The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial.

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

Differences in quality of life and emotional status between infertile women and their partners.

STUDY QUESTION: Do the quality of life (QoL) and the risk factors for emotional problems during and after treatment of infertile women differ from their partners? SUMMARY ANSWER: Women have lower levels of fertility-related QoL, and more and differing risk factors for emotional problems during and after treatment than their partners. WHAT IS KNOWN ALREADY?: The psychological impact of infertility in patients negatively affects their QoL and is also related to increased discontinuation of treatment. Moreover, psychological factors might positively affect pregnancy rates. However, it is still unclear if differences in QoL and emotional status exist between infertile women and their partners. So far, research mainly focused on generic instruments to measure patients' QoL in the area of fertility care. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of infertile couples within 32 Dutch fertility clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women and their partners (both heterosexual and lesbian couples) under any treatment and at any stage of treatment in one of the 32 participating clinics. Per clinic, 25-75 patients were randomly selected depending on clinic size. In total, 1620 women and their partners were invited separately to complete the FertiQoL and SCREENIVF questionnaires to measure their level of QoL and risk factors for emotional problems during and after treatment, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 946 women (response rate 58%) and 670 partners (response rate 41%) completed the questionnaire set. As 250 women and 150 partners were already pregnant, questionnaires from 696 women and 520 partners could be analysed. Women scored significantly lower on the FertiQoL total scores [B = -6.31; 95% confidence interval (CI) = -7.63 to 4.98] and three of the FertiQoL subscales (Emotional, Mind-Body and Social) than their partners, indicating lower QoL. Scores on the SCREENIVF questionnaire were significantly higher for women (B = 0.22; 95% CI = 0.06-0.38), indicating that women are more at risk for developing emotional problems (and these factors differed from those of their partners) during and after fertility treatment than their partners. LIMITATIONS, REASONS FOR CAUTION: Although the number of participants is high (n = 1216), the relatively low response rate, especially for partners (41%), may have influenced the results through selection bias. An analysis of non-responders could not be performed. The FertiQoL and SCREENIVF questionnaires, which have been validated only in women starting a first IVF cycle, should also be validated for studying partners. In addition, the SCREENIVF questionnaire has been validated in Dutch women only and further research in an international setting is also required. WIDER IMPLICATIONS OF THE FINDINGS: Our study results represent the Dutch infertile population as more than one-third of all Dutch clinics participated in the study. As the FertiQoL questionnaire is an internationally validated questionnaire already, these results can be put in a more broader and international perspective. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Merck Sharp & Dohme (MSD), The Netherlands. There are no competing interests.

Predicting dropout in fertility care: a longitudinal study on patient-centredness.

STUDY QUESTION: Are clinic factors, including patients' experiences with patient-centred care, associated with dropout in fertility care? SUMMARY ANSWER: Clinic factors, including patients' experiences with patient-centred care, are not related to dropout. WHAT IS KNOWN ALREADY: In fertility care, a significant proportion of patients do not achieve pregnancy because they discontinue treatment prematurely. Many studies have tried to identify factors predicting dropout, showing incompatible results. However, these studies mainly focus on factors at the treatment and patient level, while clinic factors have received little attention. STUDY DESIGN, SIZE, DURATION: This prospective, longitudinal study was nested within a large RCT, which aims to improve the level of patient-centredness of Dutch fertility care. Of the 1620 infertile women who were invited to participate, the baseline measurement of the study (T0) included 693 women who completed a questionnaire about their experiences with patient-centred fertility care. The follow-up of the patients was 1 year (T1). PARTICIPANTS/MATERIALS, SETTING, METHODS: All included women suffered from infertility and were undergoing treatment in one of the 32 Dutch clinics involved in the trial. Levels of patient-centredness were determined using the Patient-Centredness Questionnaire-Infertility (PCQ-Infertility) at T0. Meanwhile, a professionals' questionnaire was used to gather additional information on characteristics of the clinic (e.g. the number of patients per year or the presence of a fertility nurse). After 1 year, at T1 measurement, patients completed a questionnaire on their current status in fertility care, including their main reason for discontinuation if applicable. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 693 non-pregnant women completed the questionnaire set at T0 and 534 women (77.1%) provided consent for follow-up. At T1 measurement, 434 women (81.3%) completed the questionnaire and 153 of these women (35.2%) continued treatment while 76 women (17.5%) dropped out. Another 175 women (40.3%) had achieved pregnancy and 30 patients (7.9%) were advised to discontinue treatment for medical reasons. Neither levels of patient-centredness nor the additional clinic characteristics differed significantly between dropouts and compliers. However, patients who did not receive assisted reproduction treatment (ART; e.g. underwent intrauterine insemination, IUI) before they dropped out had significantly lower scores on the PCQ-Infertility subscale 'Respect for patients' values' than patients who continued their treatment [odds ratio (OR) 0.57; 95% confidence interval (CI) 0.34-0.95]. Patients who received ART and, subsequently, dropped out had higher scores on the PCQ-Infertility subscale 'Patient involvement' than those receiving non-ART (OR 2.39; 95% CI 1.02-5.59). LIMITATIONS, REASONS FOR CAUTION: We were not able to follow-up a significant proportion (ca. 19%) of the 1620 women who were invited for T0 measurement, which might have biased our results. We also excluded patients who were still in the diagnostic work-up stage and this might have influenced our results as it is known that patients dropout at this stage. As the PCQ-Infertility was validated in patients who were already undergoing treatment, we decided to focus on this patient group only. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide a better insight into those factors influencing dropout from the perspective of factors in the clinic itself. Although most clinic factors were not related to dropout, clinic factors might be of use when predicting dropout for specific patient groups, such as patients receiving ART and non-ART. Future research should involve an exploration of more specific predictors of dropout at the patient, treatment and clinic levels. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Merck Serono, the Netherlands. No competing interests declared.

