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Donor sperm treatment is advised to be performed with frozen-thawed donor semen. A disadvantage of frozen-thawed semen is lower pregnancy rates compared to inseminations with fresh semen. Semen parameters affect ongoing pregnancy rates in intracervical inseminations with frozen-thawed donor semen. In an attempt to translate this into clinical relevance, cohort studies have tried to find cut-off values for semen parameters after thawing for intracervical insemination, but these studies assessed only one semen parameter per study, thereby overlooking the intricate interplay between all semen parameters. We performed a retrospective cohort study and tried to calculate thresholds for all semen parameters that lead to the best possible ongoing pregnancy rates in intracervical insemination with frozen-thawed donor semen. Between April 1999 and December 2015, data from 1,186 women who underwent 7,103 cycles of intracervical insemination with donor semen from 129 sperm donors were available for analysis. Our results showed that total motility and total motile count (TMC) after thawing were associated with ongoing pregnancy rate. The best possible ongoing pregnancy chances after intracervical insemination were obtained at a total motility of ≥20% and a total motile count (TMC) of ≥8 × 106 after thawing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

When intended parents choose to have donor sperm treatment (DST), this may entail wide-ranging and long-lasting psychosocial implications related to the social parent not having a genetic tie with the child, how to disclose donor-conception and future donor contact. Counselling by qualified professionals is recommended to help intended parents cope with these implications. The objective of this study is to present findings and insights about how counsellors execute their counselling practices. We performed a qualitative study that included 13 counsellors working in the 11 clinics offering DST in the Netherlands. We held a focus group discussion and individual face-to-face semi-structured interviews, which were fully transcribed and analysed using thematic analysis. The counsellors combined screening for eligibility and guidance within one session. They acted according to their individual knowledge and clinical experience and had different opinions on the issues they discussed with intended parents, which resulted in large practice variations. The counsellors were dependent on the admission policies of the clinics, which were mainly limited to regulating access to psychosocial counselling, which also lead to a variety of counselling practices. This means that evidence-based guidelines on counselling in DST need to be developed to provide consistent counselling with less practice variation. [ABSTRACT FROM AUTHOR]

Introduction At present, studies comparing intrauterine insemination in the natural cycle versus intracervical insemination in the natural cycle in women undergoing artificial insemination with donor sperm are scarce. Methods and analysis We perform a randomised controlled non-inferiority trial among five secondary and tertiary fertility clinics in the Netherlands and one tertiary fertility clinic in Belgium. Women eligible for artificial insemination with donor sperm are included. We perform six cycles of artificial insemination with donor sperm within a time horizon of 8 months comparing intrauterine insemination in the natural cycle with intracervical insemination in the natural cycle. The primary outcome is ongoing pregnancy leading to live birth conceived within eight months after randomisation. Secondary outcomes are clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, pregnancy complications (preterm birth, birth weight <2500 g, pregnancy induced hypertension, (pre-) eclampsia, Hemolysis Elevated Liver enzymes Low Platelets (HELLP)), time to ongoing pregnancy, direct and indirect costs. To demonstrate the non-inferiority of intracervical insemination with a margin of 12%, we need 208 women per arm. Ethics and dissemination The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on research involving human subjects (47330-018-13). The boards of the participating hospitals approved the study. Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. [ABSTRACT FROM AUTHOR]

Objectives: We aimed at exploring the wishes of Dutch donor-conceived offspring for parental support, peer support and counseling and sought to contribute to the improvement of health care for all parties involved with assisted reproductive technologies.Methods: We held semi-structured in-depth interviews with 24 donor-conceived offspring (Mage = 26.9, range 17-41) born within father-mother, two-mother and single mother families. The majority of the donor offspring was conceived with semen of anonymous donors. All offspring were recruited by network organizations and snowball sampling. The interviews were fully transcribed and analyzed using the constant comparative method.Results: Donor-conceived offspring wished that their parents had talked openly about donor conception and had missed parental support. They wished that their parents would have received counseling before donor sperm treatment on how to talk with their children about donor conception in several stages of life. They valued the availability of peer contact to exchange stories with other donor-conceived offspring and would have liked assistance in getting access to trustworthy information about characteristics and identifying information of their donor. Donor-conceived offspring wished to know where to find specialist counseling when needed.Conclusions: Peer support and counseling by professionals for donor-conceived offspring should be available for those who need it. The findings also support professional counseling for intended parents before treatment to improve parental support for donor-children. [ABSTRACT FROM AUTHOR]

