Oil-Based or Water-Based Contrast for Hysterosalpingography in Infertile Women.

BACKGROUND: Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect. METHODS: We performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle. RESULTS: A total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups. CONCLUSIONS: Rates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270 .).

A revised prediction model for natural conception.

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61).

Presence of human papillomavirus in semen in relation to semen quality.

STUDY QUESTION: Is the presence of human papillomavirus (HPV) in semen associated with impairment of semen quality? SUMMARY ANSWER: In a large cohort of males seeking fertility evaluation, no associations were observed between seminal HPV presence and semen parameters. WHAT IS KNOWN ALREADY: HPV is commonly detected in semen samples. Whether the presence of HPV is related to impairment of semen quality, remains unclear. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included a cohort of 430 males. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners in couples seeking fertility evaluation provided one semen sample per person. Semen samples were tested for HPV-DNA using GP5+/6+-PCR. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. The presence of antisperm antibodies was assessed by a mixed agglutination reaction (MAR)-test. MAIN RESULTS AND THE ROLE OF CHANCE: Overall HPV was detected in 14.9% (64/430) of semen samples, including 2.1% (9/430) that contained both high-risk (hr) HPV and low-risk (lr) HPV types, 8.8% (38/430) with exclusively hrHPV types and 4.0% (17/430) with exclusively lrHPV types. The presence of HPV in semen was not associated with the age of the participants, seminal pH, semen volume, total sperm count, sperm concentration, progressive motility or the presence of antisperm antibodies. LIMITATIONS, REASONS FOR CAUTION: This study did not observe an association between HPV presence in semen and impairment of semen quality. However, we cannot exclude an effect of seminal HPV on early embryo development and clinical reproductive outcomes. WIDER IMPLICATIONS OF THE FINDINGS: As HPV is frequently present in semen, screening of donor semen for HPV should be considered to prevent iatrogenic cervical HPV infections in the recipient. However our findings do not support standardized HPV testing of semen in the diagnostic work-up of subfertile couples. STUDY FUNDING/COMPETING INTERESTS: This study was sponsored by an unrestricted grant of Stichting Researchfonds Pathology Amsterdam, the Netherlands. P.J.F.S. has been on the speakers bureau of Roche, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell B.V. J.B. has been on the speakers bureau of Qiagen and has been a consultant for Roche, DDL Diagnostic Laboratory, GlaxoSmithKline and Merck. D.A.M.H. has been member of the scientific advisory boards of Amgen and Pfizer, and has been on the speakers bureau of Hologic/Gen-Probe. C.J.L.M.M. has been on the speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Seegene, has served occasionally on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck, Roche and Genticel, and has occasionally been a consultant for Qiagen. Formerly, C.J.L.M.M. was a minority shareholder of Delphi Biosciences, which bankrupted in 2014. C.J.L.M.M. is a minority shareholder of Diassay B.V. P.J.F.S., D.A.M.H. and C.J.L.M.M. have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center. R.L., M.G.D., P.G.A.H., D.T.M.P., and I.H. do not have any conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Reporting multiple cycles in trials on medically assisted reproduction.

Trials assessing effectiveness in medically assisted reproduction (MAR) should aim to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess the extent to which multiple cycles are reported in MAR trials. A sample of randomized controlled trials (RCT) was collected on MAR, published in four time periods, in 11 pre-specified peer-reviewed journals; 253 trials were included: 196 on IVF, 37 on intrauterine insemination and 20 on ovulation induction. Forty-eight (19%) reported on multiple cycles, which was significantly more common in trials on intrauterine insemination and ovulation induction compared with trials on IVF (P < 0.01). Both trials on IVF were multi-centre trials, and those using live birth as primary outcome, reported significantly more often on multiple cycles (OR 3.7 CI 1.1 to 12.5) and (OR 8.7 CI 1.8 to 40.3), respectively. Trials designed to compare protocol variations reported multiple cycles less often (OR 0.07 CI 0.01 to 0.74). Most RCT on MAR, especially those on IVF, do not report cumulative pregnancy rates. As not all women become pregnant in their first cycle, the clinical significance of these trials is limited.

Diagnostic accuracy of hysterosalpingo-foam-sonography to confirm tubal occlusion after Essure® placement as treatment for hydrosalpinges.

