[Show abstract][Hide abstract] ABSTRACT: Simultaneous transfer of multiple embryos in an assisted reproductive technology (ART) cycle results in a high rate of multiple pregnancy. Besides the medical complications associated with multiple pregnancy, the financial burden of the resultant preterm infants is also substantial. The current review evaluates the costs associated with the care of preterm infants that are born as a result of ART-associated multiple pregnancies.
In 2006, 30% of all ART live births were multiple infant deliveries in the USA. This resulted in 48% of all ART neonates being the product of a multiple infant delivery. In the same year, 62% of ART twins and 97% of ART triplets were delivered preterm, corresponding to approximately 17 000 infants. The Board of Health Sciences Policy has estimated the mean cost of each preterm infant to be US$ 51 600. Therefore, the financial burden of ART-associated preterm deliveries is estimated to be approximately US$ 1 billion annually. This figure has remained essentially unchanged between 2001 and 2006, despite decreasing number of embryos transferred, due to increasing total number of ART cycles performed.
Preterm deliveries that result from ART-associated multiple pregnancies add a substantial burden to overall US healthcare expenditure annually. Policies limiting the number of embryos transferred should be considered with a perspective to increase elective single embryo transfers.
Current opinion in obstetrics & gynecology 03/2011; 23(3):168-73. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the impact of mandated IVF insurance coverage on ET practices and resulting multiple pregnancy rates.
Retrospective analysis of all fresh, nondonor IVF cycles performed in the United States in 2006.
A total of 91,753 fresh, nondonor IVF cycles in the United States.
Pregnancy rate, live-birth rate, embryos transferred, multiple pregnancy rate.
Overall, nonmandated states had a significantly higher pregnancy rate (38.8% vs. 35%) and live-birth rate (32.2% vs. 29.1%) than mandated states. Nonmandated states also had a significantly higher twin rate (28.1% vs. 26%) and triplet rate (3.9% vs. 3.4%). The average number of embryos transferred was also significantly higher in nonmandated states (2.6 vs. 2.2). These findings were more pronounced in the <35 and 35-37 age groups.
In the last 8 years, despite a reduction in the average number of embryos transferred and multiple pregnancy rates, there is a continued association between mandated IVF coverage, the transfer of fewer embryos, and lower rates of multiple pregnancies and births, particularly in the younger age groups.
Fertility and sterility 03/2011; 95(3):964-9. · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p < 0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p < 0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland.
[Show abstract][Hide abstract] ABSTRACT: To investigate the oocyte-to-baby rate when controlled ovarian stimulation was performed on a highly successful donor population and to evaluate whether they produce a higher proportion of reproductively competent oocytes compared with standard donors.
Retrospective analysis of clinical and embryological database.
A total of 191 oocyte donation cycles were analyzed from 53 donors (28 best-prognosis donors and 23 standard donors).
Total number of oocytes collected, the number of embryos transferable (fresh and frozen). and corresponding oocyte to live baby born (LBB) rates. In patients with remaining frozen embryos, the final LBB rate was estimated according to our reported rates.
A total of 130 oocyte retrievals from the best-prognosis donors yielded 2,470 oocytes. The total LBB per oocyte retrieved and LBB per embryo transferred was 7.3% and 24.6%, respectively. A total of 61 oocyte retrievals from the standard donors yielded 1,044 oocytes. The total LBB per oocyte and LBB per embryo transferred was 5.0% and 16.6%, respectively. This is significantly different from the best-prognosis donor group. Success rates were also analyzed after grouping donors based on the number of oocytes retrieved per cycle. In the best-prognosis group, the oocyte use rate increased significantly when fewer oocytes were retrieved, whereas the oocyte-to-baby rate was similar regardless of the number of oocytes for the standard donor group.
This retrospective analysis revealed the existence of a subset of good-prognosis donors who produce a higher oocyte-to-baby rate that is indicative of a more biologically efficient reproductive system. Their identification, albeit a posteriori, has clinical implications for safety, by reducing ovarian hyperstimulation syndrome and multiple pregnancies, as well as for assisted reproductive technology success.
Fertility and sterility 03/2010; 94(6):2064-8. · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bisphenol-A (BPA) is a nonsteroidal estrogen that is ubiquitous in the environment. The homeobox gene Hoxa10 controls uterine organogenesis, and its expression is affected by in utero BPA exposure. We hypothesized that an epigenetic mechanism underlies BPA-mediated alterations in Hoxa10 expression. We analyzed the expression pattern and methylation profile of Hoxa10 after in utero BPA exposure. Pregnant CD-1 mice were treated with BPA (5 mg/kg IP) or vehicle control on d 9-16 of pregnancy. Hoxa10 mRNA and protein expression were increased by 25% in the reproductive tract of mice exposed in utero. Bisulfite sequencing revealed that cytosine-guanine dinucleotide methylation was decreased from 67 to 14% in the promoter and from 71 to 3% in the intron of Hoxa10 after in utero BPA exposure. Decreased DNA methylation led to an increase in binding of ER-alpha to the Hoxa10 ERE both in vitro as and in vivo as determined by EMSA and chromatin immunoprecipitation, respectively. Diminished methylation of the ERE-containing promoter sequence resulted in an increase in ERE-driven gene expression in reporter assays. We identify altered methylation as a novel mechanism of BPA-induced altered developmental programming. Permanent epigenetic alteration of ERE sensitivity to estrogen may be a general mechanism through which endocrine disruptors exert their action.