Background: Testicular sperm extraction (TESE) is a surgical procedure to retrieve spermatozoa from the testes of men with azoospermia to help them achieve biological parenthood. Although effective, the surgical procedure is not without complications and haematoma, devascularization, inflammation and a decrease in testosterone levels have been described as such. The prevalence and duration of hypogonadism and associated symptoms after TESE have not been studied systematically.Objective and Rationale: In this systematic review we addressed the following research questions: Are serum testosterone levels decreased after TESE and, if so, do these levels recover over time? What is the prevalence of symptoms and signs related to hypogonadism after TESE and are they related to testosterone levels?Search Methods: We searched the databases Pubmed and Embase from 1 January 1993 to 26 June 2017. We combined subject headings with terms in title and/or abstract for participants, intervention and outcomes. We included all studies that reported on TESE, regardless of the specific technique used, that measured testosterone and/or LH, and/or had information on signs or symptoms related to hypogonadism as defined by hypogonadism guidelines. An additional inclusion criterion was that studies described these measurements both before and after TESE. The quality of the included studies was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions tool.Outcomes: We identified 15 studies reporting on total testosterone levels of which five studies also reported on testicular volume and one study on erectile dysfunction. Men with Klinefelter syndrome and men with non-obstructive azoospermia had the strongest decrease in total testosterone levels 6 months after TESE, with a mean decrease of 4.1 and 2.7 nmol/l, respectively, which recovered again to baseline levels 26 and 18 months after TESE, respectively. At 6 months after TESE, some studies reported serum total testosterone concentrations below a cut-off value of 12 nmol/l, where symptoms and signs related to hypogonadism may appear. Furthermore, an increased prevalence of erectile dysfunction related to decreased total testosterone levels 6 months after TESE was reported. Also, in some men a decrease in testicular volume was reported. However, it is not clear if this is related to low testosterone levels.Wider Implications: The transient, but statistically significant, decrease in total testosterone levels indicates that men are at risk of developing a temporary hypogonadism after TESE, but there is insufficient evidence for whether patients actually experience clinical symptoms in case of decreased serum testosterone levels. To be able to properly counsel TESE patients, more large-scale monitoring on signs and symptoms of hypogonadism, in combination with testosterone measurements, needs to be performed in men undergoing TESE. [ABSTRACT FROM AUTHOR]

Being a donor-child: wishes for parental support, peer support and counseling Most studies on donor-conceived offspring have shown that secrets in families about the genetic origin of the child can harm the parent-child relationship and as a consequence early disclosure of donor conception is recommended. Data on whether donor-conceived offspring appreciate guidance to cope with their questions and feelings related to being a donor-child are not available. We held semi-structured in-depth interviews with male and female donor-conceived offspring (Mage = 26.9, range 17-41) born within father-mother (n = 11), two-mother (n = 7), or single mother families (n = 6). The majority of donor offspring (n = 20) were descendants of anonymous donors. The interviews were fully transcribed and analyzed using the constant comparative method. Donor-conceived offspring would have appreciated openness from their parents about being a donor-child and wished that their parents would have received specialist guidance before donor sperm treatment. They valued the availability of peer contact to exchange stories and would have liked assistance in getting access to trustful information about characteristics and identifying information of their donor. Donor-conceived offspring wished to know where to find counsellors for guidance when needed. Donor-conceived offspring missed guidance by their parents, appreciated peer-support and the availability of guidance by counsellors for themselves. Our findings demonstrate that peer support and guidance by counsellors for donor-conceived offspring should be available for those who need it. The findings also support counselling to intended parents before donor sperm treatment. [ABSTRACT FROM AUTHOR]

Background: Obesity in women of reproductive age has deleterious effects on reproductive and offspring health. In this study, we aimed to evaluate the association between the magnitude of periconceptional body-mass index (BMI) change and maternal and neonatal outcomes in obese infertile women who participated in the LIFEstyle study. The LIFEstyle study was a randomized controlled trial, evaluating if a six-month lifestyle intervention program prior to infertility treatment in obese infertile women improved birth rates, compared to prompt infertility treatment. Methods and findings: This is an exploratory post hoc analysis of the LIFEstyle study. We recorded periconceptional BMI change in women with an ongoing pregnancy, pooling data of all women, regardless of randomization arm. Periconceptional BMI change was calculated using weight at randomization and the periconceptional weight (measured in kilograms 12 weeks before or after conception and expressed as BMI change in units BMI (kg/m2)). Subsequently, women were categorized into quartiles according to the magnitude of their periconceptional change in BMI. The odds of maternal and neonatal outcomes were calculated using logistic regression analysis, comparing women in each of the first three weight change quartiles separately, and combined, to women in the fourth quartile. The fourth quartile was chosen as reference group, since these women had the least weight loss. We adjusted for periconceptional BMI, nulliparity and smoking status. In addition, we performed a subgroup analysis for singleton pregnancies. In the LIFEstyle study, 321 obese infertile women achieved an ongoing pregnancy which was conceived within 24 months after randomization. Periconceptional BMI change was available in 244 of these women (76%). Median BMI at randomization was 35.9 kg/m2. Women in the first quartile (Q1) had a periconceptional BMI change of <-2.1 kg/m2, women in the second quartile (Q2) -2.1 to -0.9 kg/m2, women in the third quartile (Q3) -0.9 to 0.1 kg/m2 and women in the fourth quartile (Q4) gained ≥0.1 kg/m2. There were no significant differences between women in the quartiles regarding rates of excessive gestational weight gain (in term pregnancies), gestational diabetes, preterm birth, induction of labor, spontaneous vaginal birth and Caesarean section. Compared to women in Q4, the adjusted odds ratios, aOR, and 95% confidence interval for a hypertensive complication were; 0.55 (0.22–1.42) for women in Q1, 0.30 (0.12–0.78) for women in Q2, 0.39 (0.16–0.96) for women in Q3 and 0.39 (0.19–0.82) for women in Q1 to Q3 combined. In the subgroup analysis, investigating singleton pregnancies only, the statistically significant decreased rate of a hypertensive complication remained in women in Q2 (aOR 0.27, 95% CI 0.10–0.72) and Q3 (aOR 0.39, 95%CI 0.16–0.98) and when comparing women in Q1 to Q3 together to women in Q4 (aOR 0.38, 95%CI 0.18–0.80). Furthermore, there was a significantly decreased aOR (95%CI) of preterm birth in women in Q2 (0.24, 0.06–0.98) and when combining women in Q1 to Q3 (0.37, 0.14–0.97) compared to women in Q4. Conclusions: These results suggest that a periconceptional decrease in BMI in obese infertile women could lead to a decrease of the rates of hypertensive pregnancy complications and preterm birth. The results are limited by the exploratory nature of the analyses and further evidence is necessary to provide more definitive conclusions. [ABSTRACT FROM AUTHOR]

