Oil-based or water-based contrast for hysterosalpingography in infertile women: a cost-effectiveness analysis of a randomized controlled trial.

OBJECTIVE: To determine the cost effectiveness of the use of oil-based versus water-based contrast in infertile women undergoing hysterosalpingography (HSG). DESIGN: Economic evaluation alongside a multicenter randomized trial. SETTING: Hospitals. PATIENT(S): Infertile women with an ovulatory cycle, 18-39 years of age, low risk of tubal pathology. INTERVENTION(S): Use of oil-based versus water-based contrast during HSG. MAIN OUTCOME MEASURE(S): Costs per additional ongoing pregnancy and per live birth within 6 months of randomization, incremental cost-effective ratios (ICERs). RESULT(S): A total of 1,119 women were randomized to HSG (oil-based contrast, n = 557; water-based contrast, n = 562). After HSG, most women had no additional treatment; a minority had IUI or IVF. In the oil group, 39.7% women had an ongoing pregnancy within 6 months of randomization versus 29.1% women in the water group. There was a 10.7% increase in the live birth rate in the oil group. For ongoing pregnancy, the mean costs per couple were US$2,014 in the oil group and US$1,144 in the water group, with a corresponding ICER of US$8,198 per additional ongoing pregnancy. For live birth, the mean costs per couple were US$11,532 in the oil group and US$8,310 in the water group, with a corresponding ICER of US$30,112 per additional live birth. CONCLUSION(S): Hysterosalpingography with oil-based contrast results in higher 6-month ongoing pregnancy and live birth rate. If society is willing to pay US$8,198 for an additional ongoing pregnancy, HSG with oil-based contrast is a cost-effective strategy compared with HSG with water-based contrast for infertile, ovulatory women at low risk for tubal pathology. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, NTR 6577 (www.trialregister.nl).

Cost-effectiveness of single versus double embryo transfer in IVF in relation to female age.

OBJECTIVE: To evaluate the cost-effectiveness of single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available, as compared to double embryo transfer in relation to female age. STUDY DESIGN: We used a decision tree model to evaluate the costs from a healthcare provider perspective and the pregnancy rates of two embryo transfer policies: one fresh single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available (strategy I), and double embryo transfer (strategy II). The analysis was performed on an intention-to-treat basis. Sensitivity analyses were carried out to evaluate the robustness of our model and to identify which model parameters had the strongest impact on the results. RESULTS: SET followed by an additional frozen-thawed single embryo transfer if available was dominant, less costly and more effective, over DET in women under 32 years. In women aged 32 or older DET was more effective than SET followed by an additional frozen-thawed single embryo transfer if available but also more costly. CONCLUSION: SET followed by an additional frozen-thawed single embryo transfer should be the preferred strategy in women under 32 undergoing IVF. The choice for SET followed by an additional frozen-thawed single embryo transfer or DET in women aged 32 or older depends on individual patient preferences and on how much society is willing to pay for an extra child. There is a strong need for a randomized clinical trial comparing the cost and effects of SET followed by an additional frozen-thawed single embryo transfer and DET in the latter category of women.

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

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

A revised prediction model for natural conception.

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

The effectiveness of intrauterine insemination: A matched cohort study.

OBJECTIVE: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception. STUDY DESIGN: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment. RESULTS: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p=0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p=0.86). CONCLUSIONS: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples.

Reporting multiple cycles in trials on medically assisted reproduction.

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

Reducing Inter-Laboratory Differences between Semen Analyses Using Z Score and Regression Transformations.

BACKGROUND: Standardization of the semen analysis may improve reproducibility. We assessed variability between laboratories in semen analyses and evaluated whether a transformation using Z scores and regression statistics was able to reduce this variability. MATERIALS AND METHODS: We performed a retrospective cohort study. We calculated between-laboratory coefficients of variation (CVB) for sperm concentration and for morphology. Subsequently, we standardized the semen analysis results by calculating laboratory specific Z scores, and by using regression. We used analysis of variance for four semen parameters to assess systematic differences between laboratories before and after the transformations, both in the circulation samples and in the samples obtained in the prospective cohort study in the Netherlands between January 2002 and February 2004. RESULTS: The mean CVBwas 7% for sperm concentration (range 3 to 13%) and 32% for sperm morphology (range 18 to 51%). The differences between the laboratories were statistically significant for all semen parameters (all P<0.001). Standardization using Z scores did not reduce the differences in semen analysis results between the laboratories (all P<0.001). CONCLUSION: There exists large between-laboratory variability for sperm morphology and small, but statistically significant, between-laboratory variation for sperm concentration. Standardization using Z scores does not eliminate between-laboratory variability.

Does the postcoital test predict pregnancy in WHO II anovulatory women? A prospective cohort study.

