertaking specific treatments have been well described, less is known about those not undergoing these treatments or the total number of children. This information is necessary for decision-making in many individual cases; not knowing this has been cited by patients and clinicians as impeding implementation of care.
STUDY DESIGN, SIZE, DURATION
The sole provider of specialist fertility care for the two southern-most regions in New Zealand enroled 1386 infertile couples from 1998 to 2005 in a longitudinal study with follow-up on all births until the end of 2014. Couples were followed in care for a median of 1.1 years and median follow-up for births was 13.1 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Clinic-collected data were linked to national maternity data to extend follow-up past the end of clinical contact. The primary outcome was the total number of live born children. Hurdle regression was used to investigate factors associated with resolving infertility and the total number of children.
MAIN RESULTS AND THE ROLE OF CHANCE
Infertility was resolved with a live birth by 61.7% (95% CI 59.1–64.2%) of couples; just over half of all first births were treatment-dependent. Among couples who resolved their infertility, 55.6% (52.2–58.9%) had at least one additional child and the mean number of children was 1.7. While female age strongly influenced outcomes, one-third of women aged 40–41 years had a child, not significantly less than those in their late 30s. The lowest levels of resolution occurred in women aged ≥42 years, couples who were infertile for >4 years and women with a BMI ≥ 35 kg/m2. Moderate obesity did not affect outcomes.
LIMITATIONS, REASONS FOR CAUTION
The main limitation of this study was insufficient data to investigate male factor infertility outcomes. It is also possible that treatment-dependent resolution could be higher in more recent cohorts with the increased use of ART.
WIDER IMPLICATIONS OF THE FINDINGS
Outcomes in these couples are comparable to those seen in other studies in high-income countries despite the relatively low contribution of ART. The prognosis for most infertile couples is positive and suggests many will not require treatment. Further research is needed to inform best practice for women in their early forties or with moderate obesity, and to develop prediction models that are more relevant for the initial management of infertility.
STUDY FUNDING/COMPETING INTEREST(S)
This study was co-funded by a University of Otago PhD Scholarship and the Department of Women's and Children's Health, University of Otago. There were no competing interests to declare.



Selective outcome reporting and sponsorship in randomized controlled trials in IVF and ICSI

2017-08-29

Abstract
STUDY QUESTION
Are randomized controlled trials (RCTs) on IVF and ICSI subject to selective outcome reporting and is this related to sponsorship?
SUMMARY ANSWER
There are inconsistencies, independent from sponsorship, in the reporting of primary outcome measures in the majority of IVF and ICSI trials, indicating selective outcome reporting.
WHAT IS KNOWN ALREADY
RCTs are subject to bias at various levels. Of these biases, selective outcome reporting is particularly relevant to IVF and ICSI trials since there is a wide variety of outcome measures to choose from. An established cause of reporting bias is sponsorship. It is, at present, unknown whether RCTs in IVF/ICSI are subject to selective outcome reporting and whether this is related with sponsorship.
STUDY DESIGN, SIZE, DURATION
We systematically searched RCTs on IVF and ICSI published between January 2009 and March 2016 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the publisher subset of PubMed. We analysed 415 RCTs.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Per included RCT, we extracted data on impact factor of the journal, sample size, power calculation, and trial registry and thereafter data on primary outcome measure, the direction of trial results and sponsorship.
MAIN RESULTS AND THE ROLE OF CHANCE
Of the 415 identified RCTs, 235 were excluded for our primary analysis, because the sponsorship was not reported. Of the 180 RCTs included in our analysis, 7 trials did not report on any primary outcome measure and 107 of the remaining 173 trials (62%) reported on surrogate primary outcome measures. Of the 114 registered trials, 21 trials (18%) provided primary outcomes in their manuscript that were different from those in the trial registry. This indicates selective outcome reporting. We found no association between selective outcome reporting and sponsorship. We ran additional analyses to include the trials that had not reported sponsorship and found no outcomes that differed from our primary analysis.
LIMITATIONS, REASONS FOR CAUTION
Since the majority of the trials did not report on sponsorship, there is a risk on sampling bias.
WIDER IMPLICATIONS OF THE FINDINGS
IVF and ICSI trials are subject, to a large extent, to selective outcome reporting. Readers should be aware of this to avoid implementation of false or misleading results in clinical practice.
STUDY FUNDING/COMPETING INTERESTS
No funding received and there are no conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A



Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing

2017-08-29

Abstract
STUDY QUESTION
Does a novel heterozygous KHDRBS1 variant, identified using whole-exome sequencing (WES) in two patients with primary ovarian insufficiency (POI) in a pedigree, cause defects in mRNA alternative splicing?
SUMMARY ANSWER
The heterozygous variant of KHDRBS1 was confirmed to cause defects in alternative splicing of many genes involved in DNA replication and repair.
WHAT IS KNOWN ALREADY
Studies in mice revealed that Khdrbs1 deficient females are subfertile, which manifests as delayed sexual maturity and significantly reduced numbers of secondary and pre-antral follicles. No mutation of KHDRBS1, however, has been reported in patients with POI.
STUDY DESIGN SIZE, DURATION
This genetic and functional study used WES to find putative mutations in a POI pedigree. Altogether, 215 idiopathic POI patients and 400 healthy controls were screened for KHDRBS1 mutations.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Two POI patients were subjected to WES to identify sequence variants. Mutational analysis of the KHDRBS1 gene in 215 idiopathic POI patients and 400 healthy controls were performed. RNA-sequencing was carried out to find the mis-regulation of gene expression due to KHDRBS1 mutation. Bioinformatics was used to analyze the change in alternative splicing events.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified a heterozygous mutation (c.460A > G, p.M154V) in KHDRBS1 in two patients. Further mutational analysis of 215 idiopathic POI patients with the KHDRBS1 gene found one heterozygous mutation (c.263C > T, p.P88L). We failed to find these two mutations in 400 healthy control women. Using RNA-sequencing, we found that the KGN cells expressing the M154V KHDRBS1 mutant had different expression of 66 genes compared with wild-type (WT) cells. Furthermore, 145 genes were alternatively spliced in M154V cells, and these genes were enriched for DNA replication and repair function, revealing a potential underlying mechanism of the pathology that leads to POI.
LIMITATIONS: REASONS FOR CAUTION
Although the in vitro assays demonstrated the effect of the KHDRBS1 variant on alternative splicing, further studies are needed to validate the in vivo effects on germ cell and follicle development.
WIDER IMPLICATIONS OF THE FINDINGS
This finding provides researchers and clinicians a better understanding of the etiology and molecular mechanism of POI.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Ministry of Science and Technology of China (2012CB944704; 2012CB966702), National Research Institute for Family Planning (2017GJZ05), the National Natural Science Foundation of China (31171429) and Beijing Advanced Innovation Center for Structural Biology. The authors declare no conflict of interest.



Assisted reproductive technology in Europe, 2013: results generated from European registers by ESHRE