Feasibility of screening patients for emotional risk factors before in vitro fertilization in daily clinical practice: a process evaluation.

STUDY QUESTION: Is patient screening for emotional risk factors before starting IVF treatment feasible? SUMMARY ANSWER: Introduction of screening for emotional risk factors by a validated instrument (SCREENIVF) in couples treated by IVF or ICSI is feasible, indicated by a moderate to high and stable uptake rate, a high acceptance of the process of SCREENIVF, and a high acceptability of the presented risk profile by the patients. WHAT IS KNOWN ALREADY: SCREENIVF is a validated screening tool to identify women at risk for emotional maladjustment preceding the start of their IVF/ICSI treatment. STUDY DESIGN, SIZE AND DURATION: This was a prospective cohort study, including data of two cohorts of patients (304 and 342 patients), with a duration of 3 months per cohort. For the first cohort, we sent a process evaluation to 210 patients and it was completed by 91 patients. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All 304 patients (male and female) who started IVF/ICSI between 1 December 2009 and 28 February 2010 in our tertiary IVF clinic were eligible. The uptake rate of SCREENIVF was assessed as the response rate to the screening questionnaire. One year later, we re-assessed the uptake rate in 342 new patients to assess the stability of the uptake rate. A non-responder assessment in patients who did not complete SCREENIVF was carried out. Finally, patients' characteristics and their experiences with SCREENIVF as well as their consequent actions were assessed by an additional process evaluation questionnaire sent some months later to 210 patients. MAIN RESULTS AND THE ROLE OF CHANCE: The uptake rate of SCREENIVF was 78-80%. One-third of the responders were found to be at risk for emotional maladjustment, which was comparable with previous studies using SCREENIVF. Of 27 non-responders to SCREENIVF, 41% explained non-response by 'no actual need for psychological help' and 19% forgot to complete the screening. The response rate to the process evaluation was 43% (n = 91). Of these, 90% found the screening was useful, and almost all patients were positive about the SCREENIVF questionnaire. Furthermore, 93% recognized themselves in the risk profile based on SCREENIVF. Of the patients at risk, 21% reported planning to seek professional help, but 46% of the at-risk patients experienced travelling distance as an obstacle to seek psychological help. We concluded that screening patients for emotional risk factors is feasible. In future, psychosocial care offered by the Internet may be promising in meeting the barrier of travelling distance. LIMITATIONS, REASONS FOR CAUTION: People were asked to fill in SCREENIVF for clinical purposes pretreatment. There might be a selection bias in the people who did not fill in SCREENIVF, which may be due to already existing psychological problems or language problems. The low response rate of the process evaluation questionnaire and the mono-centre evaluation may be confounders and may have influenced our analysis opportunities. WIDER IMPLICATIONS OF THE FINDINGS: The generalizability of this data is unknown with respect to other ethnic groups. Furthermore, more research is needed to evaluate psychosocial factors in male partners. Future research should also focus on the barriers and facilitators for help-seeking behaviour. STUDY FUNDING/COMPETING INTEREST(S): There was no funding for this study and no conflict of interest.

