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Couples in whom the results of an initial fertility workup fail to identify the presence of any obvious barriers to conception are diagnosed with unexplained subfertility. Couples who have tried to conceive for a relatively short time have a good chance of natural conception and thus may not benefit from immediate access to ART. As fertility decreases over time, the main dilemma that clinicians and couples face is when to abandon an expectant approach in favour of active treatment. Several prognostic or predictive models have been used to try to discriminate between couples with high and low chances of conception but have been unable to compare individualized chances of conception associated with ART relative to chances of natural conception at various time points. These models are also unable to recalculate the chances of pregnancy at subsequent time points in those who return after a period of unsuccessful expectant management. In this paper, we discuss currently available models. We conclude that in order to provide accurate, individualized and dynamic fertility prognoses associated with and without treatment at different points in time, we need to develop, validate and update clinical prediction models which are fit for purpose. We suggest several steps to move the field forwards. [ABSTRACT FROM AUTHOR]

The Kaplan-Meier, Nelson-Aalen and Breslow estimators are widely used in the analysis of right-censored time to event data in medical applications. These methods are fully non-parametric and do not put any restriction on the shape of the hazard curve. In some applications, this leads to implausible estimates of the hazard course over time. With non-parametric shape-constrained estimation techniques, one can facilitate an increasing or decreasing hazard and thus generate estimators that better match the biological reasoning, without being as restrictive as parametric methods. We illustrate the advantage of such techniques in the analysis of a large clinical trial in cardiology. Simulation results show that in case the true hazard is monotone, the non-parametric shape-constrained estimators are more accurate than the traditional estimators on the hazard level. On the (cumulative) distribution function level, the shape-constrained estimators show similar performance as the traditional ones. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can mixture survival models help distinguish infertility from subfertility in couples with an unexplained unfulfilled child wish? SUMMARY ANSWER Mixture models estimated that 47% of the couples were infertile; female age and previous pregnancy were significantly related to infertility, whereas duration of child wish was associated with a longer time to pregnancy for subfertile couples. WHAT IS KNOWN ALREADY To differentiate between couples who require assisted conception and couples who still have good chances of natural, i.e. unassisted, conception, several prediction models of natural conception have been developed. Prognostic factors in these models are usually assessed by Cox proportional hazard models that cannot differentiate between couples with an unfulfilled child wish who are subfertile, i.e. have reduced ability to conceive naturally, and couples who are really infertile, i.e. are completely unable to conceive naturally. We evaluated whether a mixture survival model can make such a distinction. STUDY DESIGN, SIZE, DURATION Consecutive couples presenting at the fertility clinics of 38 centres in the Netherlands between January 2002 and February 2004 joined a prospective cohort study. Of the 7860 couples in the cohort, 3917 couples met our inclusion criteria. The median follow-up was 219 days, with a maximum of 5 years. PARTICIPANTS, SETTING, METHODS Couples had to present with an unexplained cause of an unfulfilled child wish. A mixture model was used to estimate the proportion of couples who were infertile and the time to pregnancy for the subfertile couples. MAIN RESULTS AND THE ROLE OF CHANCE During the follow-up, 794 couples conceived naturally. The mixture model estimated that 47% [95% confidence interval (CI): 33–56%] of couples were infertile, despite the absence of objective factors indicating a cause for infertility. Of the evaluated prognostic factors, female age, duration of child wish, previous pregnancy, semen quality, BMI and cycle length, female age [odds ratio (OR): 1.11, 95% CI: 1.03–1.19] and previous pregnancy (0.22, 95% CI: 0.07–0.67) were significant predictors of infertility. Among subfertile couples, a longer duration of a child wish (FFR: 0.72, 95% CI: 0.61–0.85) was a significant prognostic factor for time to pregnancy. In the Cox models, all variables except BMI were significant predictors of time to pregnancy. LIMITATIONS, REASONS FOR CAUTION The mixture model had limited power due to a low number of couples at the end of the follow-up period. Mixture model analyses on external, long-term follow-up data are necessary to validate our results. WIDER IMPLICATIONS OF THE FINDINGS Mixture models could be a useful tool in selecting couples who require assisted reproductive technology because the effects of prognostic factors can be subdivided into effects on the fraction of infertile couples and effects on the time to pregnancy for subfertile couples, which is not possible in conventional models. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grant 945/12/002 from ZonMw, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands. [ABSTRACT FROM AUTHOR]

