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RESEARCH QUESTION: How do cumulative live birth rates (CLBR), cumulative multiple live birth rates (CMLBR) and dropout rates over six IVF and intracytoplasmic sperm injection (ICSI) cycles change over time? DESIGN: Prospective longitudinal cohort (n = 16,073 patients; 48,946 cycles) starting a first fresh assisted reproductive technology cycle between 1 January 2014 and 31 December 2016, with follow-up until 31 December 2017. Outcomes between the periods 2014-2017 and 2009-2012 were compared. RESULTS: Conservative estimates of CLBR after six complete cycles were significantly higher in women younger than 35 years after every cycle: one to three, adjusted P-value [p adj] < 0.0001; four, p = 0.01; five, p adj = 0.03; six, p adj = 0.04) and after the first cycle in women aged 35-37 years (p adj = 0.04) in 2014-2017 versus 2009-2012. For an optimal estimate, the CLBR was significantly higher after the first three cycles in women younger than 35 years (all p adj < 0.0001) and after the first cycle in women aged 35-37 years (p adj = 0.04). The CMLBR rate decreased from 5.1% ± 0.19 (SE) to 4.1% ± 0.16 for the conservative estimate and from 8.6% ±0.37 (SE) to 6.7% ± 0.30 for the optimal estimate after six complete cycles for the whole cohort. Dropout rates of complete cycles were 26.5% 29.4%, 33.4%, 38.9% and 47.3% after the first to fifth cycle, respectively. Compared with 2009-2012, the dropout rate in the current period was significantly higher for the first (P < 0.0001) and second (P = 0.0124) cycle. CONCLUSION: Over six complete IVF/ICSI cycles, CLBR and dropout rates increased and multiple live birth rates decreased when 2014-2017 was compared with 2009-2012. ispartof: REPRODUCTIVE BIOMEDICINE ONLINE vol:42 issue:4 pages:717-724 ispartof: location:Netherlands status: published

Research question The objective of this investigation was to determine the daily follitropin delta dose (µg) providing a similar ovarian response to 150 IU/day follitropin alfa. Design The study was a post-hoc analysis of ovarian response in 1591 IVF/intracytoplasmic sperm injection (ICSI) patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol in two recent randomized, assessor-blind, controlled trials in the development programme for follitropin delta: a phase II dose–response trial with a reference arm of a fixed daily dose of 150 IU follitropin alfa throughout stimulation, and a phase III efficacy trial with a comparator arm of 150 IU/day follitropin alfa as a starting dose. Results Daily follitropin delta doses of 10.0 µg (95% confidence interval [CI] 7.9–12.8) and 10.3 µg (95% CI 9.7–10.8) yielded the same number of oocytes as 150 IU/day follitropin alfa for all patients participating in the phase II and III trials, respectively. When analysing patients with either normal or high ovarian reserve (based on serum anti-Mullerian hormone ≥15 pmol/l) and no dose changes, the same number of oocytes was obtained with 150 IU/day follitropin alfa and daily doses of follitropin delta of 9.7 µg (95% CI 7.5–12.4) and 9.3 µg (95% CI 8.6–10.1) in the two trials. Daily follitropin delta doses in the range 9.5–10.4 µg were consistently estimated to correspond to 150 IU/day follitropin alfa for serum oestradiol concentration and number of follicles ≥12 mm at the end of stimulation across analysis populations in the phase III trial. Conclusions A daily follitropin delta dose of 10 µg provides a similar ovarian response to 150 IU/day follitropin alfa in IVF/ICSI patients.

