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PubMed2004

What is the most relevant standard of success in assisted reproduction?: no single outcome measure is satisfactory when evaluating success in assisted reproduction; both twin births and singleton births should be counted as successes.

The 2002 recommendation of the consensus meeting of the European Society of Human Reproduction and Embryology (ESHRE) that the outcome measure of assisted reproductive technology (ART) and non-ART should be 'singleton live birth rate' could profoundly effect the ability of infertility patients to become pregnant. We reviewed published reports and new data concerning elective single embryo transfer (eSET) vs. double embryo transfer (DET) and the outcome of twin pregnancies in the United States, as well as recommendations of other Societies concerning number of embryos to transfer and methods used to measure ART success. We found that no single outcome measure of ART is ideal. Mandatory eSET would result in 42%-70% fewer births compared to DET. Infertility treatments account for only 12% of all twin pregnancies and 4% of all premature births in the United States. Twin and singleton births due to ART do not occur earlier than spontaneously conceived twins and singletons unless they started as triplet and higher order pregnancies. Multiple outcome measures are necessary when evaluating ART success. Twin as well as singleton births should be counted as ART successes. The essential aim of infertility treatment should be a healthy low order (singleton or twin) birth.

Embryo Transfer↗

PubMed1993

Pregnancy and implantation rates in normal replacement versus stimulated cycles.

The relative importance that endometrial development and embryo quality have on implantation rates achieved with assisted reproductive technology (ART) is the subject of controversy. Ovarian stimulation has been repeatedly mentioned as having a detrimental effect on endometrial receptivity (Paulson et al., 1990, Fertil. Steril., 53, 870-874). We compared pregnancy and implantation rates achieved with ART during stimulated cycles and hormonal replacement cycles, in patients matched for the following criteria: age < 35 years for the patient donating oocytes; transfer of at least two good quality embryos/oocytes and good quality transfer. All transfer cases performed during hormonal replacement cycles were done with donated oocytes. Comparison of results between techniques was not attempted due to potential differences in populations. The pregnancy and implantation rates achieved with each technique during stimulated and hormonal replacement cycles were not statistically different. In contradiction to previous results, our data suggest that differences in uterine receptivity between stimulated and hormonal replacement cycles in the age group studied are not of critical importance in embryo implantation. Good embryo quality appears to be the dominant factor in determining the success of ART.

Adult↗

PubMedDate not supplied

Mitochondria: potential roles in embryogenesis and nucleocytoplasmic transfer.

This review examines current understanding of mammalian mitochondria and mitochondrial DNA in the light of new reproductive technologies. Mitochondria are central to ageing, apoptosis, metabolism and many diseases. They are controlled by a dual genome system, with cooperation between endogenous mitochondrial genes and mitochondrial genes translocated to the nucleus over the course of evolution. This translocation has been accompanied by extreme compression of the mitochondrial genome, with little tolerance for mutations or heteroplasmy (multiple genomes). The highly compact mitochondrial genome appears to be maintained by a stringent numerical bottleneck in embryogenesis and oogenesis, followed by clonal expansion from a highly selected subset of precursor molecules. The dual nature of control between nucleus and cytoplasm sets up potential conflicts, which are normally resolved by natural selection. Such potentially opposing interests and mechanisms are probably partly to blame for the poor rates of success in cloning animals by nuclear transfer. The ability to construct cell systems and animal embryos with novel combinations and permutations of nuclear and cytoplasmic genes will provide powerful tools for examining these fundamental biological questions. Clinically, attempts to 'rescue' abnormal human oocytes or embryos by cytoplasmic transfer risk complex and unpredictable outcomes emerging from disharmonious nuclear-cytoplasmic interactions.

Aging↗

PubMed1999

Elevated day 3 serum follicle stimulating hormone and/or estradiol may predict fetal aneuploidy.

OBJECTIVE: To determine whether baseline serum FSH and/or E2 concentrations can predict the risk for fetal chromosomal abnormalities. DESIGN: Case control study. SETTING: Reproductive technology program at a university hospital. PATIENT(S): Patients who underwent dilation and curettage (D + C), and whose products of conception were karyotyped. INTERVENTION(S): Patients underwent natural conception or controlled ovarian hyperstimulation followed by intrauterine insemination, in vitro fertilization and embryo transfer, gamete intrafallopian transfer, or zygote intrafallopian transfer. MAIN OUTCOME MEASURE(S): Baseline serum FSH and E2 concentrations and fetal karyotype. RESULT(S): Genetic evaluation of 78 D + C specimens revealed 34 normal and 44 abnormal fetal karyotypes. A significantly greater proportion of women with abnormal fetal karyotype had elevated baseline serum FSH (> or =15 mIU/mL [RIA] or 10 mIU/mL [Immulite]) and/or E2 > or = 50 pg/mL [Immulite]) compared with women of normal fetal karyotype. Among karyotypically abnormal abortuses, autosomal trisomy was the most common abnormality noted (79.5%), followed by mosaicism (6.8%), triploidy (6.8%), monosomy XO (4.5%), and balanced translocation (2.3%). CONCLUSION(S): Baseline serum FSH and/or E2 concentrations may be valuable as predictors of fetal aneuploidy.

