Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts.

STUDY QUESTION: Is there a relationship between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy and the semen quality of their sons? SUMMARY ANSWER: Our results suggest an association between maternal occupational exposure to potential EDCs, especially to pesticides, phthalates and heavy metals, and a decrease in several semen parameters. WHAT IS KNOWN ALREADY: Sexual differentiation, development and proper functioning of the reproductive system are largely dependent on steroid hormones. Although there is some animal evidence, studies on maternal exposure to EDCs during pregnancy and its effect on the semen quality of sons are scarce and none have focused on maternal occupational exposure. STUDY DESIGN, SIZE, DURATION: A cross-sectional study aiming to evaluate semen quality was carried out among Swiss conscripts aged 18 to 22 years between 2005 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Conscript and parent questionnaires were completed prior to the collection of a semen sample. Semen parameters were categorised according to the guidelines of the World Health Organization (WHO). Data on maternal employment during pregnancy were provided by the parent questionnaire. Maternal occupational exposure to potential EDC categories was defined using a job-exposure matrix (JEM). Logistic regressions were used to analyse the relationship between maternal occupational exposure to EDCs and each semen parameter adjusted for potential confounding factors. Results are presented using odds ratios and 95% confidence intervals. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1,737 conscripts provided a conscript and parent questionnaire, as well as a semen sample; among these 1,045 of their mothers worked during pregnancy. Our study suggests an association between occupational exposure of mothers during pregnancy to potential EDCs and low semen volume and total sperm count, particularly for exposure to pesticides (OR 2.07, 95% CI 1.11-3.86 and OR 2.14, 95% CI 1.05-4.35), phthalates (OR 1.92, 95% CI 1.10-3.37 and OR 1.89, 95% CI 1.01-3.55), and heavy metals (OR 2.02, 95% CI 1.14-3.60 and OR 2.29, 95% CI 1.21-4.35). Maternal occupational exposure to heavy metals was additionally associated with a low sperm concentration (OR 1.89, 95% CI 1.06-3.37). LIMITATIONS, REASONS FOR CAUTION: Several limitations should be noted, such as the indirect method for maternal occupational exposure assessment during the pregnancy (JEM) and the cross-sectional design of the study. WIDER IMPLICATIONS OF THE FINDINGS: Our observations reinforce the need to inform pregnant women of potential hazards during pregnancy that could impair their child's fertility. Additional studies are needed to confirm the involvement of EDCs. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Swiss Centre for Applied Human Toxicology: SCAHT and the 'Fondation privée des Hôpitaux Universitaires de Genève'. The collection of human biological material used for this study was supported by the FABER Foundation, the Swiss National Science Foundation (SNSF): NFP 50 'Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems', the Medical Services of the Swiss Army (DDPS) and Medisupport. The authors declare they have no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

[Rare diseases from a life insurance perspective]. / Seltene Erkrankungen aus Sicht der Lebensversicherungswirtschaft.

A rare disease is defined as a disease that affects a maximum of 5 in 10,000 people. As of today there are roughly 7000 different rare diseases known. On account of this one can say that "rare diseases are rare, but people affected by them are common". For Germany this amounts to: 4 million people that are affected by a rare disease. Diagnosis, therapeutic options and prognosis have substantially improved for some of the rare diseases. Besides the general medical advances--especially in the area of genetics--this is also due to networking and sharing information by so-called Centres of Competence on a national and international scale. This results in a better medical care for the corresponding group of patients. Against this backdrop, the number of people applying for life assurance who are suffering from a complex or rare disease has risen steadily in the last years. Due to the scarce availability of data regarding long-term prognosis of many rare diseases, a biomathematical, medical and actuarial expertise on the part of the insurer is necessary in order to adequately assess the risk of mortality and morbidity. Furthermore there is quite a focus on the issue of rare diseases from not only politics but society as well. Therefore evidence based medical assessment by insurers is especially important in this group of applicants--thinking of legal compliance and reputational risk.

Implementation of structured physical activity in the pediatric stem cell transplantation.

