Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis.

STUDY QUESTION: Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances? SUMMARY ANSWER: We found no evidence for an association between EMT and pregnancy chances. WHAT IS KNOWN ALREADY: It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT. MAIN RESULTS AND THE ROLE OF CHANCE: Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: -0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: -0.33, 95% CI: -0.64 to -0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: -0.84, 95% CI: -1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: -0.79, 95% CI: -1.37 to -0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: -1.31, 95% CI: -2.08 to -0.53). LIMITATIONS, REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: We found no evidence for an association between EMT and pregnancy rates during IUI -OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: N/A.

Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression.

Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.

Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT.

STUDY QUESTION: Does hysteroscopic proximal tubal occlusion by intratubal devices as a treatment for hydrosalpinges result in comparable ongoing pregnancy rates following IVF/ICSI when compared with laparoscopic salpingectomy? SUMMARY ANSWER: Hysteroscopic proximal tubal occlusion by intratubal devices is inferior to laparoscopic salpingectomy in the treatment of hydrosalpinges in women undergoing IVF/ICSI with respect to ongoing pregnancy rates. WHAT IS KNOWN ALREADY: It is known that women with hydrosalpinges undergoing IVF have poorer pregnancy outcomes compared with women with other forms of tubal infertility. In these women, both laparoscopic salpingectomy and laparoscopic proximal tubal ligation are known to improve IVF outcomes. At present, it is unclear whether a less-invasive hysteroscopic treatment with intratubal devices leads to similar ongoing pregnancy rates following IVF when compared with laparoscopic salpingectomy. STUDY DESIGN, SIZE, DURATION: A two-centre, randomized, controlled, non-inferiority trial. Between October 2009 and December 2014 a total of 85 women were included in this study; of whom, 42 were randomized to hysteroscopic proximal occlusion by intratubal device placement and 43 were randomized to laparoscopic salpingectomy. Randomization was based on a computer-generated randomization list. The study was unblinded. The primary outcome was ongoing pregnancy rate, defined as a fetal heartbeat on ultrasound beyond 10-week gestation following one IVF/ICSI treatment (fresh and frozen-thawed embryo transfers). PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied women aged 18-41 years, with uni- or bilateral ultrasound visible hydrosalpinges who were scheduled for an IVF/ICSI treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rates per patient according to the intention-to-treat principle were 11/42 (26.2%) after hysteroscopic proximal occlusion by intratubal devices (intervention group) versus 24/43 (55.8%) after laparoscopic salpingectomy (control group) (P = 0.008) [absolute difference: 26.1%; 95% confidence interval (CI): 0.5-51.7, relative risk (RR): 0.56; 95% CI: 0.31-1.03, P = 0.01]. In the per protocol analysis, the ongoing pregnancy rate per patient following hysteroscopic proximal occlusion by intratubal devices was 9/27 (33.3%) compared with 19/32 (59.4%) following laparoscopic salpingectomy (P = 0.067) (absolute difference: 29.6%; 95% CI: 7.1 to 49.1, RR: 0.47; 95% CI: 0.27-0.83, P = 0.062). LIMITATIONS, REASONS FOR CAUTION: Masking participants and investigators would be difficult due to the nature of both interventions. Since we had objective outcome measurements, we withheld sham procedures, leaving the study unblinded. Furthermore, our low sample size resulted in wide CIs. A larger sample size would result in a more accurate treatment effect; however, this was non-feasible for recruitment and inclusion. WIDER IMPLICATIONS OF THE FINDINGS: In the treatment of hydrosalpinges prior to IVF/ICSI, hysteroscopic proximal occlusion by intratubal devices is inferior to laparoscopic salpingectomy. STUDY FUNDING/COMPETING INTERESTS: The intratubal devices were received from Conceptus, Inc., San Carlos, CA, USA, which was acquired by Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA in 2013. Conceptus, Inc./Bayer HealthCare Pharmaceuticals, Inc. had no role in the study design, data collection and analyses, decision to publish or preparation of the manuscript. The study as a whole was funded by the SWOG (foundation for scientific investigation in obstetrics and gynaecology of the VU University Medical Centre, Amsterdam, the Netherlands). P.G.A.H. has received non-financial support from Conceptus, Inc. during the conduct of this study. He has received grants from Ferring B.V., Merck Serono and Abbott outside the submitted work. M.H.E. has received personal fees from Smith and Nephew and IQ Medical Ventures outside the submitted work. TRIAL REGISTRATION NUMBER: The Dutch Trial Register: NTR 2073. TRIAL REGISTRATION DATE: October 21, 2009. DATE OF FIRST PATIENT'S ENROLMENT: October 26, 2009.