2017-08-28

AbstractSTUDY QUESTIONAre there any changes in the treatments involving ART and IUI initiated in Europe during 2013 compared with previous years?SUMMARY ANSWERAn increase in the overall number of ART cycles resulting from a higher number of countries reporting data was evident, the pregnancy rates (PRs) in 2013 remained stable compared with those reported in 2012, the number of transfers with multiple embryos (3+) was lower than ever before yet the multiple delivery rates (DRs) remained unchanged, and IUI activity and success rates were similar to those of last years.WHAT IS KNOWN ALREADYSince 1997, ART data in Europe have been collected and reported in 16 manuscripts, published in Human Reproduction.STUDY DESIGN, SIZE, DURATIONRetrospective data collection of European ART data by the European IVF-monitoring Consortium for ESHRE. Data for cycles between 1 January and 31 December 2013 were collected from National Registers, when existing, or on a voluntary basis by personal information.PARTICIPANTS/MATERIALS, SETTINGS, METHODSFrom 38 countries (+4 compared with 2012), 1169 clinics reported 686 271 treatment cycles including 144 299 of IVF, 330 367 of ICSI, 154 712 of frozen embryo replacement (FER), 40 244 of egg donation (ED), 247 of IVM, 9791 of PGD/PGS and 6611 of frozen oocyte replacements. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1095 IUI labs in 22 countries. A total of 175 467 IUI-H and 43 785 IUI-D cycles were included.MAIN RESULTS AND THE ROLE OF CHANCEIn 17 countries where all clinics reported to their ART register, a total of 374 177 ART cycles were performed in a population of around 310 million inhabitants, corresponding to 1175 cycles per million inhabitants (range, 235–2703 cycles per million inhabitants).For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.6% (29.4% in 2012) and 34.5% (33.8% in 2012), respectively. For ICSI, the corresponding rates also were stable with 27.8% (27.8% in 2012) and 32.9% (32.3% in 2012). In FER-cycles, the PR per thawing/warming increased to 27.0% (23.1% in 2012). In ED cycles, the PR per fresh transfer increased to 49.8% (48.4% in 2012), to 38.5% (35.9% in 2012) per thawed transfer, and to 46.4% for transfers after FOR (45.1% in 2012). The DRs after IUI remained stable at 8.6% (8.5% in 2012) after IUI-H and was slightly lower after IUI-D (11.1% versus 12.0% in 2012).In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 31.4, 56.3, 11.5, and 1.0% of the cycles, respectively (corresponding numbers were 30.2, 55.4, 13.3 and 1.1% in 2012). The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82., 17.5 and 0.5%, respectively, resulting in a total multiple DR of 18.0% compared to 17.9% in 2012. In FER-cycles, the multiple DR was 12.8% (12.5% twins and 0.3% triplets), nearly the same as in 2012 (12.5, 12.2 and 0.3% respectively).Twin and triplet DRs associated with IUI cycles were 9.5%/0.6% and 7.5%/0.3%, following treatment with husband/donor semen, respectively.LIMITATIONS, REASONS FOR CAUTIONThe method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, the results should be interpreted with caution.WIDER IMPLICATIONS OF THE FINDINGSThe 17th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 685 000 cycles reporte[...]



Complex CatSper-dependent and independent [Ca 2+ ] i signalling in human spermatozoa induced by follicular fluid

