STUDY QUESTION Does intrauterine insemination in the natural cycle lead to better pregnancy rates than intracervical insemination (ICI) in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. SUMMARY ANSWER In a large cohort of women undergoing artificial insemination with cryopreserved donor sperm, there was no substantial beneficial effect of IUI in the natural cycle over ICI in the natural cycle. WHAT IS KNOWN ALREADY At present, there are no studies comparing IUI in the natural cycle versus ICI in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. STUDY DESIGN, SIZE, DURATION We performed a retrospective cohort study among all eight sperm banks in the Netherlands. We included all women who underwent artificial insemination with cryopreserved donor sperm in the natural cycle between January 2009 and December 2010. We compared time to ongoing pregnancy in the first six cycles of IUI and ICI, after which controlled ovarian stimulation was commenced. Ongoing pregnancy rates (OPRs) over time were compared using life tables. A Cox proportional hazard model was used to compare the chances of reaching an ongoing pregnancy after IUI or ICI adjusted for female age and indication. PARTICIPANTS/MATERIALS, SETTING, METHODS We included 1843 women; 1163 women underwent 4269 cycles of IUI and 680 women underwent 2345 cycles of ICI with cryopreserved donor sperm. MAIN RESULTS AND THE ROLE OF CHANCE Baseline characteristics were equally distributed (mean age 34.0 years for the IUI group versus 33.8 years for the ICI group), while in the IUI group, there were more lesbian women than in the ICI group (40.6% for IUI compared with 31.8% for ICI). Cumulative OPRs up to six treatment cycles were 40.5% for IUI and 37.9% for ICI. This corresponds with a hazard rate ratio of 1.02 [95% confidence interval (CI) 0.84-1.23] after controlling for female age and indication. Increasing female age was associated with a lower OPR, in both the IUI and ICI groups with a hazard ratio for ongoing pregnancy of 0.94 per year (95% CI 0.93-0.97). LIMITATIONS, REASONS FOR CAUTION This study is prone to selection bias due to its retrospective nature. As potential confounders such as parity and duration of subfertility were not registered, the effect of these potential confounders could not be evaluated. WIDER IMPLICATIONS OF THE FINDINGS In women inseminated with cryopreserved donor sperm in the natural cycle, we found no substantial benefit of IUI over ICI. A randomized controlled trial with economic analysis alongside, it is needed to allow a more definitive conclusion on the cost-effectiveness of insemination with cryopreserved donor sperm. STUDY FUNDING/COMPETING INTERESTS No funding was used and no conflicts of interest are declared.

Objective: To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis.Design: Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis.Setting: Reproductive medicine center in an university hospital.Patient(s): 158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients.Intervention(s): Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively).Main Outcome Measure(s): Ongoing pregnancy rate (OPR) per started cycle.Result(s): The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n = 1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P.Conclusion(s): From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low. ((C)2014 by American Society for Reproductive Medicine.)

To review the literature and present original data to answer the question of whether in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is associated with an increase in imprinted diseases in offspring. If the answer is positive, to investigate whether there is a causal relationship between IVF or ICSI and the imprinted diseases.Review study.Eight epidemiologic studies were suitable to calculate the weighted relative risk for the birth of a child with Beckwith-Wiedemann syndrome following IVF or ICSI compared with the risk in the normal population. This relative risk was 5.2 (95% CI 1.6-7.4). In one study the relative risk was corrected for parents' fertility problems and no significant association was found. Data on the Silver-Russell syndrome are too sparse to draw conclusions, but a positive association with IVF or ICSI treatment is probable. No significant associations were found between the incidences of the Angelman and Prader-Willi syndromes and IVF or ICSI treatments. Children with Prader-Willi syndrome or Angelman syndrome are more likely to be born to parents with fertility problems. All retinoblastomas in children born after IVF or ICSI could be explained by de novo mutations in the RB1 gene and were not associated with imprinted genes. Imprinted diseases result from methylation errors already present in sperms or oocytes. There is no proof of a causal relationship between imprinted diseases and IVF or ICSI treatments.Imprinting disorders are more prevalent after human IVF or ICSI. Future studies should correct for fertility problems in the affected and comparison groups. It is highly improbable that assisted reproduction technologies cause imprinted diseases in humans.