Short-term changes in hormonal profiles after laparoscopic ovarian laser evaporation compared with diagnostic laparoscopy for PCOS.

STUDY QUESTION: Which reproductive endocrine changes are attributed exclusively to laparoscopic ovarian drilling in polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Laser evaporation-specific endocrine effects were the prevention of an immediate increase in inhibin B and a sustained decrease in testosterone, androstenedione and anti-Müllarian hormone (AMH). WHAT IS KNOWN ALREADY: All ovarian drilling procedures result in reproductive endocrine changes. It is not known which of these changes are the result of ovarian drilling and which are related to the surgery per se. STUDY DESIGN, SIZE, DURATION: This prospective controlled study was performed at an outpatient academic fertility clinic. Between 2007 and 2010, a total of 21 oligo- or amenorrheic PCOS patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were oligo- or amenorrheic PCOS patients with all three of the Rotterdam criteria and luteinizing hormone (LH) >6.5 U/l. All PCOS patients had an indication for diagnostic surgery due to subfertility. There were 12 PCOS patients who chose to undergo ovarian laser evaporation (CO2 laser, 25 W, 20 times/ovary) and 9 PCOS who chose a diagnostic laparoscopy only (controls). Reproductive endocrinology was measured before, and until 5 days after, surgery, and four gonadotrophin-releasing hormone (GnRH) 'double pulse' tests were included. The main outcome measures were changes in reproductive endocrinology and pituitary sensitivity/priming to GnRH after laser evaporation compared with diagnostic laparoscopy only. MAIN RESULTS AND THE ROLE OF CHANCE: In the first hours after surgery, both groups showed an increase in LH, follicle stimulating hormone, estrogen and a decrease in testosterone, androstenedione, AMH and insulin growth factor-1 (P < 0.05). Inhibin B increased in the laparoscopy only group (P < 0.05). In the first days after surgery, testosterone, androstenedione and AMH remained at lower than baseline levels exclusively in the laser group (P < 0.05). Pituitary sensitivity/priming to GnRH was not altered after either laser evaporation or laparoscopy only. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study are the short follow-up period and the relatively small groups. WIDER IMPLICATIONS OF THE FINDINGS: The strength of this study is the integrally measured endocrine profiles in combination with an optimal control group of PCOS patients undergoing diagnostic laparoscopy only. Interestingly, most of the immediate endocrine changes after laser evaporation could be related to the surgical context and not to the ovarian drilling procedure itself. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Foundation of Scientific Research in Obstetrics and Gynaecology and the study medication, Lutrelef, was donated by Ferring, The Netherlands, Hoofdorphe There were no conflicts of interests mentioned by the authors.

No evidence that embryo selection by near-infrared spectroscopy in addition to morphology is able to improve live birth rates: results from an individual patient data meta-analysis.

