Surgery, gonadotropin-releasing hormone agonist downregulation and in vitro fertilisation in women with infertility and endometriomas.

INTRODUCTION: Tonsillectomy is one of the most common procedures in the field of ear, nose and throat procedures. In 2012, the annual incidence in Denmark was 129.4 per 100,000 inhabitants. A common complication is post-tonsillectomy haemorrhaging (PTH). The overall PTH rates vary widely among studies ranging from 0.5% to 33%. METHODS: This was a nationwide open-population, retrospective and registry-based cohort study in Danes who underwent tonsillectomy complicated by PTH in hospitals and private otorhinolaryngology (ORL) offices in the period from 1991 to 2012. RESULTS: In the 1991-2012 period, a total of 177,211 tonsillectomies were performed among which 9,221 had a registered PTH (rPTH) (5.2%). The annual incidence rate of rPTH increased from 3% in 1991 to 13% in 2012 (p less-than 0.05). Males aged 20-40 years had a significantly higher risk of rPTH with the highest increase in rPTH incidence rates from 9.0% in 1998 to 16.4% in 2012 (p less-than 0.05). Approx. 12% had a primary rPTH within the first 24 hours; the maximum incidence of rPTH was on day six (14%). CONCLUSIONS: The rate of rPTH increased from 1991 to 2012 in hospitals and in private ORL office settings alike. There was a significantly higher rate of rPTH in the age group of 20-40 years and a significant geographical difference in rPTH. The highest risk of rPTH was observed on the day of surgery and on day six. TRIAL REGISTRATION: The Danish Data Protection Agency (record number 2012-41-0158) approved this study. FUNDING: The Olga Bryde Nielsen Foundation and H. Skouby & E. Skouby's Foundation supported this study financially.

Trends over 15 years in ART in Europe: an analysis of 6 million cycles.

STUDY QUESTION: Was the European IVF Monitoring (EIM) Consortium, established in 1999 by ESHRE, able to monitor the trend over time of ART in Europe? SUMMARY ANSWER: The initial aims of the EIM programme (to collect and publish regional European data on census and trends on ART utilization, effectiveness, safety and quality) have been achieved. WHAT IS ALREADY KNOWN: ART data in Europe have been collected and reported annually in Human Reproduction. STUDY DESIGN SIZE DURATION: A retrospective data analysis and summary of the first 15 years of ART activity in Europe (1997-2011) was carried out, using the key figures from the annual ESHRE reports and focusing on how the practice of ART has evolved over the years. PARTICIPANTS/MATERIALS SETTING METHOD: A total of 5 919 320 ART cycles are reported, including IVF, ICSI, frozen embryo relacment and egg donation, resulting in the birth of more than 1 million infants. A total of 1 548 967 IUIs are also reported, including husband/partner's semen and donor semen cycles. The most relevant and complete data are analysed and discussed. MAIN RESULTS AND THE ROLE OF CHANCE: With some fluctuations, the number of countries and clinics reporting to EIM increases significantly from 1997 to 2011. A constant increase was also registered in the number of annual cycles reported. Since 2005, the estimation of the EIM coverage on the total European activity was >80%. In countries with 100% of coverage, the mean availability of ART increased from 765 cycles per million inhabitants in 1997 to 1269 cycles per million inhabitants in 2011, and the proportion of ART infants of the total number of infants born in the country increased from 1.3% to 2.4%. The proportion of women aged > 39 years undergoing IVF and ICSI cycles gradually increased. For 12 consecutive years, the proportion of ICSI versus IVF cycles showed a marked increase before reaching a plateau from 2008. The proportion of transfers with three or more embryos decreased constantly and the proportion of SETs increased over the time period. The triplets deliveries were reduced from 3.7% in 1997 to less than 1% since 2005 (0.6% in 2011). The effectiveness (evaluated as clinical pregnancy rate per aspiration and per embryo transfer) increased until 2007, then the figure remained stable. The cumulative percentage of documented pregnancy losses was 17%. No differences have been noted in terms of outcomes in the IUI cycles. LIMITATIONS REASONS FOR CAUTION: The data presented are accumulated from countries with different collection systems, regulations, insurance coverage and different practices. Each year a number of countries have been unable to provide some of the data. WIDER IMPLICATIONS OF THE FINDINGS: The first summary of 15 years of the EIM reports offers interesting data on census and trends on ART utilization, safety and quality in Europe. The primary aim of the ESHRE effort in supporting European data collection has been reached. Owing to its importance inside and outside the professional community, European data collection and publication on ART have to be supported and implemented. STUDY FUNDING/COMPETING INTERESTS: None.

Family intentions and personal considerations on postponing childbearing in childless cohabiting and single women aged 35-43 seeking fertility assessment and counselling.

