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Thrombophilia is a group of inherited or acquired coagulation disorders that have been associated with reproductive failure. However, there are still no clear recommendations on whether its inclusion in the initial study of the infertile couple or patients with recurrent implantation failure is necessary. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of the repercussions of thrombophilia screening and treatment in reproduction are evaluated. To avoid possible subjectivity in the analysis and results of this study, researchers followed Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed bibliography seem to indicate that, pending new evidence, it would be advisable not to include thrombophilia screening in the initial baseline study of the infertile couple. There is no evidence to support a clear association between thrombophilia and implantation failure or infertility. Thrombophilia testing in this setting may increase cost, with minimal potential benefit and lead to inappropriate use of anticoagulants with possible deleterious adverse effects. Future well-designed studies are needed to assess the possible benefit of anticoagulant therapy in infertile thrombophilic patients with implantation failure.

Chronic endometritis is a pathology often associated with reproductive failure, but there are still no clear recommendations on whether its inclusion in the initial study of infertile couples is necessary. In this discussion paper, based on a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis, the different aspects of the repercussions of chronic endometritis in fertility are evaluated. To avoid possible subjectivity in the analysis and results of this study, the researchers followed the Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed literature seem to indicate that, pending new evidence, it would be advisable not to include chronic endometritis in the initial baseline study before assisted reproduction in order not to delay other assisted reproduction treatments. However, it would be advisable in cases of repetitive implantation failure and pregnancy loss after having undergone IVF with viable embryos and before continuing with costly reproductive processes, since results could be improved. The development of randomized studies assessing the impact of antibiotic treatment as a possible therapeutic option in infertile women with chronic endometritis, as well as the possible impact on endometrial microbiota and receptivity/implantation, would allow for the establishment of more precise clinical guidelines in this regard.

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.

To compare reproductive outcomes of the ROPA method (reception of oocytes from partner) to IVF with autologous oocytes. To study the impact of the absence of a genetic link between the embryo and its recipient in reproductive outcomes.Retrospective multicentric cohort study performed from January 2011 to December 2020 in 18 fertility clinics in Spain. A total of 99 ROPA (73 couples) and 2929 non-ROPA cycles (2334 couples or single patients) of women younger than 38 years old with no known female fertility disorder were included. Clinical outcomes were compared between both groups and included positive pregnancy test, clinical pregnancy, miscarriage, ectopic pregnancy, pre-term birth, live birth, weeks of gestation at birth, and newborn weight at birth.No differences were found between groups in clinical outcomes. The total clinical pregnancy rates per embryo transfer were 57% and 50.2% (p = 0.15) and the live-birth rates were 46.1% and 40.9% (p = 0.14) for the ROPA and non-ROPA groups, respectively. When adjusted to age and BMI of donors and recipients, there were also no differences in live-birth rates between both groups. The cumulative live-birth rate per ROPA cycle was 73.7% and the cumulative live-birth rate per couple was 78.3%.Clinical outcomes following the ROPA method and IVF with autologous oocytes were found to be similar. These findings suggest no impact of the absence of genetic ties between the embryo and the uterus on reproductive treatments' outcomes. Data regarding the outcomes of the ROPA method are reassuring.

Does serum progesterone concentration vary on the day of embryo transfer according to female body mass index (BMI)?Retrospective analysis including 3210 infertile patients undergoing an embryo transfer in the context of an artificial endometrial preparation cycle with sequential administration of oestrogens and micronized vaginal progesterone (MVP) (400 mg/12 h). Serum progesterone was measured on the day of embryo transfer, 6 ± 2 h after last MVP administration. Serum progesterone concentrations were subdivided into optimal (≥9.2 ng/ml) or suboptimal (9.2 ng/ml) concentrations, and the cut-off point was defined according to our previous results. The primary objective was the correlation between progesterone concentrations on the day of embryo transfer and patient BMI, as a continuous variable and according to four ranges (underweight:18.5 kg/mMean serum progesterone concentrations and the ratio of patients with progesterone concentrations above the cut-off point of 9.2 ng/ml fell progressively as BMI increased. Overweight and obese patients had lower mean serum progesterone concentrations than underweight and normal weight women (P0.001). A trend was observed towards impaired reproductive results in obese patients with suboptimal progesterone concentrations, absent when concentrations were optimal.Serum progesterone concentrations on the day of embryo transfer in artificial cycles with MPV decrease as BMI increases. It is highly recommended that serum progesterone concentrations are moitored to ensure optimal concentrations and reproductive outcomes.

