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Ultrasound prediction of risk of spontaneous miscarriage in live embryos from assisted conceptions.

OBJECTIVE: An accurate method to predict subsequent miscarriage in live embryos has not yet been established. This pilot study aimed to determine the most discriminatory ultrasound-based model for predicting spontaneous miscarriage after embryonic life was first detected in assisted conceptions. A method for estimating individual risk of miscarriage was developed. METHODS: This was a prospective cross-sectional survey of 322 live singleton embryos in women from an assisted reproductive technology program. Mean sac diameter (MSD), crown-rump length (CRL), embryonic heart rate (EHR), maternal age and gestational age at the first transvaginal scan detecting embryonic life (between 42 and 62 days) were observed. These variables were included in a multivariate model for predicting spontaneous miscarriage occurring prior to 20 weeks. MSD, CRL and MSD minus CRL were assessed in univariate logistic regression analyses. The global diagnostic accuracy of each model was compared directly using receiver-operating characteristics (ROC) curves. RESULTS: The multivariate model demonstrated the best ROC curve for predicting miscarriage (ROC area 0.87; 95% CI, 0.80-0.95). The separate univariate analyses had less diagnostic accuracy. In particular, MSD - CRL had a significantly smaller ROC area (0.65) than did the multivariate model (P < 0.01). CONCLUSIONS: The most discriminatory test for predicting spontaneous miscarriage in live embryos was a multivariate model, which allows estimation of individual risk levels.

Abortion, Spontaneous↗

Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19.

Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth syndrome-namely, Beckwith-Wiedemann syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART-five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS-four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring syndrome reported in ruminants.

Adult↗

Quality management in the ART laboratory.

Unlike most medical laboratories that play a diagnostic role, laboratories for assisted reproductive technologies, ART laboratories, are involved in the treatment of infertile couples. Handling human gametes and producing human embryos in order to achieve much-sought pregnancies form the key tasks of an ART laboratory. The impact of the activities and the possible risks makes it necessary to ensure the safety and reproducibility of all methods. To achieve and maintain the highest level of patient care and the highest success rates, a quality management system should be implemented. Several guidelines, compiled by professional associations of ART experts, official international standards and quality management models have been developed and issued and can be applied. Irrespective of the choice, establishing a quality management system in an ART laboratory leads to a huge amount of additional work and requires a lot of investment in all kind of areas. However, due to the increased standardization and efficiency of all procedures as well as the improved transparency and traceability of all actions performed, the quality of service provided by the laboratory will improve substantially and the effort will be worthwhile.

Humans↗

Hydatidiform moles associated with multiple gestations after assisted reproduction: diagnosis by analysis of DNA fingerprint.

In spite of the widespread use of assisted reproductive technology, there have been, to our knowledge, only two reported cases of molar pregnancies after gamete intra-Fallopian transfer and five reported cases after in-vitro fertilization and embryo transfer. We report here a case of a complete hydatidiform mole in a twin pregnancy after gamete intra-Fallopian transfer, as well as a case of a complete hydatidiform mole in a triplet pregnancy after in-vitro fertilization and embryo transfer. The genetic constitution of each conceptus was determined by examination of the restriction fragment length polymorphism of the DNA with four different single-locus probes. This analysis revealed that both hydatidiform moles were of androgenetic origin and probably of monospermic origin. Moreover, the analysis confirmed that the pregnancies were dizygotic and trizygotic pregnancies respectively. The diagnostic utility of the analysis of DNA polymorphism is discussed in cases of a molar pregnancy with coexisting fetuses.

Adult↗

How to make a blastocyst.

Several of the new reproductive technologies have been cultivated from our current understanding of the genetic programming and cellular processes that are involved in the major morphogenetic events of mammalian preimplantation development. Research directed at characterizing the patterns of gene expression during early development has shown that the embryo is initially under maternal control and later superseded by new transcriptional activity provided by the activation of the embryonic genome. Several embryonic transcripts encoding: (i) growth factors, (ii) cell junctions, (iii) plasma membrane ion transporters, and (iv) cell adhesion molecules have been identified as contributing directly to the progression of the embryo through the preimplantation interval of development. In this brief review, we have outlined the patterns of expression and the integral roles that these gene families play in the morphogenetic events of compaction and cavitation. Research of this type has greatly facilitate our understanding of the control processes that underlie preimplantation development and represent but one area of this exciting and vigorous field of research.