STUDY QUESTION: What characterizes childless women aged 35 years and above seeking fertility assessment and counselling in relation to their reproduction and are there significant differences between single and cohabiting women? SUMMARY ANSWER: Despite the women's advanced age and knowledge of the age-related decline in fecundity, 70% of the single women sought fertility assessment and counselling to gain knowledge regarding the possibility of postponing pregnancy. WHAT IS KNOWN ALREADY: Recent studies have indicated an increasing demand for ovarian reserve testing in women without any known fertility problem to obtain knowledge on their reproductive lifespan and pro-fertility advice. Women postpone their first pregnancy, and maternal age at first birth has increased in western societies over the past two to four decades. Postponed childbearing implies a higher rate of involuntary childlessness, smaller families than desired and declining fertility rates. STUDY DESIGN, SIZE, AND DURATION: Baseline data from a cross-sectional cohort study of 340 women aged 35-43 years examined at the Fertility Assessment and Counselling (FAC) Clinic at Copenhagen University Hospital from 2011 to 2014. The FAC Clinic was initiated to provide individual fertility assessment and counselling. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible women were childless and at least 35 years of age. All completed a web-based questionnaire before and after the consultation including socio-demographic, reproductive, medical, lifestyle and behavioural factors. Consultation by a fertility specialist included transvaginal ultrasound, full reproductive history and AMH measurement. MAIN RESULTS AND THE ROLE OF CHANCE: The study comprised 140 cohabiting and 200 single women. The majority (82%) were well-educated and in employment. Their mean age was 37.4 years. Nonetheless, the main reasons for attending were to obtain knowledge regarding the possibility of postponing pregnancy (63%) and a concern about their fecundity (52%). The majority in both groups (60%) wished for two or more children. The women listed their ideal age at birth of first child and last child as 33 (±4.7) years and 39 (±3.5) years, respectively. Of the single women, 70% would accept use of sperm donation compared with 25% of the cohabiting women (P < 0.001). In general, 45% considered oocyte vitrification for social reasons, yet only 15% were positive towards oocyte donation. The two groups were comparable regarding lifestyle factors, number of previous sexual partners, pregnancies, and ovarian reserve parameters. LIMITATIONS, REASONS FOR CAUTION: The women in the present study were conscious of the risk of infertility with increasing age and attended the FAC Clinic due to a concern about their remaining reproductive lifespan, which in combination with their high educational level could impair the generalizability to the background population. WIDER IMPLICATIONS OF THE FINDINGS: The results indicate that in general women overestimate their own reproductive capacity and underestimate the risk of future childlessness with the continuous postponement of pregnancies.

Ovarian reserve assessment in users of oral contraception seeking fertility advice on their reproductive lifespan.

STUDY QUESTION: To what extent does oral contraception (OC) impair ovarian reserve parameters in women who seek fertility assessment and counselling to get advice on whether their remaining reproductive lifespan is reduced? SUMMARY ANSWER: Ovarian reserve parameters defined by anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume were found to be significantly decreased by 19% (95% CI 9.1-29.3%), 18% (95% CI 11.2-24.8%) and 50% (95% CI 45.1-53.7%) among OC users compared with non-users. WHAT IS KNOWN ALREADY: AMH and AFC have proved to be reliable predictors of ovarian ageing. In women, AMH declines with age and data suggest a relationship with remaining reproductive lifespan and age at menopause. OC may alter parameters related to ovarian reserve assessment but the extent of the reduction is uncertain. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of 887 women aged 19-46 attending the Fertility Assessment and Counselling Clinic (FACC) from 2011 to 2014 comparing ovarian reserve parameters in OC users with non-OC users. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FAC Clinic was initiated to provide individual fertility assessment and counselling. All women were examined on a random cycle day by a fertility specialist. Consultation included; transvaginal ultrasound (AFC, ovarian volume, pathology), a full reproductive history and AMH measurement. Women were grouped into non-users and users of OC (all combinations of estrogen-progestin products and the contraceptive vaginal ring). Non-users included women with an intrauterine device (IUD) or no hormonal contraception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 887 women, 244 (27.5%) used OC. In a linear regression analyses adjusted for age, ovarian volume was 50% lower (95% CI 45.1-53.7%), AMH was 19% lower (95% CI 9.1-29.3%), and AFC was 18% lower (95% CI 11.2-24.8%) in OC users compared with non-users. Comparison of AMH at values of <10 pmol/l OC was found to have a significant negative influence on AMH (OR 1.6, 95% CI 1.1; 2.4, P = 0.03). Furthermore, we found a significant decrease in antral follicles sized 5-7 mm (P < 0.001) and antral follicles sized 8-10 mm (P < 0.001) but an increase in antral follicles sized 2-4 mm (P = 0.008) among OC users. The two groups (OC users versus non-users) were comparable regarding age, BMI, smoking and maternal age at menopause. LIMITATIONS, REASON FOR CAUTION: The study population comprised women attending the FAC Clinic. Recruitment was based on self-referral, which could imply a potential selection bias. Ovarian reserve was examined at a random cycle day. However, both AMH and AFC can be assessed independently of the menstrual cycle. The accuracy in predicting residual reproductive lifespan is still needed in both users and non-users of OC. WIDER IMPLICATIONS OF THE FINDINGS: OC has a major impact on the ovarian volume, and a moderate impact on AFC and AMH with a shift towards the smaller sized antral follicle subclasses. The most evident reduction occurs in the antral follicles of 5-7 and 8-10 mm with the highest number of AMH secreting granulosa cells. It is essential to be aware of the impact of OC use on ovarian reserve parameters when guiding OC users on their fertility status and reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: The FAC Clinic was established in 2011 as part of the ReproHigh collaboration. This study received funding through the Capital Region Research Fund and by EU-regional funding. There are no competing interests. TRIAL REGISTRATION NUMBER: The biobank connected to FAC Clinic is approved by the Scientific Ethical Committee (H-1-2011-081).

Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?

STUDY QUESTION: Are singletons born after frozen embryo transfer (FET) at increased risk of being born large for gestational age (LGA) and if so, is this caused by intrinsic maternal factors or related to the freezing/thawing procedures? SUMMARY ANSWER: Singletons after FET have an increased risk of being born LGA. This cannot solely be explained by intrinsic maternal factors as it was also observed in sibling pairs, where the sibling conceived after FET had an increased risk of LGA compared with the sibling born after Fresh embryo transfer. WHAT IS KNOWN ALREADY: FET singletons have a higher mean birthweight than singletons born after transfer of fresh embryos, and FET singletons may be at an increased risk of being born LGA. STUDY DESIGN, SIZE, DURATION: The national register-based controlled cohort study involves two populations of FET singletons. The first population (A: total FET cohort) consisted of all FET singletons (n = 896) compared with singletons born after Fresh embryo transfer (Fresh) (n = 9480) and also with that born after natural conception (NC; n = 4510) in Denmark from 1997 to 2006. The second population (B: Sibling FET cohort) included all sibling pairs, where one singleton was born after FET and the consecutive sibling born after Fresh embryo transfer or vice versa from 1994 to 2008 (n = 666). The sibling cohort included n = 550 children with the sibling combination first child Fresh/second child FET and n = 116 children with the combination first child FET/second child Fresh. PARTICIPANTS/MATERIALS, SETTING, METHODS: Main outcome measures were LGA defined as birthweight of >2 SD from the population mean (z-score >2) according to Marsáls curves. Macrosomia was defined as birthweight of >4500 g. Crude and adjusted odds ratios (AORs) of LGA and macrosomia were calculated for FET versus Fresh and versus NC singletons in the total FET cohort. Similarly, AOR was calculated for FET versus Fresh in the sibling cohort. Adjustments were made for maternal age, parity, child sex, year of birth and birth order in the sibling analyses. Meta-analyses were performed by pooling our data with the previously published cohort studies on LGA and macrosomia. MAIN RESULTS AND THE ROLE OF CHANCE: The AORs of LGA (z-score >2) and macrosomia in FET singletons versus singletons conceived after Fresh embryo transfer were 1.34 [95% confidence interval (95% CI) 0.98-1.80] and 1.91 (95% CI 1.40-2.62), respectively. The corresponding risks for FET versus NC singletons were 1.41 (95% CI 1.01-1.98) for LGA and 1.67 (95% CI 1.18-2.37) for macrosomia. The increased risk of LGA and macrosomia in FET singletons was confirmed in the sibling cohort also after adjustment for birth order. Hence, the increased risk of LGA in FET singletons cannot solely be explained by being the second born or by intrinsic maternal factors, but may also partly be related to freezing/thawing procedures per se. In the meta-analysis, the summary effects of LGA and macrosomia in FET versus singletons conceived after Fresh embryo transfer were AOR 1.54 (95% CI 1.31-1.81) and AOR 1.64 (95% CI 1.26-2.12), respectively. The corresponding figures for FET versus NC singletons were for LGA AOR 1.32 (95% CI 1.07-1.61) and macrosomia AOR 1.41 (95% CI 1.11-1.80), respectively. LIMITATIONS, REASONS FOR CAUTION: Adjustment for body mass index as a possible confounder was not possible. The size of the FET/Fresh sibling cohort was limited; however, the complete sibling cohort was sufficiently powered to explore the risk of LGA. A bias is very unlikely as data coding was based on national registers. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with the previous Nordic studies and thus can be generalized to the Nordic countries. The causes for LGA in FET singletons should be further explored. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this project. None of the authors have any conflict of interest to declare.

Intrafollicular endocrine milieu after addition of hCG to recombinant FSH during controlled ovarian stimulation for in vitro fertilization.