BACKGROUND Prediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan–Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan–Meier and Cox models. METHODS In a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis. RESULTS The estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74. CONCLUSIONS Given the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests. [ABSTRACT FROM AUTHOR]

Study Question: Can we develop an IVF prediction model to estimate individualized chances of a live birth over multiple complete cycles of IVF in couples embarking on their second complete cycle of treatment?Summary Answer: Yes, our prediction model can estimate individualized chances of cumulative live birth over three additional complete cycles of IVF.What Is Known Already: After the completion of a first complete cycle of IVF, couples who are unsuccessful may choose to undergo further treatment to have their first child, while those who have had a live birth may decide to have more children. Existing prediction models can estimate the overall chances of success in couples before commencing IVF but are unable to revise these chances on the basis of the couple's response to a first treatment cycle in terms of the number of eggs retrieved and pregnancy outcome. This makes it difficult for couples to plan and prepare emotionally and financially for the next step in their treatment.Study Design, Size, Duration: For model development, a population-based cohort was used of 49 314 women who started their second cycle of IVF including ICSI in the UK from 1999 to 2008 using their own oocytes and their partners' sperm. External validation was performed on data from 39 442 women who underwent their second cycle from 2010 to 2016.Participants/materials, Setting, Methods: Data about all UK IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA) database. Using a discrete time logistic regression model, we predicted the cumulative probability of live birth from the second up to and including the fourth complete cycles of IVF. Inverse probability weighting was used to account for treatment discontinuation. Discrimination was assessed using c-statistic and calibration was assessed using calibration-in-the-large and calibration slope.Main Results and the Role Of Chance: Following exclusions, 49 314 women with 73 053 complete cycles were included. 12 408 (25.2%) had a live birth resulting from their second complete cycle. Cumulatively, 17 394 (35.3%) had a live birth over complete cycles two to four. The model showed moderate discriminative ability (c-statistic: 0.65, 95% CI: 0.64 to 0.65) and evidence of overprediction (calibration-in-the-large = -0.08) and overfitting (calibration slope 0.85, 95% CI: 0.81 to 0.88) in the validation cohort. However, after recalibration the fit was much improved. The recalibrated model identified the following key predictors of live birth: female age (38 versus 32 years-adjusted odds ratio: 0.59, 95% CI: 0.57 to 0.62), number of eggs retrieved in the first complete cycle (12 versus 4 eggs; 1.34, 1.30 to 1.37) and outcome of the first complete cycle (live birth versus no pregnancy; 1.78, 1.66 to 1.91; live birth versus pregnancy loss; 1.29, 1.23 to 1.36). As an example, a 32-year-old with 2 years of non-tubal infertility who had 12 eggs retrieved from her first stimulation and had a live birth during her first complete cycle has a 46% chance of having a further live birth from the second complete cycle of IVF and an 81% chance over a further three cycles.Limitations, Reasons For Caution: The developed model was updated using validation data that was 6 to 12 years old. IVF practice continues to evolve over time, which may affect the accuracy of predictions from the model. We were unable to adjust for some potentially important predictors, e.g. BMI, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. These were not available in the linked HFEA dataset.Wider Implications Of the Findings: By appropriately adjusting for couples who discontinue treatment, our novel prediction model will provide more realistic chances of live birth in couples starting a second complete cycle of IVF. Clinicians can use these predictions to inform discussion with couples who wish to plan ahead. This prediction tool will enable couples to prepare emotionally, financially and logistically for IVF treatment.Study Funding/competing Interest(s): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. The authors have no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

BACKGROUND Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics. METHODS We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model. RESULTS We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age [factor 0.93 per year (P = 0.05)]. The specificity of HSG was very stable across all subgroups. CONCLUSIONS The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples. [ABSTRACT FROM AUTHOR]