Abortion, Missed↗

PubMed2003

Changing the start temperature and cooling rate in a slow-freezing protocol increases human blastocyst viability.

OBJECTIVE: To determine the effect of start temperature and cooling rate of a slow freezing protocol on human blastocyst viability. DESIGN: Controlled-rate freezing of human blastocysts using different start temperatures and cooling rates. SETTING: Private assisted reproductive technology unit. PATIENT(S): Patients donated with consent cryopreserved pronucleate embryos. INTERVENTION(S): Culture of thawed pronucleate embryos in G III series media, containing hyaluronan, followed by cryopreservation of 36 blastocysts with subsequent noninvasive analysis of embryo metabolism. MAIN OUTCOME MEASURE(S): Pyruvate and glucose consumption and blastocyst reexpansion and quality. RESULT(S): Glucose consumption and blastocyst reexpansion after thaw were significantly higher when a start temperature of -6 degrees C and a cooling rate of 0.5 degrees C/min to -32 degrees C were used compared with a start temperature of 20 degrees C and a cooling rate of 2 degrees C to -6 degrees C, followed by cooling at 0.3 degrees C to -35 degrees C. Pyruvate uptake after thaw was not affected by the freezing procedure. Clinical use of the lower start temperature and quicker cooling rate, combined with culture in hyaluronan-based media, has led to the establishment of a 30% implantation rate. CONCLUSION(S): Human embryos cultured to the blastocyst stage in hyaluronan-based sequential media are readily cryopreserved and maintain their viability after thaw.

Blastocyst↗

PubMed2005

Current trends in evaluation of sperm function: in vitro selection and manipulation of male gametes for assisted conception.

With increasing medical utilization of assisted reproductive technology (ART), scientists and clinicians have been able to study extensively multiple cell functions operating synchronously and flawlessly during the events preceding, before and after fertilization. Critical evaluation of the functional status of spermatozoa for in vitro techniques such as sperm-mucus interaction, acrosome reaction status, sperm-zona pellucida binding and penetration tests, hyaluronic acid binding assay, and computer assisted semen analysis etc. can direct a male partner of an infertile couple to more aggressive forms of treatments. In vitro selection of functionally competent sperm cells is a pre-requisite for successful outcome in in vitro fertilization or in intracytoplasmic sperm injection (ICSI). Direct injections of acrosome-intact spermatozoa into oocyte during ICSI bypassing the normal events of sperm oocyte interaction and fusion events have raised concerns with regard to fertilization abnormalities and genetic issues. The present communication briefly reviews the sperm function tests with emphasis on its correlation with fertility outcome, and the currently employed sperm selection and manipulation procedures which may have implications in assisted conception programs.

Acrosome Reaction↗

PubMed1995

The use of progestins for programming assisted reproductive cycles and gonadotropin-releasing hormone agonist flare-up protocols in older patients.

OBJECTIVES: To determine if the use of norethisterone acetate (NET) in the previous cycle affects the ovarian response to GnRH agonist (GnRH-a) in flare-up protocols and controlled ovarian hyperstimulation in older patients. DESIGN: Retrospective analysis of the outcome of the assisted reproductive technology (ART) cycle. PATIENTS: Eighty women > 37 years old undergoing controlled ovarian hyperstimulation (COH) for a ART cycle (GIFT, IVF, zygote intrafallopian transfer). Forty received NET during the luteal phase of the previous cycle for programming the procedure and 40 did not receive NET (control group). Gonadotropin-releasing hormone agonist in follicular phase (flare-up) protocols were administered to all the patients. MAIN OUTCOME MEASURES: Cycle outcome: amount of gonadotropins used, oocyte production and quality, fertilization, and pregnancy rates. Estradiol, FSH, and LH levels the first 3 days of COH in eight patients. RESULTS: There were no differences between both groups in the cycle outcome. Estradiol levels during the first 3 days of COH were higher in the patients that did not receive NET in the previous cycle. Follicle-stimulating hormone and LH levels were similar in both groups. CONCLUSIONS: The administration of NET in the previous cycle in patients > 37 years old does not affect the ovarian response to the combination of follicular phase GnRH-a and gonadotropins for COH.