Introduction: How do parents feel about psychosocial counseling during donor sperm treatment?Methods: We performed a qualitative study based on semi-structured in-depth interviews, conducted from July 2012 until August 2013, with 24 Dutch parents who had had children through donor sperm treatment between 2000 and 2012.Results: During counseling, parents sometimes felt screened for their eligibility for parenthood rather than guided, and therefore felt discouraged about bringing up topics that were important for them. Parents of all family types would value extended psychological counseling before and after successful donor sperm treatment, that is in several stages of parenthood. Only after childbirth topics such as disclosure, fear of rejection of the social parent and future contact of the child with the sperm donor became more pertinent.Conclusions: Both before and after childbirth, parents of all family types would value expert advice on when and how to disclose. Psychosocial guidance should be offered separately from psychosocial screening for treatment eligibility and should be offered in several stages of parenthood. [ABSTRACT FROM AUTHOR]

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 CVB was 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. [ABSTRACT FROM AUTHOR]

Background: Gonadotrophin-releasing hormone (GnRH) antagonists reduce ovarian hyperstimulation syndrome (OHSS) at the price of a small reduction in effectiveness compared to GnRH agonists. The aim of this study was to investigate patients' preferences on effectiveness, safety and burden of GnRH analogs. Methods: A discrete choice experiment (DCE) and a trade-off question were designed. Patients embarking on assisted reproductive technique treatment were asked to choose between two hypothetical medications which differed in effectiveness, safety and burden. Results: A total of 172 questionnaires were analyzed. All attributes of the DCE had a statistically significant impact on the preference of the respondents. Respondents were willing to trade off 0.87 and 0.81% effectiveness for a decrease in OHSS risk and for fewer side effects, respectively. Respondents were not willing to trade off effectiveness for 'importance of compliance' (trade-off 0.40%) or a shorter 'duration of treatment' (trade-off 0.26%). The trade-off questions showed that already at a 2.0% increase in pregnancy rate in favor of the agonists, the majority of the respondents changed their preference from antagonists to agonists (2.0%, 95% CI 1.7-2.1). Conclusion: Safety and burden are important to patients, but are not important enough to make up for a small decrease in pregnancy rate. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 ... [ABSTRACT FROM PUBLISHER]

Background: Prognostic models in reproductive medicine can help to identify subfertile couples who would benefit from fertility treatment. Expectant management in couples with a good chance of natural conception, i.e., tailored expectant management (TEM), prevents unnecessary treatment and is therefore recommended in international fertility guidelines. However, current implementation is not optimal, leaving room for improvement. Based on barriers and facilitators for TEM that were recently identified among professionals and subfertile couples, we have developed a multifaceted implementation strategy. The goal of this study is to assess the effects of this implementation strategy on the guideline adherence on TEM. Methods/design: In a cluster randomized trial, 25 clinics and their allied practitioners units will be randomized between the multifaceted implementation strategy and care as usual. Randomization will be stratified for in vitro fertilization (IVF) facilities (full licensed, intermediate/no IVF facilities). The effect of the implementation strategy, i.e., the percentage guideline adherence on TEM, will be evaluated by pre- and post-randomization data collection. Furthermore, there will be a process and cost evaluation of the strategy. The implementation strategy will focus on subfertile couples and their care providers i.e., general practitioners (GPs), fertility doctors, and gynecologists. The implementation strategy addresses three levels: patient level: education materials in the form of a patient information leaflet and a website; professional level: audit and feedback, educational outreach visit, communication training, and access to a digital version of the prognostic model of Hunault on a website; organizational level: providing a protocol based on the guideline. The primary outcome will be the percentage guideline adherence on TEM. Additional outcome measures will be treatment-, patient-, and process-related outcome measures. Discussion: This study will provide evidence about the effectiveness and costs of a multifaceted implementation strategy to improve guideline adherence on TEM. [ABSTRACT FROM AUTHOR]

