Highlights of the American Society for Reproductive Medicine (ASRM) 62nd Annual Conference

October 21-25, 2006; New Orleans, Louisanna

Peter Kovacs, MD

Disclosures

April 18, 2007

Introduction

The American Society for Reproductive Medicine (ASRM) held its 62nd annual conference in New Orleans in late October, 2006. After last year's hurricane, it was questionable whether New Orleans was going to be able to host the 2006 meeting. However, in spite of early adversity, the conference was very successful and well attended by participants from both North America and Europe. A record number of abstracts were submitted; more than 1000 were accepted for oral or poster presentations.

The most significant topics at the meeting were polycystic ovary syndrome (PCOS), contraception, preimplantation genetic diagnosis (PGD), and measures that could improve assisted reproductive technology (ART) outcome -- primarily single embryo transfer. The following summary will provide highlights from some of the presentations that focused on these topics.

During the past quarter-century, ART has undergone tremendous improvements. New drugs, better understanding of early embryo development, and other technological improvements have contributed to continuously increasing rates of success.

However, as implantation has become more successful, the occurrence of multiple gestations has emerged as a major problem related to in vitro fertilization (IVF). According to recent reports, 25% to 50% of IVF pregnancies are multiple gestations. Because a multifetal pregnancy is associated with excess maternal and fetal/ neonatal risks, most experts consider even a twin pregnancy to be an adverse outcome. Understanding the magnitude of the problem, most reproductive societies or professional organization now recommend limiting the number of embryos transferred. Indeed, in some countries the number of embryos that can be transferred is limited to 1.

Although limiting the number of embryos transferred has been the professional response to the increased rate of multiple gestations, patient needs must still be considered. Van der Veen and colleagues[1] surveyed patients (n = 244) about feelings and choices related to single embryo transfer (SET). Specifically, they wanted to determine if women were willing to accept the lower success rate associated with SET to avoid the possibility of a multiple gestation and whether they were willing to undergo additional IVF cycles if needed to achieve a pregnancy.

When the pregnancy rates after single and double embryo transfer were set at a similar level, only 46% of women indicated they would choose SET. If the pregnancy rate with SET was 1%, 3%, or 5% below the pregnancy rate following double embryo transfer, the percent of women selecting SET further decreased to 34%, 24%, and 15%, respectively. If 4, 5, or 6 cycles of SET were needed to achieve similar cumulative pregnancy rates similar to those with use of 3 cycles of double embryo transfer, the proportion of women choosing SET dropped to 40%, 36%, and 35%, respectively.

The conclusion was that some patients may not be ready to accept lower pregnancy rates achieved with SET; they would rather take the risk associated with a multiple gestation. Therefore, the desire for a singleton pregnancy by the medical community and the patients' desire for high success rates both need to be considered.

Databases from numerous clinics were used to identify patients for which elective SET might be appropriate. Typically, patient, cycle, and embryo characteristics were considered. Jackson[2] presented findings from an evaluation of outcome following day 3 single (n = 98) or double (n = 87) embryo transfers among women younger than 35 years of age undergoing a first IVF cycle and who had at least 3 top quality embryos. In those cycles, where less than 4 surplus embryos were available for cryopreservation, cumulative pregnancy rates (fresh + frozen embryo transfer) were lower with SET. However, in cycles where more than 4 surplus embryos were available for cryopreservation, cumulative pregnancy rates did not differ following single or multiple embryo transfer. The investigators concluded that in patients with good prognoses, where 5 or more embryos were available for cryopreservation, pregnancy rates were not compromised by elective SET on day 3.

