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Study question What is the prevalence of metabolic dysfunction, like insulin resistance, hyperglycaemia, hypertension, and/or dyslipidaemia, among subfertile women compared to healthy controls? Summary answer Signs of metabolic dysfunction were not observed more frequently in subfertile women than in controls. Overweight and obese patients were at risk for metabolic dysfunction. What is known already Metabolic dysfunction is known to impair female fecundity as it is linked to a longer time-to-pregnancy and to subfertility. Three times as many PCOS patients are diagnosed with metabolic syndrome than age matched controls. Moreover, a recent study showed a higher prevalence among the entire subfertile population. Metabolic disorders have been connected to the impairment of normal ovarian function and pituitary-hypothalamic axis. Obesity is correlated with menstrual irregularities, ovulation disorders and infertility. On top, it can increase risk of miscarriage and reduce chances with assisted reproductive technologies. Therefore, metabolic dysfunction might also be a driving factor behind unexplained subfertility. Study design, size, duration This cross-sectional observational case control study was performed in a secondary and tertiary care fertility clinic (MUMC+, Maastricht, The Netherlands). Patients were referred to the fertility clinic with either primary or secondary subfertility (inability to conceive after one year of regular unprotected intercourse), controls were healthy, parous women. All participants were aged between 18 and 41 years at time of inclusion. 119 patients and 68 controls were included over a time span of 3 years. Participants/materials, setting, methods A basic medical history was collected using questionnaires. Physical examination included measurement of weight, height, waist and hip circumference, blood pressure and pulse. Venipuncture was performed after an overnight fast on cycle day 2-4; including insulin, glucose, triglycerides, high-density lipid cholesterol, total cholesterol, glomerular filtration rate, urea, uric acid, creatinine, follicle stimulating hormone, estradiol and anti-Mullarian hormone. Urine was collected to measure protein and creatinine. Metabolic syndrome was diagnosed according to Adult Treatment Panel-III guidelines. Main results and the role of chance Body weight and BMI were similarly distributed between patients and controls. Main causes of subfertility comprised male factor (12%), anovulation (20%) and unexplained subfertility (47%). Comparing patients to controls, unexplained subfertility only had slightly higher HDL cholesterol levels (p = 0.046). Anovulatory patients showed 2% higher glucose (p = 0.003) and 133% higher AMH levels (p In a comparison of overweight and obese patients to normal weight patients we observed resp. 16% and 37% higher waist circumference (p Limitations, reasons for caution Participants were young and remarkably healthy, which might account for the low prevalence of metabolic disorders. It is known that the prevalence of metabolic dysfunction is strongly dependent on socioeconomic and geographic determinants in various populations. Our findings apply to a largely ethnically homogeneous Caucasian female population in the Netherlands. Wider implications of the findings We found that the presence or specific cause of subfertility per se, cannot be regarded as a reliable and strong predictor of metabolic dysfunction, even in anovulatory subfertility. As can be expected, metabolic dysfunction is highly associated with BMI and obese patients should consider lifestyle intervention to prevent future complications. Trial registration number Not applicable