Study Question: What is the predictive performance of a currently recommended prediction model in an external Dutch cohort of couples with unexplained recurrent pregnancy loss (RPL)?Summary Answer: The model shows poor predictive performance on a new population; it overestimates, predicts too extremely and has a poor discriminative ability.What Is Known Already: In 50-75% of couples with RPL, no risk factor or cause can be determined and RPL remains unexplained. Clinical management in RPL is primarily focused on providing supportive care, in which counselling on prognosis is a main pillar. A frequently used prediction model for unexplained RPL, developed by Brigham et al. in 1999, estimates the chance of a successful pregnancy based on number of previous pregnancy losses and maternal age. This prediction model has never been externally validated.Study Design, Size, Duration: This retrospective cohort study consisted of 739 couples with unexplained RPL who visited the RPL clinic of the Leiden University Medical Centre between 2004 and 2019.Participants/materials, Setting, Methods: Unexplained RPL was defined as the loss of two or more pregnancies before 24 weeks, without the presence of an identifiable cause for the pregnancy losses, according to the ESHRE guideline. Obstetrical history and maternal age were noted at intake at the RPL clinic. The outcome of the first pregnancy after intake was documented. The performance of Brigham's model was evaluated through calibration and discrimination, in which the predicted pregnancy rates were compared to the observed pregnancy rates.Main Results and the Role Of Chance: The cohort included 739 women with a mean age of 33.1 years (±4.7 years) and with a median of three pregnancy losses at intake (range 2-10). The mean predicted pregnancy success rate was 9.8 percentage points higher in the Brigham model than the observed pregnancy success rate in the dataset (73.9% vs 64.0% (95% CI for the 9.8% difference 6.3-13.3%)). Calibration showed overestimation of the model and too extreme predictions, with a negative calibration intercept of -0.46 (95% CI -0.62 to -0.31) and a calibration slope of 0.42 (95% CI 0.11-0.73). The discriminative ability of the model was very low with a concordance statistic of 0.55 (95% CI 0.51-0.59). Recalibration of the Brigham model hardly improved the c-statistic (0.57; 95% CI 0.53-0.62).Limitations, Reasons For Caution: This is a retrospective study in which only the first pregnancy after intake was registered. There was no time frame as inclusion criterium, which is of importance in the counselling of couples with unexplained RPL. Only cases with a known pregnancy outcome were included.Wider Implications Of the Findings: This is the first study externally validating the Brigham prognostic model that estimates the chance of a successful pregnancy in couples with unexplained RPL. The results show that the frequently used model overestimates the chances of a successful pregnancy, that predictions are too extreme on both the high and low ends and that they are not much more discriminative than random luck. There is a need for revising the prediction model to estimate the chance of a successful pregnancy in couples with unexplained RPL more accurately.Study Funding/competing Interest(s): No external funding was used and no competing interests were declared.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic total mesorectal excision (TME) surgery for rectal cancer has important technical limitations. Robotassisted and transanal TME (TaTME) may overcome these limitations, potentially leading to lower conversion rates and reduced morbidity. However, comparative data between the three approaches are lacking. The aim of this study was to compare short-term outcomes for laparoscopic TME, robot-assisted TME and TaTME in expert centres. Methods: Patients undergoing rectal cancer surgery between 2015 and 2017 in expert centres for laparoscopic, robot-assisted or TaTME were included. Outcomes for TME surgery performed by the specialized technique in the expert centres were compared after propensity score matching. The primary outcome was conversion rate. Secondary outcomes were morbidity and pathological outcomes. Results: A total of 1078 patients were included. In rectal cancer surgery in general, the overall rate of primary anastomosis was 39.4, 61.9 and 61.9 per cent in laparoscopic, robot-assisted and TaTME centres respectively (P<0.001). For specialized techniques in expert centres excluding abdominoperineal resection (APR), the rate of primary anastomosis was 66.7 per cent in laparoscopic, 89.8 per cent in robot-assisted and 84.3 per cent in TaTME (P<0.001). Conversion rates were 3.7, 4.6 and 1.9 per cent in laparoscopic, robotassisted and TaTME respectively (P=0.134). The number of incomplete specimens, circumferential resection margin involvement rate and morbidity rates did not differ. Conclusion: In the minimally invasive treatment of rectal cancer more primary anastomoses are created in robotic and TaTME expert centres. [ABSTRACT FROM AUTHOR]