Adult↗

PubMed2005

Ovulation induction, assisted conception and childhood cancer.

Rapid advances have been made in the treatment of infertility over the last 30 years following the introduction of in vitro fertilisation and intracytoplasmic sperm injection. Whilst effects of assisted reproductive technology (ART) on birth outcomes are well documented little is known about effects on child health after the neonatal period. Childhood cancer is one area warranting further examination. The hypothesis that cancer in children may be initiated during early fetal development means that events leading up to and around conception may be important. Whilst the few large-scale epidemiological studies that have looked at childhood cancer incidence following ART have failed to find any significant increased risk, some case-control studies have reported an increased risk of specific cancers. However, it is important not to over interpret these findings as the reason for the infertility may be the predisposing factor, rather than the procedure itself. Recent recommendations by the UK's National Health Service to offer intra-uterine insemination and one free treatment cycle for infertile couples will result in increasing numbers of children born following ART. More detailed investigations that include larger numbers plus sufficient follow-up periods and information on the underlying causes of the infertility are needed since long term outcomes for these children, in particular the risk of developing cancer, remain largely unknown.

Adult↗

PubMed2000

Impact of uterine fibroids on ART outcome.

Our objective was to investigate the effect of subserosal (SS), intramural (IM), and submucosal (SM) fibroids on the outcome of assisted reproductive technology (ART) treatment. A retrospective comparative study at a tertiary referral center for infertility was designed. The treatment outcome of 106 ART cycles in 88 patients with uterine fibroids (33 SS, 46 IM without cavity distortion, 9 SM) was compared with that of 318 ART cycles in age-matched patients without fibroids. The main outcome measure(s) were the findings on transvaginal uterine ultrasonography performed before the initiation of treatment and pregnancy and implantation rates. The pregnancy rates per transfer were 34.1, 16.4, 10, and 30.1% in the patients with SS fibroids, IM fibroids, SM fibroids, and no fibroids, respectively. The implantation rates were 15.1, 6.4, 4.3, and 15.7%, respectively. Both rates were significantly lower in patients with IM fibroids than in those with SS fibroids or no fibroids. We conclude that pregnancy and implantation rates were significantly lower in the groups of patients with IM and SM fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of SS fibroids. Surgical or medical treatment should be considered in infertile patients who have IM and/or SM fibroids before resorting to ART treatment.

Adult↗

PubMed2026

Impact of BRCA1/2 status on young women's sexual function, relationships, and reproduction after predictive genetic testing.

The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on women's reproduction, intimate partner relationships, and sexual functioning. Australian women aged 18-40 years who had predictive BRCA1/2 testing, received either a positive or negative result, and had no personal cancer history, completed an online survey that used a case-control design. Outcome measures included childbearing, use of reproductive technologies, relationship status, and sexual functioning. 579 women participated (62.0% with a BRCA1/2 PV; 38.0% without a BRCA1/2 PV). More women with a BRCA1/2 PV had children compared to those who did not (49.0% c.f., 40.5%; p = 0.045). BRCA1/2 status did not predict whether women were partnered at survey completion (Odds Ratio 1.20; 95% CI 0.80, 1.78) or their sexual functioning over the previous month (β-coefficient -0.08; 95% CI -1.15, 0.98). Women with a BRCA1/2 PV were more likely to have children after genetic testing (OR 1.83: 95% CI 1.05, 3.21) and were more likely to have a greater number of children after genetic testing (β-coefficient 0.41; 95% CI 0.10, 0.73) compared to women without a BRCA1/2 PV, after adjustment for confounders. Receiving a positive predictive BRCA1/2 result is associated with an increased likelihood of childbearing and having a greater number of children compared to receiving a negative predictive BRCA1/2 result. These findings contribute to the evidence base to inform long-term follow-up for women after predictive BRCA1/2 testing.

Humans↗

PubMed1999

Long-term effects on women of assisted reproduction.

The long-term health sequelae for women from assisted reproductive technology (ART) have not been studied extensively. There are a number of reasons that women's health may be compromised after ART procedures, including the consequences of the increased incidence of multiple births, operative deliveries, and preterm infants, the possible adverse effects of the drug regimens used for ovarian stimulation, and the instrumentation involved in ART procedures. In this paper we review the existing literature in these areas. It emphasizes the effects of the drugs used for ovarian stimulation, and in particular the incidence of cancer among women who have undergone ART. The review indicates that there is cause for concern about the long-term effects on women from ART treatments. It highlights the lack of research undertaken in almost all areas related to women's long-term health after ART. In the area of ART and cancer, it draws attention to the lack of conclusive evidence in relation to the posited association between fertility treatments and cancer, resulting from the limited number of very large studies and the need for longer follow-up periods. We make a number of recommendations regarding further research that is needed to address the current shortcomings in the published literature.