Study question Does the endometrial synthesis and inactivation of 17β- estradiol differ between receptive and non-receptive endometrium in women undergoing IVF/ICSI? Summary answer The synthesis and inactivation of 17β-estradiol is similar in the endometrium of women who did and did not achieve a clinical pregnancy through IVF/ICSI. What is known already Implantation failure of high-quality embryos is a main concern in IVF/ICSI treatment. Blood sex-steroid concentrations do not reflect their corresponding concentrations in endometrial tissue. This is in line with the concept that blood steroids (and precursors) are locally converted to bioactive metabolites and vice versa, by expressing steroid-metabolising enzymes, such as 17β-hydroxy steroid dehydrogenase (17β-HSD). Studies indicate that alterations in intracrinology might modulate endometrial receptivity. We hypothesize that the local 17β-HSD activity during the window of implantation (WOI) differs between pregnant and non-pregnant IVF/ICSI patients. Study design, size, duration Case-control study of 40 patients that were recruited in the SCRaTCH study (NL5193/NTR5342), a randomised trial exploring whether ‘endometrial scratching’ in patients with a previous IVF/ICSI cycle failure affects pregnancy outcome in a subsequent IVF/ICSI cycle. For the present investigation, 20 endometrial biopsies from women who achieved clinical pregnancy after fresh embryo transfer (ET) were compared with 20 endometrial biopsies of women that did not conceive after fresh ET. Participants/materials, setting, methods Endometrial biopsies and serum were obtained at LH + 5-8 days (urinary test) in a natural cycle, prior to the fresh ET cycle. Cases (negative pregnancy test, n = 20) and controls (clinically pregnant, n = 20) were matched for primary vs. secondary infertility, embryo quality and age. Reduction of estrone to 17β-estradiol (synthesizing 17β-HSDs) and oxidation of 17β-estradiol to estrone (inactivating 17β-HSDs) were determined by high-performance liquid chromatography (HPLC). Results were compared with the Wilcoxon-Mann-Whitney Rank Sum Test. Main results and the role of chance Activity of 17β-HSDs responsible for the reduction of estrone to 17β-estradiol (mainly 17β-HSD type 1) was detected in all samples and ranged from 55 to 1864 pmol 17β-estradiol formed/mg protein/24 h. The values obtained from pregnant women (median: 1054) were not significantly different to those obtained from non-pregnant women (median: 997), p = 0.97. The activity of enzymes responsible for the oxidation of 17β-­ estradiol (mainly 17β-HSD type 2) into the less active estrone ranged from 32 to 1731 estrone formed/mg protein/24 h. The values obtained from pregnant women (median: 737) were not significantly different to those obtained from non-pregnant women (median: 624), p = 0.90. The ratio of 17β-HSD type 1:17β-HSD type 2 had a median of 1.63 in the pregnant woman compared to 1.95 in the group of non-pregnant woman (p = 0.57). Limitations, reasons for caution The study is pilot in nature and study population is small. Primary and secondary infertility patients were analysed together. A chance phenomenon could have occurred as included women were included after their first IVF/ICSI cycle, hence not every included study person met the criteria for repeated implantation failure (RIF). Wider implications of the findings 17β-estradiol metabolism takes place during the WOI, controlling the final 17β-estradiol level. Although the present investigation did not show differences between pregnant and non-pregnant women, it remains important to explore if estrogen balance deviations, e.g. in other cycle phases plays a role in clinical conditions such as primary infertility/RIF. Trial registration number NL5193/NTR5342

STUDY QUESTION Do children conceived by ART have an increased risk of cancer?SUMMARY ANSWER Overall, ART-conceived children do not appear to have an increased risk of cancer.WHAT IS KNOWN ALREADY Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.STUDY DESIGN, SIZE, DURATION A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.PARTICIPANTS/MATERIALS, SETTING, METHODS All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers' questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).MAIN RESULTS AND THE ROLE OF CHANCE The median follow-up was 21 years (interquartile range (IQR): 17-25) and was shorter in ART-conceived children (20 years, IQR: 17-23) compared with naturally conceived children (24 years, IQR: 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81-2.85; 1.80, 95% CI: 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81-7.37) and melanoma (HR = 1.86, 95% CI: 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.LIMITATIONS, REASONS FOR CAUTION Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.WIDER IMPLICATIONS OF THE FINDINGS Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.STUDY FUNDING/COMPETING INTEREST(S) This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women's cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests.

Purpose This study aims to describe the motives and considerations of couples carrying a structural chromosomal abnormality deciding on preimplantation genetic testing (PGT). Methods A qualitative exploratory study was conducted using semi-structured dyadic interviews with 13 couples (N = 26) carrying a structural chromosomal abnormality. All couples had an informative consultation in our PGT centre in the Netherlands. Results Almost all couples considered PGT or natural conception combined with prenatal diagnosis (PND) as the only two reproductive options. Among several considerations mentioned, the majority indicated that the wish to increase the chance of a successful pregnancy was the most important motive to opt for PGT. All couples who opted for PGT had first tried to conceive spontaneously and entered the PGT programme because of their adverse experiences during these attempts (infertility, recurrent miscarriage, termination of pregnancy, birth of an affected child). Couples that refrained from PGT were of advanced maternal age and expressed the long trajectory of PGT as the main reason to refrain. If conceiving spontaneously would not lead to an ongoing pregnancy, these couples also indicated that they would use PGT. Conclusion This study shows that couples carrying a structural chromosomal abnormality consider PGT and spontaneous conception with PND as relevant reproductive options. They are looking for the option that is in their opinion the fastest way to establish a successful pregnancy. Information on the perceived pros and cons of PGT or spontaneous conception in these couples can help to optimize counselling and psychological support during the decision-making process.

