Lora K. Shahine

Poor Prognosis with In Vitro Fertilization in Indian Women Compared to Caucasian Women Despite Similar Embryo Quality

Background Disease prevalence and response to medical therapy may differ among patients of diverse ethnicities. Poor outcomes with in vitro fertilization (IVF) treatment have been previously shown in Indian women compared to Caucasian women, and some evidence suggests that poor embryo quality may be a cause for the discrepancy. In our center, only patients with the highest quality cleavage stage embryos are considered eligible for extending embryo culture to the blastocyst stage. We compared live birth rates (LBR) between Indian and Caucasian women after blastocyst transfer to investigate whether differences in IVF outcomes between these ethnicities would persist in patients who transferred similar quality embryos. Methodology/Principal Findings In this retrospective cohort analysis, we compared IVF outcome between 145 Caucasians and 80 Indians who had a blastocyst transfer between January 1, 2005 and June 31, 2007 in our university center. Indians were younger than Caucasians by 2.7 years (34.03 vs. 36.71, P = 0.03), were more likely to have an agonist down regulation protocol (68% vs. 43%, P<0.01), and were more likely to have polycystic ovarian syndrome (PCOS), although not significant, (24% vs. 14%, P = 0.06). Sixty eight percent of Indian patients had the highest quality embryos (4AB blastocyst or better) transferred compared to 71% of the Caucasians (P = 0.2). LBR was significantly lower in the Indians compared to the Caucasians (24% vs. 41%, P<0.01) with an odds ratio of 0.63, (95%CI 0.46–0.86). Controlling for age, stimulation protocol and PCOS showed persistently lower LBR with an adjusted odds ratio of 0.56, (95%CI 0.40–0.79) in the multivariate analysis. Conclusions/Significance Despite younger age and similar embryo quality, Indians had a significantly lower LBR than Caucasians. In this preliminary study, poor prognosis after IVF for Indian ethnicity persisted despite limiting analysis to patients with high quality embryos transferred. Further investigation into explanations for ethnic differences in reproduction is needed.

Defining human embryo phenotypes by cohort-specific prognostic factors.

Background Hundreds of thousands of human embryos are cultured yearly at in vitro fertilization (IVF) centers worldwide, yet the vast majority fail to develop in culture or following transfer to the uterus. However, human embryo phenotypes have not been formally defined, and current criteria for embryo transfer largely focus on characteristics of individual embryos. We hypothesized that embryo cohort-specific variables describing sibling embryos as a group may predict developmental competence as measured by IVF cycle outcomes and serve to define human embryo phenotypes. Methodology/Principal Findings We retrieved data for all 1117 IVF cycles performed in 2005 at Stanford University Medical Center, and further analyzed clinical data from the 665 fresh IVF, non-donor cycles and their associated 4144 embryos. Thirty variables representing patient characteristics, clinical diagnoses, treatment protocol, and embryo parameters were analyzed in an unbiased manner by regression tree models, based on dichotomous pregnancy outcomes defined by positive serum ß-human chorionic gonadotropin (ß-hCG). IVF cycle outcomes were most accurately predicted at ∼70% by four non-redundant, embryo cohort-specific variables that, remarkably, were more informative than any measures of individual, transferred embryos: Total number of embryos, number of 8-cell embryos, rate (percentage) of cleavage arrest in the cohort and day 3 follicle stimulating hormone (FSH) level. While three of these variables captured the effects of other significant variables, only the rate of cleavage arrest was independent of any known variables. Conclusions/Significance Our findings support defining human embryo phenotypes by non-redundant, prognostic variables that are specific to sibling embryos in a cohort.

Deep phenotyping to predict live birth outcomes in in vitro fertilization

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVFBT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003–2006, followed by external validation with 634 cycles from 2007–2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVFBT, that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p < 0.05), and increased discrimination by receiver–operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVFBT provided predictions that were more accurate for ∼83% of C1 and ∼60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.

Asian ethnicity and poor outcomes after in vitro fertilization blastocyst transfer.