Objective: Neurodevelopmental delay is frequently encountered in children with a congenital heart defect (CHD). Fetuses with major CHD have a smaller head circumference (HC), irrespective of altered cerebral flow or brain oxygenation. This cohort study compared head growth in cases with isolated vs those with non-isolated CHD to evaluate the effect of additional pathology on head size in these fetuses.Method: All CHD cases diagnosed prenatally in the period January 2002-July 2014 were selected from our regional registry, PRECOR. Cases of multiple pregnancy, and those affected by maternal diabetes, severe fetal structural brain anomalies or functional CHD were excluded. Subjects were divided into groups according to whether the CHD was isolated, and the non-isolated group was subdivided into three groups: cases with genetic anomaly, extracardiac malformation or placental pathology. In both isolated and non-isolated CHD groups, CHDs were also grouped according to their potential effect on aortic flow and oxygen saturation. Mean HC Z-scores at 20 weeks and increase or decrease (Δ) of HC Z-scores over the course of pregnancy were compared between isolated and non-isolated groups, using mixed linear regression models.Results: Included were 916 cases of CHD diagnosed prenatally, of which 378 (41.3%) were non-isolated (37 with placental pathology, 217 with genetic anomaly and 124 with extracardiac malformation). At 20 weeks, non-isolated cases had significantly lower HC Z-scores than did isolated cases (Z-score = -0.70 vs -0.03; P < 0.001) and head growth over the course of pregnancy showed a larger decrease in this group (Δ HC Z-score = -0.03 vs -0.01 per week; P = 0.01). Cases with placental pathology had the lowest HC Z-score at 20 weeks (Z-score = -1.29) and the largest decrease in head growth (Δ HC Z-score = -0.06 per week). In CHD subjects with a genetic diagnosis (Z-score = -0.73; Δ HC Z-score = -0.04 per week) and in those with an extracardiac malformation (Z-score = -0.49; Δ HC Z-score = -0.02 per week), HC Z-scores were also lower compared with those in subjects with isolated CHD. CHDs that result in low oxygenation or flow to the brain were present more frequently in isolated than in non-isolated cases.Conclusions: Smaller HC in fetuses with CHD appears to be associated strongly with additional pathology. Placental pathology and genetic anomaly in particular seem to be important contributors to restricted head growth. This effect appears to be irrespective of altered hemodynamics caused by the CHD. Previously reported smaller HC in CHD should, in our opinion, be attributed to additional pathology. Neurodevelopment studies in infants with CHD should, therefore, always differentiate between isolated and non-isolated cases. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Study Question: Which couples with unexplained subfertility can expect increased chances of ongoing pregnancy with IVF compared to expectant management?Summary Answer: For couples in which the woman is under 40 years of age, IVF is associated with higher chances of conception than expectant management.What Is Known Already: The clinical indications for IVF have expanded over time from bilateral tubal blockage to include unexplained subfertility in which there is no identifiable barrier to conception. Yet, there is little evidence from randomized controlled trials that IVF is effective in these couples.Study Design, Size, Duration: We compared outcomes in British couples with unexplained subfertility undergoing IVF (n = 40 921) from registry data to couples with the same type of subfertility on expectant management. Those couples on expectant management (defined as no intervention aside from the advice to have intercourse) comprised a prospective nation-wide Dutch cohort (n = 4875) and a retrospective regional cohort from Aberdeen, Scotland (n = 975). We excluded couples who had tried for <1 year to conceive and also those with anovulation, uni- or bilateral tubal occlusion, mild or severe endometriosis or male subfertility i.e. impaired semen quality according to World Health Organization criteria.Participants/materials, Setting, Methods: We matched couples who received IVF and couples on expectant management based on their characteristics to control for confounding. We fitted a Cox proportional hazards model including patient characteristics, IVF treatment and their interactions to estimate the individualized chance of conception over 1 year-either following IVF or expectant management for all combinations of patient characteristics. The endpoint was conception leading to ongoing pregnancy, defined as a foetus reaching a gestational age of at least 12 weeks.Main Results and the Role Of Chance: The adjusted 1-year chance of conception was 47.9% (95% CI: 45.0-50.9) after IVF and 26.1% (95% CI: 24.2-28.0) after expectant management. The absolute difference in the average adjusted 1-year chances of conception was 21.8% (95%CI: 18.3-25.3) in favour of IVF. The effectiveness of IVF was influenced by female age, duration of subfertility and previous pregnancy. IVF was effective in women under 40 years, but the 1-year chance of an IVF conception declined sharply in women over 34 years. In contrast, in woman over 40 years of age, IVF was less effective, with an absolute difference in chance compared to expectant management of 10% or lower. Regardless of female age, IVF was also less effective in couples with a short period of secondary subfertility (1 year) who had chances of natural conception of 30% or above.Limitations, Reasons For Caution: The 1-year chances of conception were based on three cohorts with different sampling mechanisms. Despite adjustment for the three most important prognostic patient characteristics, namely female age, duration of subfertility and primary or secondary subfertility, our estimates might not be free from residual confounding.Wider Implications Of the Findings: IVF should be used selectively based on judgements on gain compared to continuing expectant management for a given couple. Our results can be used by clinicians to counsel couples with unexplained subfertility, to inform their expectations and facilitate evidence-based, shared decision making.Study Funding/competing Interest(s): This work was supported by Tenovus Scotland [grant G17.04]. Travel for RvE was supported by the Amsterdam Reproduction & Development Research Group [grant V.000296]. SB reports acting as editor-in-chief of HROpen. Other authors have no conflicts. [ABSTRACT FROM AUTHOR]