STUDY QUESTION: What is the value of embryo selection by metabolomic profiling of culture medium with near-infrared (NIR) spectroscopy as an adjunct to morphology, compared with embryo selection by morphology alone, based on an individual patient data meta-analysis (IPD MA)? SUMMARY ANSWER: The IPD MA indicates that the live birth rate after embryo selection by NIR spectroscopy and morphology is not significantly different compared with the live birth rate after embryo selection by morphology alone. WHAT IS KNOWN ALREADY: Retrospective proof of principle studies has consistently shown that high NIR viability scores are correlated with a high implantation potential of embryos. However, randomized controlled trials (RCTs) have generally shown no benefit of the NIR technology over embryo morphology, although there have been some conflicting results between pregnancy outcomes on different days of embryo transfer. STUDY DESIGN, SIZE, DURATION: This IPD MA included all existing RCTs (n = 4) in which embryo selection by morphology was compared with embryo selection by morphology and the use of NIR spectroscopy of spent embryo culture medium by the Viametrics-E(™). PARTICIPANTS/MATERIALS, SETTING, METHODS: Searches of PubMed, the Cochrane Library and the WHO International Clinical Trials Registry were conducted and the sole manufacturer of the Viametrics-E(™) was consulted to identify clinics where an RCT comparing embryo selection by morphology to embryo selection by morphology and the use of the Viametrics-E(™) (NIR viability score) was performed. A total of 20 citations were potentially eligible for inclusion, two of which met the inclusion criteria. The manufacturer of the Viametrics-E(™) provided two additional clinical sites of use. In total, four RCTs were identified as eligible for inclusion. The IPD MA was based on a fixed effect model due to the lack of heterogeneity between included studies. Differences between study groups were tested and reported using logistic regression models adjusted for significant confounders. The pooled analysis of the primary outcome led to a total sample size of 924 patients: 484 patients in the control group (embryo selection by morphology alone) and 440 patients in the treatment group (embryo selection by morphology plus NIR spectroscopy). MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rates in the control group and the NIR group were 34.7% (168 of 484) and 33.2% (146 of 440), respectively. The pooled odds ratio (OR) was 0.98 [95% confidence interval (CI) 0.74-1.29], indicating no difference in live birth rates between the two study groups. The data of the four studies showed no significant heterogeneity (I(2) = 26.2% P = 0.26). The multivariate regression analysis including all confounders show that maternal age (OR 0.90, 95% CI 0.87-0.94) and the number of previous IVF cycles (OR 0.83, 95% CI 0.71-0.96) were significantly related to live birth. The study group (i.e. embryo selection by morphology or embryo selection by morphology plus NIR) was not related to live birth (OR 0.97, 95% CI 0.73-1.29). LIMITATIONS AND REASONS FOR CAUTION: The availability of at least two similar best quality embryos as an inclusion criterion prior to transfer in the two largest RCTs might have caused a selection bias towards a better prognosis patient group. WIDER IMPLICATIONS OF THE FINDINGS: There is at present no evidence that NIR spectroscopy of spent embryo culture media in its current form can be used in daily practice to improve live birth rates.

How long should we continue clomiphene citrate in anovulatory women?

STUDY QUESTION: What is the effectiveness of continued treatment with clomiphene citrate (CC) in women with World Health Organization (WHO) type II anovulation who have had at least six ovulatory cycles with CC but did not conceive? SUMMARY ANSWER: When women continued CC after six treatment cycles, the cumulative incidence rate of the ongoing pregnancy rate was 54% (95% CI 37-78%) for cycles 7-12. WHAT IS KNOWN ALREADY: If women with WHO type II anovulation fail to conceive with CC within six ovulatory cycles, guidelines advise switching to gonadotrophins, which have a high risk of multiple gestation and are expensive. It is however not clear what success rate could be achieved by continued treatment with CC. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of women with WHO II anovulation who visited the fertility clinics of five hospitals in the Netherlands between 1994 and 2010. We included women treated with CC who had had at least six ovulatory cycles without successful conception (n = 114) after which CC was continued using dosages varying from 50 to 150 mg per day for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follow-up was a total of 12 treatment cycles. Primary outcome was the cumulative incidence rate of an ongoing pregnancy at the end of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: We recruited 114 women that had ovulated on CC for at least six cycles but had not conceived. Of these 114 women, 35 (31%) had an ongoing pregnancy resulting in a cumulative incidence rate of an ongoing pregnancy of 54% after 7-12 treatment cycles with CC. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are its retrospective approach. WIDER IMPLICATIONS OF THE FINDINGS: Randomized trials comparing continued treatment with CC with the relatively established second line treatment with gonadotrophins are justified. In the meantime, we suggest to only begin this less convenient and more expensive treatment for women who do not conceive after 12 ovulatory cycles with CC. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

Costs and benefits of individuals conceived after IVF: a net tax evaluation in The Netherlands.