Consensus globally is that hydrosalpinges need to be treated before IVF owing to their negative influence on outcomes. The current standard treatment is laparoscopic salpingectomy. A potential less invasive treatment is proximal occlusion of a hydrosalpinx by hysteroscopic placement of an Essure® device. Tubal occlusion after Essure® placement needs to be verified by hysterosalpingography (HSG). However, this is a painful examination, that exposes patients to radiation. Hysterosalpingo-foam sonography (HyFoSy) is a less invasive alternative test to confirm proximal tubal occlusion. This prospective diagnostic accuracy study evaluated if HyFoSy is as accurate as HSG to confirm proximal tubal occlusion after placement of an Essure® device as treatment for a hydrosalpinx before IVF. Thirty-eight treated hydrosalpinges in 26 women were evaluated. Proximal occlusion was verified by HyFoSy (index test) and HSG (standard reference). The accuracy of HyFoSy was 97.4% (95% CI 92.3% to 100.0%). Sensitivity and specificity were 97.1% (95% CI.84.6% to 99.5%) and 100.0% (95% CI 40.2% to 100.0%), respectively. After an Essure® device is placed as treatment for a hydrosalpinx before IVF, HyFoSy is as able as HSG to confirm proximal tubal occlusion. If HyFoSy demonstrates tubal patency, a subsequent HSG needs to be carried out to validate this finding.

Cost-effectiveness of assisted conception for male subfertility.

Intrauterine insemination (IUI), with or without ovarian stimulation, IVF and intracytoplasmatic sperm injection (ICSI) are frequently used treatments for couples with male subfertility. No consensus has been reached on specific cut-off values for semen parameters, at which IVF would be advocated over IUI and ICSI over IVF. The aim of this study was to evaluate the cost-effectiveness of interventions for male subfertility according to total motile sperm count (TMSC). A computer-simulated cohort of subfertile women aged 30 years with a partner was analysed with a pre-wash TMSC of 0 to 10 million. Three treatments were evaluated: IUI with and without controlled ovarian stimulation; IVF; and ICSI. Main outcome was expected live birth; secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. The choice of IVF over IUI with ovarian stimulation and ICSI over IVF depends on the willingness to pay for an extra live birth. If only cost per live birth is considered for each treatment, above a pre-wash TMSC of 3 million, IUI is less costly than IVF and, below a pre-wash, TMSC of 3 million ICSI is less costly. Effectiveness needs to be confirmed in a large randomized controlled trial.

Semen analysis and prediction of natural conception.

STUDY QUESTION: Do two semen analyses predict natural conception better than a single semen analysis and will adding the results of repeated semen analyses to a prediction model for natural pregnancy improve predictions? SUMMARY ANSWER: A second semen analysis does not add helpful information for predicting natural conception compared with using the results of a single semen analysis and addition of the second analysis to a prediction model for natural conception did not improve predictions. WHAT IS KNOWN ALREADY: A major problem with semen analyses is the large variability of results within an individual. High-quality evidence is lacking on how many semen analyses need to be performed during the fertility workup to achieve an accurate prediction of conception. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of 897 consecutive couples presenting with subfertility in two university hospitals in the period 2002-2004 in the Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: The laboratories scored sperm parameters according to the 1999 WHO criteria. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. All assessments were performed by trained laboratory technicians. Follow-up started at the completion of the infertility workup and ended after 12 months. Primary end-point was natural conception resulting in an ongoing pregnancy. We constructed models for three strategies for the prediction of natural conception, using univariable and multivariable Cox hazard regression analyses. We evaluated the performance of the three strategies by comparing goodness-of-fit, discrimination and calibration. First, we analysed the semen parameters only. Secondly, we analysed the semen parameters in addition to the multivariable Hunault prediction model. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 897 couples, 132 (15%) achieved a pregnancy by natural conception. Using the results of a single semen analysis only, the calculated probabilities of natural conception within 12 months across the study population ranged from 0.12 to 0.38, with a median of 0.16 (IQR: 0.16-0.17). Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56. Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. Using the results of two semen analyses in combination with the Hunault model did not significantly increase goodness-of-fit compared with using a single semen analysis. The Hunault model with the addition of the semen parameters fitted the data significantly better than the Hunault model itself (difference in -2 Log likelihood: 13; 3 df; P = 0.002). Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. LIMITATIONS, REASONS FOR CAUTION: The academic setting possibly explains the relatively low natural conception rates, with only 15% achieving a natural conception within 1 year. Men with azoospermia were excluded. WIDER IMPLICATIONS OF THE FINDINGS: Performing more than one semen analysis will not increase the prognostic power of the test in clinical practice. Adding the first semen analysis to the Hunault model for the prediction of natural conception improved performance significantly compared with using the Hunault model alone. External validation, in other populations, should follow to confirm our conclusions, and to evaluate the generalizability or transportability of the extended Hunault model. STUDY FUNDING/COMPETING INTEREST(S): No external funding was involved in this study. None of the authors has any conflict of interest to declare.