OBJECTIVE: To assess the capacity of the postcoital test (PCT) to predict pregnancy in WHO II anovulatory women who are ovulatory on clomiphene citrate (CC). In these women, an abnormal PCT result could be associated with lower pregnancy chances, but this has never been proven or refuted. STUDY DESIGN: Prospective cohort study was performed between December 2009 and September 2012 for all women who started ovulation induction with CC in one university clinic and two teaching hospitals in the Netherlands. A PCT was performed in one of the first three ovulatory cycles. Ovulation induction with CC was continued for at least six cycles. The PCT was judged to be positive if at least one progressive motile spermatozo was seen in one of five high power fields at 400× magnification. The primary outcome was time to ongoing pregnancy, within six ovulatory cycles. RESULTS: In 152 women the PCT was performed. 135 women had a reliable, well-timed PCT. The ongoing pregnancy rate was 44/107 (41%) for a positive and 10/28 (36%) for a negative PCT. The hazard rate for ongoing pregnancy was 1.3 (95% CI 0.64-2.5) for a positive versus a negative PCT. Thirty five of 77 (46%) women with clear mucus had an ongoing pregnancy versus 12 of 45 (27%) women in whom the mucus was not clear (HR 2.0; 95% CI 1.02-3.84, p=0.04). CONCLUSION: The present study suggests that the outcome of the postcoital test in women with WHO-II anovulation that undergo ovulation induction with CC does not have a large effect on ongoing pregnancy chances over time.

Does polycystic ovary syndrome affect cognition? A functional magnetic resonance imaging study exploring working memory.

OBJECTIVE: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). DESIGN: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. SETTING: Department of reproductive medicine, university medical center. PATIENT(S): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. INTERVENTION(S): Antiandrogenic hormone treatment. MAIN OUTCOME MEASURE(S): Functional MRI response during a working memory task. RESULT(S): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. CONCLUSION(S): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

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

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

Presence of human papillomavirus in semen of healthy men is firmly associated with HPV infections of the penile epithelium.

OBJECTIVE: To study the source of human papillomavirus (HPV) in semen. DESIGN: Observational study (CCMO-NL3248800010). SETTING: Academic hospital-based laboratory. PATIENT(S): Healthy male volunteers (n = 213). INTERVENTION(S): One penile scrape and three semen samples were obtained per participant for HPV-DNA testing by both GP5+/6+ polymerase chain reaction (PCR) and SPF10-PCR to detect moderate/high and low viral loads, respectively; flat penile lesions (FPL) were detected by penoscopy. MAIN OUTCOME MEASURE(S): HPV-DNA presence in semen and penile scrapes, and the presence of FPL. RESULT(S): HPV-DNA at moderate/high viral loads (i.e., GP5+/6+ PCR-positive) was detected in ≥1 semen sample(s) in 27% of participants. Most men with moderate/high viral loads in the penile scrape also had moderate/high viral loads in semen (85%). Men with a HPV-negative penile scrape were very unlikely to have moderate/high viral loads in semen (3%). The presence of HPV in semen was associated with the presence of HPV in the penile scrape also on a genotype-specific level. Having FPL was a risk factor for HPV presence in semen. CONCLUSION(S): HPV-DNA presence in semen of healthy men is common and associated with HPV infections of the penile epithelium. HPV-DNA presence in semen may result from desquamation of HPV-infected penile cells.

Cost-effectiveness of assisted conception for male subfertility.

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

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

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

Impact of assisted reproductive technology on the incidence of multiple-gestation infants: a population perspective.

OBJECTIVE: To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants. DESIGN: Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilization and single-embryo transfer (SET) rates. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The contribution of ART multiple-gestation infants to the total number of multiple-gestation infants in a population was calculated in relation to utilization of ART and SET rates. RESULT(S): The number of ART treatments leading to embryo transfer varied from 304 per million inhabitants in the U.S. to 1,518 in Denmark. The percentage of ART cycles that utilized SET varied from 8.8% in South Korea to 53.3% in Australia. Reflecting both utilization rates and SET rates, the percentage of multiple-gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark. CONCLUSION(S): In seven countries, the contribution of ART multiple-gestation infants to all multiple-gestation infants varies from 14.7% to 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient.

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

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

Hysterosalpingo-foam sonography, a less painful procedure for tubal patency testing during fertility workup compared with (serial) hysterosalpingography: a randomized controlled trial.

OBJECTIVE: To determine whether hysterosalpingo-foam sonography (HyFoSy) is a less painful first line tubal patency test than serial hysterosalpingography (HSG). DESIGN: A two-center, prospective, open-label, randomized, controlled trial. SETTING: University hospital and teaching hospital. PATIENT(S): 40 subfertile women, ages 18 to 41 years, with an indication for tubal patency testing as part of the fertility workup according to the Dutch Nederlandse Vereniging voor Obsteterie & Gynaecologie-guidelines. INTERVENTION(S): Tubal patency testing by HyFoSy versus serial HSG. MAIN OUTCOME MEASURE(S): Visual Analogue Scale (VAS) pain scores during tubal patency testing. RESULT(S): The median VAS score for pain perception during the HyFoSy procedure was 1.7 cm (interquartile range: 2.1) compared with 3.7 cm (interquartile range: 4.2) during HSG. The HyFoSy procedure also had a statistically significantly shorter procedure time compared with HSG, with a median of 5.0 minutes (interquartile range: 3.0) for HyFoSy versus 12.5 minutes (interquartile range: 16.0) for HSG. CONCLUSION(S): The HyFoSy procedure is a less painful and less time-consuming tubal patency test compared with HSG. CLINICAL TRIAL REGISTRATION NUMBER: Netherlands National Trial Register NTR3457.

Semen analysis and prediction of natural conception.

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

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

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

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

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

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

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