The FASEB Journal 02/2010; 24(7):2273-80. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, much progress has been made in the area of cryopreservation of ovarian tissue, one of the only options for fertility preservation available to women who require immediate gonadotoxic chemotherapy. Human ovarian cortical tissue strips have been cryopreserved, thawed, and autotransplanted with successful reproductive function. Cryopreservation of ovarian cortical strips, however, is limited by the ischemia that occurs at the time of retransplantation. Thus for patients that desire long-term resumption of endocrine function, cryopreservation of the whole ovary with an intact pedicle and vascular supply may be a better option. This article describes recent advances in whole ovary cryopreservation in both animal and human models, with a focus on surgical technique for removal, choice of cryoprotectants, freezing and thawing protocols, and preliminary results with organ retransplantation. Although no human cases of whole ovary retransplantation after cryopreservation have been performed to date, these preliminary studies have been encouraging, and it is likely that this option for fertility preservation will be a viable treatment option in the future.
Seminars in Reproductive Medicine 11/2009; 27(6):465-71. · 3.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diethylstilbestrol (DES) is a nonsteroidal estrogen that induces developmental anomalies of the female reproductive tract. The homeobox gene HOXA10 controls uterine organogenesis, and its expression is altered after in utero DES exposure. We hypothesized that an epigenetic mechanism underlies DES-mediated alterations in HOXA10 expression. We analyzed the expression pattern and methylation profile of HOXA10 after DES exposure. Expression of HOXA10 is increased in human endometrial cells after DES exposure, whereas Hoxa10 expression is repressed and shifted caudally from its normal location in mice exposed in utero. Cytosine guanine dinucleotide methylation frequency in the Hoxa10 intron was higher in DES-exposed offspring compared with controls (P = 0.017). The methylation level of Hoxa10 was also higher in the caudal portion of the uterus after DES exposure at the promoter and intron (P < 0.01). These changes were accompanied by increased expression of DNA methyltransferases 1 and 3b. No changes in methylation were observed after in vitro or adult DES exposure. DES has a dual mechanism of action as an endocrine disruptor; DES functions as a classical estrogen and directly stimulates HOXA10 expression with short-term exposure, however, in utero exposure results in hypermethylation of the HOXA10 gene and long-term altered HOXA10 expression. We identify hypermethylation as a novel mechanism of DES-induced altered developmental programming.
[Show abstract][Hide abstract] ABSTRACT: Infertile patients over the age of 40 are generally considered to have a low chance of success with assisted cycles despite high numbers of embryos transferred. The risk of multiple pregnancy in this group of patients is not well established. The present study determined the rate of embryos that fail to produce a live birth and the rate of multiple pregnancies in a cohort of women over the age of 40 undergoing IVF/intracytoplasmic sperm injection cycles, utilizing Society for Assisted Reproductive Technology reported cycle outcomes from national summaries as well as from two university-based IVF centres. The rate of embryo wastage for women over the age of 40 is approximately 95% and these women have a correspondingly low rate of multiple pregnancy per cycle started (2.5% and 1.6% for women aged 41-42 years and 43-44 years, respectively). These data underscore the low reproductive efficiency of oocytes in women over the age of 40 and the very low probability of a multiple-gestation live birth despite the high number of embryos transferred. This information is an important additional counselling tool at the time of embryo transfer in this group of patients.
[Show abstract][Hide abstract] ABSTRACT: In the last several decades, both the growing number of reproductive age cancer survivors, and the trend of women from western countries delaying child-bearing to a later age have been markedly increasing. The confluence of these two epidemiologic trends has led to the need for better and more widely available strategies for fertility preservation. In this paper, we will first review both the established and experimental methodologies which can be utilized for either the preservation or postponement of female fertility. These options currently include embryo and oocyte cryopreservation, cortical and whole ovary cryopreservation, ovarian transplantation, ovarian transposition, and gonadotropin releasing hormone agonist protection. As laboratory and surgical techniques for oocyte and ovary cryopreservation continue to improve, modalities now considered experimental will become part of routine practice for reproductive medicine specialists.
[Show abstract][Hide abstract] ABSTRACT: The present article describes the current status of embryo assessment in assisted reproductive technologies and discusses two important issues that derive, at least in part, from our inability to adequately assess the reproductive potential of individual embryos: low implantation rates and high multiple pregnancy rates. After an overview of studies evaluating embryo metabolism as a predictor of embryo viability, use of metabolomics and additional emerging approaches for rapid, noninvasive, embryo assessment are discussed.