Efficacy and safety of intrauterine insemination in patients with moderate-to-severe endometriosis.

Performing intrauterine insemination (IUI) in moderate-to-severe endometriosis patients is not implemented in international guidelines, as only limited data exist on treatment efficacy and safety. This retrospective study examined the efficacy and safety of two IUI treatment strategies performed between January 2007 and July 2012 in moderate-to-severe endometriosis patients. Eight (40.0%) versus seven (15.6%) ongoing pregnancies were accomplished in patients undergoing IUI with ovarian stimulation (n=20, 61 cycles) versus IUI without ovarian stimulation in the first three cycles followed by IUI with ovarian stimulation (IUI with natural/ovarian stimulation; n=45, 184 cycles). Preceding long-term pituitary down-regulation tended to result in a higher ongoing pregnancy rate (adjusted HR 1.8) and a higher chance of endometriosis recurrence (adjusted HR 2.3). Eight (40.0%) versus 16 (35.6%) recurrences of endometriosis complaints were reported in patients receiving IUI with ovarian stimulation versus IUI with natural/ovarian stimulation. IUI might be a valuable treatment in moderate-to-severe endometriosis patients and IUI with ovarian stimulation should be offered over IUI with natural/ovarian stimulation. Preceding long-term pituitary down-regulation might positively influence the ongoing pregnancy rate and can be considered. Whether this treatment strategy can be structurally offered prior to IVF must be investigated in a randomized controlled trial.

Efficacy and safety of IVF/ICSI in patients with severe endometriosis after long-term pituitary down-regulation.

Long-term pituitary down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist for 3­6 months prior to IVF/intracytoplasmic sperm injection (ICSI) improves clinical pregnancy rates in endometriosis patients. However, some discussion about this treatment strategy still exists. This retrospective study from a tertiary-care university hospital examined the efficacy and safety of IVF/ICSI with and without long-term pituitary down-regulation in severe endometriosis patients (surgically confirmed American Society for Reproductive Medicine stages III and IV). All first IVF/ICSI treatment cycles between January 2009 and January 2012 were analysed. In patients treated with (n = 68) and without (n = 45) long-term pituitary down-regulation, 13 (19.1%) versus nine (20.0%) ongoing pregnancies after fresh embryo transfer (adjusted OR 0.58, 95% CI 0.18­1.86,) and 24 (35.3%) versus 10 (22.2%) ongoing pregnancies after fresh and cryopreserved embryo transfers (adjusted OR 1.62, 95% CI 0.60­4.38) were accomplished, respectively. Three complications (2.7%) and three recurrences (2.7%) were reported, only in patients treated with long-term pituitary down-regulation. The 1-year cumulative endometriosis recurrence rate was 7.3%. IVF/ICSI in patients with severe endometriosis is safe with low complication and recurrence rates. A favourable effect, albeit non-significant, of long-term pituitary down-regulation in achieving an ongoing pregnancy was observed only after including cryopreserved embryo transfers.

IVF with planned single-embryo transfer versus IUI with ovarian stimulation in couples with unexplained subfertility: an economic analysis.