This study evaluated the lifetime future net tax revenues from individuals conceived after IVF relative to those naturally conceived. A model based on the method of generational accounting was developed to evaluate investments in IVF. Calculations were based on average investments paid and received from the government by an individual. All costs were discounted to their net present values and adjusted for survival. The lifetime net present value of IVF-conceived individuals was -€81,374 (the minus sign reflecting negative net present value). The lifetime net present value of IVF-conceived men and women were -€47,091 and -€123,177, respectively. The lifetime net present value of naturally conceived individuals was -€70,392; respective amounts for men and women were -€36,109 and -€112,195. The model was most sensitive to changes in the growth of healthcare costs, economic growth and the discount rate. Therefore, it is concluded that, similarly to naturally conceived individuals in the Netherlands, IVF-conceived individuals have negative discounted net tax revenue at the end of life. The analytic framework described here undervalues the incremental value of an additional birth because it only considers the fiscal consequences of life and does not take into consideration broader macroeconomic benefits. This study evaluated the lifetime future net tax revenues from individuals conceived after IVF relative those naturally conceived. A model based on the method of generational accounting to evaluate investments in IVF was used. Calculations were based on average investments paid and received from the government by an individual. The lifetime net present value of IVF-conceived individuals was -€81,374 (the minus sign reflecting negative net present value). The lifetime net present value of IVF-conceived men and women were -€47,091 and -€123,177, respectively. The lifetime net present value of naturally conceived individuals was -€70,392; respective amounts for men and women were -€36,109 and -€112,195. The model was most sensitive for changes in the growth in healthcare costs, economic growth and the discount rate. Just as naturally conceived individuals in the Netherlands, IVF-conceived individuals have negative discounted net tax revenue at the end of life. The analytic framework described here undervalues the incremental value of an additional birth because it only considers the fiscal consequences of life and does not take into consideration broader macroeconomic benefits.

Long-term follow up of couples initially randomized between immobilization and immediate mobilization subsequent to IUI.

A previous randomized clinical trial compared immobilization for 15 min with immediate mobilization subsequent to intrauterine insemination (IUI) and showed higher ongoing pregnancy rates in couples immobilizing subsequent to IUI. The current study compared the long-term effectiveness of immobilization subsequent to IUI. All couples (n = 391) included in the trial were followed for 3 years after randomization and pregnancies and treatments were recorded. After the initial trial period, couples in both groups were offered treatment according to local protocol. The primary outcome was an ongoing pregnancy during the 3 years after the initial trial. In this time period, there were 143 ongoing pregnancies in the immobilization group (n = 199 couples) and 112 ongoing pregnancies in the immediate mobilization group (n = 192). The ongoing pregnancy rates were 72% and 58%, respectively (relative risk 1.2, 95% CI 1.1-1.4). The persistent significant difference in ongoing pregnancy rates underpins the importance of immobilization after IUI. There is no valid reason to withhold women from immobilizing for 15 min after IUI.

Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF: a meta-analysis with individual patient data.

STUDY QUESTION: Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients? SUMMARY ANSWER: The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women. WHAT IS KNOWN ALREADY: Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion. STUDY DESIGN, SIZE, DURATION: We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n = 131 treated with aspirin, n = 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n = 187) and preterm delivery (n = 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30-0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22-1.7) and OR 0.52 (95% CI 0.16-1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35-4.4) and OR 1.6 (95% CI 0.51-5.0), respectively. LIMITATIONS, REASONS FOR CAUTION: We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis. WIDER IMPLICATIONS OF THE FINDINGS: Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted.

Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.

STUDY QUESTION: Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER: Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY: In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION: A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS: Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Dutch trial register (ISRCTN10841210).

Tailored expectant management: a nationwide survey to quantify patients' and professionals' barriers and facilitators.