CONTEXT: The role of human chorionic gonadotropin (hCG) supplementation on the intrafollicular steroid milieu has been studied. OBJECTIVE: The objective of the study was to assess the impact on steroid levels in follicular fluids (FFs) after different doses of hCG supplementation to recombinant FSH for controlled ovarian stimulation. SETTING: This was a prospective randomized dose-response study conducted at Copenhagen University Hospital, Rigshospitalet, Denmark. PATIENTS: From 62 in vitro fertilization patients, 334 FFs were selected for analyses. INTERVENTIONS: Patients were treated using a GnRH agonist protocol with recombinant FSH 150 IU/d and randomized from stimulation day 1 to supplementation with hCG: D0, 0 IU/d; D50, 50 IU/d; D100, 100 IU/d; and D150, 150 IU/d. MAIN OUTCOME MEASURE: Intrafollicular hormone concentrations in relation to treatment groups, follicular sizes, and embryo quality were measured. RESULTS: In large follicles, hCG supplementation induced a nearly 3-fold increase of estradiol (nanomoles per liter) [D0: 1496; D50: 3138; D100: 4338; D150: 4009 (P < .001)], a significant 3-fold increase of androstenedione, and a 5-fold increase of T (nanomoles per liter) [D0: 15; D50: 38; D100: 72; D150: 56 (P < .001)]. The estradiol to T ratio decreased significantly, with the lowest ratio in D100 and the highest in D0. Large follicles giving rise to good-quality embryos had significantly higher estradiol and progesterone levels and estradiol to T, estradiol to androstenedione, and progesterone to estradiol ratios, compared with small follicles, leading to poor-quality embryos. CONCLUSIONS: Increasing doses of hCG supplementation markedly stimulated the intrafollicular concentration of both estradiol and androgens, with a shift toward a more androgenic milieu. In large follicles with oocytes giving rise to good-quality embryos, the FFs were significantly more estrogenic than in small follicles with oocytes developing into poor quality embryos.

Ovarian antral follicle subclasses and anti-mullerian hormone during normal reproductive aging.

CONTEXT: The interindividual variation in the age-related decline of ovarian follicles is wide. Hence, it is important to identify reliable, sensitive, and specific markers to assess the ovarian reserve of the individual woman. OBJECTIVE: The aim of this study was to characterize the relation between age and ovarian reserve parameters in a population of healthy women with regular menstrual cycle. DESIGN AND SETTING: We conducted a prospective, population-based, cross-sectional study. PARTICIPANTS: A total of 366 health care workers aged 21-41 years employed at a University Hospital were included. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Serum anti-Müllerian hormone (AMH) concentration, antral follicle count (AFC), antral follicle size categories (small: 2-4 mm; intermediate: 5-7 mm; and large: 8-10 mm), and ovarian volume were measured. RESULTS: Serum AMH level declined by 5.6% per year (95% confidence interval 3.7-7.4%, P < .001), AFC (2-10 mm) declined by 4.4% per year (3.2-5.7%, P < .001), and ovarian volume declined by 1.1% per year (0.2-2.0, P = .002), respectively. The mean proportion of small follicles decreased with age (P = .04), the proportion of intermediate follicles displayed no significant change with age (P = .58), and the mean proportion of large follicles increased with age (P < .001). The prevalence of large follicles increased with decreasing serum AMH concentration [odds ratio 1.04 per 1 pmol/L (1.02-1.06), P < .001, area under the curve 0.66], and with decreasing total AFC [odds ratio 1.04 per follicle (1.02-1.05), P < .001, area under the curve 0.62]. CONCLUSION: Chronological age was inversely related to serum AMH concentration, total AFC, and ovarian volume. Subclasses of AFC sized 2-4 and 5-7 mm decreased with increasing age, whereas AFC sized 8-10 mm increased with increasing age. Within AFC, a shift toward larger follicles with increasing age was observed. The occurrence of large follicles was more strongly related to biological age in terms of AMH and AFC than chronological age.

A randomized controlled dose-response pilot study of addition of hCG to recombinant FSH during controlled ovarian stimulation for in vitro fertilization.

