Search

STUDY QUESTION Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER Serum P levels WHAT IS KNOWN ALREADY We previously found that serum P levels STUDY DESIGN, SIZE, DURATION This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE Women with serum P levels LIMITATIONS, REASONS FOR CAUTION Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03272412.

Study question Is postponing the start of ART (to promote a reduction in female BMI) beneficial for cumulative live birth rates (CLBR) when accounting for the female/male ageing this delay will cause? Summary answer Postponing ART treatment in one year to promote female weight loss could be detrimental in women of advanced maternal age (AMA, >35 years-old). What is known already Overweight/obese couples are frequently encouraged to lose weight prior to infertility treatment to enhance ART outcomes. However, a meaningful weight loss is often difficult to achieve for these couples, frequently taking at least one year to accomplish. Given that both female and male ageing are also important for ART success, we were interested in understanding the combined impact on CLBR of BMI reduction and ageing following a one-year delay. Study design, size, duration A retrospective study including patients performing their first ART cycle using autologous gametes between 2013–2018 in one of 39 participating ART centres. Only GnRH antagonist cycles were included (n = 14260). CLBR was the primary outcome. Secondary outcomes included time-to-pregnancy, birthweight and gestational age. Participants/materials, setting, methods Patients were subdivided according to female BMI (Kg/m2) in either underweight ( Main results and the role of chance Overweight (36.8%) and obese (33.0%) women had significantly lower CLBR when compared to the underweight (42.6%) and normal-weight (41.4%). When assessing the confounder-adjusted net-effect of male/female age and BMI, the predicted benefit of promoting a meaningful BMI reduction was lower than the estimated hindrance due to male/female ageing as soon as women reached AMA (n = 8365, 58.6%). This absence of benefit was especially important in women >38 years-old, in which even extreme weight-loss did not compensate for the age-related reduction in CLBR caused by the one-year delay. Moreover, male weight-loss failed to provide any additional benefit when accounted for in the regression models. Finally, obesity was also associated with a modest but statistically significant one-month delay in time-to-pregnancy and a 96.1 g (95% confidence interval: 39.9–152.4) increase in birth weight. The diagram of predicted outcomes presented in this study may serve as a useful tool to counsel patients before treatment, namely when recommending treatment postponement to promote short-term (i.e. 3–6 months) or long-term (i.e. 1 year) weight loss. Limitations, reasons for caution Caution is recommended when extrapolating these results into everyday practice owing to the retrospective nature of the study and the fact that only GnRH antagonist cycles were included. Wider implications of the findings: Patients are frequently confronted with the dilemma to either postpone treatment (and promote weight loss) or start treatment immediately (to avoid further ageing). Our results seem to show that women in AMA may have hindered CLBR if recommended to delay treatment even if the desired weight loss is ultimately achieved. Trial registration number Not applicable

Study question Are there any proteomic differences between receptive (R) and non-receptive (NR) endometrial receptivity array (ERA)-diagnosed endometria obtained on the same day of a hormonal replacement therapy (HRT) treatment cycle? Summary answer There is a different proteomic signature between R and NR ERA-diagnosed endometrium obtained on the same day of HRT cycles. What is known already The human endometrial transcriptome has been extensively investigated in the last decade resulting in the development of a new diagnostic test based on the transcriptomic signature of the window of implantation (WOI). Much less is known about the proteomics derived from the transcripts present during the WOI. Study design, size, and duration This study was a basic proteomic analysis of human endometrial biopsies taken from twelve IVF patients. Participants/materials, setting, and methods Human endometrial biopsies were collected during HRT cycles after 5 days of progesterone (P) administration, and diagnosed as receptive (R; n = 6) or non-receptive (NR; n = 6) by the ERA test. Endometrial proteins were extracted, labelled and separated using differential in-gel electrophoresis (DIGE). Proteins were identified using mass spectrometry, followed up by in silico analysis. Validation studies using western blots and immunolocalization were performed for the progesterone receptor membrane component 1 (PGRMC1) and annexin A6 (ANXA6) proteins. Main results and the role of chance DIGE analysis followed by protein identification by MALDI-MS and database searches revealed 24 differentially expressed proteins in R versus NR samples. In silico analysis showed two pathways which were significantly different between R and NR samples. Expression of PGRMC1 and ANXA6 was validated and localized by western blots and immunohistochemistry. These results highlight these proteins as key targets likely to be important in the comprehension of human endometrial receptivity. Limitations, reasons for caution This was mainly a descriptive study with no functional studies on the proteins found. We also used a low number of human endometrial samples for the DIGE analysis. Wider implications of the findings This study identified the proteomic profile associated with receptive or non-receptive human endometria. Our findings suggest that although histological dating indicates a putative 'receptive' status within the WOI, a different transcriptomic and proteomic profile is observed in these samples. We should move towards using more personalized WOIs, where identification of the correct endometrial receptivity status, and consequently the success of IVF, relies on individual molecular signatures rather than traditional endometrial dating. Study funding/competing interests F.D.'s participation in this work was supported by the Spanish Ministry of Economy and Competitiveness, through the Miguel Servet Programme (CP13/00075) co-founded by FEDER. The project was also supported by a grant from the Spanish Ministry of Economy and Competitiveness, through the FIS Programme (PI12/00450). The authors have no financial/commercial conflicts of interest to declare.