BACKGROUND: Prognostic models for natural conception help to identify subfertile couples with high chances of natural conception, who do not need fertility treatment yet. The use of such models and subsequent tailored expectant management (TEM) is not always practiced. Previous qualitative research has identified barriers and facilitators of TEM among patients and professionals. The aim of this study was to assess the prevalence of those barriers and facilitators and to evaluate which factors predict patients' appreciation of TEM and professionals' adherence to TEM. METHODS: We performed a nationwide survey. Based on the previously identified barriers and facilitators two questionnaires were developed and sent to 195 couples and 167 professionals. Multivariate analysis was performed to evaluate which factors predicted patients' appreciation of TEM and professional adherence to TEM. RESULTS: In total, 118 (61%) couples and 117 (70%) professionals responded and 96 couples and 117 professionals were included in the analysis. Patients' mean appreciation of TEM was 5.7, on a 10-point Likert scale. Patients with a lower appreciation of TEM had a higher need for patient information (P = 0.047). The professionals reported a mean adherence to TEM of 63%. Adherence to TEM was higher when professionals were fertility doctors (P = 0.041). Facilitators in the clinical domain were associated with a higher adherence to TEM (P = 0.091). Barriers in the professional domain had a negative impact on adherence to TEM (P = 0.008). CONCLUSIONS: The limited implementation of TEM is caused by both patient and professional-related factors. This study provides practical tools to improve the implementation of TEM.

Factors associated with dizygotic twinning after IVF treatment with double embryo transfer.

BACKGROUND: Dizygotic twin pregnancies after IVF treatment are the result of multiple embryos transferred into the uterine cavity, followed by successful double implantation. Factors that increase the chance of multiple implantation after IVF are relatively unknown. The present study aimed to investigate whether features of body composition, such as maternal height, weight and body mass index (BMI) are associated with an increased chance of dizygotic twinning after IVF with double embryo transfer (DET). METHODS: This study was conducted using data from a large Dutch nationwide cohort that comprised 19 861 women who had IVF or ICSI treatment between 1983 and 1995 (OMEGA study). First 'fresh' IVF and ICSI cycles with DET resulting in a delivery of a singleton or twin (living as well as stillborn) were selected. A multivariable logistic regression analysis was performed, with the delivery of a singleton or twin as the dependent variable and height, weight, BMI, maternal age, number of retrieved oocytes, use of alcohol, smoking, highest level of education and parity as independent variables. RESULTS: Of the 6598 women who completed their first IVF or ICSI cycle, 2375 had DET, resulting in 496 deliveries of 371 singletons and 125 twins. Multivariable regression analysis revealed that tall women (>1.74 cm) and women with a high number of retrieved oocytes (>8) had an increased chance of dizygotic twinning [OR: 1.8 (95% CI: 1.0-3.4) and OR: 2.2 (95% CI: 1.3-3.8), respectively]. CONCLUSIONS: Our data demonstrate that tall stature and increased number of retrieved oocytes independently increase the chance of dizygotic twinning after IVF with DET.

Standardization of catheter load speed during embryo transfer: comparison of manual and pump-regulated embryo transfer.

The position of transfer air bubbles after embryo transfer is related to the pregnancy rate. With the conventional manual embryo-transfer technique it is not possible to predict the final position of the air bubbles. This position mainly depends on the catheter load speed at transfer (injection speed), a parameter that remains uncontrollable with the conventional technique even after standardization of the protocol. Therefore, the development of an automated device that generates a standardized injection speed is desirable. This study aimed to examine the variation in injection speeds in manual embryo transfer and pump-regulated embryo transfer (PRET). Seven laboratory technicians were asked to perform simulated transfers using the conventional embryo-transfer technique. Their injection speeds were compared with that of a PRET device. The results indicate that in manually performed transfers, even after standardization of the protocol, there is still a large variation in injection speed, while a PRET device generates a reliable and reproducible injection speed and therefore brings new possibilities for further standardization of the embryo-transfer procedure. Future research should reveal whether these experiments mimic real clinical circumstances and if a standardized injection speed results in more exact positioning of the transferred embryos and therefore higher pregnancy rates.

The prognostic profile of subfertile couples and treatment outcome after expectant management, intrauterine insemination and in vitro fertilisation: a study protocol for the meta-analysis of individual patient data.