Couples with unexplained subfertility are often treated with intrauterine insemination (IUI) with ovarian stimulation, which carries the risk of multiple pregnancies. An explorative randomized controlled trial was performed comparing one cycle of IVF with elective single-embryo transfer (eSET) versus three cycles of IUI-ovarian stimulation in couples with unexplained subfertility and a poor prognosis for natural conception, to assess the economic burden of the treatment modalities. The main outcome measures were ongoing pregnancy rates and costs. This study randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were 24% in with IVF-eSET versus 21% with IUI-ovarian stimulation, with two and three multiple pregnancies, respectively. The mean cost per included couple was significantly different: €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation (P<0.01). The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET cost an additional €900 per couple compared with three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. When IVF-eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment. Couples that have been trying to conceive unsuccessfully are often treated with intrauterine insemination (IUI) and medication to improve egg production (ovarian stimulation). This treatment carries the risk of multiple pregnancies like twins. We performed an explorative study among those couples that had a poor prognosis for natural conception. One cycle of IVF with transfer of one selected embryo (elective single-embryo transfer, eSET) was compared with three cycles of IUI-ovarian stimulation. The aim of this study was to assess the economic burden of both treatments. The Main outcome measures were number of good pregnancies above 12weeks and costs. We randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were comparable: 24% with IVF-eSET versus 21% with IUI-ovarian stimulation. There were two multiple pregnancies with IVF-eSET and three multiple pregnancies with IUI-ovarian stimulation. The mean cost per included couple was significantly different, €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation. The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET costed an additional €900 per couple compared to three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. We conclude that IUI-ovarian stimulation is the preferred treatment to start with. When IVF-eSET results in a higher ongoing pregnancy rate (>38%), IVF would be the preferred treatment.

Patient satisfaction concerning assisted reproductive technology treatments in moderate to severe endometriosis.

A prospective observational cohort study was performed to examine patient satisfaction after one Assisted Reproductive Technology (ART) treatment cycle in moderate to severe endometriosis patients. From May 2012 till September 2013, 25 patients with surgically proven endometriosis stage III-IV were included per group and received intrauterine insemination (IUI), in vitro fertilization (IVF) or IVF preceded by long-term pituitary down-regulation (IVF-ultralong). The median patient satisfaction scores were 8.3, 7.9 and 8.0 in patients receiving IUI (n = 22), IVF (n = 24) and IVF-ultralong (n = 23), respectively (p = 0.89). Both deterioration in pain and quality-of-life could not be identified as determinants of decreased patient satisfaction scores. Satisfaction was higher in women receiving their first ART treatment attempt (p = 0.002), after treatment accomplishment (p = 0.04) and after a positive pregnancy test (p = 0.04). A median satisfaction score concerning preceding long term pituitary down-regulation of 6.1 (IVF-ultralong n = 25, IUI n = 8) was reported. Only three patients would refrain from this preceding therapy in a next treatment attempt. We concluded that patient satisfaction scores were comparable between the three different ART treatments. Since patient satisfaction was in particular dependent on treatment outcomes, it is recommended to compare those three ART treatments in a randomized controlled trial investigating the efficacy, safety and cost-effectiveness.

The association of the blastomere volume index (BVI), the blastomere symmetry index (BSI) and the mean ovality (MO) with ongoing implantation after single embryo transfer.

PURPOSE: To generate novel, objective variables that resemble embryo quality and relate them to ongoing implantation, using multilevel imaging of single-transferred embryos. METHODS: Retrospective analysis of multilevel images of 659 day 3 single-transferred embryos. Each embryo was photographed on seven different levels, in order to measure the largest diameter of every blastomere within an embryo. The volume of each blastomere was calculated using the equation [Formula: see text]. The blastomere volume index (BVI) represented the ratio between the total blastomeric volume of an embryo and the mean cytoplasmic volume of an oocyte on day 0. The blastomere symmetry index (BSI) represented the ratio between the greatest blastomere volume and the smallest blastomere volume within an embryo. The mean ovality (MO) represented the presence of non-spherical blastomeres. Analyses were performed to compare the BVI, BSI and MO between patients with and without an ongoing implantation. RESULTS: The mean BVI was significantly higher for embryos in the ongoing implantation group compared to the no ongoing implantation group. The mean BSI was associated with ongoing implantation for unevenly cleaved embryos. The MO of blastomeres within an embryo was similar for embryos in the ongoing implantation group compared to the no ongoing implantation group. The association of the BVI and BSI with ongoing implantation was confounded, because only female age and cleavage rate were significantly associated with ongoing implantation in multiple logistic regression analyses. CONCLUSIONS: The BVI, BSI and MO are objective variables that resemble embryo quality, but they are not suitable to use as embryo selection tools.

The influence of the type of embryo culture medium on neonatal birthweight after single embryo transfer in IVF.