Animals↗

[Analysis of factors affecting the results of assisted reproduction using a system for information mining of the SHLUK database].

OBJECTIVE: To retrospective explorating computer analysis of data about therapeutic cycles in assisted reproduction technology (ART) to confirm applicability of system for data mining SHLUK in partial analysis of fertilisation phase of therapeutic cycle. Relations between parameters of sperm count analysis and outcome of in vitro fertilisation were analyzed. DESIGN: Retrospective analysis. SETTING: 1st Depart of Obstet. and Gynaecol., Masaryk University, Brno; FEI, VSB, Ostrava. METHODS AND MATERIAL: Conditions of successful therapy in single phases of ART therapeutic cycles, were analysed using system SHLUK, which included a lot of methods for data mining. Analysis of relation between reasons and results in ART therapeutic cycles was done through method IMPL and method of group implication GRIMPL. Analysed file included data about 8516 therapeutic cycles ART in 4470 patients and data about 666 clinical pregnancies stored in electronical form in clinical data register. The model analysis of fertilisation tested relations between parameters of sperm analysis and outcome of in vitro fertilisation. Fertilisation rate (FR)--ratio of fertilized oocytes/obtained oocytes was evaluated as fertilisation stage outcome. RESULTS: Significantly higher FR--60.9% was in the group with sperm concentration before preparation 41-60 mil/ml. When sperm concentration before preparation was under 10 mil/ml--FR was significantly lower--42.2%. Motility of sperm before preparation under 10%--FR was significantly lower--45.3%. Motility of sperm before preparation 41-50%--FR was significantly higher--56.9%. Significantly higher FR--minimal 56.0% was in group of examinations with sperm after preparation was 41-90%, then FR was significantly higher--53.5%. In sperm survival test, where more than 30% of sperm survive 24 hours of cocultivation with oocytes FR was significantly higher--minimal 55.9%. CONCLUSION: Applicability of system for data mining SHLUK in the analysis of factors with influence on assisted reproduction outcome was proved. System for data mining SHLUK makes possible to define statistically significant relations between attributes of fertilisation stage of ART cycles and it is able to postulate basic hypothesis about existing reasons and results in therapeutic cycles of ART.

Data Interpretation, Statistical↗

Perioperative complications arising after transvaginal oocyte retrieval.

OBJECTIVE: To determine the incidence of perioperative morbidity in patients undergoing transvaginal oocyte retrieval and to identify those patients at greatest risk for complications. METHODS: A retrospective analysis was performed on 674 patients of reproductive age who underwent transvaginal retrieval of oocytes for assisted reproduction technologies during a 3-year period. All procedures were performed by surgeons with extensive experience with transvaginal retrieval. Patients were entered into the program with a primary diagnosis of unexplained infertility (16%), endometriosis (32%), pelvic adhesions and/or tubal occlusion (38%), or infertility from male or immunologic factors (14%). RESULTS: Of the 674 patients studied, ten (1.5%) required hospital admission because of perioperative complications. Nine of these patients needed intravenous antibiotics and one required admission and observation for an expanding broad-ligament hematoma. Six of nine women admitted for antibiotic therapy had a history of extensive pelvic adhesions with or without a history of salpingitis. Five of nine patients had a history of salpingitis. In addition, two patients experienced impressive vaginal arterial bleeding during the procedure. CONCLUSION: This study suggests that transvaginal retrieval may not be as innocuous as is often expressed and that the primary factor predisposing to perioperative morbidity is a history of previous pelvic inflammatory disease and/or adnexal adhesions.

Adult↗

Changes in the freezing protocol for human zygotes alter embryonic development and pregnancy rates.