STUDY QUESTION: Is it possible to define an optimal dose of hCG in combination with rFSH from the first day of stimulation in the GnRH agonist protocol applied to IVF? SUMMARY ANSWER: Supplementation with hCG from the first day of stimulation may increase the number of top-quality embryos per patient. Daily doses of hCG up to 150 IU are compatible with good live birth rates. A ceiling level of estradiol (E(2)) was reached with hCG doses above 100 IU/day. A positive dose-response was seen for pre-ovulatory progesterone, but concentrations remained below values for which an impairment of endometrial receptivity has been previously reported. We suggest a large clinical trial to be proceeded with a group given 100 IU hCG daily versus a control group. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Prospective multicentre studies have indicated increased live birth rates and increased number of top-quality embryos when low doses of hCG were associated with FSH. We analysed the clinical, embryological and endocrine aspects of adding increasing doses of hCG to rFSH from the first day of stimulation for IVF. DESIGN: A prospective randomized, controlled, open-label dose-response pilot study was conducted between February 2009 and June 2010 at Copenhagen University Hospital, Rigshospitalet, Denmark. Adequate allocation concealment was assured from sequentially numbered, opaque, sealed envelopes prepared from a computer-generated list. Scoring of the embryos was done in an assessor-blinded way. PARTICIPANTS AND SETTING: Endocrinologically normal IVF patients aged 25-37 years, BMI 18-30 kg/m(2), regular cycles and FSH <12 IU/l, were treated with a fixed dose of rFSH 150 IU/day and randomized to daily hCG dose of 0, 50, 100 or 150 IU from Day 1 of stimulation. Primary end-point was the total number of top-quality embryos on Day 3. DATA ANALYSIS METHOD: Data were analysed by analysis of variance, Kruskal-Wallis test, chi-squared test or Poisson distribution count. MAIN FINDINGS: A total of 62 patients were randomized into four hCG dose groups: Dose 0 (D0; n= 16), Dose 50 (D50; n= 15), Dose 100 (D100; n= 16) and Dose 150 (D150; n= 15). Two patients in D150 were withdrawn after randomization because of major (10- to 30-fold) hCG dosing errors, leaving 13 patients in this group. Thus, the results are based on the per protocol population. The mean numbers of top-quality embryos per patient were D0: 0.8 ± 1.2, D50: 0.5 ± 0.7, D100: 1.2 ± 1.7 and D150: 1.5 ± 1.7 (P= 0.04). All pregnancies were singleton gestations, and the live birth rates per started cycle were D0: 25%, D50: 27%, D100: 25% and D150: 31% (P= 0.98). Steady state level of serum (s)-hCG was reached on Day 6 of stimulation. S-hCG levels (IU/l) on the day of hCG administration were D0: <0.1, D50: 3.1 (2.6-3.6), D100: 5.5 (4.1-7.4) and D150: 11.0 (8.9-13.6) (P< 0.01). The patients receiving hCG supplementation were stratified by 33 and 66% percentiles into three groups according to the concentration of s-hCG on Day 6 of stimulation: 0.5-3.5 IU/l (n= 16), 3.5-8.0 IU/l (n= 14) and 8.0-21.1 IU/l (n= 14). The mean numbers of top-quality embryos in the three groups were 0.5 ± 0.9, 1.1 ± 1.8 and 1.5 ± 1.5, respectively (P= 0.03). The progesterone increments from stimulation Day 1 to the day of hCG triggering were D0 = 49%, D50 = 79%, D100 = 110% and D150 = 160% (P= 0.02). S-androstenedione level was highest in D150 (P< 0.01). S-E(2) was 2-fold higher in the D100 and D 150 compared with D0 (P= 0.09). BIAS, LIMITATION, GENERALISABILITY: Our study has a limited sample size. Supplementation with daily hCG dose up to 150 IU throughout stimulation has never been used before. Hence, this had to be tested in a small study before conducting a larger trial. STUDY FUNDING/COMPETING INTERESTS: Ferring Pharmaceuticals, Research and Development, provided funds for the endocrine measurements. CLINICALTRIAL.GOV REGISTRATION: NCT00844311.

Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE.

BACKGROUND: This 11th European IVF-monitoring report presents the results of assisted reproductive technology (ART) treatments initiated in Europe during 2007. METHODS: From 33 countries, 1029 clinics reported 493 184 treatment cycles: IVF (120 761), ICSI (256 642), frozen embryo replacement (91 145), egg donation (15 731), preimplantation genetic diagnosis/preimplantation genetic screening (4638), in vitro maturation (660) and frozen oocytes replacements (3607). Overall, this represents a 7.6% increase since 2006, mostly related to an increase in all registers. IUI using husband/partner's (IUI-H) and donor (IUI-D) semen was reported from 23 countries: 142 609 IUI-H (+6.2%) and 26 088 IUI-D (+7.2%). RESULTS: In 18 countries where all clinics reported, 376 971 ART cycles were performed in a population of 425.6 million (886 cycles per million). The clinical pregnancy rates per aspiration and per transfer were 29.1 and 32.8% for IVF, and 28.6 and 33.0% for ICSI. Delivery rate after IUI-H was 10.2% in women aged < 40 years. In IVF/ICSI cycles, 1, 2, 3 and ≥4 embryos were transferred in 21.4, 53.4, 22.7 and 2.5% of cycles, with no decline in the number of embryos per transfer since 2006. The proportion of multiple deliveries (22.3: 21.3% twin and 1.0% triplet), did not decrease compared with 2006 (20.8%) and 2005 (21.8%). In women < 40 years undergoing IUI-H, twin deliveries occurred in 11.7% and triplets in 0.5%. CONCLUSIONS: In comparison with previous years, the reported number of ART cycles in Europe increased in 2007; pregnancy rates increased marginally, but the earlier decline in the number of embryos transferred and multiple births did not continue.

Predictive factors of ovarian response and clinical outcome after IVF/ICSI following a rFSH/GnRH antagonist protocol with or without oral contraceptive pre-treatment.