OBJECTIVE: The current evidence concerning the best treatment option for couples with unexplained and male subfertility is inconclusive. Most studies that have evaluated the effectiveness of treatment options, such as expectant management (EM), intrauterine insemination (IUI), with or without controlled ovarian stimulation (COS), and in vitro fertilisation (IVF), have not taken the couples' prognosis into account. It is very likely that the individual prognosis of the couple influences the effect of treatment. Individual patient data analyses allow us to take these prognostic factors into account, and to evaluate their effect on treatment outcome. This study aims to use anonymised data from relevant published trials to perform an individual patient data meta-analysis, evaluating the effect of couples' prognosis on the effectiveness of EM, IUI, with or without COS, and IVF. METHODS: Based on earlier systematic reviews and an updated search, randomised controlled trials will be considered for inclusion. Untreated subfertile couples with unexplained or male subfertility included in trials comparing EM, IUI, with or without COS, and IVF are included. Authors of the included studies will be invited to share their original anonymised data. The data will be assessed on validity, quality and completeness. The prognosis of the individual couple will be calculated with existing prognostic models. The effect of the prognosis on treatment outcome will be analysed with marker-by-treatment predictiveness curves, illustrating the effect of prognosis on treatment outcome. This study is registered in PROSPERO (registration number CRD42011001832). CONCLUSION: Ultimately, this study may help to select the appropriate fertility treatment, tailored to the needs of an individual couple.

Patients' and professionals' barriers and facilitators of tailored expectant management in subfertile couples with a good prognosis of a natural conception.

BACKGROUND: European guidelines on fertility care emphasize that subfertile couples should receive information about their chances of a natural conception and should not be exposed to unnecessary treatments and risks. Prognostic models can help to estimate their chances and select couples with a good prognosis for tailored expectant management (TEM). Nevertheless, TEM is not always practiced. The aim of this study was to identify any barriers or facilitators for TEM among professionals and subfertile couples. METHODS: A qualitative study was performed with semi-structured in-depth interviews of 21 subfertile patients who were counselled for TEM and three focus-group interviews of 21 professionals in the field of reproductive medicine. Two theoretical models were used to guide the interviews and the analyses. The primary outcome was the set of identified barriers and facilitators which influence implementation of TEM. RESULTS: Among the subfertile couples, main barriers were a lack of confidence in natural conception, a perception that expectant management is a waste of time, inappropriate expectations prior to the first consultation, misunderstanding the reason for expectant management and overestimation of the success rates of treatment. Both couples and professionals saw the lack of patient information materials as a barrier. Among professionals, limited knowledge about prognostic models leading to a decision in favour of treatment was recognized as a main barrier. A main facilitator mentioned by the professionals was better management of patients' expectations. CONCLUSIONS: We identified several barriers and facilitators which can be addressed to improve the implementation of TEM. These should be taken into account when designing future implementation strategies.

Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS.

BACKGROUND: Insulin resistance, i.e. impaired insulin-mediated glucose uptake (IMGU), is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). Insulin-induced capillary recruitment (IICR) is considered a significant determinant of IMGU. We investigated whether IICR is a determinant IMGU in obese and lean women with and without PCOS. METHODS: The study included 36 women with PCOS (20 lean, BMI 21.9 ± 2.3 kg/m(2) and 16 obese, BMI 35.9 ± 6.0 kg/m(2)) and 27 age-matched healthy controls (14 lean, BMI 22.2 ± 1.8 kg/m(2) and 13 obese, BMI 40.5 ± 7.0 kg/m(2)). IICR was evaluated by capillary microscopy during an isoglycemic-hyperinsulinemic clamp. IMGU was expressed as M/I value. RESULTS: The M/I value was significantly lower in obese PCOS women compared with obese controls [0.5 (0.2-1.1) versus 0.8 (0.3-1.4) (mg kg(-1) min(-1) pmol l(-1)) × 100, P < 0.01], whereas the small difference between lean PCOS and lean control women was non-significant [1.5 (0.5-2.6) versus 1.7 (1.0-3.7) (mg kg(-1) min(-1) pmol l(-1)) × 100, P = 0.17]. Hyperinsulinemia increased capillary recruitment in lean controls (53.5 ± 20.3 versus 64.9 ± 27.4 n/mm(2), P < 0.05), but not in either PCOS group nor in obese controls. IICR and androgens were a determinant of M/I value only in lean women with or without PCOS. CONCLUSIONS: PCOS per se is associated with impaired IICR. Obese women with PCOS, in part independent of obesity, demonstrated a profound insulin resistance, whereas the difference between lean PCOS women and healthy controls was small and statistically non-significant. IICR was a determinant of IMGU in lean, but not in obese, women regardless of the presence of PCOS.