Current cancer treatment regimens do not only target tumor cells, but can also have devastating effects on the spermatogonial stem cell pool, resulting in a lack of functional gametes and hence sterility. In adult men, fertility can be preserved prior to cancer treatment by cryopreservation of ejaculated or surgically retrieved spermatozoa, but this is not an option for prepubertal boys since spermatogenesis does not commence until puberty Cryopreservation of a testicular biopsy taken before initiation of cancer treatment, followed by in vitro propagation of spermatogonial stem cells and subsequent autotransplantation of these stem cells after cancer treatment, has been suggested as a way to preserve and restore fertility in childhood cancer survivors. This strategy, known as spermatogonial stem cell transplantation, has been successful in mice and other model systems, but has not yet been applied in humans. Although recent progress has brought clinical application of spermatogonial stem cell autotransplantation in closer range, there are still a number of important issues to address. In this paper, we describe the state of the art of spermatogonial stem cell transplantation and outline the hurdles that need to be overcome before clinical implementation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

BACKGROUND Although chromosomal mosaicism in human preimplantation embryos has been described for almost two decades, its exact prevalence is still unknown. The prevalence of mosaicism is important in the context of preimplantation genetic screening in which the chromosomal status of an embryo is determined by the analysis of a single cell from that embryo. METHODS Here we report a systematic review and meta-analysis of studies on the chromosomal constitution of human preimplantation embryos. In 36 studies, out of 2117 citations that met our search criteria, data were provided extensively enough to allow classification of each analysed embryo with prespecified criteria for its chromosomal makeup. The main outcome of this classification was the prevalence of chromosomal mosaicism in human preimplantation embryos. RESULTS A total of 815 embryos could be classified. Of these, 177 (22%) were diploid, 599 (73%) were mosaic, of which 480 (59% of the total number of embryos) were diploid–aneuploid mosaic and 119 (14% of the total number of embryos) were aneuploid mosaic, and 39 (5%) contained other numerical chromosomal abnormalities. The distribution of the embryos over these categories was associated with the developmental stage of the embryos, the method used for analysis and the number of chromosomes analysed. CONCLUSIONS Diploid–aneuploid mosaicism is by far the most common chromosomal constitution in spare human preimplantation embryos after IVF. This undermines the reliable determination of the ploidy status of a cleavage-stage embryo based on the analysis of a single cell. Future research should determine the origin and developmental potential of mosaic embryos. [ABSTRACT FROM AUTHOR]

Objective. Guidelines on recurrent miscarriage are poorly implemented in daily clinical practice. To ensure proper implementation, we identified existing barriers and facilitators for guideline adherence according to professionals and patients. Design. Qualitative research. Setting. Two different regions in the Netherlands. Population. Forty-two professionals: gynecologists, residents in obstetrics and gynecology, fertility doctors and clinical geneticists. Ten patients with recurrent miscarriage. Methods. Focus group interviews were performed with professionals and individual in-depth interviews with patients. Reports from the interviews were analyzed and barriers were identified. Main Outcome Measures. Identified barriers, categorized in four domains, including characteristics of: (I) the guideline, (II) professionals, (III) patients, (IV) organization. Results. Ninety-six barriers, at all four domains, were identified among professionals. The most frequently mentioned barriers were: guideline being too complicated in the consultancy room and finding it difficult to refuse demands of insistent patients. Patients mentioned 40 barriers, of which lack of up-to-date patient information and lack of detailed knowledge about family history were most frequently mentioned. Potential facilitators, such as an electronic decision tool and patient questionnaires prior to their first visit, were mentioned by both professionals and patients. All participants agreed that complete adherence to the guideline was theoretically achievable. Conclusions. Both professionals and patients experienced barriers and facilitators for guideline adherence in recurrent miscarriage. Guideline implementation strategies should take these identified barriers into account. [ABSTRACT FROM AUTHOR]

Systematic reviews and accompanying meta-analyses are the cornerstones of evidence-based medicine. Systematic reviews summarize clinical evidence; meta-analyses provide summary estimates of the treatment effect or the diagnostic test accuracy. Although deemed to provide the highest level of evidence, their clinical value is limited as they can only summarize aggregated data. In these meta-analyses the true variability of the treatment effects cannot be explored to the desired extent, because the meta-analyses cannot distinguish between patients with different clinical profiles. Systematic reviews and meta-analyses based on individual patient data (IPD), described as the ‘gold standard’ for systematic reviews are a promising approach that might overcome these limitations. IPD meta-analyses allow treatment effects and diagnostic accuracy to be estimated at the level of relevant patient subgroups. This enables researchers to investigate the effectiveness of treatment in patients with different profiles. In this article, we address the opportunities of systematic reviews and meta-analyses using IPD in reproductive medicine. We discuss its potential based on three clinical examples: single versus double embryo transfer in IVF, the diagnosis of tubal pathology and the prognostic value of ovarian reserve tests. We propose to show potential advantages of IPD systematic reviews and meta-analyses in providing stratified clinical evidence, which could improve medical care. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Recently, dopamine agonists were proposed as a prophylactic treatment for ovarian hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. [ABSTRACT FROM PUBLISHER]