The peripheral blood stem cell transplantation (PBSCT) represents a specific, but stressful therapy for hemato-oncological diseases. While for adults, data suggest positive eff ects for a supportive sport therapy, this question is not evaluated sufficiently for children. The objective of this study was to examine the integration of sports activity into pediatric PBSCT and to indicate attainable results. This 2-step case-control-study included 23 children and adolescents from the PBSCT: During the isolation phase 13 patients trained 3 times per week on a cycle ergometer and passed a course with different sports equipment. Apart from recording physiologic adaptations, quality of live was inquired in a pre-post design using questionnaires. Guided interviews according to necessity and requirements for sports activity at the PBSCT unit completed the evaluation and were used for the intervention as well as for the control group (n = 10) without sports therapy. On the ergometer, patients trained average 25 min with 0.6 watt / kg. In the majority, a loss of muscular power could be avoided. Quality of life and fatigue symptoms improved by trend. Interview analysis showed general acceptance of physical activity during PBSCT. After initial skepticism due to the additional burden, our implementation study showed the feasibility of supportive sports therapy in PBSCT. Quality and flexibility of the equipment should be higher than normal and different physical and psychological conditions of the patients should be anticipated and integrated into the training program.

Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study.

BACKGROUND: Sperm counts have been steadily decreasing over the past five decades with regional differences in the Western world. The reasons behind these trends are complex, but numerous insights indicate that environmental and lifestyle factors are important players. OBJECTIVE: To evaluate semen quality and male reproductive health in Switzerland. MATERIALS AND METHODS: A nationwide cross-sectional study was conducted on 2523 young men coming from all regions of Switzerland, recruited during military conscription. Semen volume, sperm concentration, motility, and morphology were analyzed. Anatomy of the genital area and testicular volume was recorded. Testicular cancer incidence rates in the general population were retrieved from Swiss regional registries. RESULTS: Median sperm concentration adjusted for period of sexual abstinence was 48 million/mL. Comparing with the 5th percentile of the WHO reference values for fertile men, 17% of men had sperm concentration below 15 million/mL, 25% had less than 40% motile spermatozoa, and 43% had less than 4% normal forms. Disparities in semen quality among geographic regions, urbanization rates, and linguistic areas were limited. A larger proportion of men with poor semen quality had been exposed in utero to maternal smoking. Furthermore, testicular cancer incidence rates in the Swiss general population increased significantly between 1980 and 2014. DISCUSSION: For the first time, a systematic sampling among young men has confirmed that semen quality is affected on a national level. The median sperm concentration measured is among the lowest observed in Europe. No specific geographical differences could be identified. Further studies are needed to determine to what extent the fertility of Swiss men is compromised and to evaluate the impact of environmental and lifestyle factors. CONCLUSION: A significant proportion of Swiss young men display suboptimal semen quality with only 38% having sperm concentration, motility, and morphology values that met WHO semen reference criteria.

Quantitative morphometrical characterization of human pronuclear zygotes.

BACKGROUND: Identification of embryos with high implantation potential remains a challenge in in vitro fertilization (IVF). Subjective pronuclear (PN) zygote scoring systems have been developed for that purpose. The aim of this work was to provide a software tool that enables objective measuring of morphological characteristics of the human PN zygote. METHODS: A computer program was created to analyse zygote images semi-automatically, providing precise morphological measurements. The accuracy of this approach was first validated by comparing zygotes from two different IVF centres with computer-assisted measurements or subjective scoring. Computer-assisted measurement and subjective scoring were then compared for their ability to classify zygotes with high and low implantation probability by using a linear discriminant analysis. RESULTS: Zygote images coming from the two IVF centres were analysed with the software, resulting in a series of precise measurements of 24 variables. Using subjective scoring, the cytoplasmic halo was the only feature which was significantly different between the two IVF centres. Computer-assisted measurements revealed significant differences between centres in PN centring, PN proximity, cytoplasmic halo and features related to nucleolar precursor bodies distribution. The zygote classification error achieved with the computer-assisted measurements (0.363) was slightly inferior to that of the subjective ones (0.393). CONCLUSIONS: A precise and objective characterization of the morphology of human PN zygotes can be achieved by the use of an advanced image analysis tool. This computer-assisted analysis allows for a better morphological characterization of human zygotes and can be used for classification.

DG Connect Funded Projects on Information and Communication Technologies (ICT) for Old Age People: Beyond Silos, CareWell and SmartCare.