2017-08-28

AbstractSTUDY QUESTIONDoes progesterone in human follicular fluid (hFF) activate CatSper and do other components of hFF modulate this effect and/or contribute separately to hFF-induced Ca2+ signaling?SUMMARY ANSWERhFF potently stimulates CatSper and increases [Ca2+]i, primarily due to high concentrations of progesterone, however, other components of hFF also contribute to [Ca2+]i signaling, including modulation of CatSper channel activity and inhibition of [Ca2+]i oscillations.WHAT IS KNOWN ALREADYCatSper, the principal Ca2+ channel in spermatozoa, is progesterone-sensitive and essential for fertility. Both hFF and progesterone, which is present in hFF, influence sperm function and increase their [Ca2+]i.STUDY DESIGN, SIZE, DURATIONThis basic medical research study used semen samples from >40 donors and hFF from >50 patients who were undergoing surgical oocyte retrieval for IVF/ICSI.PARTICIPANTS/MATERIALS, SETTING, METHODSSemen donors and patients were recruited in accordance with local ethics approval (13/ES/0091) from the East of Scotland Research Ethics Service REC1. Activities of CatSper and KSper were assessed by patch clamp electrophysiology. Sperm [Ca2+]i responses were examined in sperm populations and single cells. Computer-assisted sperm analysis (CASA) parameters and penetration into viscous media were used to assess functional effects.MAIN RESULTS AND THE ROLE OF CHANCEhFF and progesterone significantly potentiated CatSper currents. Under quasi-physiological conditions, hFF (up to 50%) failed to alter membrane K+ conductance or current reversal potential. hFF and progesterone (at an equivalent concentration) stimulated similar biphasic [Ca2+]i signals both in sperm populations and single cells. At a high hFF concentration (10%), the sustained (plateau) component of the [Ca2+]i signal was consistently greater than that induced by progesterone alone. In single cell recordings, 1% hFF-induced [Ca2+]i oscillations similarly to progesterone but with 10% hFF generation of [Ca2+]i oscillations was suppressed. After treatment to ‘strip’ lipid-derived mediators, hFF failed to significantly stimulate CatSper currents but induced small [Ca2+]i responses that were greater than those induced by the equivalent concentration of progesterone after stripping. Similar [Ca2+]i responses were observed when sperm pretreated with 3 μM progesterone (to desensitize progesterone responses) were stimulated with hFF or stripped hFF. hFF stimulated viscous media penetration and was more effective than the equivalent does of progesterone.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis was an in vitro study. Caution must be taken when extrapolating these results in vivo.WIDER IMPLICATIONS OF THE FINDINGSThis study directly demonstrates that hFF activates CatSper and establishes that the biologically important effects of hFF reflect, at least in part, action on this channel, primarily via progesterone. However, these experiments also demonstrate that other components of hFF both contribute to the [Ca2+]i signal and modulate the activation of CatSper. Simple in vitro experiments performed out of the context of the complex in vivo environment need to be interpreted with caution.STUDY FUNDING/COMPETING INTEREST(S)Funding was provided by MRC (MR/K013343/1, MR/012492/1) (S.G.B., S.J.P., C.L.R.B.) and University of Abertay (sabbatical for S.G.B.). Additional funding was provided by TENOVUS SCOTLAND (S.M.D.S.), Chief Scientist Office/NHS Research Scotland (S.M.D.S). C.L.R.B. is EIC of MHR and Chair of the WHO ESG on Diagnosis of Male infertility. The remaining authors ha[...]



Hyperspectral microscopy can detect metabolic heterogeneity within bovine post-compaction embryos incubated under two oxygen concentrations (7% versus 20%)

2017-08-28

AbstractSTUDY QUESTIONCan we separate embryos cultured under either 7% or 20% oxygen atmospheres by measuring their metabolic heterogeneity?SUMMARY ANSWERMetabolic heterogeneity and changes in metabolic profiles in morula exposed to two different oxygen concentrations were not detectable using traditional fluorophore and two-channel autofluorescence but were detectable using hyperspectral microscopy.WHAT IS KNOWN ALREADYIncreased genetic and morphological blastomere heterogeneity is associated with compromised developmental competence of embryos and currently forms the basis for embryo scoring within the clinic. However, there remains uncertainty over the accuracy of current techniques, such as PGS and time-lapse microscopy, to predict subsequent pregnancy establishment.STUDY DESIGN, SIZE, DURATIONThe impact of two oxygen concentrations (7% = optimal and 20% = stressed) during post-fertilisation embryo culture was assessed. Cattle embryos were exposed to the different oxygen concentrations for 8 days (D8; embryo developmental competence) or 5 days (D5; metabolism measurements). Between 3 and 4 experimental replicates were performed, with 40–50 embryos per replicate used for the developmental competency experiment, 10–20 embryos per replicate for the fluorophore and two-channel autofluorescence experiments and a total of 21–22 embryos used for the hyperspectral microscopy study.PARTICIPANTS/MATERIALS, SETTING, METHODSIn-vitro produced (IVP) cattle embryos were utilised for this study. Post-fertilisation, embryos were exposed to 7% or 20% oxygen. To determine impact of oxygen concentrations on embryo viability, blastocyst development was assessed on D8. On D5, metabolic heterogeneity was assessed in morula (on-time) embryos using fluorophores probes (active mitochondria, hydrogen peroxide and reduced glutathione), two-channel autofluorescence (FAD and NAD(P)H) and 18-channel hyperspectral microscopy.MAIN RESULTS AND THE ROLE OF CHANCEExposure to 20% oxygen following fertilisation significantly reduced total blastocyst, expanded and hatched blastocyst rates by 1.4-, 1.9- and 2.8-fold, respectively, compared to 7% oxygen (P < 0.05), demonstrating that atmospheric oxygen was a viable model for studying mild metabolic stress. The metabolic profiles of D5 embryos was determined and although metabolic heterogeneity was evident within the cleavage stage (i.e. arrested) embryos exposed to fluorophores, there were no detectable difference in fluorescence intensity and pattern localisation in morula exposed to the two different oxygen concentrations (P > 0.05). While there were no significant differences in two-channel autofluorescent profiles of morula exposed to 7% and 20% oxygen (main effect, P > 0.05), morula that subsequently progressed to the blastocyst stage had significantly higher levels of FAD and NAD(P)H fluorescence compared to arrested morula (P < 0.05), with no change in the redox ratio. Hyperspectral autofluorescence imaging (in 18-spectral channels) of the D5 morula revealed highly significant differences in four features of the metabolic profiles of morula exposed to the two different oxygen concentrations (P < 0.001). These four features were weighted and their linear combination revealed clear discrimination between the two treatment groups.LIMITATIONS, REASONS FOR CAUTIONMetabolic profiles were assessed at a single time point (morula), and as such further investigation is required to determine if differences in hyperspectral signatures can be detected in pre-compaction embryos and oocytes, using both cattle an[...]



