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Study Question: Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation?, Summary Answer: Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer., What Is Known Already: Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown., Study Design, Size, Duration: This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration., Participants/materials, Setting, Methods: During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle., Main Results and the Role of Chance: No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome., Limitations, Reasons for Caution: The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation., Wider Implications of the Findings: Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence., Study Funding/competing Interest(s): The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work., Trial Registration Number: NTR4108., Trial Registration Date: 6 August 2013., Date of First Patient’s Enrolment: 30 January 2014., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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.

Study Question: Can modified natural cycle IVF or ICSI (MNC) be a cost-effective alternative for controlled ovarian hyperstimulation IVF or ICSI (COH)?, Summary Answer: The comparison of simulated scenarios indicates that a strategy of three to six cycles of MNC with minimized medication is a cost-effective alternative for one cycle of COH with strict application of single embryo transfer (SET)., What Is Known Already: MNC is cheaper per cycle than COH but also less effective in terms of live birth rate (LBR). However, strict application of SET in COH cycles reduces effectiveness and up to three MNC cycles can be performed at the same costs as one COH cycle., Study Design, Size, Duration: The cost-effectiveness of MNC versus COH was evaluated in three simulated treatment scenarios: three cycles of MNC versus one cycle of COH with SET or double embryo transfer (DET) and subsequent transfer of cryopreserved embryos (Scenario 1); six cycles of MNC versus one cycle of COH with strictly SET and subsequent transfer of cryopreserved embryos (Scenario 2); six cycles of MNC with minimized medication (hCG ovulation trigger only) versus one cycle of COH with SET or DET and subsequent transfer of cryopreserved embryos (Scenario 3). We used baseline data obtained from two retrospective cohorts of consecutive patients (2005-2008) undergoing MNC in the University Medical Center Groningen (n = 499, maximum six cycles per patient) or their first COH cycle with subsequent transfer of cryopreserved embryos in the Academic Medical Center Amsterdam (n = 392)., Participants/materials, Setting, Methods: Data from 1994 MNC cycles (958 MNC-IVF and 1036 MNC-ICSI) and 392 fresh COH cycles (one per patient, 196 COH-IVF and 196 COH-ICSI) with subsequent transfer of cryopreserved embryos (n = 72 and n = 94 in MNC and COH cycles, respectively) in ovulatory, subfertile women <36 years of age served as baseline for the three simulated scenarios. To compare the scenarios, the incremental cost-effectiveness ratio (ICER) was calculated, defined as the ratio of the difference in IVF costs up to 6 weeks postpartum to the difference in LBR. Live birth was the primary outcome measure and was defined as the birth of at least one living child after a gestation of ≥25 weeks., Main Results and the Role of Chance: In the baseline data, MNC was not cost-effective, as COH dominated MNC with a higher cumulative LBR (27.0 versus 24.0%) and lower cost per patient (€3694 versus €5254). The simulations showed that in scenario 1 three instead of six cycles lowered the costs of MNC to below the level of COH (€3390 versus €3694, respectively), but also lowered the LBR per patient (from 24.0 to 16.2%, respectively); Scenario 2: COH with strict SET was less effective than six cycles MNC (LBR 17.5 versus 24.0%, respectively), but also less expensive per patient (€2908) than MNC (€5254); Scenario 3: improved the cost-effectiveness of MNC but COH still dominated MNC when medication was minimized in terms of costs, i.e. €855 difference in favor of COH and 3% difference in LBR in favor of COH (ICER: €855/-3.0%)., Limitations, Reasons for Caution: Owing to the retrospective nature of the study, the analyses required some assumptions, for example regarding the costs of pregnancy and delivery, which had to be based on the literature rather than on individual data. Furthermore, costs of IVF treatment were based on tariffs and not on actual costs. Although this may limit the external generalizability of the results, the limitations will influence both treatments equally, and would therefore not bias the comparison of MNC versus COH., Wider Implications of the Findings: The combined results suggest that MNC with minimized medication might be a cost-effective alternative for COH with strict SET. The scenarios reflect realistic alternatives for daily clinical practice. A preference for MNC depends on the willingness to trade off effectiveness in terms of LBR against the benefits of a milder stimulation regimen, including a very low rate of multiple pregnancies and hyperstimulation syndrome and ensuing lower costs per live birth., Study Funding/competing Interest(s): The study was supported by research grants from Merck Serono and Ferring Pharmaceuticals. The authors declare no conflicts of interest., Trial Registration Number: Not applicable.

