Pieternel Steures

Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial

BACKGROUND Intrauterine insemination with controlled ovarian hyperstimulation is commonly used as first-line treatment for couples with unexplained subfertility. Since such treatment increases the risk of multiple pregnancy, a couples chances of achieving an ongoing pregnancy without it should be considered to identify those most likely to benefit from treatment. We aimed to assess the incremental effectiveness of intrauterine insemination with controlled ovarian hyperstimulation compared with expectant management in couples with unexplained subfertility and an intermediate prognosis of a spontaneous ongoing pregnancy. METHODS 253 couples with unexplained subfertility and a 30-40% probability of a spontaneous ongoing pregnancy within 12 months were randomly assigned either intrauterine insemination with controlled ovarian hyperstimulation for 6 months or expectant management for 6 months. The primary endpoint of this hospital-based study was ongoing pregnancy within 6 months. Analysis was by intention to treat. This trial is registered with the Dutch Trial Register and as an International Standard Randomised Clinical Trial, number ISRCTN72675518. FINDINGS Of the 253 couples enrolled, 127 were assigned intrauterine insemination with controlled ovarian hyperstimulation and 126 expectant management. In the intervention group, 42 (33%) women conceived and 29 (23%) pregnancies were ongoing. In the expectant management group, 40 (32%) women conceived and 34 (27%) pregnancies were ongoing (relative risk 0.85, 95% CI 0.63-1.1). There was one twin pregnancy in each study group, and one woman in the intervention group conceived triplets. INTERPRETATION A large beneficial effect of intrauterine insemination with controlled ovarian hyperstimulation in couples with unexplained subfertility and an intermediate prognosis can be excluded. Expectant management for 6 months is therefore justified in these couples.

Prediction models in reproductive medicine: a critical appraisal†

BACKGROUND Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. METHODS We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. RESULTS We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis. CONCLUSIONS Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated.

Role of semen analysis in subfertile couples

OBJECTIVE To evaluate the associations between the results of the male partners semen analysis (classified according to the World Health Organization [WHO] criteria) and fathering a child without any treatment. DESIGN Prospective multicenter cohort study. SETTING Twenty subfertility centers in The Netherlands. PATIENT(S) A total of 3,345 consecutive couples presenting for subfertility. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Associations between the results of the male partners semen analysis, classified according to the WHO criteria, and fathering a child without any treatment within a time horizon of 1 year. Subsequently, we redefined semen quality criteria and reevaluated the associations. RESULT(S) Follow-up data of 3,129 couples (94%) were available, of which 517 (17%) had a healthy pregnancy without treatment. The 1-year pregnancy rate in men with WHO normozoospermia did not differ significantly from that in men with WHO impaired semen (24% vs. 23%). In contrast, we observed lower chances of fathering a child for sperm concentrations <40 × 10(6)/mL, total sperm count <200 × 10(6), and sperm morphology <20% normal forms. With a multivariable regression model based on the redefined male semen subfertility criteria we were able to make a finer differentiation between subfertile men, with probabilities of fathering a child ranging from 7% to 41%. CONCLUSION(S) The current WHO criteria for semen quality do not discriminate between fertile and subfertile men. Our redefined and graded semen criteria have strong predictive value. If interpreted correctly, the fast and inexpensive semen analysis remains the gold standard for defining a mans role in subfertility.

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

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

Reproducibility and reliability of repeated semen analyses in male partners of subfertile couples