STUDY QUESTION: Does the type of medium used to culture fresh and frozen-thawed embryos influence neonatal birthweight after single embryo transfer (SET) in IVF? SUMMARY ANSWER: A comparison of two commercially available culture media showed no significant influence on mean birthweight and mean birthweight adjusted for gestational age, gender and parity (z-scores) of singletons born after a fresh or frozen-thawed SET. Furthermore, we show that embryo freezing and thawing cycles may lead to a significantly higher mean birthweight. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Animal studies have shown that culture media constituents are responsible for changes in birthweight of offspring. In human IVF, there is still little knowledge of the effect of medium type on birthweight. Until now, only a small number of commercially available culture media have been investigated (Vitrolife, Cook(®) Medical and IVF online medium). Our study adds new information: it has a larger population of singleton births compared with the previously published studies, it includes outcomes of other media types (HTF and Sage(®)), not previously analysed, and it includes data on frozen-thawed SETs. DESIGN: This study was a retrospective analysis of birthweights of singleton newborns after fresh (Day 3) or frozen-thawed (Day 5) SET cycles, using embryos cultured in either of two different types of commercially available culture media, between 2008 and 2011. PARTICIPANTS AND SETTING: Before January 2009, a single-step culture medium was used: human tubal fluid (HTF) with 4 mg/ml human serum albumin. From January 2009 onwards, a commercially available sequential medium was introduced: Sage(®), Quinn's advantage protein plus medium. Singletons born after a fresh SET (99 embryos cultured in HTF and 259 in Sage(®)) and singletons born after a frozen-thawed SET (32 embryos cultured in HTF only, 41 in HTF and Sage(®) and 86 in Sage(®) only) were analysed. Only patients using autologous gametes without the use of a gestational carrier were considered. Also excluded were (vanishing) twins, triplets, babies with congenital or chromosomal abnormalities and babies born before 22 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis of 358 singletons born after a fresh SET and 159 singletons born after a frozen-thawed SET showed no significant difference between the HTF and Sage(®) groups in terms of birthweight. Gestational age, parity and gender of the baby were significantly related to birthweight in multiple linear regression analyses, and other possible confounding factors included maternal age, BMI and smoking, the number of blastomeres in the transferred embryo and the type of culture medium. Maternal age, BMI and smoking, gestational age at birth, gender of the baby and the percentage of firstborns did not differ significantly between the HTF and Sage(®) groups; however, among the fresh embryos, those cultured in Sage(®) had significantly more blastomeres at the time of embryo transfer compared with the embryos cultured in HTF. Birthweights adjusted for gestational age and gender or gestational age and parity (z-scores) were not significantly different between the HTF and Sage(®) groups for fresh or frozen-thawed SETs. Mean birthweight, as well as the mean birthweight among firstborns and the mean birthweights adjusted for gestational age and gender or parity (z-scores) were significantly higher in the cryopreservation group compared with the fresh embryo transfer group. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Our study is limited by its retrospective design and only two commercially available types of culture media were tested. More research is necessary to investigate the potential influence of culture media on gene expression. GENERALIZABILITY TO OTHER POPULATIONS: Although our data do not indicate the major influences of the HTF and Sage(®) culture media on birthweight, our results cannot be extrapolated to other culture media types. Furthermore, there remains a potential influence of embryo culture environment on epigenetic variation not represented by birthweight differences but by more subtle features.

Long-term outcome in couples with unexplained subfertility and an intermediate prognosis initially randomized between expectant management and immediate treatment.

BACKGROUND: We recently reported that treatment with intrauterine insemination and controlled ovarian stimulation (IUI-COS) did not increase ongoing pregnancy rates compared with expectant management (EM) in couples with unexplained subfertility and intermediate prognosis of natural conception. Long-term cost-effectiveness of a policy of initial EM is unknown. We investigated whether the recommendation not to treat during the first 6 months is valid, regarding the long-term effectiveness and cumulative costs. METHODS: Couples with unexplained subfertility and intermediate prognosis of natural conception (n=253, at 26 public clinics, the Netherlands) were randomly allocated to 6 months EM or immediate start with IUI-COS. The couples were then treated according to local protocol, usually IUI-COS followed by IVF. We followed couples until 3 years after randomization and registered pregnancies and resources used. Primary outcome was time to ongoing pregnancy. Secondary outcome was treatment costs. Analysis was by intention-to-treat. Economic evaluation was performed from the perspective of the health care institution. RESULTS: Time to ongoing pregnancy did not differ between groups (log-rank test P=0.98). Cumulative ongoing pregnancy rates were 72-73% for EM and IUI-COS groups, respectively [relative risk 0.99 (95% confidence interval (CI) 0.85-1.1)]. Estimated mean costs per couple were € 3424 (95% CI € 880-€ 5968) in the EM group and € 6040 (95% CI € 4055-€ 8125) in the IUI-COS group resulting in an estimated saving of € 2616 per couple (95% CI € 385-€ 4847) in favour of EM. CONCLUSIONS: In couples with unexplained subfertility and an intermediate prognosis of natural conception, initial EM for 6 months results in a considerable cost-saving with no delay in achieving pregnancy or jeopardizing the chance of pregnancy. Further comparisons between aggressive and milder forms of ovarian stimulation should be performed.