STUDY QUESTION: Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old singleton IVF children?SUMMARY ANSWER: The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development.WHAT IS KNOWN ALREADY: Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1 (TM) Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life.STUDY DESIGN, SIZE, DURATION: In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1 (TM) Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016.PARTICIPANT/MATERIALS, SETTINGS, METHODS: Parents were invited to attend our clinic with their child for a single visit lasting similar to 2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m(2) (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95% CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm [95% CI: 0.27-6.62]). Both systolic (adj. beta 0.364 [95% CI: -2.129 to 2.856],) and diastolic (adj. beta 0.275 [95% CI: -2.105 to 2.654]) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable.LIMITATIONS, REASONS FOR CAUTION: A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures.WIDER IMPLICATIONS OF THE FINDINGS: This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development.STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

Item does not contain fulltext BACKGROUND: Chemotherapy for breast cancer may have a negative impact on reproductive function due to gonadotoxicity. Fertility preservation via banking of oocytes or embryos after ovarian stimulation with FSH can increase the likelihood of a future live birth. It has been hypothesized that elevated serum estrogen levels during ovarian stimulation may induce breast tumour growth. This has led to the use of alternative stimulation protocols with addition of tamoxifen or letrozole. The effectiveness of these stimulation protocols in terms of oocyte yield is unknown. METHODS/DESIGN: Randomized open-label trial comparing ovarian stimulation plus tamoxifen and ovarian stimulation plus letrozole with standard ovarian stimulation in the course of fertility preservation. The study population consists of women with breast cancer who opt for banking of oocytes or embryos, aged 18-43years at randomisation. Primary outcome is the number of oocytes retrieved at follicle aspiration. Secondary outcomes are number of mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during ovarian stimulation. DISCUSSION: Concerning the lack of evidence on which stimulation protocol should be used in women with breast cancer and the growing demand for fertility preservation, there is an urgent need to undertake this study. By performing this study, we will be able to closely monitor the effects of various stimulation protocols in women with breast cancer and pave the way for long term follow up on the safety of this procedure in terms of breast cancer prognosis. TRIAL REGISTRATION: NTR4108.

STUDY QUESTION: Do age, ovulatory status, severity of obesity and body fat distribution affect the effectiveness of lifestyle intervention in obese infertile women? SUMMARY ANSWER: We did not identify a subgroup in which lifestyle intervention increased the healthy live birth rate however it did increase the natural conception rate in anovulatory obese infertile women. WHAT IS KNOWN ALREADY: Obese women are at increased risk of infertility and are less likely to conceive after infertility treatment. We previously demonstrated that a 6-month lifestyle intervention preceding infertility treatment did not increase the rate of healthy live births (vaginal live birth of a healthy singleton at term) within 24 months of follow-up as compared to prompt infertility treatment in obese infertile women. Natural conceptions occurred more frequently in women who received a 6-month lifestyle intervention preceding infertility treatment. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of a multicentre RCT (randomized controlled trial), the LIFEstyle study. Between 2009 and 2012, 577 obese infertile women were randomly assigned to a 6-month lifestyle intervention followed by infertility treatment (intervention group) or to prompt infertility treatment (control group). Subgroups were predefined in the study protocol, based on frequently used cut-off values in the literature: age (≥36 or

STUDY QUESTION: Do embryo culture media used during an IVF/ICSI treatment have an effect on cognitive development of singleton IVF children at 9 years of age?SUMMARY ANSWER: Cognitive development of children born after culture in two different embryo culture media is comparable.WHAT IS KNOWN ALREADY: Previously, we have shown that the culture medium used in an IVF/ICSI treatment affects birthweight and weight at 2 years of age after alternating assignment to embryo culture in either K-SCICM (Cook) or G1™ Version 3 (Vitrolife). Children with low birthweight are known to have an increased risk for learning disabilities. Data on cognitive development in general of children born after ART are still conflicting, and the only study reporting on the effects of culture medium on cognitive development shows significant differences in cognitive development between two culture medium groups.STUDY DESIGN SIZE DURATION: In this observational cohort follow-up study (MEDIUM-KIDS), parents of all singletons from our abovementioned study were approached after the ninth birthday of their child to participate in an additional follow-up study. Of the 294 eligible children included in the original study, 119 children (70 Vitrolife and 49 Cook) participated in the current study.PARTICIPANTS/MATERIALS SETTING METHODS: All follow-up measurements were performed between March 2014 and December 2016. CITO (Dutch Central Institute for Test Development) developed the Dutch pupil monitoring system, which involves nationwide independent, standardized, academic achievement score tests to monitor the child's school performance twice a year at fixed time points from third grade onward. The tests include language skills (vocabulary and orthography), mathematics and reading capability and comprehension. Results from the tests performed between third and sixth grades, expressed as ability scores, were obtained from the school. To investigate school performance development over the years, we used a mixed effects multilevel model. The least complex model with the best fit was selected to analyze whether culture medium affects cognitive development in our cohort. The study had enough power to detect a difference in ability score that reflects at least one performance category between the two groups.MAIN RESULTS AND THE ROLE OF CHANCE: No differences were seen in baseline characteristics between participants and non-participants (both parental and children characteristics). For all domains, the random intercept model was used. All analyses showed comparable results for the two culture medium groups. No significant differences were observed for any of the cognitive development domains, even after correction for potential confounders. Parental level of education was higher in the IVF group (45%) if compared to the national average level of education (35%), which most likely explains the higher CITO scores for the IVF children if compared to the National ability scores.LIMITATIONS REASONS FOR CAUTION: A limitation of the study was its pseudo-randomized design and the relatively low participation rate of 40.5%. This and the number of missing data prevent us from drawing robust causal conclusions. However, as this is the first and therewith oldest cohort of children where culture medium was allocated alternatingly and used in a blinded setting, in the same period, with all other conditions identical this study gives up until now the best available evidence.WIDER IMPLICATIONS OF THE FINDINGS: Our study analyzes the effects of culture medium on school performance of children born after IVF/ICSI in a prospective cohort study. Although further research on long-term academic skills and also on behavior is essential, our results are reassuring and should make parents of children born after IVF/ICSI feel comfortable with their children's cognitive development.STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the March of Dimes (Grant no. #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBER: NTR4220.