Studies comparing risk of specific congenital malformations (CM) between multiple pregnancies resulting from IVF/intracytoplasmic sperm injection (ICSI) and those conceived naturally report conflicting results; furthermore, there is a lack of a complete overview. This meta-analysis aimed to address which types of CM are increased in IVF/ICSI multiple pregnancies compared with those conceived naturally. All studies testing the association between IVF/ICSI multiple pregnancies and specific CM identified in various databases were considered. The literature search yielded 856 records, of which 21 cohort studies were included for analysis. Overall, multiple pregnancies achieved with IVF/ICSI experienced a significantly higher risk of chromosomal defects (relative risk [RR] = 1.36; 95% confidence interval [CI]: 1.04-1.77), urogenital (RR = 1.18; 95% CI: 1.03-1.36) and circulatory (RR = 1.22; 95% CI: 1.01-1.47) system malformations. However, the remaining specific CM, such as cleft lip and/or palate, eye, ear, face and neck, respiratory, musculoskeletal, nervous and digestive system malformations, were similar in the two groups. No substantial heterogeneity was observed for most outcomes except for digestive (P = 0.094; I2 = 38.3%) and circulatory (P = 0.070; I2 = 35.2%) system malformations. These findings provide additional information on risks of IVF/ICSI for use when counselling patients.

This study explored the correlation between serum anti-Mullerian hormone (AMH) concentration and the number of retrieved oocytes after ovarian stimulation in Chinese infertile women undergoing assisted reproductive technology treatment and AMH cut-off values predicting low and high ovarian response. This was a prospective, multi-centre, observational study. A total of 615 subjects were included in nine assisted reproductive centres in China for outcome analysis. Subjects received assisted reproductive technology treatment and used recombinant human FSH (r-HFSH) or r-HFSH plus recombinant LH (rLH) for ovarian stimulation according to conventional treatment regimens. The main outcome variables were correlations between AMH and the number of retrieved oocytes and the cut-off values of AMH predicting low and high ovarian response. Serum AMH concentration was positively correlated with the number of oocytes retrieved in Chinese infertile women treated with IVF/intracytoplasmic sperm injection (ICSI) (Pearson correlation coefficient = 0.4754, P < 0.0001). The optimal AMH cut-off value was 2.6 ng/ml (sensitivity: 81.28%, specificity: 59.51%) in predicting high and normal response, and 1.1 ng/ml (sensitivity: 52.27%, specificity: 87.23%) in predicting low and normal response. In conclusion, serum AMH concentration can be used as a biomarker to predict ovarian response in Chinese infertile women treated with assisted reproductive technology.

This retrospective study assessed the predictive value of endometrial thickness (EMT) on HCG administration day for the clinical outcome of fresh IVF and intracytoplasmic sperm injection (ICSI) cycles. A total of 8690 consecutive women undergoing 10,787 cycles over a 5-year period were included. The 5th, 50th and 95th centiles for EMT were determined as 8, 11 and 15 mm, respectively. Group analysis according to these centiles (Group 1:8 mm; Group 2: ≥ 8 and ≤11 mm; Group 3:11 and ≤15 mm; Group 4:15 mm) demonstrated significant differences (P0.001) in clinical pregnancy rates (23.0%, 37.2%, 46.2% and 53.3%, respectively), live birth rates per clinical pregnancy (63.3%, 72.0%, 78.1% and 80.3%, respectively), spontaneous abortion rates (26.7%, 23.8%, 19.9% and 17.5%, respectively), and ectopic pregnancy rates (10.0%, 4.3%, 2.1% and 2.2%, respectively). Logistic regression analyses showed EMT as one of the independent variables predictive of clinical pregnancy (OR = 1.097; P0.001), live birth (OR = 1.078; P0.001), spontaneous abortion (OR = 0.948; P0.001), and ectopic pregnancy (OR = 0.851; P0.001). Future research should aim to understand the underlying mechanisms relating EMT to conception, ectopic implantation and spontaneous abortion.