BACKGROUND: Prediction of ovarian response prior to the first controlled ovarian stimulation (COS) cycle is useful in determining the optimal starting dose of recombinant FSH (rFSH). However, potentially predictive factors may be subject to inter-cycle variability and many patients are pre-treated with oral contraceptives (OC) for scheduling purposes. Our objective was to determine predictive factors of ovarian response for patients undergoing COS with rFSH in a gonadotrophin-releasing hormone antagonist protocol and to determine the inter-cycle variability of these factors. METHODS: In this multinational trial, 442 patients were randomized to receive either OC treatment or no treatment prior to their first COS cycle. For candidate predictive factors, patient characteristics were collected at screening, and endocrine and sonographic data were collected during the early follicular phase of the two subsequent cycles. A treatment regimen of 200 IU rFSH and 0.25 mg ganirelix was applied during the second cycle. Predictive factors of ovarian response and of too low (<6 oocytes) or too high (>18 oocytes) ovarian responses were determined using stepwise linear regression and stepwise logistic regression, respectively. RESULTS: Anti-Müllerian hormone (AMH) and basal FSH were statistically significant predictors of the number of oocytes retrieved and of an excessive ovarian response. For low ovarian response, AMH was the only significant predictive factor. In the non-OC group, the predictive value was higher than in the OC group and higher at the early follicular phase of the stimulation cycle than of the previous cycle. The inter-cycle variation for AMH was low compared with the inter-cycle variation of other hormones. Between the two groups, there were no differences in the number or quality of embryos obtained or transferred, but the implantation rate was significantly lower in the OC group (24.1 versus 30.1%, P= 0.03), resulting in an ongoing pregnancy rate of 26.3% compared with 35.7% in the non-OC group (P= 0.05). CONCLUSIONS: The best predictive model of ovarian response was in the non-OC group and included both AMH and basal FSH determined at the early follicular phase of the stimulation cycle. In the proceeding cycle, AMH alone had sufficient predictive value since it was not affected by inter-cycle variability or OC pretreatment.

Mid-luteal progesterone concentrations are associated with live birth rates during ovulation induction.

This retrospective study investigated whether mid-luteal serum progesterone concentrations are associated with live birth rates in women with WHO group II anovulatory infertility undergoing ovulation induction. Data were from women (n=335) stimulated with gonadotrophins using a low-dose step-up protocol, of which women with presumptive ovulation (n=279), defined as a mid-luteal progesterone concentration ⩾7.9ng/ml (⩾25nmol/l; range 7.9-194ng/ml) were included. Of the women with presumptive ovulation, 57 (20.4%) had a live birth and their serum mid-luteal progesterone concentration was significantly (P=0.016) higher than that of the non-live birth group. There were significant associations between the number of large (⩾15mm) and medium-sized follicles (12-14mm) at human chorionic gonadotrophin administration and the mid-luteal progesterone concentration (P<0.001), while the total number of large and medium-sized follicles was not significantly associated with live birth rate. In conclusion, mid-luteal progesterone concentrations above the cut-off values currently used for defining ovulation were positively associated with live birth rates in normogonadotrophic anovulatory women undergoing ovulation induction with gonadotrophins. The mid-luteal progesterone concentration, apart from being a consequence of the number of corpora lutea, may also reflect the quality of the follicle/oocyte/corpus luteum. Measurement of blood concentration of the steroid hormone progesterone in the mid-postovulatory phase of the menstrual cycle is frequently used to determine ovulation. The aim of this study was to investigate whether increasing blood concentrations of progesterone in the mid-postovulatory phase was associated with higher chances of achieving a live birth in a group of 335 women with anovulatory infertility, who had undergone stimulation with gonadotrophin hormones for the purpose of inducing ovulation. Statistical analysis, performed on the 279 women with presumptive ovulation (defined as a mid-postovulatory progesterone concentration ⩾7.9ng/ml serum), showed that the mid-postovulatory progesterone concentration was significantly positively associated with live birth rate. There was also a significant association between follicular development at end of gonadotrophin stimulation and the mid-postovulatory progesterone concentration, but follicular development could not explain live birth rate as mid-postovulatory progesterone concentrations could. In conclusion, increased blood concentrations of progesterone in the mid-postovulatory phase of the menstrual cycle above the threshold values currently used for defining ovulation were associated with increased live birth rates in anovulatory women undergoing ovulation induction with gonadotrophin hormones. The mid-postovulatory progesterone concentration, apart from being a consequence of the quantity of follicular development, may therefore also reflect the quality of the ovarian follicles and eggs.

Prospective investigation of serum anti-Müllerian hormone concentration in ovulatory intrauterine insemination patients: a preliminary study.