Classic galactosemia is a rare inherited disorder of galactose metabolism. Primary ovarian insufficiency (POI) with subfertility affects > 80% of female patients and is an important concern for patients and their parents. Healthcare providers are often consulted for subfertility treatment possibilities. An option brought up by the families is intrafamilial oocyte donation (mother-to-daughter or sister-to-sister). In addition to POI, galactosemia patients can also present varying cognitive and neurological impairments, which may not be fully clear at the time when mother-to-daughter oocyte donation is considered. Ethical and societal aspects arise when exploring this option. This study aimed to provide guidance in aspects to consider based on the views of different groups involved in the oocyte donation process. A qualitative study using in-depth semi-structured interviews with > 50 participants (patients, family members, and healthcare providers) was conducted. From these interviews, themes of concern emerged, which are illustrated and reviewed: (1) family relations, (2) medical impact, (3) patients’ cognitive level, (4) agreements to be made in advance and organization of counseling, (5) disclosure to the child, and (6) need for follow-up. We conclude that discussing and carrying out intrafamilial oocyte donation in galactosemia patients requires carefully addressing these themes. This study adds value to the already existing recommendations on intrafamilial oocyte donation in general, since it highlights important additional aspects from the perspectives of patients and their families. Electronic supplementary material The online version of this article (10.1007/s10545-018-0179-y) contains supplementary material, which is available to authorized users.

Hereditary breast and ovarian cancer caused by a BRCA1/2 mutation is the most frequent indication for preimplantation genetic diagnosis (PGD) in the Netherlands. The extent to which involved professionals are informed about this option, however, is unclear. The few available international studies mostly represent a limited range of professionals, and suggest that their knowledge about PGD for hereditary cancer syndromes is sparse and referral for PGD is based on limited understanding. A cross-sectional survey assessing awareness, knowledge, acceptability and PGD-referral for BRCA was completed by 188 professionals involved in the field of breast and ovarian cancer or reproduction. One-half of professionals were aware of PGD for BRCA, and most had a low to moderate level of knowledge. A total of 86% considered PGD for BRCA acceptable and 48% had referred patients with BRCA for PGD. Awareness and knowledge was higher among professionals who worked at a university hospital (compared with a general hospital). Knowledge of PGD was positively associated with discussing and referring for PGD, and PGD acceptability was associated with previous awareness. Although PGD counselling is the primary responsibility of the geneticist, other involved professionals may be gatekeepers as patients rely on them for raising awareness and referral. (C) 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

OBJECTIVE Reproductive decision making for couples with hereditary breast and ovarian cancer (HBOC) is complex and can result in decisional conflict or regret. This study investigated couples' support needs and aimed to identify vulnerable couples. Ultimately, we should strive to develop a clear standard of care guideline regarding reproductive decision support. METHODS Mixed methods were used for data collection. A focus group study was conducted among 18 couples (N = 35) with HBOC who had made a reproductive decision after reproductive counselling. Subsequently, 129 similar couples (N = 258) were invited to complete a cross-sectional survey based on the focus group study. RESULTS Clinical and practical aspects of reproductive counselling were positively evaluated in the focus group study, although couples indicated a need for additional support with emotional and social concerns in which their relationship, social environment, and the way they picture their desired family were key elements. The survey was completed by 86 participants. Making a reproductive choice was experienced as (very) difficult by 43%, and 69% showed a need for additional support during decision making. Younger participants and those who opted for a natural pregnancy experienced more difficulty with reproductive decision making, and partners showed a higher need for psychological support than carriers. CONCLUSIONS Couples with HBOC who need to make a reproductive decision have specific needs for guidance and support, of which the desired content and methods can vary. It is therefore important to identify vulnerable couples and to attune counselling to couples' needs.