Information and communication technologies (ICT) are promising for the long-term care of older and frequently frail people. These innovations can improve health outcomes, quality of life and efficiency of care processes, while supporting independent living. However, they may be disruptive innovations. As all European member states are facing an increasing complexity of health and social care, good practices in ICT should be identified and evaluated. Three projects funded by DG CNECT are related to Active and Healthy Ageing (AHA) and frailty: (i) BeyondSilos, dealing with independent living and integrated services, (ii) CareWell, providing integrated care coordination, patient empowerment and home support and (iii) SmartCare, proposing a common set of standard functional specifications for an ICT platform enabling the delivery of integrated care to older patients. The three projects described in this paper provide a unique pan-European research field to further study implementation efforts and outcomes of new technologies. Below, based on a description of the projects, the authors display four domains that are in their views fundamental for in-depth exploration of heterogeneity in the European context: 1. Definition of easily transferable, high level pathways with solid evidence-base; 2. Change management in implementing ICT enabled integrated care; 3. Evaluation and data collection methodologies based on existing experience with MAST and MEDAL methodologies; and 4. Construction of new models for delivery of health and social care. Understanding complementarity, synergies and differences between the three unique projects can help to identify a more effective roll out of best practices within a varying European context.

Why lose an in vitro fertilization cycle when stimulation fails?

Different protocols using agonists of GnRH-a have been proposed for the ovarian stimulation in IVF cycles. In case of stimulation failure with the flare-up protocol, we have investigated whether an immediate switch to pituitary blockade by the long-acting analog may avoid the cycle to be canceled. This procedure allows a rescue of cycles among poor responders and does not have any deleterious effect on the recruitment of follicles, oocyte quality, fertilization, and pregnancy rates.

Prospective randomized study of two cryopreservation policies avoiding embryo selection: the pronucleate stage leads to a higher cumulative delivery rate than the early cleavage stage.

OBJECTIVE: To compare the cumulative live birth rates obtained after cryopreservation of either pronucleate (PN) zygotes or early-cleavage (EC) embryos. DESIGN: Prospective randomized study. SETTING: University hospital. PATIENT(S): Three hundred eighty-two patients, involved in an IVF/ICSI program from January 1993 to December 1995, who had their supernumerary embryos cryopreserved either at the PN (group I) or EC (group II) stage. For 89 patients, cryopreservation of EC embryos was canceled because of poor embryo development (group III). Frozen-thawed embryo transfers performed up to December 1998 were considered. MAIN OUTCOME MEASURE(S): Age, oocytes, zygotes, cryopreserved and transferred embryos, damage after thawing, cumulative embryo scores, implantation, and cumulative live birth rates. RESULT(S): The clinical pregnancy and live birth rates were similar in all groups after fresh embryo transfers. Significantly higher implantation (10.5% vs. 5.9%) and pregnancy rates (19.5% vs. 10.9%; P< or = .02 per transfer after cryopreserved embryo transfers were obtained in group I versus group II, leading to higher cumulative pregnancy (55.5% vs. 38.6%; P < or = .002 and live birth rates (46.9% vs. 27.7%; P< or = .0001. CONCLUSION(S): The transfer of a maximum of three unselected embryos and freezing of all supernumerary PN zygotes can be safely done with significantly higher cumulative pregnancy chances than cryopreserving at a later EC stage.

Microdissection of mouse and human zona pellucida using a 1.48-microns diode laser beam: efficacy and safety of the procedure.

OBJECTIVE: To investigate the efficacy and safety of a small and affordable 1.48-microns continuous wave diode laser for zona pellucida (ZP) microdissection. DESIGN: Mouse and human oocytes and zygotes were submitted to ZP drilling. The hole characteristics and possible laser-induced structural alterations of the neighboring cytoplasm were investigated with scanning and transmission electron microscopy. The safety of the procedure was checked on control and drilled zygotes by determining their ability to develop in vitro and in vivo. SETTING: Collaborative study between three Swiss academic centers. INTERVENTIONS: The collimated diode laser beam was delivered through a 45x objective of an inverted microscope and focused through the culture dish and culture medium in 1- to 3-microns spots. MAIN OUTCOME MEASURE: Safety assessment of the laser drilling procedure. RESULTS: The 1.48-microns radiation achieves a rapid, precise, and easily controlled lysis of the ZP without any micromanipulative handling of the eggs. Different shapes of holes can be produced by varying the laser beam intersection site on the ZP, laser power, and irradiation time. The energy needed to drill holes of a given diameter is greater for zygotes than for oocytes. Safety of the drilling procedure is confirmed by the lack of damage at the ultrastructural and biologic levels. CONCLUSIONS: The low-cost 1.48-microns diode laser allows an easy, objective-driven, nontouch microdissection of the ZP. The procedure is safe, as drilled embryos give rise to normal and fertile offspring.