Endometrial scratching or injury was first suggested a decade ago as a simple intervention to improve endometrial receptivity in patients undergoing ART. More than a decade later, based on weak evidence some doctors have adopted this strategy, although there is not yet agreement about its real benefit. In this opinion paper, we analyze the methodological and plausibility problem beneath 'the Scratching Case'. This is also applicable to several other examples of spurious associations reported in the literature. In particular, we emphasize what should be done so as not to dilute evidence-based medicine by a vicious circle created by the over-exploitation of inadequate or insufficient data to compute incorrect or incomplete conclusions.

Background Ovarian hyperstimulation syndrome (OHSS) is a result of ovarian overexpression of vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR2). VEGF/VEGFR2 binding disrupts cellular junctions and increases vascular permeability (VP), a characteristic of OHSS, but enhances angiogenesis, which is a fundamental step in implantation. In animals, the dopamine agonist Cabergoline (Cb2) prevents VP without affecting angiogenesis. In humans, Cb2 averts OHSS, but a possible detrimental effect on angiogenesis and implantation has not been explored. A pilot study was designed to analyze whether or not Cb2 administration, as a procedure for preventing OHSS, affects the outcome of assisted reproduction treatment (ART). Methods A retrospective study with endpoints of implantation and ongoing/term pregnancy rates. Women (n = 35) at risk of OHSS (20-30 follicles developed and >20 oocytes collected) took a daily oral dose of 0.5 mg Cb2 for 8 days, beginning on the day of hCG. They were matched with controls treated during the same period and who were similar with respect to age, number and quality of the embryos replaced, embryonic stage at transfer and sperm quality. Results No difference was detected between the groups in fertilization, implantation or pregnancy rates. A total of 14 ongoing (beyond 32 weeks) or full term pregnancies were registered in each group. No major problem was detected during pregnancy or after delivery in any of these babies. Conclusions Administration of Cb2 in order to prevent OHSS is safe and does not appear to affect ART outcome.

BACKGROUND: Serum biochemical markers [free betahCG (fbetahCG); pregnancy-associated plasma protein-A (PAPP-A)] used in first trimester Down's syndrome screening have not been fully investigated in pregnancies achieved by assisted reproduction techniques. We present data on pregnancies conceived by all types of assisted reproduction techniques, including pregnancies following ovum donation (OD) and a large sample by ICSI. METHODS: First trimester Down's syndrome screening was performed in 1054 normal singleton pregnancies: natural conception (n = 498), ovulation induction (OS, n = 97), IVF (n = 47), ICSI (n = 222) and OD (n = 190). RESULTS: No differences in maternal levels of fbetahCG and PAPP-A, measured by the Kryptor system, appeared between naturally conceived pregnancies (n = 498) and those obtained with assisted reproduction techniques (n = 556). Several differences were apparent when comparing fbetahCG levels between different technologies but PAPP-A levels only differed between OS and IVF pregnancies (P < 0.05). In a further small study, no differences were observed using frozen embryos (n = 37), preimplantation genetic diagnosis (n = 53) or sperm from testicular biopsy (n = 21). CONCLUSIONS: Data accumulated so far suggest that first trimester biochemical markers either do not need any adjustments (e.g. in pregnancies obtained after OS and ICSI), or have very little impact (e.g. IVF pregnancies) or no impact (e.g. OD pregnancies) on the false positive rates.

Background Intravenous albumin administration has been described for many years as a debatable, but probably useful preventive measure in ovarian hyperstimulation syndrome (OHSS). The present study details the largest randomized controlled trial to date of albumin infusion versus no treatment in IVF patients with a high risk of developing moderate to severe OHSS. Methods Between March 1999 and February 2002, women undergoing IVF at the IVI Valencia with >20 retrieved oocytes were included. A total of 988 patients was initially enrolled. Immediately after oocyte retrieval, patients were allocated to two groups based on a computer randomization: the first group received 40 g human albumin; the second group received no treatment. Subjects were weighed and a blood analysis performed immediately after oocyte retrieval and again 7 days later. Women were monitored on an outpatient basis until menstruation, or until fetal heart activity was detected. Twelve subjects were excluded due to follow-up loss, leaving 976 women (377 of them oocyte donors), with 488 in each group. Results No difference was found between the two groups in terms of patient characteristics and outcome. Moderate-severe and severe-only OHSS rates were similar. The incidence of haemoconcentration and liver and renal dysfunction at 7 days after oocyte retrieval was similar in the two groups. In women who developed moderate/severe (n = 66) or only severe (n = 46) OHSS, there was no difference based on prior albumin administration between blood parameters or body weight on the day of oocyte retrieval, 7 days later, and even when comparing variation between both measurements. Moreover, the number of patients with paracentesis, hospital admissions, complications and days of OHSS until resolution did not differ. Conclusions Albumin infusion on the day of oocyte retrieval is not a useful means of preventing the development of moderate-severe OHSS.