Study Question: Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility?Summary Answer: Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis.What Is Known Already: Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations.Study Design, Size, Duration: A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.Participants/materials, Setting, Methods: A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands.Main Results and the Role Of Chance: A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment.Limitations, Reasons For Caution: We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort.Wider Implications Of the Findings: For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey.Study Funding/competing Interest(s): This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest. [ABSTRACT FROM AUTHOR]

Objective: To evaluate if immediate catheter removal (ICR) after laparoscopic hysterectomy is associated with similar retention outcomes compared with delayed removal (DCR).Study Design: Non-inferiority randomised controlled trial.Population: Women undergoing laparoscopic hysterectomy in six hospitals in the Netherlands.Methods: Women were randomised to ICR or DCR (between 18 and 24 hours after surgery).Primary Outcome: The inability to void within 6 hours after catheter removal.Results: One hundred and fifty-five women were randomised to ICR (n = 74) and DCR (n = 81). The intention-to-treat and per-protocol analysis could not demonstrate the non-inferiority of ICR: ten women with ICR could not urinate spontaneously within 6 hours compared with none in the delayed group (risk difference 13.5%, 5.6-24.8, P = 0.88). However, seven of these women could void spontaneously within 9 hours without additional intervention. Regarding the secondary outcomes, eight women from the delayed group requested earlier catheter removal because of complaints (9.9%). Three women with ICR (4.1%) had a urinary tract infection postoperatively versus eight with DCR (9.9%, risk difference -5.8%, -15.1 to 3.5, P = 0.215). Women with ICR mobilised significantly earlier (5.7 hours, 0.8-23.3 versus 21.0 hours, 1.4-29.9; P ≤ 0.001).Conclusion: The non-inferiority of ICR could not be demonstrated in terms of urinary retention 6 hours after procedure. However, 70% of the women with voiding difficulties could void spontaneously within 9 hours after laparoscopic hysterectomy. It is therefore questionable if all observed urinary retention cases were clinically relevant. As a result, the clinical advantages of ICR may still outweigh the risk of bladder retention and it should therefore be considered after uncomplicated laparoscopic hysterectomy.Tweetable Abstract: The advantages of immediate catheter removal after laparoscopic hysterectomy seem to outweigh the risk of bladder retention. [ABSTRACT FROM AUTHOR]

Abstract Research question Hysterosalpingography (HSG) with an oil-based contrast has been shown to increase ongoing pregnancy rates compared with HSG with water-based contrast, but it remains unclear if an effect of HSG occurs compared with no HSG. Design A secondary data-analysis of a prospective cohort study among 4556 couples that presented with unexplained subfertility in 38 clinics in the Netherlands between January 2002 and December 2004. A time-varying Cox regression with inverse probability of treatment weighing was used to analyse ongoing pregnancy rates in women after undergoing the HSG procedure (with the use of either water- or oil-based contrast media) compared with women who did not undergo HSG. Results The probability of natural conception within 24 months after first presentation at the fertility clinic was increased after HSG, regardless of the type of contrast medium used, compared with no HSG (adjusted hazard ratio 1.48, 95% CI 1.26 to 1.73, corresponding to an absolute increase in 6-month pregnancy rate of +6%). When this analysis was limited to HSGs that were made with water-contrast, the treatment effect remained (adjusted hazard ratio 1.40, 95% CI 1.16 to 1.70). Conclusions HSG increases the ongoing pregnancy rate of couples with unexplained subfertility compared with no HSG, regardless of the contrast medium used. Results need to be validated in future, preferably randomized, studies. [ABSTRACT FROM AUTHOR]