Breast Neoplasms↗

PubMed2005

Emerging drugs in assisted reproduction.

Infertility affects approximately 15% of couples of reproductive age. In assisted reproductive technology (ART), medications play a crucial role in stimulating ovaries to produce several oocytes and prepare the endometrium to be receptive after replacing one or more embryos into the uterine cavity. The availability of recombinant human follicle stimulating hormone, luteinising hormone and human chorionic gonadotrophin; of gonadotrophin-releasing hormone (GnRH) agonists and antagonists; and of luteal supplementation with progesterone have allowed the tailoring of several stimulation schemes, which have enhanced the pregnancy outcome after ART treatment. However, the remaining risk of ovarian hyperstimulation syndrome, the still low implantation rates, the unacceptably high rates of multiple pregnancies and the daily parenteral administration of medications do not constitute the features of a patient-friendly procedure. Therefore, a number of molecules with gonadotrophin-like activity, inhibition of GnRH receptor ability, or endometrium receptivity enhancement properties are currently under active investigation. Orally bioactive therapeutic preparations, in particular, may revolutionize in vitro fertilisation (IVF) treatment in the near future. Nevertheless, the implementation of mild ovarian stimulation protocols with single embryo transfer policy and further development of oocyte in vitro maturation techniques may lead to a less drug orientated IVF treatment.

Clinical Trials as Topic↗

PubMed2004

Research hurdles complicating the analysis of infertility treatment and child health.

Research aimed at the empirical evaluation of infertility treatment including assisted reproductive technologies (ART) on child health and development is hampered by investigators' inability to methodologically separate possible treatment effects from underlying fecundity impairments. While the literature continues to identify ART as a risk factor for many child health outcomes, less attention has been paid to the methodologic rigor needed to answer this question. We identify aspects of fecundity and the nuances of medical practice that need to be considered and captured when designing epidemiologic investigations aimed at assessing ART and child health. These include: (i) the use of prospective study designs in which the unit of analysis (cycle versus individual versus couple) is defined; (ii) data collection on relevant time-varying covariates at, before and during treatment; and (iii) the use of statistical techniques appropriate for hierarchical data and correlated exposures. While none of these issues in and by itself is unique to ART research, attention to these issues has been lacking in much of the published research limiting our ability to evaluate health consequences for children. Longitudinal studies of children conceived with ART will benefit from attention to these issues and, hopefully, produce answers to lingering questions about safety.

Adult↗

PubMed1990

Selective termination: clinical experience and residual risks.

Assisted reproductive technologies have aided thousands of couples, but complications have resulted in multifetal pregnancies creating a bitter irony for infertility patients. In an effort to increase the rate of intact survival, we have successfully performed transabdominal first-trimester selective termination procedures on 22 pregnancies including one octuplet, five quintuplet, twelve quadruplet, and four triplet gestations. There have been eight sets of twins, and two singletons delivered, seven twin pregnancies are ongoing, and one early and four late losses of pregnancies. With experience we now counsel as to a high likelihood of a technically successful procedure, but we still have concerns for late losses. We have tried to balance the arguments about the direct harms of performing selective termination and the obstetric risks of not performing selective termination. We believe that selective termination should not be considered a "social" procedure. Our data do not yet make clear whether one, two, or three is the optimal number of embryos to leave. Therefore, on the basis of both current obstetric risk factors and ethical reasoning we will continue to support our protocol of optimally leaving twins.

Abortion, Induced↗

PubMed2003

Dealing with cryopreserved embryos upon divorce: a contractual approach aimed at preserving party expectations.

The development of assisted reproductive technologies, including cryopreservation, or freezing, of embryos created through in vitro fertilization, has given rise to complex legal questions. Because cryopreservation permits indefinite storage of embryos, if couples fail to specify disposition directions, they may disagree regarding embryo treatment upon the occurrence of contingencies such as divorce. Few courts have resolved such disputes, and those that have appear to uphold the rights of the party seeking to prevent implantation in the absence of a written agreement specifying otherwise. In this Comment, Sara Petersen proposes that courts should draw upon contract law principles in determining whether the parties to such conflicts actually reached agreements regarding embryo disposition in the event of divorce. After analyzing existing precedent, the author assesses proposed approaches for deciding which party's interests should prevail and concludes that these methods are inherently ineffective. She then argues that, in an effort to preserve party expectations and to provide fair results, courts instead should examine whether the parties executed binding contracts or achieved mutual assent. Furthermore, she suggests that couples undergoing cryopreservation will be more likely to contemplate and to provide for various outcomes if they know that courts will look at evidence of their conversations and thought processes prior to cryopreserving their excess embryos.