Deep infiltrating endometriosis of the bowel: MR imaging as a method to predict muscular invasion.

PURPOSE: To evaluate magnetic resonance (MR) imaging morphologic- and signal intensity abnormalities of deep infiltrating endometriosis (DIE) of the bowel wall and to assess its value in predicting depth and extent of bowel wall infiltration. MATERIALS AND METHODS: This single-center study was performed in a tertiary referral center for endometriosis. All patients (n = 28) who underwent segmental bowel resection (2004-2010) were retrospectively studied. MR images were analyzed by two experienced readers independently (number of lesions, location, size, signal intensity, and depth of bowel wall infiltration) and this was correlated with histopathology. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy for diagnosis of endometriosis infiltrating the muscular layer of the bowel were 100%, 75%, 96%, 100%, and 96%, respectively. The inter-rater agreement was 0.84. "Fan shaped" configurations with hypointensity on T2- and T1-weighted imaging were characteristic for thickening of indigenous smooth muscle and smooth muscle hyperplasia at histopathology, as a consequence of infiltration by endometriosis. Thickening of the (sub)mucosa corresponded to edema with or without infiltration of endometriosis. CONCLUSION: MR imaging at 1.5 Tesla is useful to predict muscular infiltration of the bowel in endometriosis, whereas it is of limited value in diagnosis of (sub)mucosal infiltration.

Non-invasive viability assessment of day-4 frozen-thawed human embryos using near infrared spectroscopy.

This study investigated if metabolomic profiling of culture media using near infrared (NIR) spectroscopy was related to live-birth rates after single-embryo transfer of frozen-thawed embryos. Analysis of culture media of frozen-thawed embryos was performed by NIR spectroscopy. A viability score was calculated using a predictive multivariate algorithm of fresh day-5 embryos with known pregnancy outcomes. This algorithm generated with fresh day-5 embryos could help to identify the live-birth group from the no live-birth group. Multivariable regression models that tested the predictive ability of the viability score for live birth showed an odds ratio in the crude analysis of 1.50 (P=0.008), after adjustment for embryo morphology, 1.44 (P=0.022), and after adjustment for all variables, 1.71 (P=0.005); based on a 0.1 step increase in viability scores. In conclusion, higher viability scores resulted in higher live-birth rates. An algorithm generated from fresh embryos might be used to predict viability of frozen-thawed embryos. Frozen-thawed embryos have different metabolic activity which is related to implantation potential. Therefore, this method might be useful to select the best embryo for transfer within a group of embryos with similar morphology.

Blood-borne angiogenic factors and sustained multiple implantation: a comparison of singleton and twin pregnancies.

This study aimed to compare longitudinal serum concentrations of angiogenic implantation factors between ongoing singleton and twin pregnancies after double-embryo transfer and to investigate whether these are involved in sustained double implantation. Sixteen patients with an ongoing singleton and nine patients with an ongoing twin pregnancy after double-embryo transfer were included in this prospective observational study. Main outcome measures were concentrations of vascular endothelial growth factor-A (VEGF-A), inhibin A, glycodelin A, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein-3 (IGFBP-3) at baseline, during the IVF treatment and in early pregnancy. It appeared that VEGF-A concentrations prior to any treatment and at early implantation as well as body mass index (BMI) were higher in women who conceived a twin pregnancy (P = 0.04). Soon after implantation, inhibin A concentrations were higher in twin pregnancies (P=0.02). Secretion profiles of glycodelin A and members of the IGF family did not differ between singleton and twin pregnancies. VEGF-A appears to play a role in sustained double implantation. Furthermore a high BMI is associated with ongoing double implantation. Future studies should investigate the predictive value of VEGF-A for having an ongoing singleton or twin pregnancy.

Appearance of abdominal wall endometriosis on MR imaging.