Recently, a technique of assisted reproduction was developed to allow lesbian women to share biological motherhood of their offspring - the ROPA method (in Spanish - Recepción de Ovocitos de Pareja; in English - Reception of Partner's Oocytes), also known as lesbian shared in vitro fertilization. One mother provides the oocytes (genetic mother) and the other receives the embryo and gets pregnant (gestational mother). As for most issues related to medically assisted reproduction, this technique raises a lot of ethical questions in respect to patients, future offspring, gametes, and embryos. Furthermore, the fact that it is directed to homosexual women poses its own issues, both biological and social in nature. This is a state-of-the-art review of the main ethical dilemmas related to this technique, primarily focusing on the basic principles of bioethics, but also specific concerns directly related to this kind of treatments.

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

Objective To determine whether female body mass index (BMI) is associated with an increased risk of miscarriage after euploid embryo transfer. Design A retrospective, observational, multicenter cohort study. Setting University-affiliated in vitro fertilization center. Patient(s) In this study, 3,480 cycles of in vitro fertilization with preimplantation genetic testing for aneuploidy (PGT-A) in the blastocyst stage and euploid embryo transfer were divided into four groups according to patient BMI. Intervention(s) In vitro fertilization with PGT-A. Main Outcome Measure(s) The primary outcome was the miscarriage rate, which included both biochemical and clinical miscarriages. Secondary outcomes were implantation, pregnancy, clinical pregnancy, and live birth rates. Result(s) Cycles were divided into four groups according to BMI (kg/m2): underweight ( Conclusion(s) Women with obesity experience a higher rate of miscarriage after euploid embryo transfer than women with a normal weight, suggesting that other mechanisms than aneuploidy are responsible for this outcome.

This issue's of Views and Reviews considers the origins of lifetime health established around the time of conception in some prevalent conditions related to infertility. Reviews will look at the effects of advanced paternal and maternal age, the influence of the severe sperm factor, and the impact of some endocrinopathies commonly seen in infertile couples, especially women, like polycystic ovary syndrome, under- and overweight, diabetes, and thyroid disorders. The aim of this Views and Reviews section is to summarize current evidence on the consequences of these conditions on postnatal health to encourage research in this field and the need to develop strategies and preventative measures to reduce or prevent unfavorable outcomes in future generations.

To investigate whether the morphodynamic characterization of a euploid blastocyst's development allows a higher prediction of a live birth after single-embryo-transfer (SET).Observational cohort study conducted in two phases: training and validation.Private in vitro fertilization centers.Euploid blastocysts: 511 and 319 first vitrified-warmed SETs from 868 and 546 patients undergoing preimplantation genetic testing for aneuploidies (PGT-A) in the training and validation phase, respectively.Data collected from time of polar body extrusion to time of starting blastulation, and trophectoderm and inner-cell-mass static morphology in all embryos cultured in a specific time-lapse incubator with a continuous medium. Logistic regressions conducted to outline the variables showing a statistically significant association with live birth. In the validation phase, these variables were tested in an independent data set.Live births per SET.The average live birth rate (LBR) in the training set was 40% (N = 207/511). Only time of morulation (tM) and trophectoderm quality were outlined as putative predictors of live birth at two IVF centers. In the validation set, the euploid blastocysts characterized by tM80 hours and high-quality trophectoderm resulted in a LBR of 55.2% (n = 37/67), while those with tM ≥ 80 hours and a low-quality trophectoderm resulted in a LBR of 25.5% (N = 13/51).Time of morulation and trophectoderm quality are better predictors of a euploid blastocyst's reproductive competence. Our evidence was reproducible across different centers under specific culture conditions. These data support the crucial role of morulation for embryo development, a stage that involves massive morphologic, cellular, and molecular changes and deserves more investigation.

Parental excess weight and especially pregestational maternal obesity and excessive weight gain during pregnancy have been related to an increased risk of metabolic (obesity, type 2 diabetes, cardiovascular disease, metabolic syndrome) and nonmetabolic (cancer, osteoporosis, asthma, neurologic alterations) diseases in the offspring, probably mediated by epigenetic mechanisms of fetal programming. Maternal underweight is less common in developed societies, but the discrepancy between a poor nutritional environment in utero and a normal or excessive postnatal food supply with rapid growth catch-up appears to be the main candidate mechanism of the development of chronic diseases during the offspring's adulthood. The role of the postnatal environment in both scenarios (parental overweight or underweight) also seems to influence the offspring's health. Lifestyle interventions before and during pregnancy in both parents, but especially in the mother, as well as in children after birth, are advisable to counteract the many undesirable chronic conditions described.