The capacity of hysterosalpingography and laparoscopy to predict natural conception.

BACKGROUND: Laparoscopy has been claimed to be superior to hysterosalpingography (HSG) in predicting fertility. Whether this conclusion is applicable to a general subfertile population can be questioned as data in support of this claim were collected in third line centres. The aim of this study was to assess the prognostic capacity of HSG and laparoscopy in a general subfertile population. METHODS: In 38 centres, we prospectively studied a cohort of patients referred for subfertility between 2002 and 2004, who underwent HSG and/or laparoscopy as part of their subfertility work-up. Follow-up started immediately after tubal testing and ended 12 months thereafter. Time to pregnancy was censored at the of date last contact, when the woman was not pregnant or at the start of treatment. Kaplan-Meier curves for the occurrence of spontaneous intrauterine pregnancy were constructed for patients without tubal pathology, for those with unilateral tubal pathology and for patients with bilateral tubal pathology at HSG or laparoscopy. Multivariable Cox regression analysis was used to calculate fecundity rate ratios (FRRs) to express associations between tubal pathology and the occurrence of an intrauterine pregnancy. RESULTS: Of the 3301 included patients, 2043 underwent HSG only, 747 underwent diagnostic laparoscopy only and 511 underwent both. At HSG, 322 (13%) patients showed unilateral tubal pathology and 135 (5%) showed bilateral tubal pathology. At laparoscopy, 167 (13%) showed unilateral tubal pathology and 215 (17%) showed bilateral tubal pathology. Multivariable analysis resulted in FRRs of 0.81 [95% confidence interval (CI): 0.59-1.1] for unilateral, and 0.28 (95% CI: 0.13-0.59) for bilateral, tubal pathology at HSG. The FRRs at laparoscopy were 0.85 (95% CI: 0.47-1.52) for unilateral, and 0.24 (95% CI: 0.11-0.54) for bilateral, tubal pathology. CONCLUSIONS: Patients with unilateral tubal pathology at HSG and laparoscopy had a moderate reduction in pregnancy chances, whereas those with bilateral tubal pathology at HSG and laparoscopy had a severe reduction in pregnancy chances. This reduction was similar for HSG and laparoscopy, suggesting that HSG and laparoscopy have a comparable predictive capacity for natural conception.

Tailored expectant management: risk factors for non-adherence.

INTRODUCTION: Prediction models for spontaneous pregnancy are useful tools to prevent overtreatment, complications and costs in subfertile couples with a good prognosis. The use of such models and subsequent expectant management in couples with a good prognosis are recommended in the Dutch fertility guidelines, but not fully implemented. In this study, we assess risk factors for non-adherence to tailored expectant management. METHODS: Couples with mild male, unexplained and cervical subfertility were included in this multicentre prospective cohort study. If the probability of spontaneous pregnancy within 12 months was ≥40%, expectant management for 6-12 months was advised. Multivariable logistic regression was used to identify patient and clinical characteristics associated with non-adherence to tailored expectant management. RESULTS: We included 3021 couples of whom 1130 (38%) had a ≥40% probability of a spontaneous pregnancy. Follow-up was available for 1020 (90%) couples of whom 214 (21%) had started treatment between 6 and 12 months and 153 (15%) within 6 months. A higher female age and a longer duration of subfertility were associated with treatment within 6 months (OR: 1.06, 95% CI: 1.01-1.1; OR: 1.4; 95% CI: 1.1-1.8). A fertility doctor in a clinical team reduced the risk of treatment within 6 months (OR: 0.62; 95% CI: 0.39-0.99). CONCLUSIONS: In couples with a favorable prognosis for spontaneous pregnancy, there is considerable overtreatment, especially if the woman is older and duration of the subfertility is longer. The presence of a fertility doctor in a clinic may prevent early treatment.