This preliminary prospective study investigated serum anti-Müllerian hormone (AMH) through correlations to other basal parameters (123 patients) and according to ovarian response to 75 IU recombinant follicle-stimulating hormone (rFSH)/day (62 patients) in ovulatory patients' first rFSH treatment cycle before intrauterine insemination. Mean age of the patients was 33 years. Serum AMH significantly correlated to age (r=-0.38), antral follicle count (AFC) (r=0.68), ovarian volume (r=0.40), FSH (r=-0.31), (P<0.001) and cycle length (r=0.26, P=0.004). Serum AMH median (interquartile range; IQR) was 8.5 pmol/l (1.9-15.1) in hyporesponders (one mature follicle) versus 10.7 (7.3-17.3) in normal responders (2-3 follicles, with a maximum of two follicles 18 mm and no need for dose reduction) and 13.4 (4.4-24.2) in hyperresponders (>2-3 mature follicles or dose reduction). There was a significant trend over response groups for body weight (P=0.005), body mass index (P=0.035), AFC (P=0.031) and FSH (P=0.001). Serum AMH median (IQR) was 10.6 pmol/l (6.9-18.2) in the 23 patients who achieved an ongoing pregnancy versus 10.5 (5.9-17.2) in the 100 non-pregnant women. Serum AMH may not be the best marker of the ovarian response in these patients.

Cross border reproductive care in six European countries.

BACKGROUND: The quantity and the reasons for seeking cross border reproductive care are unknown. The present article provides a picture of this activity in six selected European countries receiving patients. METHODS: Data were collected from 46 ART centres, participating voluntarily in six European countries receiving cross border patients. All treated patients treated in these centres during one calendar month filled out an individual questionnaire containing their major socio-demographic characteristics, the treatment sought and their reasons for seeking treatment outside their country of residence. RESULTS: In total, 1230 forms were obtained from the six countries: 29.7% from Belgium, 20.5% from Czech Republic, 12.5% from Denmark, 5.3% from Slovenia, 15.7% from Spain and 16.3% from Switzerland. Patients originated from 49 different countries. Among the cross border patients participating, almost two-thirds came from four countries: Italy (31.8%), Germany (14.4%), The Netherlands (12.1%) and France (8.7%). The mean age of the participants was 37.3 years for all countries (range 21-51 years), 69.9% were married and 90% were heterosexual. Their reasons for crossing international borders for treatment varied by countries of origin: legal reasons were predominant for patients travelling from Italy (70.6%), Germany (80.2%), France (64.5%), Norway (71.6%) and Sweden (56.6%). Better access to treatment than in country of origin was more often noted for UK patients (34.0%) than for other nationalities. Quality was an important factor for patients from most countries. CONCLUSIONS: The cross border phenomenon is now well entrenched. The data show that many patients travel to evade restrictive legislation in their own country, and that support from their home health providers is variable. There may be a need for professional societies to establish standards for cross border reproductive care.

Predictors of ovarian response in intrauterine insemination patients and development of a dosage nomogram.

The objective of this prospective study was to identify predictors of ovarian response in ovulatory patients treated with low-dose recombinant FSH (rFSH), gonadotrophin-releasing hormone antagonist and intrauterine insemination (IUI), and to develop an rFSH dosage nomogram based on the findings. Patients (n = 159) were stimulated with a starting dose of 75 IU rFSH/day. Ten parameters were investigated as possible predictors of the number of mature follicles >or=15 mm: age, spontaneous cycle length, body weight, body mass index, smoking status, total ovarian volume, total number of antral follicles, total Doppler score of the ovarian stromal blood flow, baseline FSH and oestradiol. Simple and multiple linear regressions were used for the statistical analysis. Appropriate ovarian response was defined as two to three mature follicles. Body weight (P = 0.001) and the number of antral follicles (P = 0.004) were the strongest independent predictive factors of the number of mature follicles. In conclusion, body weight and antral follicle count may be used to achieve appropriate ovarian response for IUI in ovulatory patients. Based on this, a simple rFSH dosage nomogram was developed for individual ovarian stimulation prior to IUI.

Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial.

BACKGROUND: Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top-quality embryos after IVF/ICSI. METHODS: Patients were randomized to androgen priming (n = 53): anastrozole 1 mg cycle day (c.d.) 2, 3 and 4, hCG 1250 IU and cetrorelix 3 mg on c.d. 2, rFSH 150 IU from c.d. 5 following a flexible antagonist protocol; or control (n = 50): flexible antagonist protocol. RESULTS: The mean (confidence interval) number of top-quality embryos was 1.08 (0.83,1.40) and 1.43 (1.12,1.81) in the priming and control group, respectively, being 32% (-7%, 89%) higher in the control compared to priming group (P = 0.120). Stimulation duration was longer in the priming group (P < 0.001). On the day of hCG administration, the proportion of c.d. 2 antral follicles reaching >or=14 mm was higher in the priming group (P = 0.014), as were serum estradiol (E(2)) (P < 0.001) and E(2) per follicle >or=14 mm (P = 0.005). Pre-ovulatory follicular fluid levels of E(2) (P = 0.007) and testosterone (P = 0.014) were higher in the priming group. The number of oocytes retrieved was similar. The fertilization rate was lower in the priming group (P = 0.007). Ongoing pregnancy rates in priming and control group were 30 and 36% (P = 0.531). CONCLUSIONS: Administration of aromatase inhibitor and hCG before COS for IVF/ICSI failed to improve the number of top-quality embryos.