Background: In the Netherlands, 30% of subfertile women are overweight or obese, and at present there is no agreement on fertility care for them. Data from observational and small intervention studies suggest that reduction of weight will increase the chances of conception, decrease pregnancy complications and improve perinatal outcome, but this has not been confirmed in randomised controlled trials. This study will assess the cost and effects of a six-months structured lifestyle program aiming at weight reduction followed by conventional fertility care (intervention group) as compared to conventional fertility care only (control group) in overweight and obese subfertile women. We hypothesize that the intervention will decrease the need for fertility treatment, diminish overweight-related pregnancy complications, and will improve perinatal outcome. Methods/Design: Multicenter randomised controlled trial in subfertile women (age 18-39 year) with a body mass index between 29 and 40 kg/m². Exclusion criteria are azoospermia, use of donor semen, severe endometriosis, premature ovarian failure, endocrinopathies or pre-existent hypertensive disorders. In the intervention group the aim is a weight loss of at least 5% to10% in a six-month period, to be achieved by the combination of a diet, increase of physical activity and behavioural modification. After six months, in case no conception has been achieved, these patients will start fertility treatment according to the Dutch fertility guidelines. In the control group treatment will be started according to Dutch fertility guidelines, independently of the patient's weight. Outcome measures and analysis: The primary outcome measure is a healthy singleton born after at least 37 weeks of gestation after vaginal delivery. Secondary outcome parameters including pregnancy outcome and complications, percentage of women needing fertility treatment, clinical and ongoing pregnancy rates, body weight, quality of life and costs. Data will be analysed according to the intention to treat principle, and cost-effectiveness analysis will be performed to compare the costs and health effects in the intervention and control group. Discussion: The trial will provide evidence for costs and effects of a lifestyle intervention aiming at weight reduction in overweight and obese subfertile women and will offer guidance to clinicians for the treatment of these patients. [ABSTRACT FROM AUTHOR]

Background: Pregnancies induced by in vitro fertilisation (IVF) often result in twin gestations, which are associated with both maternal and perinatal complications. An effective way to reduce the number of IVF twin pregnancies is to decrease the number of embryos transferred from two to one. The interpretation of current studies is limited because they used live birth as outcome measure and because they applied limited time horizons. So far, research on long-term outcomes of IVF twins and singletons is scarce and inconclusive. The objective of this study is to investigate the short (1-year) and long-term (5 and 18-year) costs and health outcomes of IVF singleton and twin children and to consider these in estimating the cost-effectiveness of single embryo transfer compared with double embryo transfer, from a societal and a healthcare perspective. Methods/Design: A multi-centre cohort study will be performed, in which IVF singletons and IVF twin children born between 2003 and 2005 of whom parents received IVF treatment in one of the five participating Dutch IVF centres, will be compared. Data collection will focus on children at risk of health problems and children in whom health problems actually occurred. First year of life data will be collected in approximately 1,278 children (619 singletons and 659 twin children). Data up to the fifth year of life will be collected in approximately 488 children (200 singletons and 288 twin children). Outcome measures are health status, health-related quality of life and costs. Data will be obtained from hospital information systems, a parent questionnaire and existing registries. Furthermore, a prognostic model will be developed that reflects the short and long-term costs and health outcomes of IVF singleton and twin children. This model will be linked to a Markov model of the short-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies to enable the calculation of the long-term cost-effectiveness. Discussion: This is, to our knowledge, the first study that investigates the long-term costs and health outcomes of IVF singleton and twin children and the long-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies. [ABSTRACT FROM AUTHOR]

The article offers information on a study which developed in vitro propagation of human spermatogonial stem cells from small testicular biopsies to derive an adequate number of cells for successful transplantation. Testis material donated by six adult men who undergone orchidectomy as part of prostate cancer treatment was utilized during the duration of the study from April 2007 to July 2009. To determine the presence of spermatogonia and spermatogonial markers, reverse transcriptase polymerase chain reaction and immunofluorescence were applied, respectively. Main outcome measure was the propagation of spermatogonial stem cells. Also presented in details are the research findings.