Mitotic errors during early development of human preimplantation embryos are common, rendering a large proportion of embryos chromosomally mosaic. It is also known that the percentage of diploid cells in human diploid-aneuploid mosaic embryos is higher at the blastocyst than at the cleavage stage. In this study, we examined whether there is temporal and/or developmental-stage variation in the occurrence of mitotic errors in human preimplantation embryos from the first day of development onward using mitotically stable digynic tripronuclear human embryos as a model system. All the cells of the 114 digynic tripronuclear human preimplantation embryos included were analyzed by fluorescence in situ hybridization for chromosomes 1, 13, 16, 17, 18, 21, X, and Y. Embryos were grouped according to day of development (1-6) and developmental stage (2-cell to blastocyst stage). The possibility of a mitotic error was highest in the first and second mitotic divisions. The percentage of cells with mitotic errors increased during preimplantation development and was highest at the 9-16 cell stage (76%, P = 0.027). Thereafter, the percentage of cells with mitotic errors decreased to 64% at the morula and 56% at the blastocyst stage. The pattern found correlates with the activation of the embryonic genome at the 8-16 cell stage. A better insight in the timing of occurrence of mitotic errors in human preimplantation embryos could help in understanding and prevention of these errors and is relevant in the context of PGS.

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.

To optimize success rates of IVF, selection of the most viable embryo(s) for transfer has always been essential, as embryos that are cryopreserved are thought to have a reduced chance of implanting after thawing. Recent developments challenge this concept. Evidence is accumulating that all embryos can now be cryopreserved and transferred in subsequent cycles without impairing pregnancy rates or maybe even with an improvement in pregnancy rates. In such a scenario no selection method will ever lead to improved live birth rates, as, by definition, the live birth rate per stimulated IVF cycle can never be improved when all embryos are serially transferred. In fact, selection could then only lower the live birth rate after IVF. The only parameter that could possibly be improved by embryo selection would be time to pregnancy, if embryos with the highest implantation potential are transferred first.

Background: Human preimplantation embryos generated through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments show a variable rate of numerical chromosome abnormalities or aneuploidies. Preimplantation genetic screening (PGS) has been designed to screen for aneuploidies in high risk patients, with the aim of improving live birth rates in IVF/ICSI. We assessed whether the effect of PGS on live births rates differs in women of advanced maternal age with variable risks for embryonic aneuploidy, and weighed these effects against the results obtained after IVF/ICSI without PGS., Methods: The effect of PGS on live birth rates was compared between groups defined by maternal age, number of previous miscarriages, semen quality, total amount of recombinant FSH (rFSH) administered during ovarian stimulation and total number of top-quality embryos, using data from a randomized controlled trial among women of advanced maternal age (35-41 years)., Results: There was no significant differential effect of PGS in groups based on maternal age (P-value of interaction 0.16), the number of previous miscarriages (P-value of interaction 0.93), semen quality (P-value of interaction 0.26), rFSH dose (P-value of interaction 0.15) or the number of top-quality embryos (P-value of interaction 0.59). Live birth rates after IVF/ICSI with PGS were lower in all groups when compared with live birth rates after IVF/ICSI without PGS., Conclusions: The paradigm that the effect of PGS is determined by a woman's risk for embryonic aneuploidy seems incorrect. In fact, PGS has no clinical benefit over standard IVF/ICSI in women of advanced maternal age regardless of their risk for embryonic aneuploidy.

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 OPR's., 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.

Background: Obesity is increasing rapidly among women all over the world. Obesity is a known risk factor for subfertility due to anovulation, but it is unknown whether obesity also affects spontaneous pregnancy chances in subfertile, ovulatory women., Methods: We evaluated whether obesity affected the chance of a spontaneous pregnancy in a prospectively assembled cohort of 3029 consecutive subfertile couples. Women had to be ovulatory and had to have at least one patent tube, whereas men had to have a normal semen analysis. Time to spontaneous ongoing pregnancy within 12 months was the primary endpoint., Results: The probability of a spontaneous pregnancy declined linearly with a body mass index (BMI) over 29 kg/m(2). Corrected for possible related factors, women with a high BMI had a 4% lower pregnancy rate per kg/m(2) increase [hazard ratio: 0.96 (95% CI 0.91-0.99)]., Conclusions: These results indicate that obesity is associated with lower pregnancy rates in subfertile ovulatory women.