OBJECTIVE: To determine the effect of various freezing protocols on postthaw development and pregnancy rates resulting from transfer of human zygotes. DESIGN: Prospective study. SETTING: Tertiary care center. PATIENT(S): Couples undergoing assisted reproductive technology (ART) procedures who wished to have their excess zygotes cryopreserved. INTERVENTION(S): We cryopreserved zygotes with one of three protocols. MAIN OUTCOME MEASURE(S): Post-thaw survival and development of the zygotes as well as pregnancy rate after transfer of these zygotes. RESULT(S): A 3-minute hold time after seeding, followed by a final preplunging temperature of -180 degrees C, resulted in a clinical pregnancy rate of 28.6%. In contrast, a 15-minute postseed hold time and a -30 degrees C final chamber temperature resulted in a 37.3% clinical pregnancy rate. When we combined the protocols to provide a 15-minute postseed holding time and a -180 degrees C before plunging into liquid nitrogen, we achieved a 69.6% clinical pregnancy rate. CONCLUSION(S): By increasing the postseeding hold time and decreasing the temperature of the freezing chamber before plunging the zygotes into liquid nitrogen, significant improvements can be made in postthaw development and pregnancy rates.

Adult↗

What is the most relevant standard of success in assisted reproduction? Is there a single 'parameter of excellence'?

An optimal standard of success reflects all risk and safety aspects of the treatment-related procedures. In this debate, we question whether one single standard of success can cover the complexity of assisted reproduction technology (ART). To emphasize the use of different parameters as standards of success, we calculated data from all IVF and ICSI cycles initiated at the Fertility Clinic, Rigshospitalet, Copenhagen, Denmark between 1999 and 2001. Several already established parameters were computed and, additionally, new suggestions for end-points were calculated. Three parameters were proposed as the best standards of success in ART: (i) number of oocytes per aspiration (8.7); (ii) number of ongoing implantations per embryo transferred (20%); and (iii) number of deliveries per embryo transferred (14%). These parameters cover aspects of all steps in ART, i.e. the stimulation, laboratory and embryo transfer/outcome phase, also termed the pre-in vitro, in vitro and post-in vitro phase. We suggest that the final description of an ART programme should be a balanced choice of the three standards of success proposed herein. If these standards are implemented as national gold standards, the future goal of homogeneous reporting of success rates in ART is within reach.

Female↗

Analysis of national representative opinion surveys concerning gestational surrogacy in Japan.

OBJECTIVE: Although gestational surrogacy offers several advantages, this procedure has given rise to some ethical and legal issues. We aimed to clarify the factors affecting the attitude of the Japanese toward gestational surrogacy. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Nationwide opinion surveys concerning assisted reproductive technologies (ART) were carried out in 1999 and 2003. Participants included 2568 and 3647 people from the general public surveyed in 1999 and 2003, respectively (1564 people received only the questionnaire, and 2083 people received a questionnaire and brochure about ART). MAIN OUTCOME MEASURE: Multivariate-adjusted odds ratio and 95% confidence interval from logistic regression models for factors affecting the attitude toward gestational surrogacy. RESULTS: In both surveys, approximately half of respondents approved of gestational surrogacy; 20-30% disapproved of the procedure. People with high socioeconomic status clearly expressed their opinion on this issue. A liberal attitude toward gender role promoted approval of gestational surrogacy; a liberal attitude toward family had the opposite effect. CONCLUSION: Our findings suggest that socioeconomic status affects people's expression of their opinion regarding this issue, while attitudes toward this procedure were influenced by individual belief. Considering socioeconomic status and diversity of individual belief is required for further discussion on this topic.

Attitude to Health↗

Coping, quality of life and psychological symptoms in three groups of sub-fertile women.

The process of assisted reproductive technology (ART), surrogacy and adoption pose different physical and psychological burdens on sub-fertile populations. Sub-fertile women (n = 176) were assessed retrospectively by questionnaire to determine if process (undergoing ART, surrogacy or adoption) or outcome (having a successful versus unsuccessful outcome) affected quality of life, coping style and psychological symptoms. The ART group was significantly younger, had a shorter period of sub-fertility, and was least likely to have a child than the adoptive and surrogate groups. Quality of life and psychological symptoms were not significantly different between groups, although significantly higher Mental Disengagement and Denial coping strategy scores were obtained for the ART group. Social, psychological, health and functioning quality of life, and Denial coping strategies were good predictors of outcome group. Treatment specific counselling of individuals use of coping strategies early on in their in/subfertility career to cope with the reality of prolonged childlessness is indicated.

Adaptation, Psychological↗

[Conservation of human embryos in straws: safety in terms of human immunodeficiency virus 1].

