Patients from across Europe have similar views on patient-centred care: an international multilingual qualitative study in infertility care.

BACKGROUND: International patient centredness concepts were suggested but never conceptualized from the patients' perspective. Previously, a literature review and a monolingual qualitative study defined 'patient-centred infertility care' (PCIC). The present study aimed to test whether patients from across Europe value the same aspects of infertility care. METHODS: An international multilingual focus group (FG) study with 48 European patients from fertility clinics in Austria, Spain, the UK and Belgium, with deductive content analysis. RESULTS: All specific care aspects important to participants from all countries could be allocated to the 10 dimensions of PCIC, each discussed in every FG, including: 'information provision', 'attitude of and relationship with staff', 'competence of clinic and staff', 'communication', 'patient involvement and privacy', 'emotional support', 'coordination and integration', 'continuity and transition', 'physical comfort' and 'accessibility'. Most specific care aspects (65%) were discussed in two or more countries and only a few new codes (11%) needed to be added to the previously published coding tree. Rankings from across Europe clearly showed that 'information provision' is a top priority. CONCLUSIONS: The PCIC-model is the first patient-centred care (PCC) model based on the patients' perspective to be validated in an international setting. Although health-care organization and performance differ, the similarities between countries in the infertile patients' perspective were striking, as were the similarities with PCC models from other clinical conditions. A non-condition specific international PCC model and a European instrument for the patient centredness of infertility care could be developed. European professionals can learn from each other on how to provide PCC.

Promoter elements and transcription factors involved in differentiation-dependent human chorionic gonadotrophin-alpha messenger ribonucleic acid expression of term villous trophoblasts.

Differentiation of primary villous cytotrophoblasts into syncytia is associated with increasing production of alpha and beta human CG subunits, which is predominantly governed at the level of messenger RNA expression. Here, we present a detailed study on the mechanisms involved in the differentiation-dependent regulation of the trophoblast-specific CGalpha gene promoter. Site-directed mutations in each of the five DNA-elements of the composite enhancer were performed to investigate the contribution of the individual regulatory sequences to the overall transcriptional activity of the promoter at two different stages of trophoblast in vitro differentiation. We show that deletion of one cyclic AMP response element (CRE) did not affect CGalpha promoter activity in cytotrophoblasts; however, it reduced transcription by 33% in differentiating cultures. Removal of both CREs almost abolished transcription at early and later stages of in vitro differentiation. Upon mutation the enhancer elements alphaACT, JRE, and CCAAT significantly decreased luciferase reporter transcription; however their contribution to the total promoter activity did not change during in vitro differentiation. Contrary to that, mutated TSE diminished promoter activity by 19% during 12 and 48 h of cultivation but reduced luciferase expression by 78% between 48 and 84 h of differentiation. In electrophoretic mobility shift assay, the TSE interacted with activating protein (AP)-2alpha in both primary trophoblasts and choriocarcinoma cells. While CRE-interacting proteins were detectable 12 h after isolation, the TSE-binding complex did not appear before 36 h of in vitro differentiation. During syncytium formation increasing protein expression of activating transcription factor (ATF)-1, cAMP response element-binding protein (CREB)-1, and AP-2alpha was observed on Western blots. Moreover, phosphorylated CREB-1 and ATF-1 accumulated between 24 and 78 h of trophoblast cultivation. By fluorescence immunohistochemistry, we show that CREB-1 was predominantly expressed in syncytiotrophoblasts, whereas ATF-1 and AP-2alpha localized to the syncytium and some cytototrophoblasts as well as to stromal and endothelial cells of the placental villus. Phosphorylated CREB-1/ATF-1 and the coactivator protein CBP were primarily detected in syncytial nuclei, suggesting the presence of functional, cAMP-dependent transcriptional complexes in the differentiated tissue. In agreement to the in vivo situation, phosphorylated CREB-1/ATF-1 were observed in nuclei of the differentiated trophoblast cultures. The activity of the CGalpha promoter as well as CREB-1/ATF-1 phosphorylation increased upon elevation of cAMP levels and overexpression of the catalytic subunit of protein kinase A. Additionally, we demonstrate that overproduction of the enzyme enhanced protein expression and binding of AP-2alpha to the TSE. We conclude that differentiation-dependent transcription of the CGalpha gene in villous trophoblasts is mainly governed by increasing expression of AP-2alpha and PKA-dependent phosphorylation of CREB-1 and ATF-1.