Contracts↗

PubMed2002

A minimally monitored assisted reproduction stimulation protocol reduces cost without compromising success.

OBJECTIVE: To determine if a fixed-dose stimulation protocol with monitoring limited to a single ultrasound can provide acceptable outcomes in assisted reproduction technologies (ART) procedures in appropriately selected patients. DESIGN: Prospective study of all minimally monitored ART cycles from 1996 through 1998. SETTING: University ART program. PATIENTS: Eligibility included Institutional Review Board consent, age 18-37, basal FSH < or = 10, normal semen parameters, and regular menses. IVF (n = 81) and GIFT (n = 14). INTERVENTIONS: A single ultrasound was performed after 8 or 9 days of stimulation in a fixed-schedule long luteal phase leuprolide protocol. No hormone levels were obtained. Human chorionic gonadotropin was administered when at least 2 follicles were projected to reach 18 mm. MAIN OUTCOME MEASURES: Pregnancy, delivery, and implantation rates. RESULTS: The clinical pregnancy rates were 51% for IVF and 36% for GIFT. Delivery rates were 42% for IVF and 29% for GIFT. The implantation rates for IVF were 23% and 17% for GIFT. No patient was admitted for ovarian hyperstimulation. CONCLUSIONS: We were able to achieve satisfactory pregnancy and delivery rates in properly selected patients with a minimal monitoring protocol, limited to a single ultrasound near the end of a fixed-stimulation regimen. The reduced time commitment and cost led to a very high patient acceptance of this approach.

Adult↗

PubMed1997

Preprogrammed, unmonitored ovarian stimulation reduces expense without compromising the outcome of assisted reproduction.

OBJECTIVE: To determine if a novel, preprogrammed, unmonitored stimulation protocol could reduce the cost of assisted reproductive technology (ART) without compromising outcome or safety. DESIGN: Prospective, nonrandomized study of unmonitored ART versus traditional monitoring. SETTING: University ART program. PATIENT(S): Infertile women aged < 39 years, with a basal FSH level < 15 mIU/mL (conversion factor to SI unit, 1.00) and regular menstrual cycles, undergoing ART. INTERVENTION(S): Oocyte retrieval was performed at a predetermined time in 72 unmonitored cycles based on age and basal FSH level. No monitoring of any type was performed before retrieval. There were 86 monitored control cycles. MAIN OUTCOME MEASURE(S): The number of oocytes, and embryos; complications including ovarian hyperstimulation. RESULT(S): The total cost for unmonitored ART was significantly less than for monitored cycles. There was no difference between groups for patient age, number of oocytes obtained, or number of metaphase II oocytes. For non-male-factor patients, the number of oocytes fertilized, number of embryos transferred, and the clinical pregnancy rates were comparable. There was one case of severe hyperstimulation requiring hospitalization in the unmonitored group. CONCLUSION(S): This novel, unmonitored ovarian stimulation protocol provides ART at a significantly lower cost than is incurred with traditional monitoring, with no apparent compromise in outcome.

Adolescent↗

PubMed2004

[Implantation: the first maternal-embryo crosstalk].

Despite progress in assisted reproduction technologies, the lack of control of implantation remains a major obstacle to obtain successful pregnancies. It is of prime importance to determine the characteristic features of a receptive endometrium. Embryo implantation is a complex event involving apposition followed by the adhesion of the blastocyst to the maternal endometrium, and finally the invasion of this endometrium. Though implantation could occur in any human tissue, the endometrium is the only tissue where embryo implantation cannot occur except during a restricted period called the "implantation window". During this window, the endometrium is highly receptive to the embryo. Maternal-embryo crosstalk is favored by the implantation window. The molecular basis of the implantation window remains to be defined In the present study, we investigated the role of hCG, TGFbeta1, IGF1 and IGF2 in the secretion of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) by human epithelial endometrial cells in culture. Epithelial endometrial cells were obtained from endometrial biopsy in 28 fertile women. HCG and TGFbeta1 added to primary cultures of human epithelial endometrial cells showed a stimulatory effect on LIF secretion and a reducing effect on IL-6 secretion. All these findings suggest a role for hCG and TGFbeta1 in human embryo implantation.

Biomarkers↗