Research question: Does ovarian stimulation for oocyte vitrification affect disease-free survival and overall survival rates in women with early breast cancer? Design: This cohort study included 259 patients with early breast cancer; 148 patients underwent ovarian stimulation, whereas 111 patients did not. Patients were treated between January 2008 and December 2016. To calculate the disease-free survival time and overall survival rate, the time of definitive surgery was defined as the starting point. The follow-up was conducted up to 5 years. Results: Exposed and non-exposed groups were comparable in tumour, node and metastases classification, Nottingham grade, hormonal receptor status, tumour molecular phenotype, histology and pathology stage. The exposed group was younger than the non-exposed. Recurrences occurred in 9/148 women (6.1%) in the exposed group and 15/111 women (13.5%) in the non-exposed group, with no significant difference. The mean disease-free survival time was 63.9 months (95% confidence interval [CI]: 61.5-66.4) in the exposed group and 60.6 months (95% CI: 56.9-64.2) in the non-exposed, with no significant difference (log-rank [Mantel-Cox] test). Overall survival rates were comparable; 2/148 (1.4%) and 4/111 (3.6%) patients died, in exposed and non-exposed groups, respectively, during the period analysed. Mean overall survival times were 67.2 months (95% CI: 66.2-68.2) in the exposed group and 65.9 months (95% CI: 64.0-67.9) in the unexposed, with no significant difference (log-rank [Mantel-Cox] test). Conclusions: This study suggests that ovarian stimulation in patients with early-stage breast cancer is safe in the long term.

Innovations in assisted reproductive technologies (ART) have driven progress in the donor egg field since the birth of the first baby derived from a donor egg in 1983. Over time, donor oocytes have become an increasingly used option for patients unable to conceive with autologous oocytes. In donor egg, the unique separation of the oocyte source and recipient uterus has created a model that has propelled advances in ART. Progressive ART innovations that have optimized the oocyte donor and resulting embryo include the following: evaluation of ovarian reserve, controlled ovarian hyperstimulation regimens that reduce the risk of ovarian hyperstimulation syndrome, blastocyst culture, oocyte cryopreservation, and preimplantation genetic testing. For donor egg recipients, methods to optimize the endometrium to maximize implantation include endometrial receptivity testing, immunologic donor-recipient matching, and increased understanding of the uterine microbiome.

Research question Can gonadotrophin releasing hormone (GnRH) antagonist be used in egg donation recipients with ovulatory cycles for the purpose of achieving synchronization between the donor´s and recipient´s cycle? Design Prospective randomized controlled trial to compare 7-day dosage of GnRH antagonist for endometrial priming in an oocyte donation programme with a single dose of long-acting GnRH agonist. A total of 563 women were randomized in a private single centre, and 473 women underwent embryo transfer. Ongoing pregnancy rate was the primary end point. Analysis was adjusted for embryonic stage at the time of embryo transfer; data collected included days on the waiting list; number of fresh–vitrified oocytes collected; and oocyte donor´s age at the time of retrieval. Results No statistically significant differences were found between groups in per intention-to-treat analysis: adjusted OR 1.42 (CI 0.97 to 2.09); per treatment received: adjusted OR 1.43 (CI 0.97 to 2.09); per embryo transfer: adjusted OR for ongoing pregnancy rate 1.47 (CI 1.01 to 2.13), P = 0.047. Conclusions For women with ovulatory cycles undergoing oocyte donation, the outcomes are similar between GnRH antagonist and down-regulated hormone replacement protocols.

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.