Purpose The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. Methods A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. Results Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0–9.0) in the BRCA group as a whole, 6.5 (IQR 4.0–8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5–9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0–11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). Conclusions Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve. Electronic supplementary material The online version of this article (doi:10.1007/s10815-017-1014-3) contains supplementary material, which is available to authorized users.

Study question Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)? Summary answer We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility. What is known already A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI. Study design, size, duration We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples). Participants/materials, setting, methods We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1. Main results and the role of chance None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10). Limitations, reasons for caution Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations. Wider implications of the findings We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples. Study funding/competing interest(s) The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest. Trial registration number The trial was registered at the Dutch trial registry (NTR939).

Item does not contain fulltext STUDY QUESTION: To what extent are BRCA mutation carriers and their partners in the Netherlands aware about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) as reproductive options and what is their attitude towards these options? SUMMARY ANSWER: Awareness of PGD (66%) and PND (61%) among BRCA mutation carriers and their partners is relatively high and 80% and 26%, respectively, of BRCA carriers and their partners find offering PGD and PND for hereditary breast and ovarian cancer (HBOC) acceptable. WHAT IS KNOWN ALREADY: Internationally, awareness of PGD among persons with a genetic cancer predisposition appears to be relatively low (35%) and although acceptability is generally high (71%), only a small proportion of mutation carriers would consider using PGD (36%). However, for HBOC, there are no studies available that investigated the perspective of individuals with a confirmed BRCA1/2 mutation and their partners about PGD and PND including demographic and medical correlates of awareness and acceptability. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey was completed by 191 participants between July 2012 and June 2013. Participants were recruited through patient organizations (88%) and the databases of two Clinical Genetics departments in the Netherlands (12%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Male and female BRCA carriers and their partners completed an online survey, which assessed demographic and medical characteristics, and awareness, knowledge, acceptability and consideration of PGD and PND as main outcomes. Correlations between demographic and medical characteristics and the main outcomes were investigated. MAIN RESULTS AND ROLE OF CHANCE: The majority of respondents were female (87%), of reproductive age (86%) and about half reported a desire for a child in the future. About two-thirds (66%) were aware of PGD and 61% of PND for HBOC. PGD knowledge was moderate (5.5 on a 9-point scale) and acceptability of PGD and PND for HBOC was 80% and 26%, respectively. A minority would personally consider using PGD (39%) or PND (20%). Individuals with a higher educational level were more likely to be aware of PGD (P < 0.001) and PND (P < 0.001) and persons with a more immediate child wish were more often aware of PGD (P = 0.044) and had more knowledge about PGD (P = 0.001). PGD acceptability was positively associated with knowledge about PGD (P = 0.047), and PND acceptability was higher among partners in comparison to carriers (P = 0.001). Participants with a history of cancer and with a higher perceived seriousness of breast and ovarian cancer were more likely to consider using PGD (P = 0.003 and P < 0.001 respectively) or PND (P = 0.021 and P = 0.017 respectively). LIMITATIONS, REASONS FOR CAUTION: The response rate (23%) of participants invited by the clinical genetics departments was low, probably related to a simultaneous study that used a similar recruitment strategy within the same target group, which may have resulted in selection bias. Moreover, PGD knowledge was measured with an instrument that is not yet validated since to date such an instrument is not available in the literature. Finally, the cross-sectional design of this study limits us from drawing any causal conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Improvement of information provision remains needed, in order to timely inform all couples with HBOC about the available reproductive options and enable them to make a balanced reproductive decision. This may limit the risk of negative psychological impact due to decisional conflict and possible regret. STUDY FUNDING/COMPETING INTEREST(S): The Dutch breast cancer foundation Stichting Pink Ribbon (grant number 2010.PS11.C74). None of the authors have competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Item does not contain fulltext A low number of antral follicles may result in the selection of suboptimal oocytes that are prone to meiotic errors. The aim of this case-control study was to evaluate women receiving IVF treatment with low oocyte yield (defined as three or fewer oocytes retrieved after ovarian stimulation) who are at an increased risk of a trisomic pregnancy. Data were obtained from Danish and Dutch medical registries between 1983 and 2011. Analyses were carried out in 105 cases and 442 controls matched by age and year of IVF treatment. Cases were women with a trisomic pregnancy (trisomies 13, 18 or 21) resulting from fresh IVF treatment and confirmed by karyotyping. Cases were included regardless of pregnancy outcome. Controls were women with a live born child without a trisomy, resulting from fresh IVF treatment. Low oocyte yield was observed in 6.6% (29/440) of the women, of which 8.4% (7/83) were cases and 6.2% (22/357) controls. Low oocyte yield in IVF treatment was not associated with a higher risk of trisomic pregnancy (OR 1.43, 95% CI 0.64 to 3.19). Stratification for female age, adjustment for history of ovarian surgery, and gonadotrophin-releasing hormone protocol used did not change the results.