Background: Since the most recent Cochrane review on hMG versus rFSH for controlled ovarian hyperstimulation following a long down-regulation protocol, several new trials have emerged., Methods: We conducted a systematic review and meta-analysis of randomized trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles, on the primary outcome of live birth per woman randomized, as well as several other secondary outcomes. Searches were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library and databases of abstracts (last search January 2007)., Results: Seven randomized trials, consisting of a total of 2159 randomized women, were identified. A meta-analysis of these trials showed a significant increase in live birth rate with hMG when compared with rFSH (relative risk, RR = 1.18, 95% CI: 1.02-1.38, P = 0.03). The heterogeneity test was non-significant (P = 0.97), suggesting that there was no statistical inconsistency between the seven studies. The pooled risk difference (RD) for the outcome of live birth rate was 4% (95% CI: 1-7%) for these study populations. There was an increase in clinical pregnancy rates with hMG when compared with rFSH (RR = 1.17, 95% CI 1.03-1.34). No significant differences were noted for gonadotrophin use, spontaneous abortion, multiple pregnancy, cancellation and ovarian hyperstimulation syndrome rates., Conclusions: For the populations in the randomized trials, hMG was associated with a pooled 4% increase in live birth rate when compared with rFSH in IVF-ICSI treatment following a long down-regulation protocol.

Context: Basal FSH is a marker for ovarian reserve., Objectives: The objective of the study was to investigate the predictive value of basal FSH on spontaneous ongoing pregnancy in subfertile ovulatory women., Design: This was a prospective cohort study., Setting: The study was conducted in 19 fertility centers in The Netherlands., Participants: Subfertile ovulatory women without two-sided tubal pathology and in whom the man had normal sperm parameters (total motile count > or = 3 x10(6)) participated in the study., Interventions: Interventions included a fertility work-up, including a basal FSH measurement on cycle d 3., Main Outcome Measures: Spontaneous ongoing pregnancy was measured., Results: We included 3519 consecutive couples of which 562 (16%) had a spontaneous ongoing pregnancy within 1 yr. Basal FSH levels of 8 IU/liter or higher were associated with a decreased probability of spontaneous ongoing pregnancy [hazard ratio (HR) 0.93/IU.liter (95% confidence interval [CI] 0.87-0.98)]. In a multivariable analysis, female age (HR 0.97/yr, 95% CI 0.95-0.99), cycle length (HR 0.96/d, 95% CI 0.93-1.0), and FSH levels 8 IU/liter or greater (HR 0.93/IU.liter, 95% CI 0.87-0.99) were strong negative predictors for spontaneous ongoing pregnancy. Addition of FSH to a prediction model based on female age, duration of subfertility, previous pregnancy, referral status, and semen analysis changed the probability to conceive spontaneously from 30% or greater to less than 30% in 97 of 3219 couples (3.0%)., Conclusions: In ovulatory women, a basal FSH level of 8 IU/liter or higher is associated with decreasing fecundity, independent of female age and cycle length. Because the number of couples in whom the FSH level alters management decisions is low, we do not recommend routine testing of basal FSH in subfertile couples.

Background: The aim of this study was to compare the effect of three different times of onset of luteal phase support on ongoing pregnancy rate in infertile patients undergoing treatment with GnRH down-regulated IVF and embryo transfer (IVF/ET)., Materials and Methods: All consecutive eligible patients planned to undergo their first IVF treatment cycle were randomly allocated to receive vaginal progesterone as luteal support at three different time points, that is, after HCG administration for final oocyte maturation (HCG group), at the day of oocyte retrieval (OR group) or at the day of ET (ET group). The primary endpoint of this study was ongoing pregnancy rate., Results: A total of 385 women were randomized, 130 were allocated to the HCG group, 128 to the OR group and 127 to the ET group. An ongoing pregnancy rate of 20.8% was found in the HCG group versus 22.7 and 23.6% in the OR group and ET group, respectively. The mean number and quality of the retrieved oocytes and the transferred embryos did not differ., Conclusion: Based on this data, an 18% difference in ongoing pregnancy rate between the three different times of onset of luteal phase support in GnRH agonist down-regulated IVF/ET cycles can be refuted. Smaller clinically meaningful differences may be present.