Hypoxia downregulates continuous and interleukin-1-induced expression of human chorionic gonadotropin in choriocarcinoma cells.

The effects of hypoxia on JEG-3, BeWo, and JAr cells were investigated and it was demonstrated that choriocarcinoma cells can be used as a model to study the molecular mechanism of hypoxia-mediated repression of human chorionic gonadotropin (hCG). Cells were maintained under hypoxia (3.5 per cent O2) for 72 h without loss of variability, as demonstrated by the fact that 93-98 per cent of the cells excluded trypan blue. Up to 48 h, cell growth was not significantly influenced by hypoxia, and analysis by flow cytometry did not reveal major changes in cell cycle distribution. JEG-3, BeWo, and JAr cells which were grown for 48 h under hypoxia secreted 81, 67, and 71 per cent less hCG than cells cultivated under normoxic conditions. The extent of hCG reduction was dependent on the oxygen concentration. Moreover, release of the hormone from hypoxic JAr cells was not stimulated upon addition of interleukin-1 (IL-1). Treatment of JEG-3 cells with methotrexate (MTX) led to a 4.3-fold augmentation in hCG secretion and to an increase in the amount of G0/G1 cells. However, when cells were cultured in the presence of MTX and hypoxia, hCG secretion decreased 10-fold and beta hCG mRNA declined to almost undetectable levels suggesting that downregulation of beta hCG mRNA is the major cause of diminished hCG release under hypoxic conditions.

Successful clinical application of laser for micromanipulation in an in vitro fertilization program.

This is a report of our preliminary experience with assisted hatching by laser with a case of an ongoing twin pregnancy. We used an erbium laser to create a 20 to 30-micrometer opening in the zona pellucida of human embryos to facilitate the embryonic hatching after the embryo transfer. Our report proves that it is possible to obtain a pregnancy using a simple and quick laser method instead of mechanical or chemical procedures within the scope of micromanipulation.

Relationship of the individual uterine size and the endometrial thickness in stimulated cycles.

At present there is no agreement regarding the usefulness of monitoring the endometrial thickness in stimulated cycles. We tested prospectively the hypothesis of a linear relationship of the given individual uterine size and the endometrial thickness in stimulated cycles using a 240 degrees transvaginal sector scanner. There was a strong correlation of the uterine dimension with the endometrial thickness in the midfollicular and the early luteal phase. Our findings suggest that the endometrial thickness is determined by the individual uterine architecture and therefore not predictive of the likelihood of implantation.

Successful treatment of a heterotopic pregnancy by sonographically guided instillation of hyperosmolar glucose.

OBJECTIVE: To describe a new conservative approach in the treatment of heterotopic pregnancy. DESIGN: Case report. SETTING: A university hospital and an outpatient IVF center. INTERVENTION(S): Transvaginal ultrasonography-guided puncture of the ectopic gestational sac and instillation of hyperosmolar glucose. RESULT(S): The ectopic pregnancy resolved without further intervention. The intrauterine pregnancy resulted in a full-term live birth. CONCLUSION(S): Transvaginal injection of hyperosmolar glucose may be an effective conservative treatment for unruptured ectopic pregnancies in cases of heterotopic pregnancy.

Air in the uterine cavity after embryo transfer.

OBJECTIVE: To examine the effect on the pregnancy rate (PR) caused by air bubbles loaded into the transfer catheter to bracket the embryo-containing medium. DESIGN: Prospective, randomized study. SETTING: One hundred ninety-six consecutive ETs in the Institute of Sterility Treatment. INTERVENTIONS: Air bubbles were loaded into the transfer catheter concomitantly with the medium in group I (n = 98), whereas in group II (n = 98) no air bubbles were used. RESULTS: The PR of group I equals that of group II. CONCLUSIONS: Bracketing the embryo-containing medium by air bubbles offers several advantages, especially the possibility of tracking the air on the ultrasound monitor to localize the embryos after the ET. For these reasons we recommend using the proven method.