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. [ABSTRACT FROM AUTHOR]

Background: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. Methods/design: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. Discussion: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research. [ABSTRACT FROM AUTHOR]

Background: For most tubal ectopic pregnancies (EP) surgery is the treatment of first choice. Whether surgical treatment should be performed conservatively (salpingostomy) or radically (salpingectomy) in women wishing to preserve their reproductive capacity, is subject to debate. Salpingostomy preserves the tube, but bears the risks of both persistent trophoblast and repeat ipsilateral tubal EP. Salpingectomy, avoids these risks, but leaves only one tube for reproductive capacity. This study aims to reveal the trade-off between both surgical options: whether the potential advantage of salpingostomy, i.e. a better fertility prognosis as compared to salpingectomy, outweighs the potential disadvantages, i.e. persistent trophoblast and an increased risk for a repeat EP. Methods/Design: International multi centre randomised controlled trial comparing salpingostomy versus salpingectomy in women with a tubal EP without contra lateral tubal pathology. Hemodynamically stable women with a presumptive diagnosis of tubal EP, scheduled for surgery, are eligible for inclusion. Patients pregnant after in vitro fertilisation (IVF) and/or known documented tubal pathology are excluded. At surgery, a tubal EP must be confirmed. Only women with a tubal EP amenable to both interventions and a healthy contra lateral tube are included. Salpingostomy and salpingectomy are performed according to standard procedures of participating hospitals. Up to 36 months after surgery, women will be contacted to assess their fertility status at six months intervals starting form the day of the operation. The primary outcome measure is the occurrence of spontaneous viable intra uterine pregnancy. Secondary outcome measures are persistent trophoblast, repeat EP, all pregnancies including those resulting from IVF and financial costs. The analysis will be performed according to the intention to treat principle. A cost-effectiveness analysis will be performed within a decision analysis framework, based on costs per live birth, including IVF treatment whenever a spontaneous pregnancy does not occur. Patients' preferences will be assessed using a discrete choice experiment. Discussion: This trial will provide evidence on the trade off between salpingostomy and salpingectomy for tubal EP in view of the pros and cons of both interventions and will offer guidance to clinicians in making the right treatment choice. Trial registration: Current Controlled Trials ISRCTN37002267 [ABSTRACT FROM AUTHOR]

Background: Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. Methods/Design: A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/ abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment. Discussion: This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations. Trial registration: Current Controlled Trials ISRCTN 48210491 [ABSTRACT FROM AUTHOR]

Objective To compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome. Design Randomised clinical trial. Setting Multicentre trial in 20 Dutch hospitals. Participants 228 women with polycystic ovary syndrome. Interventions Clomifene citrate plus metformin or clomifene citrate plus placebo. Main outcome measure The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. Results 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference - 8%, 95% confidence interval - 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; - 6%, - 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, - 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). Conclusion Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome. [ABSTRACT FROM AUTHOR]

Objective To compare reproductive outcomes in couples carrying a structural chromosome abnormality and non-carrier couples referred for chromosome analysis after two or more miscarriages. Design Case-control study. Setting Six centres for clinical genetics in the Netherlands. Participants 278 carrier couples and 427 non-carrier couples referred for chromosome analysis between 1992 and 2000 after two or more miscarriages before 20 weeks of gestation. Couples were followed up for at least 24 months after chromosome analysis. Main outcome measures The birth of at least one healthy child, at least one more miscarriage, and viable offspring with unbalanced chromosomal abnormalities after parental chromosome analysis. Results Mean follow-up after chromosome analysis was 5.8 years. 120 of 247 (49%) carrier couples had one or more miscarriage after chromosome analysis compared with 122 of 409 (30%) non-carrier couples (difference 19%, 95% confidence interval 11% to 26%; P < 0.01). The percentage of couples with at least one healthy child was not significantly different in carrier couples (83%) and non-carrier couples (84%) (difference -1%, - 7% to 5%). Among 550 pregnancies in carrier couples, two viable unbalanced chromosome abnormalities were detected at prenatal diagnosis (0.4%) and the fetuses aborted and two children with an unbalanced karyotype were born (0.4%). Conclusions Couples whose carrier status was ascertained after two or more miscarriages have a low risk of viable offspring with unbalanced chromosomal abnormalities. Their chances of having a healthy child are as high as non-carrier couples, despite a higher risk of miscarriage. [ABSTRACT FROM AUTHOR]

