Lifestyle Risk Factors for Breast Cancer in BRCA1/2-Mutation Carriers Around Childbearing Age.

BRCA1/2-mutation carriers are at high risk of breast cancer (BC) and ovarian cancer. Physical inactivity, overweight (body mass index ≥25, BMI), smoking, and alcohol consumption are jointly responsible for about 1 in 4 postmenopausal BC cases in the general population. Limited evidence suggests physical activity also increases BC risk in BRCA1/2-mutation carriers. Women who have children often reduce physical activity and have weight gain, which increases BC risk. We assessed aforementioned lifestyle factors in a cohort of 268 BRCA1/2-mutation carriers around childbearing age (born between 1968 and 1983, median age 33 years, range 21-44). Furthermore, we evaluated the effect of having children on physical inactivity and overweight. Carriers were asked about lifestyle 4-6 weeks after genetic diagnosis at the Familial Cancer Clinic Nijmegen. Physical inactivity was defined as sports activity fewer than once a week. Carriers were categorized according to the age of their youngest child (no children, age 0-3 years and ≥4 years). In total, 48% of carriers were physically inactive, 41% were overweight, 27% smoked, and 70% consumed alcohol (3% ≥8 beverages/week). Physical inactivity was 4-5 times more likely in carriers with children. Overweight was not associated with having children. Carriers with children are a subgroup that may specifically benefit from lifestyle support to reduce BC risk.

Very high uptake of risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers: A single-center experience.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO ≤40 (BRCA1) or ≤45 (BRCA2) years of age, provided that mutation status is known by that age: 90.8% and 97.3% of BRCA1 and BRCA2 mutation carriers, respectively. CONCLUSIONS: The uptake of RRSO among BRCA1/2 mutation carriers who were counseled at our Family Cancer Clinic is extremely high. High uptake might be largely attributed to the directive and uniform way of counseling by professionals at our Family Cancer Clinic. Given the fact that RRSO is often undergone at premenopausal age in our population, future research should focus on minimizing long-term health consequences of premature surgical menopause either by optimization of hormone replacement therapy or by investigating alternative strategies to RRSO.

Follow-up of children born after ICSI with epididymal spermatozoa.

BACKGROUND: To evaluate the safety of ICSI with epididymal sperm, this study compared children born after ICSI treatment with epididymal sperm and children conceived after IVF and ICSI with ejaculated sperm. Additionally, the results of a multidisciplinary, multicentre follow-up of the children conceived with epididymal sperm at 2 years of age are described. METHODS: This follow-up study included 378 children conceived after ICSI with epididymal sperm (percutaneous epididymal sperm aspiration: PESA group) and a control group of 1192 IVF and 1126 ICSI (with ejaculated sperm) children, all with a gestational age of 20 weeks or more. Questionnaires were sent at birth, 1 year and 4 years of age, collecting data on parental, pregnancy and child factors. A total of 148 PESA children were assessed at 2 years of age for motor performance, mental- and language development and compared with the Dutch norms. RESULTS: PESA children showed no increased risks for stillbirths, total deaths and malformations. They also did not differ from IVF and ICSI children in gender rate, birthweight and gestational age. The mental Bayley score was higher (P < 0.05) for PESA singletons and parents reported fewer (P < 0.05) behavioural problems in the PESA group than the Dutch reference group. The scores for syntactic and lexical development for the PESA singletons were better (P < 0.05) than the Dutch standards. CONCLUSIONS: ICSI with epididymal sperm does not lead to more stillbirths or congenital malformations in comparison to IVF and ICSI with ejaculated sperm and does not lead to poor development in comparison with the Dutch reference group.

Karyotyping, congenital anomalies and follow-up of children after intracytoplasmic sperm injection with non-ejaculated sperm: a systematic review.

BACKGROUND: For men with azoospermia, it is possible to father their own progeny by intracytoplasmic sperm injection (ICSI) with epididymal or testicular sperm. Some studies show that children born after assisted reproductive technology (ART) are at increased risk of birth defects, other studies suggest that there is no extra concern about ICSI children conceived with epididymal or testicular sperm. METHODS: Studies about the karyotypes of fetuses, congenital anomalies and the follow-up of the children born after ICSI with non-ejaculated sperm were identified by means of a systematic literature search. RESULTS: Eight relevant studies were identified; two studies reported karyotype, five reported malformations and one reported follow-up of children after ICSI. In total, there were 55 out of 1973 (2.8%) abnormal karyotypes in the ICSI with ejaculated sperm group, 0 out of 31 in the ICSI with epididymal sperm group and 5 out of 191 (2.6%) in the ICSI with testicular sperm group. Major malformations were found in 543 out of 12 377 (4.4%) in the ICSI with ejaculated sperm group, 17 out of 533 (3.2%) in the ICSI with epididymal sperm group and 31 out of 670 (4.6%) in the ICSI with testicular sperm group. CONCLUSIONS: Although there were no statistical differences, the study groups were small and heterogenic, with a number of potential biases. We therefore recommend a standardized methodology of follow-up studies after ART, with well-defined groups of ICSI with ejaculated sperm, ICSI with epididymal sperm and ICSI with testicular sperm, and a control group of naturally conceived children.

Constitutional DNA copy number changes in ICSI children.