[Diagnostic image (261). A woman with vulval ulcera and uveitis]. / Diagnose in beeld (261). Een vrouw met vulvaire ulcera en uveitis.

A 49-year-old woman suffered from vulval and vaginal ulcera and from oral mucosal lesions and uveitis due to Behçet's disease.

The interaction between Sillence type and BMD in osteogenesis imperfecta.

Clinical studies with bisphosphonates in children with osteogenesis imperfecta (OI) show an increase in BMD and a decrease in fracture rate. Bone strength in children with OI is not only influenced by changes in BMD but also by changes in collagen I structure of the organic bone matrix. Therefore, we studied the interaction between these two factors in a cross-sectional, single center study including 54 children. We assumed that vertebral deformities in OI represent an unbalance between load and bone strength. Body weight was considered to be a well quantifiable load on vertebral bodies. BMD served as a marker, representing the amount of bone tissue available for vertebral load bearing, and the Sillence classification, either type I or III/IV, as a marker representing the quality of the organic bone matrix. Independent associations were observed between the prevalence of vertebral deformities and (1) Sillence type (OR: 5.7, 95%Cl:1.2-26.8), (2) BMD (OR: 0.003, 95%Cl: 0-0.25) and (3) body weight (OR: 1.15, 95%Cl: 1.05-1.25). Regarding the anthropometrical differences among the different types of OI, the BMD/body weight ratio was introduced to evaluate the BMD in relation to body size. Prevalent vertebral deformities were associated with low BMD/body weight ratios (OR: 0.04, 95%Cl: 0.008-0.2) in OI type I, but no association was found in type III/IV. It was concluded that BMD and Sillence type have independent relationships with vertebral deformities. The BMD/body weight ratio correlates with vertebral deformities in children with OI type I. Its meaning in types III/IV needs further research with larger samples because of the relatively high prevalence of vertebral deformities in this group.

Minimizing liver, bowel, and gastric activity in myocardial perfusion SPECT.

UNLABELLED: When using 99mTc-tetrofosmin for myocardial perfusion SPECT, increased liver, intestinal, or gastric activity may create a major problem in the visual and quantitative interpretation Of the inferoposteroseptal walls, particularly at rest. The aim of this study was to determine what measures were required to minimize this extracardial activity. METHODS: Ninety-seven patients had a SPECT scan at rest without attenuation correction. They were divided into 3 groups. Preparation consisted of no action taken (group 1), 150 mL whole milk 10 min after administration of tetrofosmin (group 2), or 450 mL water 10 min before acquisition (group 3). A further 55 patients had a SPECT scan at rest with attenuation correction. They were also divided into 3 groups, and preparation consisted of 150 mL whole milk 10 min after administration of tetrofosmin (group 4), 450 mL water 10 min before acquisition (group 5), or both whole milk and water (group 6). The presence of activity in liver, bowel, and stomach was determined visually on reconstructed images. Activity was defined as interfering when it might result in either an underestimation or an overestimation of the uptake in the myocardial wall. RESULTS: Interfering activity was seen in 83% of the patients in group 1, in 74% in group 2, in 33% in group 3, in 61% in group 4, in 67% in group 5, and in 20% of group 6. CONCLUSION: The interpretation of inferoposteroseptal wall activity on myocardial rest SPECT images is facilitated by having the patient drink both whole milk and water at specified times before data acquisition.

The long-term effects of force-transmission in an injured wrist, measured with dual-energy X-ray absorphometry: a case report.

PURPOSE: To investigate the feasibility of using a dual-energy X-ray absorphometry (DEXA) scan to predict long-term force-transmission patterns in wrists. MATERIAL AND METHODS: Both wrists of a man with morbid Kienböck stage IIIa disease of his left wrist (avascular necrosis of the lunate) were examined by a DEXA scan to determine the differences in bone density in the distal radius. RESULTS: In the distal radius of the injured wrist, a shift in bone density was seen toward the scaphoid fossa, which resembles the shift in force-transmission pattern described in force-transmission studies of the wrist. CONCLUSIONS: These differences can be interpreted as a result of an altered force-transmission pattern in the injured wrist.