Study question How do couples with a BRCA1/2 mutation decide on preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) for hereditary breast and ovarian cancer syndrome (HBOC)? Summary answer BRCA couples primarily classify PGD and/or PND as reproductive options based on the perceived severity of HBOC and moral considerations, and consequently weigh the few important advantages of PGD against numerous smaller disadvantages. What is known already Awareness of PGD is generally low among persons at high risk for hereditary cancers. Most persons with HBOC are in favour of offering PGD for BRCA1/2 mutations, although only a minority would consider this option for themselves. Studies exploring the motivations for using or refraining from PGD among well-informed BRCA carriers of reproductive age are lacking. We studied the reproductive decision-making process by interviewing a group of well-informed, reproductive aged couples carrying a BRCA1/2 mutation, regarding their decisional motives and considerations. Study design, size, duration This exploratory, qualitative study investigated the motives and considerations taken into account by couples with a BRCA1/2 mutation and who have received extensive counselling on PGD and PND and have made a well-informed decision regarding this option. Eighteen couples took part in focus group and dyadic interviews between January and September 2012. Participants/materials, setting, methods Semi-structured focus groups were conducted containing two to four couples, assembled based on the reproductive method the couple had chosen: PGD (n = 6 couples) or conception without testing (n = 8 couples). Couples who had chosen PND for BRCA (n = 4) were interviewed dyadically. Two of the women, of whom one had chosen PND and the other had chosen no testing, had a history of breast cancer. Main results and the role of chance None of the couples who opted for PGD or conception without testing found the use of PND, with possible pregnancy termination, acceptable. PND users chose this method because of decisive, mainly practical reasons (natural conception, high chance of favourable outcome). Motives and considerations regarding PGD largely overlapped between PGD users, PND users and non-users, all mentioning some significant advantages (e.g. protecting the child and family from the mutation) and many smaller disadvantages (e.g. the necessity of in vitro fertilization (IVF), low chance of pregnancy by IVF/PGD). For female carriers, the safety of hormonal stimulation and the time required for PGD before undergoing preventive surgeries were important factors in the decision. Non-users expressed doubts about the moral justness of their decision afterwards and emphasized the impact the decision still had on their lives. Limitations, reason for caution The interviewed couples were at different stages in their chosen trajectory, up to 3 years after completion. This may have led to recall bias of original motives and considerations. Couples who did not actively seek information about PGD were excluded. Therefore the results may not be readily generalizable to all BRCA couples. Wider implications of the findings The perceived severity of HBOC and, for female carriers, the safety of hormonal stimulation and the time frames for PGD planning before preventive surgeries are essential items BRCA couples consider in reproductive decision-making. The emotional impact of this decision should not be underestimated; especially non-users may experience feelings of doubt or guilt up to several years afterwards. PGD counselling with tailored information addressing these items and decisional support in order to guarantee well-informed decision-making is needed. Study funding/competing interest(s) This study was funded by the Dutch breast cancer foundation Stichting Pink Ribbon, grant number 2010.PS11.C74. None of the authors have competing interests to declare. Trial registration number Not applicable.

STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization(IVF) with conventional ovarian stimulation, single embryotransfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?.SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child.WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF.STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization.PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates.MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were (sic)7187 for IVF-SET, (sic)8206 for IVF-MNC and (sic)5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences (sic)2117; 95% CI: (sic)1544-(sic)2657 and (sic)3136, 95% CI: (sic)2519-(sic)3754, respectively). The ICER for IVF-SET compared with IUI-COH was (sic)43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs.LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months.WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice.

STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling?SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling.WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision-making after genetic counselling on PGD in these specific couples.STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012.PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD.MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410).LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with.WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction.

Objectives: To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. Design: Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. Setting: 17 centres in the Netherlands. Participants: Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. Interventions: Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. Main outcome measures: The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality Results: 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). Conclusions: In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates. Trial registration: Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.