To evaluate the usefulness of preimplantation genetic screening (PGS) using fluorescence in situ hybridization (FISH) for two different indications: repetitive implantation failure (RIF) and advanced maternal age (AMA).Two prospective, randomized controlled trials with patients allocated in two arms: blastocyst transfer on day 5 (group A) or PGS with transfer on day 5 (group B).University-affiliated private clinics.The RIF study included women40 years with three or more failed IVF cycles without other known causal factors (91 patients). The AMA study included intracytoplasmic sperm injection patients aged between 41 and 44 (183 patients).In the PGS group, single-cell day 3 biopsy was performed with aneuploidy screening for chromosomes 13, 15, 16, 17, 18, 21, 22, X, and Y. In both the blastocyst transfer group and the PGS group, ET was performed on day 5.Live-birth rate per patient and per started cycle.A significant increase in live-birth rates per patient was found in the PGS group compared with the blastocyst group for the AMA study (30/93 patients [32.3%] vs. 14/90 patients [15.5%]; odds ratio, 2.585; confidence interval, [1.262-5.295]). In the RIF study no significant differences were observed (23/48 patients [47.9%] vs. 12/43 patients [27.9%]).PGS with FISH was shown to be beneficial for the AMA group.

Objective: To determine the clinical value of preimplantation genetic diagnosis for aneuploidy screening (PGD-A) in women of advanced maternal age (AMA; between 38 and 41 years). Design: This was a multicenter, randomized trial with two arms: a PGD-A group with blastocyst transfer, and a control group with blastocyst transfer without PGD-A. Setting: Private reproductive centers. Patient(s): A total of 326 recruited patients fit the inclusion criteria, and 205 completed the study (100 in the PGD-A group and 105 in the control group). Intervention(s): Day-3 embryo biopsy, array comparative genomic hybridization, blastocyst transfer, and vitrification. Main Outcome Measure(s): Primary outcomes were delivery and live birth rates in the first transfer and cumulative outcome rates. Result(s): The PGD-A group exhibited significantly fewer ETs (68.0% vs. 90.5% for control) and lower miscarriage rates (2.7% vs. 39.0% for control). Delivery rate after the first transfer attempt was significantly higher in the PGD-A group per transfer (52.9% vs 24.2%) and per patient (36.0% vs. 21.9%). No significant differences were observed in the cumulative delivery rates per patient 6 months after closing the study. However, the mean number of ETs needed per live birth was lower in the PGD-A group compared with the control group (1.8 vs. 3.7), as was the time to pregnancy (7.7 vs. 14.9 weeks). Conclusion(s): Preimplantation genetic diagnosis for aneuploidy screening is superior compared with controls not only in clinical outcome at the first ET but also in dramatically decreasing miscarriage rates and shortening the time to pregnancy. (C) 2017 by American Society for Reproductive Medicine.

Objective To analyze the evolution of computerized cardiotocography (cCTG) parameters throughout gestation in a large archive of traces from healthy fetuses. Methods This was a cross-sectional study of the first cCTG record from 4412 singleton fetuses with good pregnancy outcome. Normal ranges of cCTG parameters for 25 to 42 weeks were derived from analysis of only one cCTG record per fetus, and the relationship between the parameters and gestational age was investigated. Results Fetal heart rate (FHR) accelerations, short- and long-term variation overall, duration of episodes of high and low variation and variation in high episodes increased with advancing gestation. In contrast, maternal perception of fetal movements, basal FHR, variation in low episodes and the time until criteria for normality were met decreased with advancing gestation. Gestational age-related changes in FHR variation were less evident at the lowest percentiles. Episodes of high FHR variation were detected in most fetuses, even at 25 weeks. Opposite trends of basal FHR and variation were observed at 42 weeks. Large decelerations and the frequency and duration of low episodes were also higher at 42 weeks. Conclusions The characteristics of the normal FHR pattern are quite defined from early on in gestation, follow a continuous trend with advancing gestation and change abruptly at 42 weeks. Gestational age-related changes are less obvious at the lowest percentiles. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

The success of assisted reproduction technology is highly dependent on a precise selection of gametes and embryos and determining the best endometrial window for embryo implantation. For many years, morphological criteria have constituted the only way to assess spermatozoon, oocytes, embryos and endometrial samples in order to improve outcomes. However, this approach has reached a ceiling of success and has been related to unacceptably high rates of multiple pregnancies. New technologies have been developed in order to improve the results and reduce risks via better selection of those gametes and embryos with the highest pregnancy potential, and of more favorable endometrial environments for embryo implantation. In addition, these technologies should ideally be objective, accurate, fast and affordable. Lately, the global strategies that are being employed in reproductive medicine include genomic, transcriptomic, proteomic, metabolomic profiling of oocytes, cummulus cells, granulosa cells, embryos, endomet...