OBJECTIVE: The possibility of offering assisted reproductive technologies (ART) to HIV-positive couples has revived questions concerning the safety of the gametes and embryos cryopreservation in liquid nitrogen tanks. PATIENTS AND METHODS: We evaluated the safety of three types of straws - polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG) and so-called 'high-security' ionomeric resin (IR) - containing HIV-1 under standard conditions of cryopreservation. Potential HIV contamination was assessed by RT-PCR and then nested PCR. RESULTS: Under cryopreservation conditions, the sealed open ends of PVC and PETG straws were not safe. The ultrasound sealing system seems to be the weak link in obtaining total imperviousness of the straws. In contrast, both ends of the IR straws were safe for HIV in the framework of their use for ART. CONCLUSION: Sealing cryopreservation straws ultrasonically could incur the risk of not assuring their impermeability. Under standard cryopreservation conditions thermosealing of IR straws appears to be safe for HIV.

Cryopreservation↗

Life table (survival) analysis to generate cumulative pregnancy rates in assisted reproduction: are we overestimating our success rates?

The variability in the numbers of treatment cycles couples may undertake with assisted reproductive technology (ART) and the length of time they may have to wait between successive cycles of treatment make the evaluation of treatment efficacy and prognosis complicated. The cumulative pregnancy rate using the life table method of analysis is being used more frequently to estimate the effectiveness of treatment. Although this approach is valid in some areas of infertility research, its use in ART is not appropriate, because the factors necessary for the analysis (particularly the scale for measuring the passage of time and lack of informative censoring) are not satisfied. Consequently, an overestimation of the effect of treatment is produced that may lead to biased decision making. Although there is no easy solution to this problem, several options for summarizing the outcome data are offered: pregnancy rate per cycle, time-limited analysis using proportions, conservative cycle-based cumulative pregnancy rate and real-time-based cumulative pregnancy rate. In this manner, more realistic information can be generated to counsel patients, evaluate the efficacy of treatments, compare rates among centres and guide the formulation of policies for infertility management and resource allocation.

Female↗

PCR-detected hepatitis C virus RNA associated with human zona-intact oocytes collected from infected women for ART.

BACKGROUND: The aim of this study was to investigate the susceptibility of human oocytes from hepatitis C virus (HCV) RNA-positive women to HCV contamination during assisted reproductive technology (ART). METHODS: A reverse transcriptase-PCR assay was used to test for the presence of HCV RNA associated with 24 unfertilized oocytes 48 h after follicular fluid aspiration in 10 IVF attempts (seven conventional IVF and three ICSI). Negative and positive controls (10 unfertilized oocytes from HCV-negative women and 20 unfertilized oocytes artificially contaminated with HCV RNA-positive plasma; HCV RNA was also quantified in plasma and follicular fluid) were included. RESULTS: HCV RNA was associated with 17/24 (70.8%) oocytes (6/7 after ICSI and 11/17 after conventional IVF) and was found in 19/20 (95%) follicular fluid samples. A weak correlation was found between plasma and follicular fluid HCV RNA loads (r = 0.73, P < 0.001). CONCLUSIONS: HCV associated with unfertilized oocytes surrounded by their intact zona pellucida from anti-HCV antibody-positive and viraemic women undergoing ART raises questions concerning the safe management of medically assisted procreation for these women and good practice of oocyte/embryo cryopreservation and donation.

Adult↗

[Maternal risks of medical assistance with procreation].

It is now well demonstrated that assisted reproductive technologies, namely intra-uterine insemination, in vitro fertilization and embryo transfer, and gamete intra fallopian transfer (GIFT) are the source of maternal complications, sometimes life-threatened. All documented hazards concern the short term. Few are related to the techniques: local, regional or general infections, severe hemorrhages. Most are the consequence of controlled ovarian hyperstimulation: ovarian hyperstimulation syndrome (OHSS), thrombosis, multiple pregnancies. High range multiple pregnancies could be prevented by a reduction in the number of embryo transfered, which is now currently limited to two or three in most centers. Similarly, good results can be obtained with intrauterine insemination, while maintaining the multiple pregnancy rate at the physiologic level, about 1%, by avoiding poly-ovulation. In comparison with spontaneous pregnancies, ART pregnancies are more complicated (toxemia, intra-uterine growth retardation, prematurity). The caesarean section rate is over 25% in singleton deliveries, 40% for twins and 89% for triplets. With a long term follow-up of 15 years, no hazard has been demonstrated. Concerns about ovarian epithelial cancer, breast cancer, and premature menopause remain hypothetic. Further studies are in development in this field.