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins.

OBJECTIVE: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN: Cohort study. SETTING: Fertility center in a university hospital. PATIENT(S): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Follicle-stimulating hormone bioactivity in idiopathic normogonadotropic oligoasthenozoospermia: double-blind trial with gonadotropin-releasing hormone.

OBJECTIVE: To identify, among patients with idiopathic normogonadotropic oligoasthenozoospermia, those with low bioactive follicle-stimulating hormone (FSH), possibly because of inadequate gonadotropin-releasing hormone (GnRH) pulsatility, whose bioactive FSH and sperm could be improved by GnRH treatment. DESIGN: Randomized, double-blind, placebo-controlled trial with intranasal (IN) GnRH, followed by open GnRH treatment. SETTING: Outpatient endocrinology clinic. PATIENTS: Twenty-eight infertile men with idiopathic normogonadotropic oligoasthenozoospermia. INTERVENTIONS: Gonadotropin-releasing hormone or placebo was self-administered IN every 2 hours. MAIN OUTCOME MEASURES: Serum immunoreactive and bioactive FSH and semen analyses. RESULTS: Ten men showed a low basal FSH bioactive/immunoreactive ratio, which increased in 5 of them under GnRH without parallel sperm modification. Sperm improvements were observed in 10 patients with no parallel evolution of FSH bioactive/immunoreactive ratio. Unpredicted by sperm changes, three pregnancies developed on placebo and 5 on GnRH. CONCLUSIONS: Low bioactive FSH was not the cause of idiopathic normogonadotropic oligoasthenozoospermia in our patients and could not predict response to GnRH. Pulsatile GnRH did not improve sperm beyond random fluctuations.

Can the results of treatment of deep venous thrombosis be improved by combining surgical thrombectomy with regional fibrinolysis?

A new mode of treatment of extensive acute and subacute deep venous thrombosis of the lower extremities is introduced. For this purpose the beneficial effects of surgical thrombectomy and of thrombolysis with streptokinase are combined during the course of a single surgical intervention. Rapid-flow regional perfusion is the vehicle used for administration of streptokinase and probably represents the third arm of this therapeutic approach by adding a hemodynamic wash-out effect. Because the thrombolytic agent is rinsed out of the circuit at the end of regional perfusion the usual side effects and contra-indications of this drug are avoided. Early and late results of this treatment are assessed clinically and with repeat venograms in a group of 9 patients. Highly satisfactory results were obtained in 6 patients with complete anatomical and functional restoration of deep veins along their entire length in three cases. It is felt that continued use of this method is warranted and that the results of treatment of deep venous thrombosis can thus be improved.

The syndrome of Klippel-Trenaunay, a polyvalent angiodysplasia.

The syndrome of Klippel and Trenaunay remains basically a venous angiodysplasia. Newer investigative methods have however allowed us to distinguish a polyvalence of the vascular morphology. The basic clinical triad: vascular nevus, varicosities and limb hypertrophy remains the main clinical diagnostic characteristic.

Molar pregnancy with a coexistent fetus after intracytoplasmic sperm injection. A case report.

BACKGROUND: Normal fertilization is usually considered to have occurred when two pronculei (2PN) and two polar bodies are observed. Exceptions are the single pronucleated zygote resulting from asynchronous pronuclei. CASE: A 29-year-old woman entered a program of intracytoplasmic sperm injection and embryo transfer because of her husband's oligoasthenoteratozoospermia. Two cleavage-stage embryos (four blastomeres, grade 1 and 2) were obtained from one fertilized oocyte containing distinct 2PN and the other a single pronucleus (1PN). At 15 weeks' gestation the patient developed severe preeclampsia requiring termination of the pregnancy. Histopathologic examination and DNA ploidy by image analysis were consistent with a twin pregnancy combining a complete hydatidiform mole and normal pregnancy. CONCLUSION: We hypothesize that this 1PN was at the origin of the hydatidiform mole. This case highlights the danger of transferring an embryo having 1PN.