This paper presents a review of the literature on the effects of cigarette smoking on the health of descendants and the possible mechanisms that lead to them. The evidence of the effects of prenatal cigarette smoke exposure on neonatal morbidity is clear. A number of birth defects have their incidence raised by maternal cigarette smoking during pregnancy. Prenatal smoke exposure also increases the risk of infant irritability, inattention, decreased response to inanimate auditory stimuli and hypertonia. In addition, the prevalence of obesity in preschool children is higher if the mother smoked during pregnancy, as well as the presence of male or female subfertility/infertility in adult life. Studies on the association between parental smoking and childhood cancer correlate paternal smoking to a higher risk of neoplasm in early life, especially of hematopoietic origin.

Objective To assess the presence of viral RNA or DNA sequences in spent culture media used after ovum pickup (OPU) or embryo culture and in liquid nitrogen (LN) used for oocyte or embryo vitrification in patients seropositive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) undergoing IVF cycles. Design Descriptive study. Setting Private university-affiliated IVF center. Patient(s) Twenty-four women who underwent controlled ovarian stimulation for oocyte vitrification or IVF/ET. A total of 6, 11, and 6 patients were seropositive for HIV, HCV, and HBV, respectively, whereas 1 patient showed a coinfection with HCV and HBV. Seven patients presented positive blood viral load (HIV, n=1; HBV, n=1; HCV, n=5). Sixty-three samples were analyzed: follicular fluid, n=3; spent culture media, n=33 (20 after OPU and 13 after embryo culture); and LN, n=27 (14 and 10 after oocyte and embryo vitrification; and 3 LN storage tank samples). Intervention(s) Ovum pickup, oocyte and/or embryo culture, and/or vitrification by the Cryotop open device. Reverse transcription–polymerase chain reaction analysis was performed for viral screening. Main Outcome Measure(s) Detection of viral sequences of HIV, HCV, and HVB. Result(s) All the samples analyzed tested negative for the detection of viral RNA or DNA sequences. Conclusion(s) We have not detected viral sequences after culture and vitrification of oocytes/embryos from HIV-, HBV-, and HCV-seropositive patients. These findings represent good evidence of the lack of risk of cross-contamination among seropositive patients, even using an open device for vitrification.

Objective To compare the efficacy of three different gonadotropin regimens in an oocyte donation program. The analysis of cost minimization also was evaluated. Design Prospective, randomized, controlled study. Setting Instituto Universitario–IVI, Valencia, Spain. Patient(s) One thousand twenty-eight donors undergoing a GnRH agonist protocol were assigned randomly to one of three groups: group 1 (n = 346), only recombinant FSH (rFSH); group 2 (n = 333), only highly purified menotropin (HP-hMG); and group 3 (n = 349), rFSH plus HP-hMG. One thousand seventy-nine oocyte recipients. Intervention(s) Controlled ovarian stimulation. Main Outcome Measure(s) Controlled ovarian stimulation parameters, IVF outcome, and cost analysis. Result(s) No differences were found among the groups with respect to days of stimulation, gonadotropin dose, final E 2 and P levels, number of oocytes retrieved, and cancellation rate. Similarly, there were no differences among the groups in terms of embryo development parameters. Moreover, implantation, pregnancy, and miscarriage rates with the three regimens were similar. However, the cost of rFSH was greater than that of the other protocols. Conclusion(s) This study suggests that in the GnRH agonist protocol the three different gonadotropin regimens evaluated herein are equally effective. Protocols using HP-hMG would appear to be the best in terms of cost-effectiveness in an oocyte donation program.

To verify whether the antral follicle count (AFC) could predict ovarian response, oocyte/embryo quality, and IVF outcome.Prospective study.Instituto Universitario-Instituto Valenciano de Infertilidad, Valencia, Spain.One thousand seventy-four donors and 975 oocyte recipient cycles.Controlled ovarian hyperstimulation (COH), endometrial preparation, IVF/intracytoplasmic sperm injection, ET.COH and oocyte/embryo quality parameters and IVF outcome.We observed lower E(2) levels and fewer mature retrieved oocyte numbers among donors who showed an AFC that was10. These donors also showed significantly higher cancellation and no-donation rates; poor and/or insufficient response was the principal cause (82%). However, there were no differences among the groups regarding embryo development parameters and IVF outcome.AFC is a noninvasive and simple tool that can improve the oocyte donor's selection of an egg donation program. This study suggests that AFC is a good predictor of ovarian response but cannot be used to predict oocyte/embryo quality or IVF outcome.