The aim of this prospective, randomized clinical trial (RCT) was to evaluate whether the supplemental protein concentration in embryo transfer (ET) medium affects the clinical outcomes in IVF-ET. A total of 750 patients undergoing IVF-ET who met the inclusion criteria were randomly divided into three groups, according to the concentration of synthetic serum substitute (SSS) in ET medium as follows: 10% (Group A), 20% (Group B) and 50% (Group C). The patient characteristics and embryology data were all similar among the groups. The rates of implantation, clinical pregnancy and live birth were compared. Clinical pregnancy (44.61%, 48.79% and 45.49%), multiple pregnancy (24.18%, 28.71% and 25.0%), implantation (28.21%, 30.68% and 29.86%) and live birth (41.67%, 43.96% and 41.70%) rates in the three groups (A, B and C, respectively) showed no significant differences. This RCT demonstrates that supplemental protein concentration in the ET medium does not affect the treatment outcomes in IVF-ET. There was no statistical evidence to support the hypothesis that supplemental protein concentration in the ET medium influences treatment outcomes in IVF-ET.

Scheduling gonadotrophin-releasing hormone antagonist (GnRH-ant) cycles for IVF intracytoplasmic sperm injection in patients is a challenge because of unpredictable ovum retrieval procedures on weekends, when less manpower is available. Recently, the use of GnRH-ant pre-treatment to delay an IVF and intracytoplasmic sperm injection (ICSI) cycle showed no negative effect on clinical pregnancy rates. An age-matched, case-control study was conducted to evaluate the effectiveness of such pre-treatment for scheduling purposes. Patients (n = 140) undergoing their first ovarian stimulation for IVF-ICSI were included. Patients starting their stimulation on Tuesdays or Wednesdays were most likely to have their ovum retrieval procedure on Saturdays. Seventy patients received a 3-day course of GnRH-ant before starting stimulation, and were compared with 70 age-matched controls not receiving pre-treatment. The main outcomes were the proportion of ovum retrieval procedures occurring on Saturdays, clinical pregnancy rate and live birth rates. A five-fold reduction in the number of ovum retrievals occurred on Saturdays compared with controls (7.1% versus 34.3%; OR 0.15; 95% CI 0.05 to 0.42; P0.001), with no significant differences in clinical pregnancy rate (40.9% versus 37.5%) and live birth rate (27.3% versus 31.3%). GnRH-ant pre-treatment is an effective tool for scheduling of GnRH-ant cycles.

Information regarding the growth and development of endometriomas during IVF–intracytoplasmic sperm injection (ICSI) cycles is lacking. In this study, the aim was to estimate the influence of IVF–ICSI on the dimension of these cysts and to assess whether this treatment contributes to the manifestation of new endometriomas in patients already affected. Women were eligible if they had been diagnosed with ovarian endometrioma(s). Recruited patients who failed to become pregnant were scanned again 3–6 months later to evaluate the modification of the dimension of the cysts and/or the manifestation of new endometriomas. Forty-eight women completed the study protocol. The median (interquartile range) values for the volume of the cysts before and after the IVF-ICSI cycle were 3.9 (2.9–7.9) ml and 4.9 (2.4–9.9) ml, respectively (Wilcoxon rank test for paired data, not significant). The development of a new endometrioma was documented in one case (2.1%, 95% confidence interval 0.1–11.1%). Fear about the growth of ovarian endometriomas in women who have to undergo IVF–ICSI is not justified.

In this retrospective cohort study, the effect of endometrial polypectomy carried out on the day of oocyte retrieval and on the first day of ovarian stimulation in patients with a large (≥10 mm) endometrial polyp undergoing IVF and intractyoplasmic sperm injection (ICSI) was investigated and compared. A total of 74 eligible IVF-ICSI cycles in 74 women who underwent endometrial polypectomy on either the day of oocyte pick-up (late polypectomy group, 39 cycles) or the first day of ovarian stimulation (early polypectomy group, 35 cycles) between January 2007 and July 2012 were included in this study. Patient characteristics between early and late polypectomy groups were similar. Total dose and days of recombinant human FSH administered, numbers of retrieved oocytes, mature oocytes, fertilized oocytes, grade 1 or 2 embryos and embryos transferred between the two groups were also similar, as was clinical pregnancy rate per cycle, embryo implantation rate and spontaneous abortion rate between the two groups. Therefore, endometrial polypectomy on the day of oocyte retrieval could be a more patient-friendly option for patients with a large endometrial polyp undergoing IVF-ICSI.