Although much structural polymorphism in the human genome has been catalogued, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length ≥12 times, the TSPY gene array changed length ≥23 times, the 3.6-Mb IR3/IR3 region changed orientation ≥12 times and the AZFc region was rearranged ≥20 times. After determining the total time spanned by all branches of this tree (∼1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: ≥2.3 × 10−4, ≥4.4 × 10−4, ≥2.3 × 10−4 and ≥3.8 × 10−4 large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the potential value of quantitative fluorescent polymerase chain reaction (QF-PCR) in the detection of chromosome abnormalities in ectopic pregnancies. Methods: Seventy chorionic villi samples of ectopic pregnancies were studied by QF-PCR. Primers for chromosomes 16, 21, X and Y in chorionic villi were evaluated. Fluorescence in situ hybridization (FISH) was performed when results of QF-PCR showed aneuploidy, in case of unexplicable QF-PCR peaks, and in 10 cases with normal QF-PCR results. Results: QF-PCR produced a result for chromosomes X and Y in 66 cases (94%), for chromosome 16 in 62 cases (89%) and for chromosome 21 in 55 cases (79%). Overall, QF-PCR produced a result for the chromosomes tested in 54 ectopic pregnancy cases (77%). Fifty-two of these results were normal disomic (96%) and two were abnormal, one trisomy 16 (2%) and one triploidy (2%). In 16 cases (23%) no definite QF-PCR results could be obtained for all chromosomes, 11 due to amplification failure, and 5 due to unexplicable QF-PCR peaks. In 10 cases with normal QF-PCR results, disomy was confirmed by FISH. The trisomy 16 was also confirmed by FISH. Furthermore, a result was obtained with FISH in 5 of the cases without definite QF-PCR results. Conclusion:Although QF-PCR can establish the chromosomal status in ectopic pregnancies for chromosomes 16, 21, X and Y in the majority of cases, the technical failure rate is still considerable and does not improve results when compared to cytogenetic techniques. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract Objective: To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with clomiphene resistant polycystic ovary syndrome. Design: Randomised controlled trial. Setting: Secondary and tertiary hospitals in the Netherlands. Participants: 168 patients with clomiphene citrate resistant polycystic ovary syndrome: 83 were allocated electrocautery and 85 were allocated recombinant follicle stimulating hormone. Intervention: Laparoscopic electrocautery of the ovaries followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or induction of ovulation with recombinant follicle stimulating hormone. Main outcome measure: Ongoing pregnancy within 12 months. Results: The cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormone was 67%. With only electrocautery it was 34%, which increased to 49% after clomiphene citrate was given. Subsequent recombinant follicle stimulating hormone increased the rate to 67% at 12 months (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). No complications occurred from electrocautery with or without clomiphene citrate. Patients allocated to electrocautery had a significantly lower risk of multiple pregnancy (0.11, 0.01 to 0.86). Conclusion: The ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or recombinant follicle stimulating hormone, seems equivalent to ovulation induction with recombinant follicle stimulating hormone, but the former procedure carries a lower risk of multiple pregnancy. [ABSTRACT FROM AUTHOR]

Many human Y-chromosomal deletions are thought to severely impair reproductive fitness, which precludes their transmission to the next generation and thus ensures their rarity in the population. Here we report a 1.6-Mb deletion that persists over generations and is sufficiently common to be considered a polymorphism. We hypothesized that this deletion might affect spermatogenesis because it removes almost half of the Y chromosome's AZFc region, a gene-rich segment that is critical for sperm production. An association study established that this deletion, called gr/gr, is a significant risk factor for spermatogenic failure. The gr/gr deletion has far lower penetrance with respect to spermatogenic failure than previously characterized Y-chromosomal deletions; it is often transmitted from father to son. By studying the distribution of gr/gr-deleted chromosomes across the branches of the Y chromosome's genealogical tree, we determined that this deletion arose independently at least 14 times in human history. We suggest that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate new gr/gr deletions. [ABSTRACT FROM AUTHOR]

Background: Transvaginal sonography, serum human chorionic gonadotrophin (hCG) measurement, and serum progesterone measurement provide the possibility to screen symptom-free women at increased risk of ectopic pregnancy. The objective of the present study was to evaluate the cost-effectiveness of screening for ectopic pregnancy, by addressing the expected benefits and costs of screening for ectopic pregnancy.Methods: Screening programs incorporating transvaginal sonography, serum hCG measurement, and serum progesterone measurement were compared with a 'watchful waiting' strategy. Data were extracted from the literature. The strategies were compared on the expected number of prevented tubal ruptures, the expected number of false-positive diagnoses, and expected costs.Results: The cost-effectiveness of screening appeared to be strongly dependent on the prevalence of ectopic pregnancy. At a prevalence of ectopic pregnancy of 6%, a screening program with transvaginal sonography and serum hCG measurement would reduce the number of patients with ruptured ectopic pregnancy from 2.1 to 0.61 per 100 screened women. Screening was expected to cost approximately Euro 933 per prevented tubal rupture, whereas the number of expected false-positive diagnoses was 0.64 per prevented tubal rupture.Conclusion: We conclude that screening for ectopic pregnancy reduces the number of patients with tubal rupture, but only at the expense of a large false-positive rate. Although sonography in symptom-free women at risk of ectopic pregnancy might be justified for psychological reasons, the medical and economic benefits of such a policy seem to be limited. [ABSTRACT FROM AUTHOR]