The current approach of the basic fertility work-up has been questioned recently in this journal. Based on new data on human fecundity, the authors advocated starting the fertility work-up after just 6 months of trying to conceive instead of the usual 12 months. In women younger than 39 years and with a regular cycle, there are several arguments why the basic fertility work-up should not be done earlier than after 12 months of child wish. Firstly, 50% of couples who have tried to conceive for 6 months without success will conceive in the next 6 months without any treatment. Secondly, the prevalence of fertility diseases is lower in couples who have been trying to conceive for 6 months as compared with those who have been trying for 12 months. Performance of a fertility work-up at this stage will lead to an increase in false-positive diagnoses compared with performing them at 12 months of subfertility. Thirdly, fertility treatment will have fewer additional effects in couples with good spontaneous conception prospects (6-12 months child wish), compared with subfertile couples who have poor prospects. At present, none of the available fertility treatments have success rates comparable with no intervention in these women, and postponement of treatment in such couples will prevent complications such as ovarian hyperstimulation syndrome and multiple pregnancies. We argue that the fertility work-up should not be offered to couples with a duration of child wish of <12 months, except for women with ovulation disorders and women of 39 years and older.

Background: Ovulation induction with recombinant FSH (rFSH) is common in women with polycystic ovary syndrome (PCOS) not responding to clomiphene citrate treatment, despite the associated risk of multiple pregnancies. We analysed clinical, ultrasonographic and endocrine parameters during initial screening of women with clomiphene citrate-resistant PCOS as predictors of ongoing pregnancy within 12 months of treatment following ovulation induction with rFSH., Methods: Eighty-five women were allocated to receive rFSH as part of a multicentre clinical trial. rFSH was administered in a chronic low-dose step-up protocol. The primary end-point was an ongoing pregnancy within 12 months. A logistic model was built using clinical, ultrasonographic and endocrine parameters to predict the response to rFSH treatment, adjusted for the number of cycles performed., Results: In total, 85 women underwent 272 treatment cycles with rFSH, of which 57 women (67%) achieved an ongoing pregnancy. Oligomenorrhoea, shorter duration of infertility and a lower free androgen index (FAI) were associated with higher chances of an ongoing pregnancy, resulting in a predictive model with a modest discriminative power (area under the curve 0.72, 95% confidence interval 0.64-0.79) that allowed us to distinguish between women with a probability of <5% of attaining an ongoing pregnancy and women with a probability of >25% of doing so., Conclusion: A model consisting of oligo/amenorrhoea, duration of infertility and FAI level allowed a distinction to be made between women with a poor chance and women with a good chance of achieving an ongoing pregnancy.

Background: Laparoscopic electrocautery has been put forward as the treatment of choice in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). In order to make an informed treatment decision it would be helpful if we could identify women with PCOS with a high probability of treatment failure following electrocautery of the ovaries., Methods: Eighty-three women with CC-resistant PCOS were allocated to receive laparoscopic electrocautery followed by CC when anovulation persisted as part of a randomized controlled trial. Multivariable logistic regression analyses using clinical, ultrasonographic and endocrinological parameters were performed to predict (i) failure to ovulate within 8 weeks after electrocautery, and (ii) failure to reach an ongoing pregnancy after electrocautery with or without CC., Results: Of the 83 women, 56 (67%) ovulated within 8 weeks after electrocautery. The model for predicting anovulation after electrocautery included LH/FSH rate, year of menarche and glucose level. Women who were younger at menarche, had a lower LH/FSH ratio and a lower glucose level were more likely to have persistent anovulation. The area under the curve was 0.74. After electrocautery and CC, 41 women reached an ongoing pregnancy. No prognostic parameters could be identified to predict failure to reach an ongoing pregnancy after electrocautery followed by CC., Conclusions: Persistence of anovulation after electrocautery could be predicted and women with a high risk of persisting anovulation could be distinguished. We were, however, not able to predict treatment failure after electrocautery followed by CC.

Background: Intrauterine insemination (IUI) is a commonly used treatment in subfertile couples. We assessed patients' preferences for IUI relative to expectant management., Methods: Forty subfertile couples were offered scenarios in which the treatment-independent pregnancy chance was varied against a fixed pregnancy chance after IUI without or with controlled ovarian hyperstimulation (COH) of 8% and 12% per cycle, respectively. The treatment-independent pregnancy chance within 12 months was initially set at 100%, and subsequently reduced until couples switched preferences. We also investigated the impact of the risks of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy on couples' preferences., Results: When pregnancy was guaranteed within a year, all couples would opt for expectant management. Most couples switched to IUI without COH at a 60% chance of a treatment-independent pregnancy and to IUI with COH between a 40% and 60% chance. Where the risk of OHSS was set at 10%, a large majority of the couples preferred expectant management to IUI. At a multiple pregnancy risk of 100%, 77% of the couples would still prefer IUI., Conclusions: The majority of couples prefer IUI with or without COH when the treatment-independent pregnancy chance in the next 12 months is <50% and <40%, respectively. The risk of a multiple pregnancy does not affect their preference for IUI, whereas IUI is rejected when the risk of OHSS exceeds 10%.