When good prognosis is defined, most infertility specialists include the criterion "younger than age 35." However, at least 50% of IVF cycles are carried out among individuals older than age 35, and at least 50% of resulting multiple gestations occur in this age group. Davis and colleagues[3] assessed whether SET had a role in an older patient population. They retrospectively analyzed IVF cycles where the patient elected to undergo elective single blastocyst transfer (elective defined as at least 2 available blastocysts). Data were available from 38 cycles; 67% of the patients had a positive pregnancy test and the ongoing pregnancy rate was 55%. They concluded that elective single blastocyst transfer does have a role in the management of infertile women older than age 35 when the embryos display good morphologic features on day 3.

Saldeen and Sundstrom[4] also evaluated results of SET in the "older" age group (aged 36-39 years, n = 418). Historic controls with double embryo transfer were used for comparison. When top quality embryos were available, no difference was found in pregnancy rates between groups (31% vs 32%), but a significant reduction in twinning rate in the SET group was demonstrated (0.9% vs 13%).

When SET was offered to patients with at least 2 top quality embryos, 53% (n = 266) elected to undergo SET. Aurell[5] found pregnancy rates lower in the SET group when compared with double embryo transfer (46.6% vs 57.6%), but the twin rate was lower as well (0.8% vs 28.8%). Overall, these investigators reported a good pregnancy rate and very low twinning rate with SET.

Anderson and colleagues[6] evaluated treatment outcome following SET or multiple embryo transfer, with outcome evaluated with respect to surplus embryo availability for cryopreservation. When additional embryos were available, the transfer of multiple embryos did not improve pregnancy rates, but was associated with a higher multiple gestation rate. In the SET group, a significantly higher pregnancy rate was achieved when cryopreservation was available (61% vs 28%). The pregnancy rate in the SET group with cryopreservation was similar to the pregnancy rate in the multiple embryo transfer group. The researchers concluded that in cycles where surplus embryos were available for cryopreservation, SET was appropriate.

Frozen vs Fresh Embryo. In a second presentation, Anderson[7] provided data from evaluation of a single transfer using frozen embryo transfer (n = 92 multiple embryo transfer and 48 SET). The pregnancy rates achieved were similar in the groups (99/192 vs 22/48). However 30% of the pregnancies were multiples in the multiple embryo transfer group.

Cumulative pregnancy rates following fresh (all SET) and frozen (1 or 2 embryos) blastocyst transfers were assessed by Waldenstrom and colleagues.[8] Based on 1072 SET cycles and resulting freeze-thaw cycles, 673 clinical pregnancies were achieved (63% cumulative pregnancy rate). Based on their results, they recommend single blastocyst transfer in cycles among women younger than 39 years of age when surplus blastocysts for cryopreservation are available.

These and data from other presentations not included in this summary point to a similar conclusion; that the elective transfer of a single embryo (mainly blastocysts) has a role in the care of infertile couples. By transferring a single embryo, multiple gestations can essentially be eliminated without compromising treatment outcome. Younger women (but according to some women up to age 39 could be considered) with at least 2 top quality embryos could especially benefit from this approach. When surplus embryos are available for cryopreservation, pregnancy rates are minimally affected and cumulative pregnancy rates (fresh + frozen embryo transfer) are similar.

Polycystic ovary disease (PCOS) was one of the main topics of this year's ASRM. The President's guest lecture, given by Dr. Andrea Dunaif,[9] was dedicated to the metabolic aspects of PCOS. The syndrome is the most common endocrine abnormality affecting reproductive age women, and is diagnosed in 80% to 90% of patients with irregular menstrual cycles. It is estimated that 5% to 7% of reproductive age women are affected by PCOS. Some racial differences have been identified; the incidence of the syndrome is higher among Hispanics and infrequent among Asians. There are important geographical differences as well; in the United States, women with PCOS typically have a higher body mass index (BMI) compared with European women with the syndrome.