Study Question: Does starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management in couples with unexplained subfertility?Summary Answer: IUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year.What Is Known Already: IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI-OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple's prognosis of natural conception.Study Design, Size, Duration: A prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup.Participants/materials, Setting, Methods: The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.Main Results and the Role Of Chance: Data from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47-2.62) compared to expectant management. The effect of treatment was modified by a couple's prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21-28%) for expectant management and 24% (95% CI: 9-36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15-19%) for expectant management and 24% (95% CI: 15-32%) for starting IUI-OS.Limitations, Reasons For Caution: The effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets.Wider Implications Of the Findings: These results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost-)effective.Study Funding/competing Interest(s): This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest. [ABSTRACT FROM AUTHOR]

Study Question: How well does a previously developed dynamic prediction model perform in an external, geographical validation in terms of predicting the chances of natural conception at various points in time?Summary Answer: The dynamic prediction model performs well in an external validation on a Scottish cohort.What Is Known Already: Prediction models provide information that can aid evidence-based management of unexplained subfertile couples. We developed a dynamic prediction model for natural conception (van Eekelen model) that is able to update predictions of natural conception when couples return to their clinician after a period of unsuccessful expectant management. It is not known how well this model performs in an external population.Study Design, Size, Duration: A record-linked registry study including the long-term follow-up of all couples who were considered unexplained subfertile following a fertility workup at a Scottish fertility clinic between 1998 and 2011. Couples with anovulation, uni/bilateral tubal occlusion, mild/severe endometriosis or impaired semen quality according to World Health Organization criteria were excluded.Participants/materials, Setting, Methods: The endpoint was time to natural conception, leading to an ongoing pregnancy (defined as reaching a gestational age of at least 12 weeks). Follow-up was censored at the start of treatment, at the change of partner or at the end of study (31 March 2012). The performance of the van Eekelen model was evaluated in terms of calibration and discrimination at various points in time. Additionally, we assessed the clinical utility of the model in terms of the range of the calculated predictions.Main Results and the Role Of Chance: Of a total of 1203 couples with a median follow-up of 1 year and 3 months after the fertility workup, 398 (33%) couples conceived naturally leading to an ongoing pregnancy. Using the dynamic prediction model, the mean probability of natural conception over the course of the first year after the fertility workup was estimated at 25% (observed: 23%). After 0.5, 1 and 1.5 years of expectant management after the completion of the fertility workup, the average probability of conceiving naturally over the next year was estimated at 18% (observed: 15%), 14% (observed: 14%) and 12% (observed: 12%). Calibration plots showed good agreement between predicted chances and the observed fraction of ongoing pregnancy within risk groups. Discrimination was moderate with c statistics similar to those in the internal validation, ranging from 0.60 to 0.64. The range of predicted chances was sufficiently wide to distinguish between couples having a good and poor prognosis with a minimum of zero at all times and a maximum of 55% over the first year after the workup, which decreased to maxima of 43% after 0.5 years, 34% after 1 year and 29% after 1.5 years after the fertility workup.Limitations, Reasons For Caution: The model slightly overestimated the chances of conception by ~2-3% points on group level in the first-year post-fertility workup and after 0.5 years of expectant management, respectively. This is likely attributable to the fact that the exact dates of completion of the fertility workup for couples were missing and had to be estimated.Wider Implications Of the Findings: The van Eekelen model is a valid and robust tool that is ready to use in clinical practice to counsel couples with unexplained subfertility on their individualized chances of natural conception at various points in time, notably when couples return to the clinic after a period of unsuccessful expectant management.Study Funding/competing Interest(s): This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). There are no conflicts of interest. [ABSTRACT FROM AUTHOR]

Study Question: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception?Summary Answer: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%).What Is Known Already: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable.Study Design, Size, Duration: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment.Participants/materials, Settings, Methods: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment.Main Results and the Role Of Chance: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%.Limitations, Reasons For Caution: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive.Wider Implications Of the Findings: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts.Study Funding/competing Interest(s): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported.Trial Registration Number: The INeS trial was registered at the Dutch trial registry (NTR 939). [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is associated with decreased birthweight (BW) compared to population-based reference charts. These results were consistent in the subgroup analysis of severe CHD (BW z-score difference -0.20) and minor CHD (BW z-score difference-0.10). BW z-score was significantly lower in CHD cases compared to their siblings (BW z-score difference -0.20, 95% CI; -0.34, -0.06, P = 0.005). [Extracted from the article]