STUDY QUESTIONDoes the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older?

STUDY QUESTION:What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)?SUMMARY ANSWER:Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation.WHAT IS KNOWN ALREADY:During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes.STUDY DESIGN, SIZE, DURATION:This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included.PARTICIPANTS/MATERIALS, SETTING, METHODS:Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6.MAIN RESULTS AND THE ROLE OF CHANCE:There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6).LIMITATIONS, REASONS FOR CAUTION:The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice.WIDER IMPLICATIONS OF THE FINDINGS:The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs.STUDY FUNDING/COMPETING INTEREST(S):This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono.TRIAL REGISTRATION NUMBER:www.clinicaltrials.gov, no. NCT00866034.

BACKGROUND The evidence underpinning the timing of an oocyte collection in IVF or ICSI is limited. The aim of this study was to assess the effect of the follicle diameter size of the dominant follicle on ongoing pregnancy rates. METHODS We conducted a randomized controlled trial, including women aged between 18 and 43 years who were scheduled for GnRH agonist down-regulated IVF/ICSI treatment in four assisted conception units. Women were randomized between timing oocyte collection when the leading follicle had a diameter of 22 mm or when the leading follicle had a diameter of 18 mm. The primary end-point was ongoing pregnancy, defined as a viable pregnancy at 12 weeks of gestation. RESULTS The trial had major problems with recruiting patients and after the planned 2 years of recruiting only half of the aimed 400 inclusions were obtained. We allocated 97 women to the 22-mm group and 93 women to the 18-mm group. In the 22-mm group more women reached an ongoing pregnancy (37 of 97 women, 38%) compared with the 18-mm group (22 of 93 women, 24%) resulting in a relative risk of 1.6 [95% confidence interval (CI): 1.03-2.5]. In a logistic regression analysis, the timing of oocyte collection, adjusted for female age, IVF/ICSI and centre, was still associated with ongoing pregnancy, although the association was no longer statistically significant (OR: 2.0; 95% CI: 0.96-4.2) CONCLUSIONS: This study suggests that delaying the timing of oocyte collection in IVF or ICSI results in better ongoing pregnancy rates, however, larger studies have to be performed to prove or refute these findings. TRIAL REGISTRATION ISRCTN24724622.

Objective: The most severe complication of IVF, death, is reported rarely. IVF-pregnancies are known to have more obstetric complications, which may result in a higher incidence of maternal deaths. In order to demand attention to this severe complication and to prevent recurrence, we collected deaths that may have been related to IVF. Materials and Methods: All deaths from 1984-2008 were collected by sending a letter to all gynaecologists in the Netherlands, and by retrieving data from a large cohort study examining the late effects of ovarian stimulation (OMEGA), and from the Dutch Maternal Mortality Committee. The total number of women that had had IVF was estimated to be 100,000. Only deaths that occurred within 1 year after IVF were studied. Results: Six deaths were directly related to IVF (6/100,000). Three women had Ovarian Hyperstimulation Syndrome, two died from sepsis and one was due to a dose error of a local anaesthetic during ovum pickup. Seventeen deaths were directly related to the IVF-pregnancy (42.5/100,000): pre-eclampsia (n=4), sepsis (n=2), vascular dissection (n=2), pulmonary embolism (n=2), liver failure (n=2), portal hypertension, small vessel disease, meningitis tuberculosa, suicide and amniotic fluid embolism. Eight deaths were not related to the IVF-procedure nor the IVF-pregnancy. Conclusions: The overall mortality in patients undergoing IVF-procedure was much lower than in the general population, whereas the overall mortality in IVF-pregnancies was much higher compared to the general population. The first observation is probably due to a 'healthy female effect' in women undergoing IVF. The high mortality in IVF-pregnancies is probably due to the fact that (donor egg) IVF is succesfully used in women who are older. The fact that only a few mortalities are reported in the literature whereas we calculated six in the Netherlands indicates that there should have been many more cases worldwide. We underline the importance to report all lethal cases and we call on everybody to report lethal cases to the ESHRE Committee 'Safety and Quality after IVF'.