Sons conceived by assisted reproduction techniques inherit deletions in the azoospermia factor (AZF) region of the Y chromosome and the DAZ gene copy number.

BACKGROUND: Deletions in the azoospermia factor (AZF) region of the Y chromosome are frequent in infertile men. The clinical consequences and the mode of inheritance of these deletions are not yet clear. METHODS: Y chromosome deletion mapping and quantitative PCR analysis of the DAZ-gene copy number, supplemented with haplogroup typing in deleted patients, were performed, in combination with clinical assessments in 264 fathers and their sons conceived by assisted reproduction techniques (ART), and in 168 fertile men with normal sperm concentration. RESULTS: In the ART fathers group, a complete AZFc deletion was detected in 0.4% (1/264). AZFc rearrangements/polymorphisms were found in 6.8% (18/264; 95% CI: 4.4-10.5), which was significantly more frequent (P = 0.021) than in the controls (3/168; 1.8%, 95% CI: 0.6-5.1). All deletions were transmitted to the sons, without any clinical symptoms in early childhood. In the fathers, there was no significant correlation between the DAZ copy number and the severity of spermatogenic failure. CONCLUSIONS: AZFc rearrangements/polymorphisms are transmitted to sons and may represent a risk factor for decreased testis function and male subfertility, which needs confirmation in further studies in larger cohorts. However, deletions of two DAZ gene copies are compatible with normal spermatogenesis and fertility.

Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE.

BACKGROUND: European results of assisted reproductive techniques from treatments initiated during 2004 are presented in this eighth report. METHODS: Data were mainly collected from existing national registers. From 29 countries, 785 clinics reported 367,066 treatment cycles including: IVF (114,672), ICSI (167,192), frozen embryo replacement (FER, 71,997), egg donation (ED, 10 334), preimplantation genetic diagnosis/screening (PGD/PGS, 2701) and in vitro maturation (IVM, 170). Overall, this represents only a marginal increase since 2003, due to a huge reduction in treatments in Germany. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 20 countries. A total of 115,980 cycles (IUI-H, 98,388; IUI-D, 17,592) were included. RESULTS: In 14 countries where all clinics reported to the IVF register, a total of 248,937 ART cycles were performed in a population of 261.6 million, corresponding to 1095 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.6% and 30.1%, respectively. For ICSI, the corresponding rates were 27.1% and 29.8%. After IUI-H, the clinical pregnancy rate was 12.6% in women below 40. After IVF and ICSI, the distribution of transfer of 1, 2, 3 and 4 or more embryos was 19.2%, 55.3%, 22.1% and 3.3%, respectively. Compared with 2003, fewer embryos were transferred, but huge differences still existed between countries. The distribution of singleton, twin and triplet deliveries after IVF and ICSI combined was 77.2%, 21.7% and 1.0%, respectively. This gives a total multiple delivery rate of 22.7% compared with 23.1% in 2003 and 24.5% in 2002. After IUI-H in women below 40 years of age, 11.9% were twin and 1.3% triplet gestations. CONCLUSIONS: Compared with earlier years, the reported number of ART cycles in Europe increased and the pregnancy rates increased marginally, even though fewer embryos were transferred and the multiple delivery rates were reduced.

Assisted reproductive technology in Europe, 2003. Results generated from European registers by ESHRE.

BACKGROUND: European results of assisted reproductive techniques (ARTs) from treatments initiated during 2003 are presented in this seventh report. METHODS: Data were mainly collected from already existing national registers. From 28 countries, 725 clinics reported 365 103 treatment cycles with: IVF 132 932, ICSI 162 149, frozen embryo replacement (FER) 60 412, oocyte donation (OD) 7548, PGD/PGS 1956 and IVM 109. Overall, this represents a 13% increase since 2002. For the third time, results on European data on intrauterine inseminations (IUIs) were reported from 19 countries. A total of 99 577 cycles (IUI-H, 82 834; IUI-D, 16 743) were included. RESULTS: In those 15 countries where all clinics reported to the register, a total of 284 765 cycles were performed in a population of 278.7 million, corresponding to 1022 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.1 and 29.6%, respectively. For ICSI, the corresponding rates were 26.5 and 28.7%. After IUI-H, the clinical pregnancy rate was 12.2% in women below 40 years and 8.8% in women > or =40 years. After IVF and ICSI, the distribution of transfer of one, two, three and four or more embryos was 15.7, 55.9, 24.9 and 3.5%, respectively. Compared to the year 2002, fewer embryos were transferred, but huge differences still exist between countries. The distribution of singleton, twin and triplet deliveries for IVF and ICSI combined was 76.7, 22.0 and 1.1%, respectively. This gives a total multiple delivery rate of 23.1% compared with 24.5% in 2002. The range of triplet deliveries after IVF and ICSI varied from 0.0 to 4.4% between countries. After IUI-H in women below 40 years of age, 11.4% were twin and 2.2% triplet gestations.