Ovarian function during low-dose oral contraceptive use.

Lowering the total steroid dose in modern oral contraceptives (OCs) has been connected with a higher incidence of ovarian follicle and cyst formation. To investigate the presence of ovarian follicles and cysts by means of vaginal ultrasonography and serum hormone determinations during use of two low-dose OCs, 65 volunteers were randomized to receive either 20 micrograms ethinylestradiol (EE) + 150 micrograms desogestrel (group A) or 35 micrograms EE + 250 micrograms norgestimate (group B) for a 2-month study period. At baseline, 39% of women in group A and 31% in group B exhibited at least one follicle < 35 mm in diameter. By the end of the second treatment cycle, the frequency of these follicles had decreased to 14% in each group. Only one subject in the higher estrogen group developed an ovarian cyst > 35 mm. One subject in each group demonstrated hormone levels characteristic of ovulation; no pregnancy occurred in either group. The 20 micrograms EE preparation was not found to lead more often to ovarian follicles or cysts when compared with a 35 micrograms EE preparation, possibly because of the type and dose of the progestogen used.

PIP: In Austria, health workers randomly allocated 28 women to the group using the low-dose oral contraceptive (OC) Mercilon (20 mcg ethinyl estradiol [EE] + 150 mcg desogestrel) and 35 women to the group using the low-dose OC Cilest (35 mcg EE + 250 mcg norgestimate). No one had used OCs for at least one month before the study. Clinicians used vaginal ultrasonography and serum hormone levels to learn the degree of ovarian suppression during use of these two low-dose OCs by looking for ovarian follicles and cysts. Before beginning to use the OCs, 39% of women in the Mercilon group and 31% of those in the Cilest group had at least one ovarian follicle. By the second treatment cycle, the frequency of ovarian follicles (35 mm) had fallen significantly to 14% in both groups as compared to baseline (p 0.05). No one in the Mercilon group developed a follicle larger than 35 mm in diameter that remained for more than 4 weeks (i.e., ovarian cyst). One woman in the Cilest group did develop an ovarian cyst (46 mm), however. It appeared during the pill-free week after the first pill cycle and steadily decreased to 40 mm during the second pill cycle. One woman in each group had hormone levels indicative of ovulation. No one in either group became pregnant. These findings suggest that the type and dose of progestogen in the Mercilon OC (desogestrel) were responsible for the lower frequency of ovarian follicles and cysts in the lower-dose OC group than that in the higher-dose OC.

Contraceptive knowledge and attitudes of Austrian adolescents after mass media reports linking third-generation oral contraceptives with an increased risk of venous thromboembolism.

We performed a representative survey to determine the level of knowledge of 1,010 Austrian adolescents aged 14 to 24 years about selected facts relating to the recent massive news coverage of the increase in the risk of venous thromboembolism in users of third-generation oral contraceptives and to assess the contraceptive behavior of this population. The overall use rate of oral contraceptives and condoms had increased significantly between 1991 and 1996. Sixty-six percent of the adolescents surveyed stated not having heard or read any media reports on oral contraceptives. Only 8% of those who had knew that most reports focused on the pill as a possible cause of venous thromboembolism, whereas the majority of respondents indicated that the media conveyed doubts regarding the health safety of oral contraceptives in general. Nearly half of adolescents were unable to define what a thrombosis was. Thus, although the mass media play an important role in transmitting medical information, the dissemination of practical, accurate advice on the risks of a drug and competent patient counseling is reserved for the health care professionals.

Hystero-salpingo scintigraphy: a routine investigation in sterile women?