University Department of Paediatics, Level 4, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.There is a risk that ICSI may increase the transmission of mtDNA diseases to children born after this technique. Knowledge of the fate and transmission of paternal mitochondrial DNA is important since mutations in mitochondrial DNA have been described in oligozoospermic males. We have used an adaptation of solid phase mini-sequencing to exclude the presence of levels of paternal mtDNA >0.001% in ICSI families. This method is more sensitive than those used in previous studies and is sufficient to detect the likely paternal contribution (approximately 0.1-0.5% from simple calculations of expected dilution during fertilization). Using this method, we were able to detect concentrations as low as 0.001% paternal mtDNA in a maternal mtDNA background. No paternal mtDNA was detected in the embryonic (blood or buccal swabs) tissue of children born after ICSI nor in extra-embryonic tissue (placenta or umbilical cord). In conclusion, we did not detect paternal mtDNA in blood, buccal swabs, placenta or umbilical cord of children born after ICSI. We have found no evidence that ICSI increases the risk of paternal transmission of mtDNA and hence of mtDNA disorders.

Purpose This study aimed to evaluate the uptake of fertility preservation, rate of pregnancy, pregnancy outcome and breast cancer outcome after diagnosis of early breast cancer in young women who were referred to Maastricht University Medical Center, from the regional hospitals in the Southeast part of the Netherlands. Patients and methods We prospectively registered the demographics of patients, who visited our university hospital for counseling on fertility preservation at diagnosis of stage I-III invasive breast cancer in the years 2008-2015. At baseline, tumor and treatment characteristics were registered. During follow-up information on fullfilled childwish and disease status was collected. To compare the fertility preservation group and the non-fertility preservation group independent samples Student t-tests and Chi-square tests were conducted. Results In total 128 women with a median age of 32 years (19 – 43) were referred for fertility preservation counseling before start of chemotherapy, with an increase in referral in the more recent years. Thirty-nine (30.5%) women chose for fertility preservation: in 26 patients embryos were frozen, in seven oocytes, and in one both embryos and oocytes. In four patients the procedure was not succesfull. Patients who had chosen for fertility preservation more often had a male partner (87.2% vs 70.8%, P = 0.05) and had a smaller tumor size (median 19 versus 23 mm, P = 0.04) at the time of diagnosis compared to those who did not chose for fertility preservation. During a median follow-up of 30.3 months (range 0 – 96.9), 27 (21.1%) patients had tried to conceive: 14 (35.9%) women in the fertility versus 13 (14.6%) in the non-fertility preservation group. All of these had recovery of ovarian function after chemotherapy-induced ovarian failure. Only two women used the cryopreserved embryos, both succesfully and combined with preimplantation genetic diagnosis of the embryos because of germline mutations in BRCA1-gene. Eight patients in the fertility preservation group and seven patients in the non-fertility preservation group became at least once pregnant. In the fertility preservation group, eight healthy babies were born, one baby had Morbus Hirschsprung, one women is pregnant at this moment and one woman had a miscarriage. Of the eleven pregnancies in the non-fertility preservation group, nine healthy babies were born and one woman had two miscarriages. Of the referred 128 women, nine (7.0%) had breast cancer recurrence, three in the fertility preservation group versus six in the non-fertility preservation group. Conclusion One third of referred patients choose for fertility preservation before start of chemotherapy. In all of these patients, the ovarian function recovered. However, two couples used their cryopreserved embryos for preimplantation genetic diagnosis and both became pregnant. Since the follow-up time is relatively short, more data are mandatory to make a statement on the effectiveness of fertility preservation techniques in young breast cancers patients. Citation Format: Vriens IJ, Butalid EM, Schepers-van der Sterren EE, van der Poel MH, Jansen-Engelen SL, van Riel A-MM, van de Wouw YJ, Vriens BE, van Haaren ER, Lemaire BM, Dercksen WW, Luiten EJ, de Boer M, de Die-Smulders CE, Derhaag JG, van Golde RJ, Tjan-Heijnen VC. Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-03.

Purpose: The objective was to estimate the risk for subfertilemales with a constitutional sex chromosomal abnormalityof transmitting such a chromosome abnormality to theirchildren, conceived by intracytoplasmic sperm injection(ICSI). Methods: Semen samples were obtained from seven severelyoligospermic ICSI candidates. Six of them had a numericalsex chromosomal abnormality, including mosaic 45,X/46,XY,mosaic 46,XY/47, XXY, 47,XXY (Klinefelter's syndrome), and47,XYY. One male had a structural abnormality, namely, aninversion of the Y chromosome. The semen was studied bythree-color fluorescent in situ hybridization (FISH) withprobes specific for chromosomes 18,X, and Y. Results: Chromosomal aneuploidy rates of any of the threechromosomes were significantly higher than the aneuploidyrates observed in three control samples but comparable tothe rates observed in 10 ICSI candidates witholigoasthenoteratozoospermia (OAT) and a normal constitutionalkaryotype. Conclusions: Our data indicate that males with (mosaic) sexchromosomal abnormalities have no higher risk of producingoffspring with a sex chromosomal abnormality by ICSI thanOAT males with a normal karyotype.