OBJECTIVE To determine the precise degree of variability that is represented by the reproducibility and reliability of semen analysis. The general assumption is that semen analyses need to be repeated because of a high degree of within-individual variability. However, the precise degree of variability is not well established in male partners of subfertile couples. DESIGN Retrospective cohort study. SETTING Two university hospitals in the Netherlands, which routinely perform two semen analyses in the male partner of subfertile couples. PATIENT(S) Male partners of subfertile couples. INTERVENTIONS None. MAIN OUTCOME MEASURE(S) We assessed the test-retest reproducibility, by calculating the coefficient of variation (CV(w)) for five semen parameters. The CV(w) expresses, on a relative scale, the degree of closeness of repeated measurements taken in the same subject. We also estimated the reliability of these semen parameters, in terms of the intraclass correlation coefficient, which expresses the ratio of the between-subject variability over the total variability. RESULT(S) We analyzed the data of 5,240 men and found that the CV(w) of all semen parameters ranged from 28% to 34%. The intraclass correlation coefficients of these semen parameters were moderate to high: volume: 0.70; concentration: 0.89; motility: 0.58; morphology: 0.60; total motile count: 0.73. CONCLUSION(S) This study affirmed the presumed large within-subject variability and the limited reproducibility of semen analyses in subfertile men. Whether this degree of variability within men justifies one or more repetitions of the semen analysis in view of consequences for clinical management should be the topic of future studies. Until then it seems reasonable to perform two semen analyses.

Intrauterine insemination: how many cycles should we perform?†

BACKGROUND In the past 20 years, various recommendations have been made about the maximum number of intrauterine insemination (IUI) cycles that should be performed, because evidence underpinning a possible limit is lacking. METHODS We performed a multicentre, retrospective cohort analysis among couples treated with IUI up to nine cycles. Primary outcome measure was ongoing pregnancy rate (OPR) per cycle. Cumulative OPRs (COPR) after three, six and nine cycles of IUI were calculated using life-table analysis. Univariable and multivariable logistic regression analysis was performed to identify variables possibly affecting OPRs. RESULTS Overall, 3714 couples with male, cervical or unexplained subfertility underwent 15,303 cycles of IUI. In 70% of cycles, controlled ovarian hyperstimulation (COH) was used (51% clomiphene-citrate, 19% gonadotropins). Mean OPR rate was 5.6% per cycle. OPR in the seventh, eighth and ninth cycle were 5.1%, 6.7% and 4.6%, respectively. Taking censored patients into account, the calculated COPR was 18% after the third cycle, 30% after the seventh cycle and 41% after the ninth cycle. If censored patients were considered to have no chance of conception, a crude COPR of 25% after nine cycles was found. Multivariable regression analysis showed no significant impact of age, type of subfertility, diagnosis, use of hyperstimulation or cycle number on OPR after the sixth treatment cycle. CONCLUSIONS OPR in high-order IUI cycles are acceptable, and do not offer a rationale for cancellation before nine cycles. Using this type of very mild COH, it may be reasonable to conduct up to nine cycles.

Intrauterine insemination in The Netherlands

The aim of this retrospective study was to assess the results of intrauterine insemination (IUI) in The Netherlands, using data from 2003 taken from hospital annual reports and reports from individual gynaecologists. By extrapolation, the total number of IUI cycles performed that year nationwide, and the related outcomes, was estimated. IUI was performed in 91 of the countrys 101 hospitals. Of these, 58 (64%) registered their IUI results and performed 19,846 IUI cycles. The mean pregnancy rate per cycle was 9.0% and the ongoing pregnancy rate per cycle was 7.3%. Multiple pregnancies occurred in 9.5% of the ongoing pregnancies. Extrapolation of the data suggested that approximately 28,500 IUI cycles were performed, of which approximately 2000 resulted in an ongoing pregnancy. The number of multiple pregnancies following IUI was estimated to be 180 (9.0%). According to the national IVF registry, 9761 IVF cycles were started in 2003, resulting in 2,028 ongoing pregnancies (20.8% per cycle) and 439 twin pregnancies (21.6% per ongoing pregnancy). In conclusion, the pregnancy rate per IUI cycle in The Netherlands (9.0%) was comparable with that reported in the international literature (8.7%). The contribution made by IUI to the number of multiple pregnancies in The Netherlands was much smaller than the contribution made by IVF.

IUI in male subfertility: are we able to select the proper patients?