BACKGROUND: Over the last three decades, technological developments facilitating assisted reproductive techniques (ART) have revolutionized the treatment of subfertile couples, including men suffering from severe oligospermia or azoospermia. In parallel with the advent of these technologies, there is a great concern about the biological safety of ART. This concern is supported by the clinical observation that the frequency of congenital malformations is slightly elevated among ART-conceived children. METHODS: In this explorative study, we have used tiling-resolution BAC array-mediated comparative genomic hybridization to investigate the incidence of de novo genomic copy number changes in a group of 12 ICSI children, compared with a control group of 30 naturally conceived children. RESULTS: In 6 of the 12 ICSI children, we found 10 apparently de novo 'same direction genomic copy number changes' [i.e. simultaneous copy number gain (or loss) with respect to both biological parents], notably losses. In statistically significant contrast, similar observations were encountered only six times in the control group in 5 of the 30 children. However, our study group was small, so a larger group is needed to confirm these findings. CONCLUSIONS: Loci at which we found de novo alterations are known from the human genome database to be prone to large DNA segment copy number changes. As discussed, various molecular mechanisms, including the consequences of delayed male meiotic synapsis and replication fork stalling at early embryonic cell cycles, might trigger these copy number changes.

Decreased ovarian reserve relates to pre-eclampsia in IVF/ICSI pregnancies.

BACKGROUND: Pre-eclampsia affects 2-10% of all pregnancies and is a major cause of maternal and fetal morbidity and mortality. As compared with the general population, IVF pregnancies are associated with a 2.7-fold risk of pre-eclampsia. An advanced age and associated subfertility in the IVF group reflects a general decrease in ovarian reserve, which itself has been linked to cardiovascular disease. We tested the hypothesis that decreased ovarian reserve is associated with pre-eclampsia as a vascular complication in IVF/ICSI pregnancies. METHODS: In this retrospective case-control study, 41 cases with a history of pre-eclampsia were compared to 82 matched controls without hypertension or (pre)eclampsia. All pregnancies were established after IVF or ICSI. Several indicators of ovarian reserve such as variables related to basal ovarian function and response to hyperstimulation were compared in both the groups by multivariate analysis. The condition of the neonates was evaluated as well. RESULTS: A higher amount of total administered FSH and FSH per day, together with a lower number of obtained oocytes during IVF treatment, were associated with an increased risk to pre-eclampsia in a subsequent pregnancy. The administered FSH per follicle and per obtained oocyte showed even stronger relationships, the latter having the best predictive value. Neonatal outcome was comparable between the groups. CONCLUSION: Diminished responsiveness of the ovaries to FSH stimulation in an IVF cycle, reflecting decreased ovarian reserve, is associated with an increased risk of developing pre-eclampsia in a subsequent pregnancy.

[Obstructive azoospermia in men who wish to father children; diagnosis and surgical sperm retrieval]. / Mannen met obstructieve azoöspermie en kinderwens; diagnostiek en chirurgische spermawinning.

OBJECTIVE: To evaluate diagnostic procedures and surgical sperm retrieval in men with suspected obstructive azoospermia who wish to father children. DESIGN: Descriptive, retrospective. METHOD: During the period 1 April 1999-31 December 2001 93 men suspected of having obstructive azoospermia underwent surgical sperm retrieval by means of percutaneous epididymal sperm aspiration (PESA). In each patient a testicular biopsy was performed to determine the Johnsen score (a score > or = 8 is equivalent to a normal spermatogenesis). Cryopreservation was performed whenever possible. The findings in both percutaneous and surgical sperm retrieval were compared. RESULTS: In 76 patients (82%) epididymal motile sperm were obtained using PESA. Their Johnsen score on the testis biopsy was 9.1 (range: 7.4-10). In 73 of the patients the Johnsen score was > or = 8. In the 17 patients (18%) in whom no sperm were found with PESA, the median Johnsen score was 5.8 (range: 2-9.8). Epididymal sperm were not found in patients with a testicular volume < 15 ml. In all 28 patients who had undergone a vasectomy in the past, motile sperm were found along with a Johnsen score > or = 8. In 23 of the 24 patients with congenital bilateral absence of the vas deferens (CABVD) the Johnsen score was > or = 8. Cryopreservation was possible in 45 (59%) of all patients and in 5 (35%) of the 13 patients with an unknown cause for the obstructive azoospermia. CONCLUSION: In men with suspected obstructive azoospermia in whom sperm were found using PESA, a diagnostic testis biopsy provided no additional relevant information about the spermatogenesis. There was always a good spermatogenesis after vasectomy. CBAVD patients probably had at least some focal areas in the testes with normal spermatogenesis. Sperm retrieval and cryopreservation could be carried out less frequently in the case of obstructions with an unknown cause.

[Obstructive azoospermia in men who wish to father children; initial clinical results of intracytoplasmatic sperm injection (ICSI) with surgically retrieved epididymal semen]. / Mannen met obstructieve azoöspermie en kinderwens; eerste klinische resultaten van intracytoplasmatische sperma-injectie met chirurgisch verkregen zaad.

OBJECTIVE: To evaluate the results of intracytoplasmatic sperm injection (ICSI) with surgically retrieved epididymal semen. DESIGN: Prospective, descriptive. METHODS: Patients with an obstructive azoospermia confirmed by cytological examination of a testis biopsy, and conforming to the regular IVF/ICSI criteria as laid down in 2001 at the University Medical Centre St Radboud Nijmegen, the Netherlands, were included for percutaneous epididymal sperm aspiration (PESA) and ICSI. The main outcome measure was the ongoing pregnancy rate per initiated cycle. RESULTS: A total of 44 cycles were started in 31 couples. In 43 cases (98%) an ovum pick-up was performed and 41 (93%) embryo transfers were carried out. In 19 (43%) cases, treatment resulted in a positive pregnancy test and 15 (34%) ongoing pregnancies were recorded. In total, 17 healthy children were born (11 boys and 6 girls). CONCLUSION: ICSI with surgically retrieved semen was successfully used as a treatment for childlessness caused by obstructive azoospermia.