Based on the spontaneous migration of radioactive tracer from the posterior vaginal fornix to the ovaries and peritoneal cavity, several attempts were made to assess hystero-salpingo scintigraphy (HSS). The low acceptance rate by sterile women of routine investigation of tubal function may be due to a fear of radiation exposure and unpleasant examination procedures. Our protocol for HSS adopts a low dose of radioactive tracer (0.2-0.3 mCi), a defined mode of application (between the external and internal os of the cervical canal) and a short imaging time (60 min). From 1990 to 1992, we investigated 60 fallopian tubes in 32 sterile women by HSS, hystero-salpingography (HSG) and/or chromopertubation during laparoscopy (LPSC). The results of HSG and HSS corresponded in 15 of 49 fallopian tubes, LPSC and HSS in 9 of 24. None of the 32 patients had become pregnant naturally during the average observation period of 17 months. Two patients became pregnant after in-vitro fertilization. HSS, performed according to our protocol, causes less pain and results in a lower dose of radiation than HSG (about 50%). It is well accepted by patients and is easy to perform. As an investigation of tubal function, HSS may serve as an additional examination technique in cases of presumed tubal sterility.

Placental insufficiency and maternal death caused by advanced stage of breast cancer in third trimester.

We describe a case with placental, and general metastases, resulting in transient intrauterine and general hypoxia, and with additionally clinical features similar to HELLP syndrome. A patient in the third trimester with dyspnea at rest developed right heart failure during c-section. During emergency thoracotomy the patient went into generalized shock and died after intense CPR. Placental insufficiency was based on a multilocal metastatic event, decreasing the utero-placental perfusion.

[Micromanipulation of human gametes within the scope of assisted reproduction]. / Mikromanipulation menschlicher Gameten im Rahmen der assistierten Reproduktion.

Poor function of spermatozoa accounts for half of all human infertility. Micromanipulation methods within the framework of in vitro fertilization treatment may enhance fertilization of the egg and may allow the establishment of an ongoing pregnancy in cases of severe male infertility. This review presents different methods of micromanipulation which are routinely applied in male factor infertility and for preimplantation diagnosis.

[Multiple pregnancy]. / Mehrlingsschwangerschaften.

The incidence of multiple pregnancies has increased considerably over the past 20 years in the western world. The number of twin pregnancies has increased by approximately 25% and the rate of triplet and higher order multiple pregnancies has more than doubled. This is due to the use of ovarian hyperstimulation and assisted reproduction techniques, and to the increasing maternal age. Multiple pregnancy can be considered as the most important adverse outcome of infertility treatment. The main determinant for outcome and management of multiple pregnancies is the chorionicity. This can be determined by ultrasound until 14 weeks of gestation. Twenty percent of all twin pregnancies are monochorionic, and 15% of these develop severe twin to twin transfusion syndrome, which is best treated by LASER separation of the communicating blood vessels. Obstetric complications associated with multiple gestation also occur more frequently in monochorionic twins. They include increased incidence of preterm labor, intrauterine growth restriction and assisted or surgical delivery. Neonatal problems include low birthweight and increased prevalence of congenital malformations. Overall, there has been a decrease in neonatal mortality of twins and triplets over the past 10 years, which is mainly due to the enormous advances in neonatal intensive care.

'Chemical curettage' using intrauterine methotrexate injection.

A 22-year-old woman with multiple urogenital anomalies presented for the second time with a blighted ovum situated in the rudimentary right horn of a uterus communicans bicornis. A dilatation and curettage was not possible owing to the inaccessibility of this horn. The first blighted ovum was aborted in 1989 (at age 21 years) following the use of intramuscular prostaglandin therapy. On this occasion, therapy was by the transvaginal, intrauterine (intra-amniotic) instillation of 100 mg methotrexate and a complete abortion of the products of conception occurred. Similar to the treatment of ectopic pregnancy, in certain cases, termination of intrauterine pregnancies using local methotrexate injection may be considered.

The use of fibrin sealant for embryo transfer: development and clinical studies.