Deep sequencing shows that oocytes are not prone to accumulate mtDNA heteroplasmic mutations during ovarian ageing

2017-08-28

AbstractSTUDY QUESTIONDoes ovarian ageing increase the number of heteroplasmic mitochondrial DNA (mtDNA) point mutations in oocytes?SUMMARY ANSWEROur results suggest that oocytes are not subject to the accumulation of mtDNA point mutations during ovarian ageing.WHAT IS KNOWN ALREADYAgeing is associated with the alteration of mtDNA integrity in various tissues. Primary oocytes, present in the ovary since embryonic life, may accumulate mtDNA mutations during the process of ovarian ageing.STUDY DESIGN, SIZE, DURATIONThis was an observational study of 53 immature oocyte–cumulus complexes retrieved from 35 women undergoing IVF at the University Hospital of Angers, France, from March 2013 to March 2014. The women were classified in two groups, one including 19 women showing signs of ovarian ageing objectified by a diminished ovarian reserve (DOR), and the other, including 16 women with a normal ovarian reserve (NOR), which served as a control group.PARTICIPANTS/MATERIALS, SETTING, METHODSmtDNA was extracted from isolated oocytes, and from their corresponding cumulus cells (CCs) considered as a somatic cell compartment. The average mtDNA content of each sample was assessed by using a quantitative real-time PCR technique. Deep sequencing was performed using the Ion Torrent Proton for Next-Generation Sequencing. Signal processing and base calling were done by the embedded pre-processing pipeline and the variants were analyzed using an in-house workflow. The distribution of the different variants between DOR and NOR patients, on one hand, and oocyte and CCs, on the other, was analyzed with the generalized mixed linear model to take into account the cluster of cells belonging to a given mother.MAIN RESULTS AND THE ROLE OF CHANCEThere were no significant differences between the numbers of mtDNA variants between the DOR and the NOR patients, either in the oocytes (P = 0.867) or in the surrounding CCs (P = 0.154). There were also no differences in terms of variants with potential functional consequences. De-novo mtDNA variants were found in 28% of the oocytes and in 66% of the CCs with the mean number of variants being significantly different (respectively 0.321, SD = 0.547 and 1.075, SD = 1.158) (P < 0.0001). Variants with a potential functional consequence were also overrepresented in CCs compared with oocytes (P = 0.0019).LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONLimitations may be due to the use of immature oocytes discarded during the assisted reproductive technology procedure, the small size of the sample, and the high-throughput sequencing technology that might not have detected heteroplasmy levels lower than 2%.WIDER IMPLICATIONS OF THE FINDINGSThe alteration of mtDNA integrity in oocytes during ovarian ageing is a recurring question to which our pilot study suggests a reassuring answer.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the University Hospital of Angers, the University of Angers, France, and the French national research centers, INSERM and the CNRS. There are nocompeting interests.[...]