Chlamydia trachomatis IgG seropositivity is associated with lower natural conception rates in ovulatory subfertile women without visible tubal pathology.

BACKGROUND: The relation between Chlamydia trachomatis infection and subsequent tubal damage is widely recognized. As such, C. trachomatis antibody (CAT) testing can be used to triage women for immediate tubal testing with hysterosalpingography (HSG) or laparoscopy. However, once invasive tubal testing has ruled out tubal pathology, CAT serology status is ignored, as its clinical significance is currently unknown. This study aimed to determine whether positive CAT serology is associated with lower spontaneous pregnancy rates in women in whom HSG and/or diagnostic laparoscopy showed no visible tubal pathology. METHODS: We studied ovulatory women in whom HSG or laparoscopy showed patent tubes. Women were tested for C. trachomatis immunoglobulin G (IgG) antibodies with either micro-immunofluorescence (MIF) or an ELISA. CAT serology was positive if the MIF titre was ≥ 1:32 or if the ELISA index was >1.1. The proportion of couples pregnant without treatment was estimated at 12 months of follow-up. Time to pregnancy was considered censored at the date of the last contact when the woman was not pregnant or at the start of treatment. The association between CAT positivity and an ongoing pregnancy was evaluated with Cox regression analyses. RESULTS: Of the 1882 included women without visible tubal pathology, 338 (18%) had a treatment-independent pregnancy within 1 year [estimated cumulative pregnancy rate 31%; 95% confidence interval (CI): 27-35%]. Because of differential censoring after 9 months of follow-up, regression analyses were limited to the first 9 months after tubal testing. Positive C. trachomatis IgG serology was associated with a statistically significant 33% lower probability of an ongoing pregnancy [adjusted fecundity rate ratio 0.66 (95% CI 0.49-0.89)]. CONCLUSIONS: Even after HSG or laparoscopy has shown no visible tubal pathology, subfertile women with a positive CAT have lower pregnancy chances than CAT negative women. After external validation, this finding could be incorporated into existing prognostic models.

Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins.

BACKGROUND: Long-term effects of laparoscopic electrocautery of the ovaries are unknown. To study the long-term effects of laparoscopic electrocautery of the ovaries and gonadotrophins, we followed women with clomiphene-resistant polycystic ovary syndrome (PCOS) randomly allocated to one of these treatments until 8-12 years after their initial treatment. METHODS: Between February 1998 and October 2001 168 women with clomiphene citrate-resistant PCOS were included in a randomized controlled trial comparing an electrocautery strategy to a strategy starting with rFSH. In 2009 these women were contacted about their reproductive outcome and menstrual cycle regularity. Analysis was by intention-to-treat. We compared time to conception resulting in live birth, subsequent pregnancies, ectopic and multiple pregnancies, menopause, as well as minimal and maximal menstrual cycle length. RESULTS: After 8-12 years, the cumulative proportion of women with a first child was 86% in women who had been allocated to electrocautery versus 81% in women who had been allocated to immediate rFSH [relative ratio (RR): 1.1; 95% confidence interval (CI): 0.92-1.2]. Treatment with electrocautery resulted in a significantly lower need for stimulated cycles to reach a live birth; 53% after electrocautery versus 76% after rFSH (RR: 0.69; 95% CI: 0.55-0.88).The cumulative proportion of women with a second child was 61% after electrocautery versus 46% after immediate rFSH (RR: 1.4; 95% CI: 1.00-1.9). Overall, there were 7 twins out of 134 deliveries (5%) after electrocautery versus 10 twins out of 124 deliveries (8%) in the rFSH group (RR: 0.65; 95% CI: 0.25-1.6). Fifty-four per cent of the women allocated to electrocautery had a regular menstrual cycle 8-12 years after randomization versus 36% in those allocated to rFSH (RR: 1.5; 95% CI: 0.87-2.6). CONCLUSION: In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries is as effective as ovulation induction with FSH treatment in terms of live births, but reduces the need for ovulation induction or ART in a significantly higher proportion of women and increases the chance for a second child. Clinicians may use these data when informing clomiphene-resistant anovulatory women about treatment options.