Obesity presents an increasing prevalence in developed countries and impairs human reproduction in both natural and assisted conception cycles. A healthy liveborn is less probable among obese women due to a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and more frequent complications during pregnancy for both mother and fetus. Gametes, embryos and uterus seem to be negatively affected by the abnormal hormonal and metabolic environment present in obese men and women. Lifestyle therapy for weight reduction based on hypocaloric diet and exercise is the best approach for improving the reproductive performance of these patients. Pharmacotherapy does not seem to be useful and bariatric surgery indicated only for fertility purposes is currently considered a risky and understudied procedure.

Lifestyle has a significant effect on human reproduction. Although great progress has been made with respect to the technical aspects of IVF treatments, the relevance of the parents’ contribution to success rates has been somewhat neglected. Few lifestyle habits have been assessed in relation to IVF outcome. Obesity reduces the possibility of pregnancy and increases miscarriage rates and obstetric complications for both mother and fetus, leading to a lower live birth rate. However, the real contribution of the oocyte, sperm, embryo and endometrium to IVF outcome is still not fully understood. Being underweight also appears to negatively affect IVF results, but again, few studies have assessed this topic. Psychological stress, consumption of caffeine and alcohol, and illicit drug use have been implicated in a poorer IVF outcome, but evidence is inconclusive due to the scarcity and inadequate methodology of related reports.

There has been an increasing tendency to delay parenthood in developed countries in recent years, and there is not enough information available regarding the effect of this on fertility. The aim of this work was to determine the role of paternal age on the outcome of assisted reproduction. A retrospective study was designed comprising a total of 2204 intrauterine insemination (IUI) cycles, 1286 IVF cycles and 1412 IVF cycles with donated oocytes during the period 2000 to 2006. Male mean age was 34.3 years (range 25-56) for IUI, 34.8 years (range 19-62) for IVF and 41.10 years (range 25-71) for ovum donation cycles. Statistics revealed no differences regarding pregnancy and miscarriage rates when the results were compared among age groups. In standard IVF and ovum donation cycles there was no clear association between embryo quality and paternal age. There was no significant relationship between male age and implantation rate. So far this is the largest study concerning the relevance of male age in assisted reproduction. As confirmed by the present data, the effect of the age of the male in the range studied is irrelevant. This finding contributes to the information that can be provided to infertile couples.

The Cryotop vitrification method has been shown to be a very useful tool for oocyte cryopreservation, giving excellent results regarding survival and clinical outcome. There are several clinical situations in which oocyte cryopreservation provides solutions that have not been available to date. This report describes three of these situations: (i) a low-responder patient who needed a single gene diagnosis due to the presence of a genetic disease; (ii) a patient undergoing endometrial bleeding on the day of oocyte retrieval who was also affected by a genetic disorder; and (iii) a patient who failed to become pregnant after the donation of vitrified oocytes and subsequently had the re-vitrified surplus embryos transferred. The resolution of these cases provides evidence of the enormous potential of the Cryotop method as a tool within assisted reproduction technology.

The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do.

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.

This article aims at reviewing the literature in order to provide a summary of the actual knowledge about the clinical factors of the oocyte recipient (other than those affecting the morphology of the uterine cavity) influencing the outcome of oocyte donation cycles. Recipient age, from 45 years onwards, is clearly associated with a poorer outcome in oocyte donation cycles as well as the presence of a hydrosalpinx. The negative impact of smoking has recently been confirmed. The exact influence of a high body mass index is under examination but it is likely that it is associated with a lower ongoing pregnancy rate. Endometriosis does not have a negative impact when standard endometrial priming protocols are used in oocyte donation. During endometrial priming, serum estradiol levels and endometrial thickness, if >5 mm, does not influence negatively the outcome; however duration of estrogen treatment of more than 7 weeks is associated with a diminished pregnancy and implantation rate.