Prevalence of occult leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of leiomyomas in reproductive-age women

2017-08-23

Abstract
STUDY QUESTION
What is the prevalence of leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of fibroids in reproductive age women?
SUMMARY ANSWER
No case of leiomyosarcomas but seven atypical leiomyomas were found in 1216 subjects.
WHAT IS KNOWN ALREADY
Although uterine sarcoma is a rare entity affecting usually older peri- or post-menopausal women, the Food and Drug Administration discourages use of laparoscopic power morcellation of uterine fibroids.
STUDY DESIGN, SIZE, DURATION
Retrospective review of data extracted from a single center database of 1216 consecutive women who underwent laparoscopic morcellation of 2582 unsuspicious leiomyomas between June 2003 and December 2015 and were followed-up until December 2016.
PARTICIPANTS/MATERIALS, SETTINGS, METHODS
A total of 1216 women, aged 18–45 years, underwent laparoscopic morcellation of 2582 apparently benign leiomyomas by the same surgeon and all specimen slides were examined by the same experienced pathologist.
MAIN RESULTS AND THE ROLE OF CHANCE
The prevalence of leiomyosarcomas and atypical leiomyomas was 0% (95% CI: 0–0.3%) and 0.6% (95% CI: 0.23–1.18%) (six atypical-bizarre and one mitotically active leiomyoma) respectively. In addition, there were identified 34 cases of adenomyomas, 45 leiomyomas with infarcts, 81 cellular leiomyomas and 133 degenerated leiomyomas. No morcellator-associated complication was recorded and none of the patients included in this study required conversion to laparotomy.
LIMITATIONS, REASONS FOR CAUTION
Retrospective and single referral center study design.
WIDER IMPLICATIONS OF THE FINDINGS
Laparoscopic morcellation of unsuspicious leiomyomas after careful preoperative work up seems to be safe in women of reproductive age.
STUDY FUNDING/COMPETING INTEREST(S)
None.



The importance of genetic parenthood for infertile men and women

2017-08-23

AbstractSTUDY QUESTIONDo men and women beginning to attend a fertility clinic prefer genetic over non-genetic parenthood?SUMMARY ANSWERNearly, all infertile men and women prefer genetic parenthood.WHAT IS KNOWN ALREADYClinicians assume that all infertile couples prefer genetic parenthood over non-genetic parenthood and, therefore, consider treatments with donor gametes an option of last resort. Previous studies of the desire for parenthood identified 30 motivations for genetic parenthood, and 51 motivations for which having a genetically related child is not strictly necessary but might be deemed required. The exact strength of the preference of infertile men and women for genetic parenthood remains unclear, as does the importance of the various motivations.STUDY DESIGN, SIZE, DURATIONA questionnaire was developed based on a literature review. It was assessed by professionals and pilot tested among patients. The coded paper–pencil questionnaire was disseminated among both partners of 201 heterosexual infertile couples after their first consultation at one of two Belgian fertility clinics between October 2015 and May 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSThe survey addressed: (i) the preference for genetic parenthood for themselves and for their partner, (ii) the importance of 30 motivations for genetic parenthood and (iii) the importance of 51 other motivations for parenthood and whether these motivations require being the genetic parent of their child to be fulfilled. To simplify presentation of the results, all 81 motivations were grouped into reliable categories of motivations using psychometric analyses.MAIN RESULTS AND THE ROLE OF CHANCEThe survey was completed by 104 women and 91 men (response rate: 49%). Almost all respondents (98%) favored genetic over non-genetic parenthood for both their partner and themselves. One-third of the respondents stated they only wanted to parent their own genetically related child. Achieving genetic parenthood for their partner was considered significantly more important than achieving genetic parenthood for themselves. Within couples, men had a stronger preference for genetic parenthood (P = 0.004), but this was not significant after correction for educational level, which was significantly associated with the preference of both men and women. The 30 motivations for becoming a genetic parent clustered into 11 categories of which ‘to experience a natural process’ was deemed most important. The 51 motivations for becoming a parent for which having a genetically related child is not strictly necessary clustered into 14 categories of which ‘to contribute to a child's well-being’ and ‘to experience the love of a child’ were most important. Respondents deemed they would need to be the genetic parent of their child to fulfill nearly all their motivations for parenthood.LIMITATIONS REASONS FOR CAUTIONWe included couples that visited the fertility clinic for the first time, and the preference for genetic parenthood might change throughout a fertility treatment trajectory. Moreover, what prospective parents expect to be important for their future well-being might not really define parents’ well-being.WIDER IMPLICATIONS OF THE FINDINGSThe presumed preference of couples for genetic parenthood was confirmed. Resistance against using donor gametes is more likely among lower educated individuals. Researching whether non-genetic parents actually feel they cannot fulfill the 51 motivatio[...]