Purpose:Genetic aspects of male subfertility and the novelty of intracytoplasmic sperm injection (ICSI) as a new technique can influence the development of zygotes and children born after ICSI. Therefore, we evaluated the outcome of ICSI compared to in vitro fertilization (IVF). Methods:Data from medical records of 233 total pregnancies and the follow-up of 132 children born after IVF and 120 after ICSI were retrospectively analyzed. Results:No differences were found between ICSI and IVF for early embryonic development and obstetric outcome. In both groups the rate of women undergoing prenatal chromosomal diagnosis was low, 30.0%. The congenital malformation rate was 3.0% after IVF and 1.7% after ICSI, which was not significantly different. Follow-up on development of children born after IVF and ICSI also showed no significant differences. Conclusions:Our results indicate that at this moment ICSI is a safe procedure. However, a consistent prospective follow-up is still mandatory to exclude possible risks.

Contains fulltext : 69812.pdf (Publisher’s version ) (Closed access) Human papillomavirus (HPV) infection is an important factor in cervical carcinogenesis. We describe 3 cases of patients with difficulties in diagnosing either a primary or recurrent cervical carcinoma. These cases illustrate that detection of integrated HPV is helpful in diagnosing cervical carcinoma.

Contains fulltext : 47546.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Radical trachelectomy is a surgical procedure for early-stage cervical carcinoma with preservation of the childbearing capacity. The current article presents a review of studies describing the results and complications of pregnancies after this procedure. METHODS: Sixteen studies were included (involving 355 radical trachelectomy procedures). Studies were reviewed for the number of patients included, the number attempting to conceive, the number who achieved pregnancy, the number of pregnancies achieved, the numbers of first and second trimester losses, and when delivery occurred in the third trimester. RESULTS: One hundred and fifty-three patients attempted to conceive during the follow-up period (range 1-144 months), this accounts for 43% of the patients that underwent radical trachelectomy. 70% of the patients attempting to conceive succeeded once or more than once. 161 pregnancies were described, finally resulting in 49% term deliveries. In about 15% of the patients who tried to conceive, cervical stenosis was found and resulted in menstrual disorders or fertility problems. Surgical dilatation resolved this problem in most cases but had to be repeated. Complications during pregnancy involved second trimester loss (13/161) and premature (< or =36 weeks AD) delivery (33/161). CONCLUSIONS: Pregnancy after radical trachelectomy is feasible. For various reasons, a number of patients (57%) did not try to get pregnant after the surgical procedure. The majority of the patients who tried to conceive after radical trachelectomy succeeded once or more than once (70%). Patients attempting to conceive need to be informed of the complications and risk factors, in particular, second trimester loss and premature delivery caused by premature rupture of membranes. Once pregnant, patients need to be carefully followed for cervical incompetence and other risk factors for premature rupture of membranes.

We have determined Y-chromosomal DNA haplotypes in 73 infertile European males carrying Y microdeletions and compared them with the haplotypes of 299 infertile males lacking microdeletions. Chromosomes were typed with a set of 11 binary Y markers, which identified 8 haplogroups in the sample. Haplogroup frequencies were compared between 3 microdeletion classes and the non-deleted infertile males. Deletions arise on many different haplotypic backgrounds. No statistically significant differences in frequency were seen, although the small number of AZFa deletions lay predominantly on one branch of the Y haplotype tree.

Genetic aspects of male subfertility and the novelty of intracytoplasmic sperm injection (ICSI) as a new technique can influence the development of zygotes and children born after ICSI. Therefore, we evaluated the outcome of ICSI compared to in vitro fertilization (IVF).Data from medical records of 233 total pregnancies and the follow-up of 132 children born after IVF and 120 after ICSI were retrospectively analyzed.No differences were found between ICSI and IVF for early embryonic development and obstetric outcome. In both groups the rate of women undergoing prenatal chromosomal diagnosis was low, 30.0%. The congenital malformation rate was 3.0% after IVF and 1.7% after ICSI, which was not significantly different. Follow-up on development of children born after IVF and ICSI also showed no significant differences.Our results indicate that at this moment ICSI is a safe procedure. However, a consistent prospective follow-up is still mandatory to exclude possible risks.