In vitro and in vivo detection of functional somatostatin receptors in canine insulinomas.

UNLABELLED: Ten dogs with hypoglycemia due to insulinomas were studied to assess the expression of somatostatin receptors (SSTRs) in canine insulinomas and its potential diagnostic value. METHODS: The response of circulating glucose and insulin concentrations to the subcutaneous administration of a somatostatin analog, octreotide, was measured. SSTRs were visualized in vitro by autoradiography. [Iodine-125-Tyr3]-octreotide and [125I-Tyr11]-somatostatin-14 (SRIF-14) were used as radioligands. SPECT was performed 6 hr after the injection of [111In-DTPA-D-Phe1]-octreotide. RESULTS: After subcutaneous injection of 50 micrograms octreotide, plasma glucose concentration rose from 2.3 +/- 0.2 mmol/liter to 3.2 +/- 0.3 mmol/liter at 3.5 hr (p < 0.05) and plasma insulin concentration decreased from 451 +/- 135 pmol/liter to a nadir of 249 +/- 115 pmol/liter at 30 min (p < 0.05). In vitro autoradiography revealed that all primary insulinomas and their metastases had specific SSTRs for both [125I-Tyr3]-octreotide and [126I-Tyr11]-SRIF-14. Scatchard analysis of SSTR binding in the tumor tissue of one dog revealed high-affinity binding sites for [125I-Tyr3]-octreotide (dissociation constant (Kd) 1.7 nM, maximum binding capacity (Bmax) 499 fmol/mg membrane protein). The primary tumor and/or metastases in five of six dogs could be visualized and localized by SPECT with [111In-DTPA-D-Phe1]-octreotide. In the remaining dog, multiple metastases (< 3 mm) were found in the liver at necropsy, apparently too small to be visualized by SPECT. CONCLUSION: The in vitro autoradiography and ligand binding studies indicate that canine insulinomas express one type of SSTR. This is in contrast with findings in humans where, on the basis of ligand binding studies, different subtypes of SSTRs have been identified. The uniformity of SSTRs, their high frequency of expression and the high incidence of metastatic disease make canine insulinomas very suitable for investigation of the value of SRIF analogs in the diagnosis and treatment of metastasized endocrine pancreatic tumors.

Can technetium 99m bisdiethylphosphinoethanebis-t butylisocyanide (99mTc-DEPIC) be used for routine radionuclide ventriculography?

Radionuclide ventriculography is a useful investigation in the evaluation of cardiac function. Generally, in vivo technetium 99m-labelled red blood cells (RBC) yield good quality images in ventriculography. However, it is widely believed that some drugs have an adverse effect on RBC labelling. Zanelli et al. (1987) developed a radiopharmaceutical (technetium 99m bis-diethylphosphinoethanebis-t-butylisocyanide, 99mTc-DEPIC) to obtain better results in patients using such drugs. We undertook a prospective study of 6 patients with cardiovascular and/or pulmonary disease using several kinds of drugs to evaluate imaging of the cardiac blood pool with 99mTc-DEPIC and in vivo labelled 99mTc-RBC. After injection, blood samples were taken, and gated equilibrium blood pool studies were performed. The radiochemical purity of the injected 99mTc-DEPIC varied from 76.4 to 93.6% (mean 86.4%, SD 5.7%). The protein (pre-albumin) binding was 100%. Biological half-life in blood varied from 3.3 to 4.7 h (mean 4.1 h, SD 0.5 h). For 99mTc-RBC no significant blood disappearance was seen for 8 h. The percentage of RBC-bound 99mTc varied from 96.9% to 98.3% (mean 97.0%, SD 0.5%) and was stable for at least 8 h. The heart-to-lung, heart-to-spleen, and heart-to-liver ratios were higher for 99mTc-RBC than for 99mTc-DEPIC. Furthermore, 99mTc-DEPIC showed a significant decline of the ejection fraction with time. Visually, the images with 99mTc-RBC were superior to those with 99mTc-DEPIC, especially a few hours after injection. According to our findings, in vivo labelling of 99mTc-RBC is still the method of choice for routine radionuclide ventriculography.(ABSTRACT TRUNCATED AT 250 WORDS)