Study Question: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility?Summary Answer: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic.What Is Known Already: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management.Study Design, Size, Duration: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded.Participants/materials, Setting, Methods: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions.Main Results and the Role Of Chance: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup.Limitations, Reasons For Caution: The dynamic prediction model needs to be validated in an external population.Wider Implications Of the Findings: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup.Study Funding/competing Interests: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests. [ABSTRACT FROM AUTHOR]

Background Care for patients with a ruptured abdominal aortic aneurysm ( rAAA) in the Amsterdam ambulance region (The Netherlands) was concentrated into vascular centres with a 24-h full emergency vascular service in cooperation with seven referring regional hospitals. Previous population-based survival after rAAA in the Netherlands was 46 (95 per cent confidence interval (c.i.) 43 to 49) per cent. It was hypothesized that regional cooperation would improve survival. Methods This was a prospective observational cohort study carried out simultaneously with the Amsterdam Acute Aneurysm Trial. Consecutive patients with an rAAA between 2004 and 2011 in all ten hospitals in the Amsterdam region were included. The primary outcome was 30-day survival after admission. Multivariable logistic regression, including age, sex, co-morbidity, intervention (endovascular or open repair), preoperative systolic blood pressure, cardiopulmonary resuscitation and year of intervention, was used to assess the influence of hospital setting on survival. Results Of 453 patients with rAAA from the Amsterdam ambulance region, 61 did not undergo intervention; 352 patients were treated surgically at a vascular centre and 40 at a referring hospital. The regional survival rate was 58·5 (95 per cent c.i. 53·9 to 62·9) per cent (265 of 453). After multivariable adjustment, patients treated at a vascular centre had a higher survival rate than patients treated surgically at a referring hospital (adjusted odds ratio 3·18, 95 per cent c.i. 1·43 to 7·04). Conclusion After regional cooperation, overall survival of patients with an rAAA improved. Most patients were treated in a vascular centre and in these patients survival rates were optimal. [ABSTRACT FROM AUTHOR]

BACKGROUND Tubal patency tests are routinely performed in the diagnostic work-up of subfertile patients, but it is unknown whether these diagnostic tests add value beyond the information obtained by medical history taking and findings at physical examination. We used individual patient data meta-analysis to assess this question. METHODS We approached authors of primary studies for data sets containing information on patient characteristics and results from tubal patency tests, such as Chlamydia antibody test (CAT), hysterosalpingography (HSG) and laparoscopy. We used logistic regression to create models that predict tubal pathology from medical history and physical examination alone, as well as models in which the results of tubal patency tests are integrated in the patient characteristics model. Laparoscopy was considered to be the reference test. RESULTS We obtained data from four studies reporting on 4883 women. The duration of subfertility, number of previous pregnancies and a history of previous pelvic inflammatory disease (PID), pelvic surgery or Chlamydia infection qualified for the patient characteristics model. This model showed an area under the receiver operating characteristic curve (AUC) of 0.63 [95% confidence interval (CI) 0.61–0.65]. For any tubal pathology, the addition of HSG significantly improved the predictive performance to an AUC of 0.74 (95% CI 0.73–0.76) (P < 0.001). For bilateral tubal pathology, the addition of both CAT and HSG increased the predictive performance to an AUC of 0.76 (95% CI 0.74–0.79). CONCLUSIONS In the work-up for subfertile couples, the combination of patient characteristics with CAT and HSG results gives the best diagnostic performance for the diagnosis of bilateral tubal pathology. [ABSTRACT FROM AUTHOR]

BACKGROUND The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays. METHODS We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction. RESULTS We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology. CONCLUSIONS In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice. [ABSTRACT FROM AUTHOR]