Objective To analyze the potential role of extraovarian factors such as endometrium in the reproductive outcome of obese patients. Design Retrospective study. Setting University-affiliated infertility clinic, between January 2001 and July 2005. Patient(s) Women undergoing a total of 2656 first ovum donation (OD) cycles with good quality embryos. Intervention(s) The oocyte donors underwent controlled ovarian hyperstimulation, and recipients received a well-established hormonal replacement therapy for endometrial preparation. In vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was performed according to semen characteristics. All first cycles (n = 2656) of ovum donation used good quality embryos and were divided into groups according to body mass index: 2 (n = 471), 20 to 24.9 kg/m 2 (n = 1613), 25 to 29.9 kg/m 2 (n = 450), and ≥30 kg/m 2 (n = 122). Main Outcome Measure(s) The recipient body mass index groups were compared regarding IVF outcome. Result(s) The rates of implantation, pregnancy, miscarriage, and ongoing pregnancy were similar among the body mass index groups, although there was a negative trend when body mass index increased. Ongoing pregnancy rates per cycle were poorer in the overweight and obese groups than in the underweight and normal groups. In addition, women under 25 kg/m 2 presented an ongoing pregnancy rate per cycle of 45.5%, compared with 38.3% for those with ≥25 kg/m 2 . Conclusion(s) Excess weight exerts an extraovarian detrimental effect. The role of the endometrium or its environment seems to be subtle but should be taken into account.

Objective To evaluate the role of transabdominal three-dimensional (3D) ultrasound in the assessment of the fetal brain and its potential for routine neurosonographic studies. Methods We studied prospectively 202 consecutive fetuses between 16 and 24 weeks' gestation. A 3D ultrasound volume of the fetal head was acquired transabdominally. The entire brain anatomy was later analyzed using the multiplanar images by a sonologist who was expert in neonatal cranial sonography. The quality of the conventional planes obtained (coronal, sagittal and axial, at different levels) and the ability of the 3D multiplanar neuroscan to visualize properly the major anatomical structures of the brain were evaluated. Results Acceptable cerebral multiplanar images were obtained in 92% of the cases. The corpus callosum could be seen in 84% of the patients, the fourth ventricle in 78%, the lateral sulcus (Sylvian fissure) in 86%, the cingulate sulcus in 75%, the cerebellar hemispheres in 98%, the cerebellar vermis in 92%, the medulla oblongata in 97% and the cavum vergae in 9% of them. The thalami and the cerebellopontine cistern (cisterna magna) were identified in all cases. At or beyond 20 weeks, superior visualization (in > 90% of cases) was achieved of the cerebral fissures, the corpus callosum (97%), the supracerebellar cisterns (92%) and the third ventricle (93%). Some cerebral fissures were seen initially at 16–17 weeks. Conclusion Multiplanar images obtained by transabdominal 3D ultrasound provide a simple and effective approach for detailed evaluation of the fetal brain anatomy. This technique has the potential to be used in the routine fetal anomaly scan. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.

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.

We report five cases of first-trimester reversed end-diastolic flow in the umbilical artery. Diagnoses were performed between 8 and 12 gestational weeks. All but one case appeared as a transient early finding. Second-trimester fetal demise occurred in two cases. One case delivered at 32 weeks with severe growth restriction but recovered well. The other two cases had a good pregnancy outcome. Our experience suggests that this early Doppler finding is not always an ominous sign.

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.

Objective To analyze the transcriptomic profile of endometrial gene alterations during the window of implantation in infertile obese patients. Design Multicenter, prospective, case–control study. Setting Three academic medical centers for reproductive medicine. Patient(s) Infertile patients, stratified into body mass index (BMI) categories according to the World Health Organization guidelines, were included in the study. Intervention(s) Endometrial samples were obtained from women undergoing standardized estrogen and P replacement cycles after 5 days of vaginal P supplementation. Main Outcome Measure(s) To identify endometrial gene expression alterations that occur during the window of implantation in infertile obese patients as compared with infertile normal-weight controls using a microarray analysis. Result(s) XCL1 , XCL2 , HMHA1 , S100A1 , KLRC1 , COTL1 , COL16A1 , KRT7 , and MFAP5 are significantly dysregulated during the window of implantation in the receptive endometrium of obese patients. COL16A1 , COTL1 , HMHA1 , KRCL1 , XCL1 , and XCL2 were down-regulated and KRT7 , MFAP5 , and S100A1 were up-regulated in the endometrium of obese patients. These genes are mainly involved in chemokine, cytokine, and immune system activity and in the structural extracellular matrix and protein-binding molecular functions. Conclusion(s) Obesity is associated with significant endometrial transcriptomic differences as compared with non-obese subjects. Altered endometrial gene expression in obese patients may contribute to the lower implantation rates and increased miscarriage rates seen in obese infertile patients. Clinical Trial Registration Number NCT02205866.