Morphology and cleavage rate remain the mainstay of embryo assessment. A number of technologies are, however, under investigation. These include the assessment of glucose, lactate, pyruvate, and amino acid metabolism, proteomic profiling, evaluation of oxygen consumption, and most recently, examination of the metabolome.
As the number of assisted reproductive technology cycles increases worldwide, improvements in the ability to quickly and noninvasively determine the best embryos for transfer remain a critical goal for reproductive medicine. Recent studies suggest that metabolomic profiling of embryo culture media may provide a useful adjunct to the current embryo assessment strategies based on morphology and cleavage rate.
Current Opinion in Obstetrics and Gynecology 07/2008; 20(3):234-41. · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many studies have provided evidence that uterine myomas have a significant effect on IVF outcomes and there is a large body of evidence that treatment of uterine myomas increases fertility and pregnancy rates, and decreases the rate of pregnancy loss. The evidence supports treatment of all very large myomas (>7 cm) and any cavity-deforming submucosal myomas. Thus, sonohysterography should be considered an invaluable tool in the management of IVF patients with fibroids. While subserosal myomas that are smaller than 7 cm in size and intramural myomas of less than 4-5 cm in diameter appear to have little effect on IVF outcomes, larger intramural and subserosal myomas present a clinical dilemma and more studies are needed to clarify a definitive plan for management.
Expert Review of Obstetrics & Gynecology 06/2008; 3(4):515-521.
[Show abstract][Hide abstract] ABSTRACT: Decreasing multiple gestations while maintaining or improving overall pregnancy rates remains one of the most significant contemporary goals in the treatment of infertility. This necessitates an improvement over our current methodology for embryo assessment that is largely based on morphology and cleavage rate. Multiple studies of animal and human embryos have demonstrated that metabolic activity of in vitro grown embryos reflect their reproductive potential. Recent studies suggest that assessment of embryo metabolism by noninvasive metabolomic profiling of embryo culture media may provide a useful adjunct to morphologic embryo assessment and improve our ability to determine the reproductive potential of individual embryos.
Expert Review of Obstetrics & Gynecology 06/2008; 3(4):441-447.
[Show abstract][Hide abstract] ABSTRACT: Many pretreatment modalities used prior to ovulation induction have been proposed to increase the success rate in women undergoing assisted reproductive technologies. However, no clear evidence from well-designed clinical trials has shown a benefit of these treatments. We conducted a systematic review to explore the effect of different pretreatment therapies on outcomes of in vitro fertilization (IVF) cycles. Studies were limited to women treated prior to undergoing controlled ovarian hyperstimulation in IVF cycles with low-dose aspirin, metformin, growth hormone, oral contraceptives, or corticosteroid supplementation versus placebo or no supplementation. Searches were conducted in the Cochrane Library, MEDLINE, EMBASE, and ISI Proceedings, and all randomized controlled trials that evaluated the effectiveness of those therapies compared with placebo or no treatment in women before IVF were included. The main outcome measures considered were clinical pregnancy and live birth rates, miscarriage rate, number of oocytes retrieved, cycle cancellations, and the incidence of ovarian hyperstimulation syndrome. We conclude that, currently, no clear evidence indicates that using any of these pretreatment modalities is superior to no treatment in IVF cycles. Even when the studies are pooled, small sample size and low power preclude a complete assessment of adjuvant treatment modalities before ovulation stimulation in IVF cycles.
Annals of the New York Academy of Sciences 05/2008; 1127:31-40. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate proliferative phase endometrial development in a heterogeneous infertility population.
University-based infertility practice.
Two hundred forty-six treatment cycles.
Clomiphene citrate or FSH ovarian stimulation, followed by IUI or IVF.
Endometrial thickness according to transvaginal ultrasonography; clinical pregnancy rate.
Endometrial growth began from a nadir of approximately 4.5 mm on cycle day 4 and increased linearly to a plateau of approximately 10 mm on cycle day 9. This same pattern was observed in all cycles, regardless of pregnancy, drug, or underlying diagnosis. Follicle-stimulating hormone-stimulated cycles showed a significantly increased endometrial thickness compared with clomiphene citrate cycles (10.1 vs. 8.3 mm). Maximum endometrial thickness achieved showed a correlation with age, body mass index, and maximum E(2) level. Subjects who carried a primary diagnosis of polycystic ovary syndrome, endometriosis, or recurrent pregnancy loss all achieved a significantly lower peak endometrial thickness than control subjects. There was a trend toward increased endometrial thickness in cycles resulting in pregnancy compared with those not (10.1 vs. 9.6 mm, respectively).
Endometrial development follows a predictable pattern, with a plateau in growth at cycle day 9. Diseases associated with infertility manifest a proliferative phase defect that can be recognized clinically.
Fertility and sterility 04/2008; 91(3):698-704. · 3.97 Impact Factor