Single embryo transfer is becoming increasingly popular in IVF/ICSI. More IVF/ICSI cycles therefore include freezing of high quality embryos, and the cumulative effect of such cycles becomes more important. To improve the results obtained using frozen–thawed embryos, the predictive value of embryo and patient characteristics was analysed retrospectively. Excess embryos were frozen on day 2 according to routine procedures and thawed 24 h before transfer. The women were either treated with oestradiol/progesterone, or the transfer took place after a natural cycle. Of 1777 embryos thawed, 1360 survived (survival rate 76.5%). In the 410 transfer cycles, 819 embryos were transferred, giving 109 positive serum HCG tests and 69 clinical pregnancies. The implantation rate was 10.4%. Five parameters were positively related to implantation: (i) four or more cells at the freezing time (day 2); (ii) resumption of mitosis after thawing; (iii) more than six cells at transfer (day 3); (iv) assisted hatching and (v) child in a previous fresh cycle. The relative predictive value of these parameters may be a guideline for the selection of embryos used for transfer. Assisted hatching may become routine in freeze–thaw cycles if its utility is confi rmed in subsequent studies.

This retrospective cohort study analyses experience with single embryo transfer (SET) in an lVF/intracytoplasmic sperm injection (ICSI) programme over a 3-year period (1998-2000): 1143 IVF/ICSI cycles were initiated, resulting in 1073 embryo transfers (93.9%). In 810 (75.4%) transfers of two (n = 580; 54%) or more than two (n = 230; 21.4%) embryos, 279 ongoing pregnancies (34.4%) were obtained. In total, there were 263 SET (24.5%): 207 of a single top quality embryo, resulting in 102 conceptions (49.3%) with 71 ongoing implantations (34.3%, one monozygotic twin); and 56 of a single non-top quality embryo, resulting in 16 conceptions (28.6%) with 11 ongoing implantations (19 .6% ). The percentage of transfers of a single top quality embryo gradually increased from 10% (1998) to 19% (1999) to 26% (2000). The total multiple pregnancy rate decreased from 34% (1998), to 32% ( 1999) and 22% (2000), without affecting the overall ongoing pregnancy rate per transfer: 38% in 1998; 29% in 1999; and 34% in 2000. The average number of transferred embryos decreased from 2.26 ( 1998) to 1.86 (2000). Transfer of a single, strictly defined top quality day 3 embryo in twin-prone IVF/ICSI patients reduced the multiple/twin-pregnancy rate but not the overall pregnancy rate.

This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) in poor ovarian responders fulfilling the Bologna criteria for poor ovarian response and identified predictors of live birth rates. Overall, 485 patients undergoing 823 ovarian stimulation cycles for IVF/ICSI with maximum gonadotrophin dose (≥ 300 IU) between January 2009 and December 2011 were included. Patients were considered eligible, irrespective of the treatment protocol, if they were classified as poor responders based on the recently developed definition for poor ovarian response by the European Society of Human Reproduction and Embryology, the Bologna criteria. Live birth rates did not significantly differ between women aged40 and women aged ≥ 40 years either per cycle (7.1 versus 5.2%, OR 1.38, 95% CI 0.77-2.46) or per patient (11.6 versus 8.8%, OR 1.36, 95% CI 0.75-2.46). In logistic regression analysis, the number of oocytes retrieved was the only variable significantly associated with live births (OR 1.92, 95% CI 1.03-3.55 for3 versus 1-3 oocytes). Bologna poor responders demonstrate very low live birth rates, irrespective of age and treatment protocol used. An increase in the number of oocytes retrieved is an independent variable related to live birth rates.