[Ovulation induction by pulsatile intravenous administration of Gn-RH to patients with hypothalamic amenorrhea]. / Induzione dell'ovulazione con somministrazione pulsatile intravenosa di Gn-RH in pazienti con amenorrea ipotalamica.

Intravenous pump administration (Zyklomat, Ferring) of GnRH (Lutrelef, Ferring) has been used to induce ovulation in 16 patients suffering from hypothalamic amenorrhea between January 1989 and December 1991. One to 6 cycles were performed for a total of 47 cycles. GnRH pulses were set at 20 micrograms/pulse every 90 min up during the follicular phase and decreased to 1 pulse/120 min during the 3-5 days following ovulation. Thereafter, the luteal phase was supported by 1000 IU HCG/48 h up to the end of the 5th week. Response to the treatment was monitored with seriC E2, P and LH and vaginal echography. Cycles (N = 3) were cancelled when E2 did not reach at least 0.25 nmol/l after 30 days. An E2 level > 0.8 nmol/l, associated with a mature follicle (> 20 mm), and the presence of a LH peak or an increased progesterone level were used to determine the day of ovulation. In case of normozoospermy (N = 9), sexual intercourse was recommended to the patients (27 cycles), whereas an intrauterine insemination was performed in case of a male factor (N = 7, 20 cycles). Results can be summarized as follows: 39 (83%) cycles were ovulatory and led to 9 (19%) clinical and 6 (13%) biochemical pregnancies. Five (8.5%) pregnancies aborted and 5 (11%) came to full term. After exclusion of the male factors, the pregnancy rate reaches 26%/initiated cycle, 28%/ovulatory cycle and 56%/patient. No patient developed a hyperstimulation syndrome or a multiple pregnancy. Three cycles (6.3%) were interrupted due to 2 superficial phlebitis and 1 pump failure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of the urologist in the management of infertile men at the time of sperm intracytoplasmic injection]. / Rôle de l'urologue dans la prise en charge de l'homme infertile à l'heure de l'injection intracytoplasmique de spermatozoïdes.

Although intracytoplasmic sperm injection (ICSI) revolutionized treatment and prognosis of male infertility, checkup (case history, clinical and paraclinical examinations) practiced by urologist in infertile man keeps all its place. Varicocele, congenital or acquired seminal duct obstruction, urogenital tract infection, or ejaculation disorder must be sought, because these affections remain accessible to treatment.

LIF and sIL-2R plasma concentrations in IVF patients on the day of embryo transfer: predictive markers of IVF outcome.

Successful implantation is still the limiting step in IVF. We hypothesized that maternal plasma concentrations of certain cytokines at the time of embryo transfer could predict the likelihood of successful implantation and pregnancy. sIL-2R, IL-6, LIF, and MMP2 concentrations were measured in plasma from 160 IVF patients (natural and stimulated IVF cycles) on the morning of the embryo transfer (ET0) and 14 days later (ET+14). Patients were ultimately subdivided into four groups depending on the IVF treatment outcome (pregnancy failure, biochemical pregnancy, first-trimester miscarriage and normal term delivery). In natural and stimulated IVF cycles at ET0, sIL-2R concentrations were threefold higher in biochemical pregnancies than in pregnancy failures (P=0.020), and in natural cycles only, 2.5-fold higher in normal term deliveries than in pregnancy failures (P=0.023). Conversely, in natural and stimulated IVF cycles at ET0, LIF concentrations were one third lower in biochemical pregnancies/first-trimester miscarriages compared with pregnancy failures (P=0.042). We suggest that high sIL-2R and low LIF concentrations in maternal plasma on the morning of the embryo transfer might be associated with increased risks of early pregnancy loss, while a basal level of sIL-2R is necessary for normal term delivery outcome. Both cytokine measurements might therefore be useful in the management of IVF patients, and modulation of their concentrations could be investigated as a therapeutic alternative for women with abnormal concentrations at the time of embryo transfer.