Many embryo transfers after in-vitro fertilization may fail because of expulsion of the embryos from the uterus. Approximately 5-8% of pregnancies resulting from embryo transfer are ectopic. The aim of our study was to find a technique to avoid ectopic pregnancies and to improve the pregnancy rate. We used a two-component fibrin sealant which also contains a fibrinolysis inhibitor (aprotinin) at various concentrations. After gaining experience with mouse embryos, the sealant was used in human embryo transfer with great success. The results of a pilot study encouraged us to perform a prospective randomized study on 546 patients (270 with fibrin sealant, 276 conventional embryo transfers). There were 47 (17.0%) orthotopic pregnancies and 6 (2.2%) ectopic pregnancies in the control group, whereas there were 51 (18.9%) intrauterine and no ectopic pregnancies in the treatment group. The difference in ectopic pregnancies was statistically significant (P less than 0.05). With regard to the aprotinin concentration, there was a trend towards better results with 100-150 kIU (28.5% clinical pregnancies) in comparison to 250-300 kIU (19.2%) or no aprotinin (20.4%) (not significant). Further improvements of the technique may raise the pregnancy rate when fibrin sealant is used. As shown in our prospective randomized study, ectopic pregnancies may be completely avoided.

Leiomyoma of the vesicovaginal septum.

A 69-year-old woman presented with a solid homogenous mass in the area of the posterior wall of the urinary bladder. A transvaginal approach was used to remove the mass located in the vesicovaginal septum. Histology revealed a benign smooth spindle cell tumor and immunohistochemistry confirmed leiomyoma.

Laser surgery under sonographic control: preliminary experimental investigations.

The laser has gained increasing importance during recent years as a useful addition to the physician's therapeutic armoury. Reports on successful prostatectomy by ultrasound-guided laser coagulation in an animal model encouraged us to evaluate the possibility of using this technique for gynecological indications (for example, ectopic pregnancy, endometriosis, ovarian cysts, and other areas of medicine). We used two different laser systems. The devices consisted of a real-time abdominal scanner (4-5 MHz) or a transvaginal sector scanner (5-7.5 MHz) coupled to a neodymium : YAG laser with a 1064 nm wavelength or a holmium : YAG laser with 2120 nm wavelength. An experimental set-up using a water bath revealed clear visibility of the fiber tip and the laser irradiation in real-time ultrasound at 7.5 MHz. Subsequently, a needle (routinely used in transvaginal puncture of ectopic pregnancy) was placed in animal and human tissue specimens and the laser fiber was inserted. The tissue was exposed to both laser systems at different energy densities, pulse rates and pulse widths. The sonographic appearance was recorded and correlated with the macroscopic findings. Results indicate that the holmium : YAG laser at a pulse rate of 5 Hz and a power of 2 watts is effective in removing substantial amounts of tissue. Moreover, it offers immediate visualization and control of the damaged area by producing a strongly echogenic focus. The neodymium : YAG laser showed comparatively poorer sonographic visibility and a precarious thermal mode of action, which are important considerations influencing its applicability. The holmium : YAG laser system with its non-thermal mode of action seems promising for the further clinical application of ultrasound-guided laser surgery.

Prognostic appraisal of success and failure in an in vitro fertilization program by transvaginal Doppler ultrasound at the time of ovulation induction.

In 323 stimulated cycles of women participating in in vitro fertilization treatment, a transvaginal Doppler examination was performed on the day of ovulation induction to investigate the value of blood flow velocimetry of the uterine artery. The results showed a significantly lower pulsatility index in patients who conceived (n = 42) compared with those who did not become pregnant (n = 272). The differences were especially marked during the first cycles. These results suggest that studies of the uterine hemodynamic response are useful in appraising the likelihood of success of implantation after embryo transfer.

Agricultural work and male infertility.

Data from couples (n = 103) seeking artificial insemination with donor sperm because of poor sperm quality and a control group of couples treated by in-vitro fertilization due to female causes were analysed according to the occupations of the spouses. Comparison of occupational categories revealed a significant difference in the prevalence of agricultural occupation (11/103 vs. 1/103, p < 0.01) between the group with male factor infertility and the normospermic controls. These patients also reported more long-term exposure to several insecticides and other pesticides. These toxic chemicals probably have a detrimental effect on male fertility and therefore we suggest more caution in the way they are handled.