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.

BACKGROUND:We assessed all deaths in the Netherlands that might have been related to IVF or to an IVF pregnancy in order to investigate this most serious complication.METHODS:All deaths related to IVF, within 1 year after IVF, from 1984 to 2008 were collected by sending a letter to all gynaecologists, and by retrieving data from a large cohort study examining the late effects of ovarian stimulation (OMEGA) and from the Dutch Maternal Mortality Committee.RESULTS:Six deaths were directly related to IVF (6/100,000), 17 deaths were directly related to the IVF pregnancy (42.5/100,000) and eight deaths were neither related to the IVF nor to the IVF-related pregnancy. The overall mortality in patients undergoing IVF procedures was lower than in the general population, whereas the overall mortality related to IVF pregnancies was higher than the maternal mortality in the general population.CONCLUSION:The decreased mortality is probably the result of a 'healthy female effect' in women undergoing IVF. The high maternal mortality in IVF pregnancies is probably related to the high number of multiple pregnancies and to the fact that (donor egg) IVF is successfully used in women who are older. The fact that only a few deaths directly related to IVF are reported in the literature whereas we observed six in the Netherlands indicates worldwide under-reporting of IVF-related mortality. We underline the importance of reporting all lethal cases to the European Society of Human Reproduction and Embryology Committee 'Safety and Quality after IVF'.

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.

Objective: To assess the accuracy of our recently developed prediction model in a prospective validation study to predict the outcome of intrauterine insemination (IUI).Design: Descriptive prospective validation study.Setting: Seven fertility centers in the Netherlands.Patient(s): Couples treated with IUI of whom the female partner had a regular cycle.Intervention(s): Intrauterine insemination with or without controlled ovarian hyperstimulation.Main Outcome Measure(s): Ongoing pregnancy after intrauterine insemination. Performance of the prediction model was assessed with calibration and discriminative capacity. Calibration was assessed by comparing the predicted ongoing pregnancy rate with the observed ongoing pregnancy rate. Discriminative capacity was assessed i with receiver operation characteristic (ROC) analysis. For daily practice, a score worksheet of the validated model was developed to estimate the chance of an ongoing pregnancy after IUI per treatment cycle.Result(s): We included 1,079 subfertile couples who underwent 4,244 cycles of IUI. There were 278 ongoing pregnancies, that is, an ongoing pregnancy rate of 6.6% per cycle. External validation of the model showed good calibration. The predicted probability never differed by more than 1.5% of the mean observed probability. The area under the ROC curve was 0.56 (95% confidence interval, 0.53-0.59) at external validation.Conclusion(S): The prediction model was able to make a good distinction between couples with a good pregnancy chance and those with a poor pregnancy chance after IUI. This model can help in deciding which couples will benefit from IUI and which couples will not.

Martinez, A. R.; Bernardus, R. E.; Vermeiden, J. P. W.; Schoemaker, J. Author Information

Part of a cost-effectiveness study of in-vitro fertilization was the evaluation of the medical results of this fertility treatment. Data were prospectively collected from > 3000 IVF treatments in five Dutch hospitals during a 2-year period. The average 'take-at-least-one-healthy-baby-home-rate' per started treatment was 10% (the average clinical pregnancy rate per embryo transfer was 20%). After more IVF treatments, about one in three to four couples were successful. Differences in results were mainly caused by patient characteristics, the treatment episode and the treating hospital. These differences remained in a multivariate logistic regression analysis.

Part of a cost-effectiveness study on in-vitro fertilisation was the evaluation of the medical results of this fertility treatment. Data were prospectively collected from more than 3000 IVF treatments in the five Dutch hospitals during a two-year period. The average take-at-least-one-healthy-baby-home rate per started treatment was 10% (the average clinical pregnancy rate per embryo transfer was 20%). After several IVF treatments about one in three or four couples were successful. Ranges in results were mainly caused by patient characteristics, the individual treatment number and the treating hospital. Male subfertility and long-lasting and primary infertility result in a bad prognosis. Success rates differed substantially between hospitals, even after correction for patient mix.