Current algorithms for the diagnosis of ectopic pregnancy do not take into account the heterogeneity in patient profiles. Such heterogeneity can lead to differences in the pre-test probability of ectopic pregnancy. In patients with clinical symptoms, for example, the probability of presence of an ectopic pregnancy is higher than in symptom-free patients. Any additional tests should then be interpreted differently, depending on the pre-test probability. We present a diagnostic algorithm that uses probabilistic decision rules for the evaluation of women with suspected ectopic pregnancy with flexible cut-off levels for test positivity We compare it with a general algorithm that uses fixed cut-off levels. Fictitious cohorts, varying in prevalence of ectopic pregnancy were put together, using data obtained from a cohort of >800 women with suspected ectopic pregnancy. In the inflexible algorithm, ectopic pregnancy was diagnosed whenever it could be visualized at transvaginal sonography, or where serum human chorionic gonadotrophin (HCG) exceeded a rigid cut-off level; ectopic pregnancy was rejected if an intrauterine pregnancy was seen or when serum HCG decreased. In the flexible algorithm, a post-test probability was obtained after each test, using pre-test probabilities and test-based likelihood ratios. Ectopic pregnancy was diagnosed whenever the post-test probability for ectopic pregnancy exceeded 95%, whereas this diagnosis was rejected if the calculated post-test probability fell below 1%. For both algorithms, sensitivity and specificity as well as predictive values were calculated. At each prevalence, the inflexible algorithm was associated with a sensitivity of 93% and a specificity of 97%. In contrast, the sensitivity and specificity of the flexible, individualized algorithm depended on the prevalence of ectopic pregnancy. Consequently, predictive values varied strongly when the inflexible algorithm was used, whereas they were much more stable after using the flexible algorithm. For five possible valuations of false positive and false negative diagnoses, the flexible algorithm reduced the expected disutility, compared with the inflexible algorithm. It is concluded that clinicians should incorporate probabilistic decision rules in algorithms used for the diagnosis of ectopic pregnancy. [ABSTRACT FROM PUBLISHER]

In this study, we compare the prognostic significance of hysterosalpingography (HSG) and laparoscopy for fertility outcome. In a prospective cohort study in 11 clinics participating in the Canadian Infertility Treatment Evaluation Study (CITES), consecutive couples who registered between 1 April 1984 and 31 March 1987 for the evaluation of subfertility and who underwent HSG and laparoscopy were included. Unilateral and bilateral tubal occlusion at HSG and laparoscopy were related to treatment-independent pregnancy. Cox regression was used to calculate fecundity rate ratios (FRR). Of the 794 patients who were included, 114 (14%) showed one-sided tubal occlusion and 194 (24%) showed two-sided tubal occlusion on HSG. At laparoscopy, 94 (12%) showed one-sided tubal occlusion and 96 (12%) showed two-sided tubal occlusion. Occlusion detected on HSG and laparoscopy showed a moderate agreement beyond chance (weighted κ-statistic 0.42). The adjusted FRR of one-sided tubal occlusion at HSG was 0.80, whereas two-sided tubal occlusion showed an FRR of 0.49. For laparoscopy, the FRR were 0.51 and 0.15 respectively. After a normal or one-sided occluded HSG, laparoscopy showed two-sided occlusion in 5% of the patients, and fertility prospects in these patients were virtually zero. If two-sided tubal occlusion was detected on HSG but not during laparoscopy, fertility prospects were slightly impaired. Fertility prospects after a two-sided occluded HSG were strongly impaired in cases where laparoscopy showed one-sided and two-sided occlusion, with FRR of 0.38 and 0.19 respectively. Although laparoscopy performed better than HSG as a predictor of future fertility, it should not be considered as the perfect test in the diagnosis of tubal pathology. For clinical practice, laparoscopy can be delayed after normal HSG for at least 10 months, since the probability that laparoscopy will show tubal occlusion after a normal HSG is very low. [ABSTRACT FROM PUBLISHER]

In 12 cows, transvaginal interstitial laser treatment (TILT) of the ovaries was performed using a neodynium: yttrium aluminium-garnet laser to investigate the feasibility of a new treatment approach for clomiphene-resistant patients with chronic hyperandrogenic anovulation. Powers of 1 and 2 W during 5 min of exposure were used. Sonographic changes of thermal damage during TILT, the extent and healing of the lesions by light microscopy and ultrasound during a 3 month follow-up and adhesion formation were studied. During laser irradiation, a hyperechogenic zone developed around the fibre tip, with a mean ± SD diameter of 4.4 ± 2.0 mm at 1 W and 6.9 ± 1.5 mm at 2 W. The mean diameters of the histological lesions 2 days after treatment were 7.3 ± 2.5 mm at 1 W and 13.0 ± 2.1 mm at 2 W. During follow-up, the mean diameter of both the histologically and the sonographically assessed lesions decreased, although transvaginal sonography (TVS) systematically and significantly underestimated the thermal damage. Lesions healed by fibrosis and no adhesions were present TILT of the ovaries in cows is easy to perform and produces central or subcapsular necrosis without adhesions. TVS gives an indication of thermal damage but underestimates the extent of tissue damage in cow ovaries. Obviously, this study does not allow conclusions to be drawn concerning its safety and efficacy in man. [ABSTRACT FROM PUBLISHER]