Breast Neoplasms↗

High quality sperm for nonhuman primate ART: production and assessment.

Factors that affect sperm quality can include method of semen collection, conditions for capacitation and whether or not agglutination is present. Media and procedures for sperm washing can also impair or improve sperm function in assisted reproductive technologies. For example, the removal of seminal fluid through large volume washing is required to eliminate decapacitation activity of seminal plasma. The forces involved with centrifugation and the metabolic stress of tightly pelleting sperm during washing procedures can have deleterious results. In contrast to human sperm, sperm from the most commonly used species of nonhuman primates, rhesus and cynomolgus macaques, do not spontaneously capacitate in vitro; rather, chemical activation with dibutryl cyclic AMP and caffeine is required. Recognizing motility patterns of non-activated and activated sperm can be accomplished with simple observation. After activation, sperm agglutination sometimes occurs and can interfere with sperm binding to the zona pellucida. Because nonhuman primate oocytes require a large investment to produce and currently, each animal can be hormonally stimulated a limited number of times, it is important to have means to evaluate quality prior to using sperm from a new male for in vitro fertilization. Methods for producing live, acrosome reacted sperm may also have application for ICSI. Because many genetically valuable males are now being identified, it may be necessary to individualize sperm preparation to accommodate male-to-male variation.

Animals↗

Medical management of male infertility.

Management of male infertility is always a difficult task. In recent years booming of artificial reproductive technologies (ART) has put infertologists and andrologists in front of a million dollar question whether to treat the person or the gametes. A basic andrology laboratory at present has become part and parcel of an infertility clinic. Hence treatment of male infertility has become institutional and collective for clinicians and basic scientists. The basic approach towards management of male infertility includes confirmation of diagnosis and to find out the cause for which pathological, endocrinological and biochemical tests are essential. In this series specific defects causing seminopathy has been found in 18% cases where treatment is straightforward and towards the cause. The main bulk of idiopathic seminal defects (82%) really poses challenge to the infertologists so far management is concerned. In this study commonest seminal defect has been found to be oligoasthenozoospermia which amounts to 63% cases. For medical management purpose drugs commonly used are clomiphene, gonadotrophins, bromocriptine, L-thyroxine, vitamin E, B12, etc. When they fail the main approach remains to be intra-uterine insemination (IUI) and ART eg, in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI).

Androgens↗

[Cochin Hospital Clinical Ethics Center: the first two years].

INTRODUCTION: In September 2002, Cochin Hospital (Paris, France) opened a Clinical Ethics Center for patients, health proxies and members of the healthcare staff to consult when they face medical decisions raising ethical issues, that is, presenting possible conflicts in values. Three years after the opening of this experimental center that remains unique in France, we evaluated its activities. OBJECTIVES: To describe and compare consultations in 2003 and 2004 and to compare our activity with that of similar units abroad. METHODS: The descriptive analysis is based on data routinely collected for all consultations. RESULTS: The Center received 47 calls in 2003 and 83 in 2004. The most frequent reasons for consultation were: end of life issues (28%), patients' rights (25%), and questions about assisted reproduction technologies (16%). Two factors explain the increase in activity between 2003 and 2004. First, patients and their proxies called much more often: 24 calls in 2004, compared with only 10 in 2003. Second, research protocols designed to focus on specific ethical questions faced by medical teams in their daily practice required them to call systematically in the relevant situations (39 calls in 2004, compared with 15 in 2003). Calls from healthcare workers about one-time or ad hoc ethics questions remained stable (22 in 2003 and 21 in 2004). DISCUSSION/CONCLUSION: Healthcare staff appear to need clinical ethics consultations less for help on ad hoc issues than for long-term collaboration on specific and frequent ethical issues that remain difficult, despite their familiarity. These findings refute earlier fears that healthcare personnel would use these consultations to avoid their own ethical responsibilities. The increasing direct demand from patients and proxies should continue during the next few years, for it corresponds to a profound social trend, to defend one's autonomy in the face of illness and to make decisions and take responsibility for oneself.

Demography↗