The reproductive consequences of the disease are well known, but the long-term metabolic complications have only gained attention in the past decade or so. Insulin resistance and pancreatic beta cell dysfunction are thought to play a key role in pathogenesis. It is now well documented that women with PCOS are at an increased risk for glucose intolerance (3-fold), type 2 diabetes (10-fold), and dyslipidemia (elevated cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides). Obesity further augments risk. The threat of metabolic syndrome (low high-density lipoprotein, elevated triglycerides, increased waist circumference [> 88 cm], elevated fasting glucose [> 110 mg/dL], elevated blood pressure [> 130/80 mm Hg]; 3 of 5 documented) is also increased.

It is very disturbing that the risk of metabolic syndrome is increasing among teenagers. It is still debated whether hyperandrogenism or insulin resistance plays the primary role in the pathogenesis of the syndrome. Increased androgen secretion alters the pituitary gonadotropin output and thus worsens insulin resistance. Insulin, on the other hand, augments ovarian androgen secretion. The higher the bioavailable androgen level, the higher the risk of the metabolic syndrome.

Therapeutic trials have shed some light on the role of insulin resistance and androgens. Metformin, an insulin sensitizer, has been shown to reduce body weight and visceral fat. Flutamide, an anti-androgen, was found to have similar effects. The combination of the 2 agents resulted in additive benefits. Such studies proved that androgens play a role in the pathogenesis of the metabolic syndrome.

In addition to metabolic factors, genetic components also play a key role in the pathogenesis of PCOS. Family studies point to a nonMendelian inheritance. Sisters and brothers of those affected by PCOS also have higher androgen levels (primarily dihydroepiandrosterone). Insulin resistance and elevated LDL cholesterol are more often seen among sisters, brothers, and mothers of patients with PCOS, with the metabolic syndrome more often diagnosed in sisters and mothers of individuals with PCOS.

Candidate genes (PCOS genes) have been mapped to the insulin receptor coding region on chromosome 19. It is now believed that those with a genetic risk are exposed to higher androgen levels in the prenatal and postnatal period. Androgens interfere with normal estradiol feedback, leading to chronically elevated leutenizing hormone (LH) levels. This would explain the reproductive phenotype. Androgens also worsen insulin resistance and therefore play a part in the pathogenesis of the metabolic syndrome. Once the exact mechanism is understood, further therapeutic options should become available. Until than, it is important to recognize that infertility care is not the only attention that patients with PCOS require. Long-term follow-up for metabolic complications is needed.[9]

Recent Findings: PCOS and Infertility. The use of various insulin sensitizing drugs has also been evaluated in those with PCOS and infertility. Based on the available published data, insulin sensitizing medications, especially metformin, seem to improve ovulation/ pregnancy rates and pregnancy outcome. However, most studies have been affected by small sample size, the evaluation of intermediate outcome parameters, and use of different inclusion criteria. Therefore, the Reproductive Medicine Network designed a multicenter, double-blind randomized trial to compare the effect of metformin to clomiphene citrate (CC) and to the combination of the 2 drugs.[10]

In the Network investigation, 626 participants with PCOS were randomized to 1 of 3 groups; CC alone, metformin alone, or CC+metaformin. Ovulation was evaluated by regular progesterone measurements. Study medications were continued until pregnancy was achieved, or for 6 cycles or 6 months of treatment.

Baseline characteristics were well matched in the 3 arms. Live birth rates were 22.5% in the CC arm, 26.5% in the combination arm, and only 7.2% in the metformin arm. CC and combination treatment were both significantly more likely to result in a live birth than metformin alone. The weight of participants did not affect this outcome.

Multiple gestation rates were low in all arms, with 6.4% in the CC group being the highest rate seen. Miscarriage rates were also similar in all arms but a trend for higher loss rate was noted in the metformin group, even though all medications were stopped once pregnancy was documented.

Findings from this study are likely to lead to significant changes in the way the treatment infertility is approached in patients with PCOS. CC is likely to regain its place as the first line drug for PCOS treatment. It still needs to be determined whether combination therapy should be offered to those who fail CC treatment, or if gonadotropins should be used as a next step. It also needs to be decided whether insulin sensitizing drugs (if used) should be continued once pregnancy has been established. ASRM is likely to come out with new practice guidelines in light of these findings.