Objectives: We investigated whether multiple biomarkers improve prognostication in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention.Background: Few data exist on the prognostic value of combined biomarkers.Methods: We used data from 1,034 STEMI patients undergoing primary percutaneous coronary intervention in a high-volume percutaneous coronary intervention center in the Netherlands and investigated whether combining N-terminal pro-brain natriuretic peptide, glucose, C-reactive protein, estimated glomerular filtration rate, and cardiac troponin T improved the prediction of mortality. A risk score was developed based on the strongest predicting biomarkers in multivariate Cox regression. The additional prognostic value of the strongest predicting biomarkers to the established prognostic factors (age, body weight, diabetes, hypertension, systolic blood pressure, heart rate, anterior myocardial infarction, and time to treatment) was assessed in multivariable Cox regression.Results: During follow-up (median, 901 days), 120 of the 1,034 patients died. In Cox regression, glucose, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide were the strongest predictors for mortality (p < 0.05, for all). A risk score incorporating these biomarkers identified a high-risk STEMI subgroup with a significantly higher mortality when compared with an intermediate- or low-risk subgroup (p < 0.001). Addition of the 3 biomarkers to established prognostic factors significantly improved prediction for mortality, as shown by the net reclassification improvement (0.481, p < 0.001) [corrected] and integrated discrimination improvement (0.0226, p = 0.03) [corrected].Conclusions: Our data suggest that addition of a multimarker to a model including established risk factors improves the prediction of mortality in STEMI patients undergoing primary percutaneous coronary intervention. Furthermore, the use of a simple risk score based on these biomarkers identifies a high-risk subgroup. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In developing countries, patients with a Wilms' tumour often present late with a high degree of malnutrition and large tumours. We investigated whether this affects vincristine pharmacokinetics. METHODS: Patients newly diagnosed with Wilms' tumour in Malawi and the UK were included. We documented anthropometric parameters, nutritional status and tumour size. Vincristine (1.50 mg/m(2)) was administered as part of the standard chemotherapy regimen. Vincristine plasma concentrations were measured at several time points by liquid chromatography-mass spectrometry. Vincristine pharmacokinetic parameters (clearance and area under the curve) were calculated by non-compartmental analysis. RESULTS: Eleven Malawian and 8 UK patients were included. Mean Z-score of (corrected) weight for height was significantly lower in the Malawian patients than in the UK patients (-2.3 versus 0.42, p<0.0001). Mean tumour weight at diagnosis was significantly larger in Malawian patients (2.8 kg versus 0.7 kg, p=0.007). Mean vincristine logClearance was lower in Malawian as compared to UK patients (2.2 versus 2.6 ml/min, p=0.001). Mean logAUC values were higher in Malawian than in UK patients (3.8 versus 3.5 microg/mlmin, p=0.003). This difference is reflected in the, on average, 1.98-fold larger vincristine AUC values for Malawian patients. The difference in AUC values was statistically significantly explained by nutritional status (p=0.043). CONCLUSION: Malnourished patients in Malawi exhibited lower vincristine clearance rates and thus higher AUC values than a comparable patient population with a better nutritional status in the UK. In malnourished patients, dose reductions may need to be considered to prevent an increased incidence and severity of toxicity. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to evaluate whether primary percutaneous coronary intervention (PCI) with combined proximal embolic protection and thrombus aspiration results in smaller final infarct size and improved left ventricular function assessed by cardiovascular magnetic resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) patients compared with primary PCI alone. Background Primary PCI with the Proxis system improves immediate microvascular flow post-procedure as measured by ST-segment resolution, which could result in better outcomes. Methods The ancillary CMR study included 206 STEMI patients who were enrolled in the PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation (PREPARE) trial. CMR imaging was assessed between 4 and 6 months after the index procedure. Results There were no significant differences in final infarct size (6.1 g/m² vs 6.3 g/m², p?=?0.78) and left ventricular ejection fraction (50% vs 50%, p?=?0.46) between both groups. Also, systolic wall thickening in the infarct area (44% vs 45%, p?=?0.93) or the extent of transmural segments (8.3% of segments vs 8.3% of segments, p?=?0.60) showed no significant differences. The incidence of major adverse cardiac and cerebral events at 6 months was similar in the Proxis and control group (8% vs 10%, respectively, p?=?0.43). Conclusions Primary PCI with combined proximal embolic protection and thrombus aspiration in STEMI patients did not result in significant differences in final infarct size or left ventricular function at follow-up CMR. In addition, there was no difference in the incidence of major adverse cardiac and cerebral events at 6 months. [ABSTRACT FROM AUTHOR]