OBJECTIVE: Abdominal wall endometriosis (AWE) is defined as endometrial tissue that is superficial to the peritoneum. AWE is often difficult to diagnose, mimicking a broad spectrum of diseases. The aim of this study was to describe the appearance of AWE on magnetic resonance (MR) imaging. METHODS: We present ten patients with AWE (12 lesions) in which MR imaging was used for diagnosis. MR imaging included T2-weighted imaging and T1-weighted imaging with fat suppression. To assess the value of diffusion-weighted imaging (DWI) in endometriosis, four patients underwent additional DWI. The apparent diffusion coefficient (ADC) was calculated using b values of 50, 400, 800 and 1,200 s/mm(2). RESULTS: In most cases, the lesion was located ventral or dorsal to the aponeurosis of the rectus oblique muscle (n = 6) or in the rectus abdominis (n = 5). MR of AWE lesions showed isointense or slightly hyperintense signal compared with muscle on T2-weighted images and showed isointense or slightly hyperintense signal compared with muscle on T1-weighted images with foci of high signal intensity, indicative of haemorrhage. The mean ADC value of AWE was 0.93 x 10(-3)/mm(2)/s. CONCLUSION: MR imaging seems to be useful in determining the location and depth of infiltration in surrounding tissue preoperatively.

The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve reproductive outcome. A randomised controlled trial.

BACKGROUND: In the Netherlands, 30% of subfertile women are overweight or obese, and at present there is no agreement on fertility care for them. Data from observational and small intervention studies suggest that reduction of weight will increase the chances of conception, decrease pregnancy complications and improve perinatal outcome, but this has not been confirmed in randomised controlled trials. This study will assess the cost and effects of a six-months structured lifestyle program aiming at weight reduction followed by conventional fertility care (intervention group) as compared to conventional fertility care only (control group) in overweight and obese subfertile women. We hypothesize that the intervention will decrease the need for fertility treatment, diminish overweight-related pregnancy complications, and will improve perinatal outcome. METHODS/DESIGN: Multicenter randomised controlled trial in subfertile women (age 18-39 year) with a body mass index between 29 and 40 kg/m2. Exclusion criteria are azoospermia, use of donor semen, severe endometriosis, premature ovarian failure, endocrinopathies or pre-existent hypertensive disorders.In the intervention group the aim is a weight loss of at least 5% to10% in a six-month period, to be achieved by the combination of a diet, increase of physical activity and behavioural modification. After six months, in case no conception has been achieved, these patients will start fertility treatment according to the Dutch fertility guidelines. In the control group treatment will be started according to Dutch fertility guidelines, independently of the patient's weight. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure is a healthy singleton born after at least 37 weeks of gestation after vaginal delivery. Secondary outcome parameters including pregnancy outcome and complications, percentage of women needing fertility treatment, clinical and ongoing pregnancy rates, body weight, quality of life and costs.Data will be analysed according to the intention to treat principle, and cost-effectiveness analysis will be performed to compare the costs and health effects in the intervention and control group. DISCUSSION: The trial will provide evidence for costs and effects of a lifestyle intervention aiming at weight reduction in overweight and obese subfertile women and will offer guidance to clinicians for the treatment of these patients. TRIAL REGISTRATION: Dutch Trial Register NTR1530.

Microvascular function has no menstrual-cycle-dependent variation in healthy ovulatory women.

OBJECTIVE: Hyper- and hypoestrogenism that persist for a long time can affect vascular and metabolic function. However, it is not clear whether the same is true for subtle sex hormone changes (i.e., during the menstrual cycle). METHODS: Twenty-one healthy normal-weight women with regular cycles were studied during the early-follicular (day 3 +/- 2), late-follicular (day 12 +/- 2), and midluteal (day 20 +/- 3) phases. Microvascular function was assessed by skin iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), by skin-capillary recruitment after arterial and venous occlusion (i.e., capillaroscopy), and by Fourier analysis of resting skin laser Doppler flow at rest (i.e., vasomotion). Insulin sensitivity (i.e., homeostasis model assessment) and blood pressure were also determined during the study days. RESULTS: Three women were excluded from analyses because they were anovulatory. Skin microvascular responses to ACh and SNP, capillary function, vasomotion, insulin sensitivity, and blood pressure did not differ between the three phases (P > or = 0.1). Further, microvascular function did not correlate with plasma-estrogen levels (r = -0.06-0.2; P> or = 0.2). CONCLUSIONS: Microvascular function does not demonstrate a clear menstrual-cycle-dependent variation.