Recent Findings: PCOS and Pregnancy. It is generally recognized that problems patients with PCOS face are not over once pregnancy has been achieved. A number of potential problems related to PCOS have been previously described. Feigenbaum and colleagues[11] assessed the risk of miscarriage among pregnant individuals with PCOS. Cases (PCOS diagnosis) and controls (other infertility diagnosis) were identified from a database; pregnancies were followed up to 20 weeks of gestation. The overall miscarriage rate was 25%, with no significant differences between groups detected. Adjustments for age, BMI, race, and treatment type did not affect miscarriage rates. These data failed to support a higher rate of pregnancy loss among women with PCOS.

Previously, a higher risk of birth defects among infants conceived through IVF was found in a retrospective analysis of 1805 infants conducted by Olson and colleagues.[12] At this meeting, further data specifically focused on whether the diagnosis of infertility was associated with any excess risk in the infant were presented.[13] Results showed that among individuals with a diagnosis of ovulatory defect/ PCOS, the risk of birth defects (major and minor) was increased 2.5-fold when compared with controls.

Preimplantation genetic diagnosis (PGD) allows genetic analysis of the embryos before implantation. Typically, 1 or 2 blastomeres are removed on day 3 after fertilization, and either polymerase chain reaction (PCR) to detect single gene defects or fluorescent in situ hybridization (FISH) to check the number and structure of chromosomes is performed.

Preimplantation genetic diagnosis has now been differentiated from preimplantation genetic screening (PGS). During PGD, a known genetic problem is ruled out; during PGS, a number of potentially abnormal chromosomes are evaluated. Although the role of genetic diagnosis is self-explanatory, the exact role of genetic screening is less obvious. It is believed that women with recurrent miscarriages, recurrent implantation failure, and those who are older might benefit. Since results from previously published studies have been controversial, it should come as no surprise that numerous presentations at ASRM were focused on PGD.

Outcomes following blastocyst transfer combined with PGS were compared with analyses of 9 chromosomes among young normal responder patients by Miller and colleagues.[14] In this investigation, the embryo biopsy did not affect development to the blastocyst stage. Clinical pregnancy and implantation rates were similar between groups. Only 37% of the embryos were normal in this cohort of patients (< 38 years).

Other groups also assessed whether embryo development could be correlated with PGS results. Kearns and colleagues[15] evaluated IVF cycles where PGS was performed (n = 147) for recurrent abortion, recurrent implantation failure, or for advanced maternal age. Overall, 22.7% of the embryos were normal for all 9 chromosomes checked. The percentage of normal embryos increased with the number of blastomeres on day 3 and an inverse relationship with the amount of fragmentation was found. Additionally, embryos that developed to the blastocyst stage were more likely to be chromosomally normal (34.1% vs 15.2%).

Harris and colleagues[16] compared embryo morphology and PGS results in a retrospective analysis of 111 IVF cycles. An embryo was considered top quality if it contained at least 4 cells on day 2, 7 cells on day 3, and the amount of fragmentation was less than 20%. Sixty-nine percent of the top-quality embryos made it to the blastocyst stage and 36.1% of them were euploid for all 9 chromosomes evaluated. Embryos not meeting these criteria were less likely to develop to the blastocyst stage (39%) and less likely to be euploid (28.9%). Clinical pregnancy and implantation rates were higher when at least 1 top-quality embryo was transferred.

Higher blastocyst formation rates and lower aneuploidy rates were found among embryos with 8 cells and less than 15% fragmentation of day by Buendia and colleagues.[17] Those with more than 8 cells and those with less than 6 were less likely to develop to the blastocyst stage and to be chromosomally normal.