Background: Intrauterine insemination (IUI) can be performed with or without controlled ovarian hyperstimulation (COH). Studies in which the additional benefit of COH on IUI for cervical factor subfertility is assessed are lacking. We assessed whether COH in IUI improved pregnancy rates in cervical factor subfertility., Methods: We performed a historical cohort study among couples with cervical factor subfertility, treated with IUI. A cervical factor was diagnosed by a well-timed, non-progressive post-coital test with normal semen parameters. We compared ongoing pregnancy rate per cycle in groups treated with IUI with or without COH. We tabulated ongoing pregnancy rates per cycle number and compared the effectiveness of COH by stratified univariable analysis., Results: We included 181 couples who underwent 330 cycles without COH and 417 cycles with COH. Ongoing pregnancy rates in IUI cycles without and with COH were 9.7% and 12.7%, respectively (odds ratio 1.4; 95% confidence interval 0.85-2.2). The pregnancy rates in IUI without COH in cycles 1, 2, 3 and 4 were 14%, 11%, 6% and 15%, respectively. For IUI with COH, these rates were 17%, 15%, 14% and 16%, respectively., Conclusions: Although our data indicate that COH improves the pregnancy rate over IUI without COH, IUI without COH generates acceptable pregnancy rates in couples with cervical factor subfertility. Since IUI without COH bears no increased risk for multiple pregnancy, this treatment should be seriously considered in couples with cervical factor subfertility.

Background: This study aimed to determine whether medical history and semen analysis can predict the result of the post-coital test (PCT)., Methods: A previously reported data set of Dutch patients collected between 1985 and 1993 was used. Our study was limited to just patients with an ovulatory cycle. Data were complete for medical history, semen analysis and PCT. We performed logistic regression analysis to evaluate whether these factors could predict the result of the PCT (PCT model). Furthermore, we evaluated the additional contribution of the PCT in the prediction of treatment-independent pregnancy (pregnancy model)., Results: Thirty-four percent (179 out of 522) had an abnormal PCT. The PCT model contained previous pregnancy [odds ratio (OR) 2.1; 95% confidence interval (CI) 1.3-3.5], semen volume (OR 0.88; 95% CI 0.77-0.99), sperm concentration (OR 0.96; 95% CI 0.94-0.97), sperm motility (OR 0.97; 95% CI 0.96-0.98) and sperm morphology (OR 2.7; 95% CI 1.2-6.8). The area under the ROC curve of the model was 0.81. In the pregnancy model, the result of the actual PCT could be replaced by the predicted result of the PCT model in about half of the couples, without compromising its predictive capacity., Conclusion: The medical history and semen analysis can predict the result of the PCT in approximately 50% of the subfertile couples with a regular cycle, without compromising its potential to predict pregnancy.

Background: The aetiology of impaired spermatogenesis is unknown in the majority of cases. Evidence of a contribution of genetic factors is still scarce. Therefore, the aim of our study was to assess whether male factor subfertility due to impaired spermatogenesis has a familial component and to test different genetic models of inheritance., Methods: Cases were all men with severe idiopathic impaired spermatogenesis attending our fertility clinic from January 1998 until December 2001. Controls were all men with normozoospermia attending our fertility clinic in the same period. Family data were collected from the medical records and by additional interviews of the probands. If subfertility of a first-degree relative was mentioned, permission was sought to contact the affected family member in order to obtain all medical information available, including the results of semen analyses., Results: In total, 160 patients and 285 controls were included in the analysis. Family size and number of brothers and sisters were equally distributed in both groups. In the patient group, 1.63% of the brothers who had tried to father a child were mentioned to be subfertile compared to 5.8% in the control group [odds ratio 3.18 (95% confidence interval 1.59-6.37)]. The subfertility among the brothers in the patient group was more often due to reduced semen parameters compared to the control group. The data did not fit with frequent autosomal dominant or recessive segregation., Conclusion: Male factor subfertility due to impaired spermatogenesis appears to cluster in families. Our data suggests that heritable genetic factors play a role in a limited number of cases. Impaired spermatogenesis is not caused by a common genetic defect, but is most likely a complex disease in which several different factors play a role.