This retrospective cohort study determined whether the total falls in serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection could predict clinical outcomes. Ninety-nine cycles, with gonadotrophin-releasing hormone-agonist down-regulation where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of severe ovarian hyperstimulation syndrome, were consecutively included. The primary clinical outcome was live-birth rate (LBR); other outcomes measured were number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates. LBR for FSH fall10 IU/l compared with 5-10 and5 IU/l were 45.4% versus 22.0% and 25.0%, respectively. Mean serum FSH fall was similar with and without live birth (8.4 ± 6.2 versus 7.3 ± 5.0 IU/l) as were mean oestradiol and FSH concentrations on HCG administration, oestradiol fall, percentage fall in FSH/oestradiol and duration of coasting. None of the variables efficiently predicted live birth on regression analysis. The AUC of FSH fall was 0.53 at 11.0 IU/l. Basal FSH, starting and total gonadotrophin dose and duration of coasting were positively correlated with FSH fall. A potentially clinically important association between live birth and FSH fall during coasting was apparent, which requires further evaluation. The purpose of this retrospective cohort study was to determine whether the magnitude of fall in the serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection cycles could predict the clinical outcomes. Gonadotrophin-releasing hormone-agonist down-regulated cycles (n=99), where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of ovarian hyperstimulation, were consecutively included. Live birth was the primary clinical outcome measured; number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates were the other outcomes examined. Live-birth rate tended to be high when FSH fall was10 IU/l, compared with 5-10 IU/l and5 IU/l, although not statistically significantly. Mean serum FSH fall were similar in live-birth and no-live-birth cycles (8.4 ± 6.2 versus 7.3 ± 5.0) as were mean oestradiol and FSH concentrations on hCG administration, oestradiol fall, percentage fall in FSH and oestradiol and duration of coasting. None of the variables efficiently predicted live birth. The area under the curve of FSH fall was 0.53. FSH fall of11.0 IU/l was found to be more likely to predict negative outcome (specificity 84.72%) than predicting positive outcome when FSH fall was11 IU/l (sensitivity 34.48%). Women's basal FSH, starting and total gonadotrophin dose of ovarian stimulation and duration of coasting had direct positive correlation with the magnitude of FSH fall. A potentially clinically important rise in live birth in association with greater FSH fall during coasting was apparent, which requires further evaluation.

International audience; Several reports have described an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success. However, not all studies agree with these findings. To further document this debate, a multicentre blinded study was performed to investigate, on a large number of IVF ES and ICSI ES, whether sHLA-G is a useful criterion for embryo selection before transfer. A total of 1405 ES from 355 patients were collected from three assisted reproductive technique (ART) centres and evaluated for their sHLA-G content in a single laboratory, using a chemiluminescence enzyme-linked immunosorbent assay. In only one centre was a significant association between sHLA-G-positive ES and successful implantation established (P = 0.0379), whereas no such association was observed in the other centres. It was found that the percentages and concentrations of sHLA-G-positive ES varied between centres, depending on culture media and ART conditions. The percentage of sHLA-G-positive ES was significantly higher in IVF ES than ICSI ES (P < 0.001 and P < 0.01 for two centres). These data demonstrate that substantial variations of sHLA-G content in ES occur between different ART centres, highlighting the influence of several technical parameters that differ from one centre to another.

First-trimester serum markers in 110 in-vitro fertilization (IVF) and 331 intracytoplasmatic sperm injection (ICSI) pregnancies were compared with 1431 pregnancies with spontaneous conception. Alterations of serum markers were evaluated with respect to small-for-gestational-age (SGA) growth and number of embryos transferred. For pregnancy-associated plasma protein A (PAPP-A), significantly lower concentrations were observed in IVF and ICSI pregnancies compared with controls (0.86 and 0.9 versus 1.06; P < 0.001). Free β-human chorionic gonadotrophin (βHCG) values were significantly higher in the IVF/ICSI groups than in controls (1.1 and 1.1 versus 0.94; P < 0.005). IVF and ICSI pregnancies showed higher rates of SGA (10.0% and 8.2%) compared with natural conception (4.6%), but differences in PAPP-A concentrations remained significant (P < 0.005) after the exclusion of SGA pregnancies. No relationship between serum values and the transfer of one, two or three embryos was observed. Centre-specific corrections may be needed to adjust screening parameters for assisted reproductive technology.