A multicenter study conducted by Munne and colleagues[18] evaluated use of PGD among translocation carriers with a history of recurrent abortion. Before PGD, 79% of the pregnancies were lost (637/808). In PGD cycles, the loss rate was reduced to 9% (9/95). Before PGD, 132/808 pregnancies (16%) resulted in live birth. The live birth rate increased to 27% following 1 cycle of IVF-PGD (80/202). Patients with translocations and a history of recurrent pregnancy loss seem to benefit from undergoing PGD.

Another yet unsettled debate is whether 1 or 2 blastomeres should be removed for analysis. By removing 2 blastomeres, the results of the FISH analysis could be confirmed in a second cell. This should increase the detection rate (fewer embryos where information cannot be given due to lack of signal) and could reduce the error rate due to mosaicism. Cinnioglu[19] evaluated the effect of mosaicism on PGD outcome based on the analysis of all cells in non-replaced embryos. They found that 6/26 embryos had all normal cells. The remaining embryos were considered normal if more than 50% of the cells had normal chromosomes. Considering these cut-off levels, 6.5% of the embryos would have been misdiagnosed (due to mosaicism) following the biopsy of 1 cell only.

Amorocho and colleagues[20] evaluated whether removal of 1 vs 2 cells affected IVF-PGD cycle outcome. Definite diagnosis could not be made in similar proportion of the cycles in the groups (5.4% vs 3.5%). However, blastocyst conversion rates were comparable; 42.2% in the 1-cell biopsy group and 45.5% of the embryos in the 2-cell group were normal. Pregnancy and implantation rates were also similar. The additional removal of a second blastomere for analysis was not found to provide additional benefit.

PGD is considered a safe method for the genetic analysis of embryos prior to transfer. It appears that morphologic characteristics of embryos show some correlation with genetic content. Embryos that progress nicely, make it to the blastocyst stage, and contain minimal fragmentation are less likely to be aneuploid. Older women, and couples with recurrent miscarriage and recurrent implantation failure seem to benefit the most with this additional evaluation.

Increasing numbers of patients ask about and/or turn to alternative medical solutions when traditional medicine fails. Patients with failed IVF are no exception. There are numerous interventions that are incorporated into daily practice without any or without sufficient evidence supporting efficacy. Several recently published studies have evaluated the effect of acupuncture during IVF. Some investigators at this year's meeting also assessed the potential benefit of acupuncture.

Benson and colleagues[21] compared needle acupuncture, laser acupuncture, relaxation, sham laser acupuncture, and no intervention in 481 women undergoing IVF. Chemical, clinical pregnancy, and implantation rates were highest in the needle acupuncture group, but none of the method differences reached statistical significance. In a retrospective analysis, Lehl and co-investigators[22] compared IVF outcome in cycles where acupuncture was used to cycles where acupuncture was not conducted. Age was controlled for. No benefit associated with acupuncture use during IVF was found.

The mechanism(s) for how acupuncture could affect infertility is not known. Magarelli and colleagues[22] evaluated a possible connection with prolactin and cortisol levels (acupuncture vs no acupuncture). These levels were measured during and after an IVF cycle in 22 patients and compared to control cycles without acupuncture. Prolactin levels tended to be higher during stimulation and were elevated in the luteal phase among patients that did not receive acupuncture. Cortisol did not follow any specific trend in either group. Based on these findings, they contended that modulation of reproductive and "stress" hormone levels with acupuncture is a possible explanation of infertility modifying effect.

Although acupuncture might improve IVF outcome, convincing evidence is not yet available. Data presented at this meeting and from other reports should serve as the basis for future randomized, placebo-controlled trials.

It is impossible to review all the important topics from the meeting. There is a constant need to further improve infertility care and make procedures safer and more efficacious. In addition to developing new interventions or medications, it is equally crucial to constantly evaluate currently applied methods. The multicenter, randomized study comparing metformin vs CC among women with PCOS is an example of such an evaluation. The findings from this study are likely to change the way PCOS-related infertility is approached. This investigation also showed that important questions can only be answered by appropriately designed and powered trials.

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