Modeling of live-birth rates and cost-effectiveness of oocyte cryopreservation for cancer patients prior to high- and low-risk gonadotoxic chemotherapy

2017-08-18

Abstract
STUDY QUESTION
What is the live-birth rate (LBR) and cost-effectiveness of fertility preservation with oocyte cryopreservation (FP–OC) compared to expectant management in cancer patients age 25–40 based on estimated gonadotoxicity of treatments 5 years after cancer diagnosis?
SUMMARY ANSWER
Oocyte cryopreservation prior to cancer treatment is more costly, yet more effective (producing more live births), than not undergoing oocyte cryopreservation but it is most beneficial for patients undergoing high-risk chemotherapy (HRC).
WHAT IS KNOWN ALREADY
The decision to undergo FP prior to treatment is multifactorial and can be costly and delay treatment. Not all treatments carry the same gonadotoxicity and patients may choose to undergo FP–OC based on the probability of premature ovarian insufficiency, predicted outcomes and cost. A comprehensive model that incorporates age at diagnosis and toxicity of treatment to help guide patients in the decision to undergo FP–OC does not yet exist.
STUDY DESIGN, SIZE DURATION
This study used a Decision Analysis Model to estimate effectiveness and cost of FP for cancer patients.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Age-based estimates of LBR and cost per live birth were calculated for ages 25–40 years based on gonadotoxicity of treatment. A decision analysis model was constructed using Treeage Pro 2015 with case base probabilities derived from national registries, practice guidelines and medical records from a national network of infertility practices (IntegraMed).
MAIN RESULTS AND THE ROLE OF CHANCE
Compared to no FP–OC, FP–OC improved LBRs for women of all ages undergoing either low-risk chemotherapy (LRC) or HRC; however, it was most cost effective for women undergoing LRC at older ages or HRC at younger ages. Although FP–OC results in higher LBRs, it was always more costly. Using donor oocyte IVF can be a successful alternative to autologous FP–OC.
LIMITATIONS REASONS FOR CAUTION
Decision tree results reflect probabilities of certain events and are compiled from multiple reputable sources but are not directly derived from a recruited cohort of patients. Outcomes are based on United States estimates and should be interpreted in the broader context of individual patient diagnoses, treatment care plans and country of origin.
WIDER IMPLICATIONS OF THE FINDINGS
The development of this analytic model will help guide practitioners in their counseling of women from age 25 to 40 years, who are considering FP–OC at the time of cancer diagnosis. It provides a realistic pathway from diagnosis to LB and accounts for the majority of costs and outcome possibilities.
STUDY FUNDING/COMPETING INTEREST(s)
This study was partially funded by a grant from National Institute of Health (NIH)/National Institute of Child Health and Human Development (NICHD) (R01 HD67683) to A.Z.S. There are no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.