There is at this time no indication as to which semen parameters from the fertility work-up discriminate between couples with male subfertility who will and will not benefit from intrauterine insemination (IUI). This study evaluated the predictive capacity of semen parameters (both pre- and post-wash) and antisperm antibodies (ASA) obtained during the fertility work-up on IUI outcome in couples with male subfertility in a retrospective cohort study. It included 290 couples, who underwent 722 IUI cycles. The overall ongoing pregnancy rate was 9% per cycle. Model I, with female age, duration of subfertility, secondary subfertility, the presence of anovulation, cervical hostility and cycle number had an area under the curve (AUC) of 0.59. Adding the presence of ASA to this model improved the AUC to 0.65 (model II). Further addition of the post-wash total motile count (TMC) to the model with ASA (model III) improved the AUC to 0.67. Using the models to exclude couples from IUI due to low expected pregnancy rates would increase the pregnancy rate to 11% per cycle with model I, and to 14% per cycle for model II and for model III. In conclusion, in the selection of patients with male subfertility for IUI, the use of prediction models including ASA can increase the efficiency of IUI.

Couples with unexplained subfertility and unfavorable prognosis: a randomized pilot trial comparing the effectiveness of in vitro fertilization with elective single embryo transfer versus intrauterine insemination with controlled ovarian stimulation

OBJECTIVE To evaluate the effectiveness of IVF with elective single embryo transfer (IVF-eSET) vs. IUI with controlled ovarian stimulation (IUI-COS) as an alternative treatment to reduce the risk for a multiple pregnancy. DESIGN Randomized pilot trial. SETTING Three academic and six teaching hospitals in the Netherlands. PATIENT(S) Couples with unexplained or mild male subfertility and an unfavorable prognosis for natural conception. INTERVENTION(S) One cycle of IVF-eSET or three cycles of IUI-COS. MAIN OUTCOME MEASURE(S) Ongoing pregnancy per couple. RESULT(S) We randomly allocated 116 women to IVF-eSET (n = 58) or IUI-COH (n = 58). There were 14 ongoing pregnancies (24%) in the IVF-eSET group and 12 pregnancies (21%) in the IUI-COS group (relative ratio 1.17; 95% confidence interval 0.60-2.30). There were two twin pregnancies in the IVF-eSET group (14%) and two twin pregnancies and one triplet pregnancy in the IUI-COH group (25%). CONCLUSION(S) In patients with unexplained or mild male subfertility and a poor prognosis for natural conception, one cycle of IVF-eSET might be as effective as three cycles of IUI-COS as primary treatment. Elective single embryo transfer does not seem an effective strategy in preventing multiple pregnancies in this particular population. In the future a strict SET policy (i.e., compulsory SET) might be an option. Our trial provides evidence for the feasibility and highlights the importance of a large definitive trial to determine the effectiveness and side effects of both strategies.

Couples dropping out of a reimbursed intrauterine insemination program: what is their prognostic profile and why do they drop out?

OBJECTIVE To evaluate whether baseline characteristics and prognostic profiles differed between couples who drop out from intrauterine insemination (IUI) and couples that continue IUI, and the reasons for couples dropping out from IUI programs. DESIGN Retrospective observational cohort study. SETTING Fertility centers. PATIENT(S) Consecutive subfertile couples undergoing IUI. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Characteristics and prognosis of ongoing pregnancy after IUI at the start of treatment of couples that dropped out compared with couples that continued treatment or achieved an ongoing pregnancy. RESULT(S) We studied 803 couples who underwent 3,579 IUI cycles of whom 221 couples dropped out (28%). Couples dropping out completed 2.8 (SD ±1.4) cycles per couple compared with 4.5 (SD ±2.3) cycles per couple for those continuing treatment. Couples dropping out had a higher female age, longer subfertility duration, and higher basal FSH. Mean prognosis to achieve an ongoing pregnancy after IUI at start of treatment was 7.9% (SD ±2.4) per cycle for couples who dropped out and 8.5% (SD ±2.5) per cycle for couples continuing treatment. Of the dropouts, 100 couples (45%) were actively censored from the IUI program, 87 couples (39%) because of poor prognosis; 121 couples (55%) were passively censored from the program, of whom 62 (28%) dropped out owing to personal reasons; 59 couples (27%) were lost to follow-up. CONCLUSION(S) We found significant differences in prognostic profile between couples continuing treatment and couples dropping out, although these differences seem limited from a clinical perspective. We conclude that overestimation of ongoing pregnancy rates after IUI due to couples dropping out is limited.