OBJECTIVE: To estimate the effect of ethnicity on in vitro fertilization (IVF) outcomes after blastocyst transfer. METHODS: We conducted a review of fresh blastocyst transfer IVF cycles from January 1, 2005, to December 31, 2006. Data collection included demographic information, infertility history, treatment protocol details, and treatment outcomes. Statistics were performed using the Student t test and &khgr;2 test. To establish the independent contribution of Asian ethnicity, a multivariable logistic regression analysis was performed. RESULTS: We reviewed 180 blastocyst transfer cycles among white (62%) and Asian (38%) women. The groups were similar in most baseline characteristics. Asian women, however, had a lower body mass index (22.6 compared with 24.2, P=.02), were more likely to be nulligravid (53% compared with 35%, P=.03), and were more likely to have had at least one prior IVF cycle (37% compared with 20%, P=.02) The groups were similar in treatment characteristics, number of oocytes retrieved, fertilization rate, and number of blastocysts transferred. However, Asian women had a thicker endometrial lining (10.9 compared with 10.2, P=.02). Despite these similarities, Asian women had a lower implantation rate (28% compared with 45%, P=.01), clinical pregnancy rate (43% compared with 59%, P=.03), and live birthrate (31% compared with 48%, P=.02). In multivariable analysis, the decreased live birthrate among Asian women persisted (adjusted odds ratio 0.48, 95% confidence interval 0.24–0.96, P=.04). CONCLUSION: When compared with white women, Asian women have lower clinical pregnancy and live birthrates after blastocyst transfer. LEVEL OF EVIDENCE: II

Recurrent Pregnancy Loss : Evaluation and Treatment

Recurrent pregnancy loss (RPL) is a multifactorial condition. Approximately half of patients with RPL will have no explanation for their miscarriages. De novo chromosome abnormalities are common in sporadic and recurrent pregnancy loss. Testing for embryonic abnormalities can provide an explanation for the miscarriage in many cases and prognostic information. Regardless of the cause of RPL, patients should be reassured that the prognosis for live birth with an evidence-based approach is excellent for most patients. The authors review current evidence for the evaluation and treatment of RPL and explore the proposed use of newer technology for patients with RPL.

Ovarian stimulation and the risk of aneuploid conceptions

OBJECTIVE To examine the rate of aneuploidy in missed abortions in patients who conceived after FSH ovarian stimulation compared with women who conceived in a natural cycle. DESIGN Retrospective cohort. SETTING Academic reproductive endocrinology and infertility center. PATIENT(S) Women with karyotyping of products of conception (POC) from a missed abortion from January 1999 through August 2007. The rate of aneuploidy was compared between patients with a history of infertility who conceived naturally and patients with a history of infertility who conceived with FSH treatment. INTERVENTION(S) Ovarian stimulation with FSH, intrauterine insemination, and in vitro fertilization; genetic testing of POC after dilation and curettage. MAIN OUTCOME MEASURE(S) Embryonic karyotype. RESULT(S) A total of 229 pregnancies met inclusion criteria, and of these, 64% had an abnormal karyotype. The rate of aneuploidy was 63% in the study group and 70% in the control group. This difference was not statistically significant. CONCLUSION(S) The incidence of embryonic aneuploidy was not higher in pregnancies conceived with FSH stimulation compared with spontaneous conceptions in infertility patients. This suggests that exogenous FSH exposure does not increase the risk of aneuploidy.

Embryo quality before and after surgical treatment of endometriosis in infertile patients

PurposeTo investigate the hypothesis that surgical treatment of endometriosis in infertile patients may improve pregnancy rates by improving embryo quality.MethodsWe conducted a retrospective evaluation of 30 infertile patients treated with in vitro fertilization (IVF) before and after surgery for endometriosis. Patients served as their own controls and only cycles with similar stimulation protocols were compared.ResultsUsing standard visual evaluation, embryo quality on day 3 was similar before and after surgical treatment of endometriosis. Fifty seven percent of patients had stage I–II endometriosis and 43% had stage III–IV disease. No patients had a live birth after the first IVF cycle and 43% of patients had a live birth with the IVF cycle after surgery.ConclusionsSurgical treatment of endometriosis does not alter embryo quality in patients with infertility treated with IVF.

Preimplantation genetic diagnosis: the earliest form of prenatal diagnosis.

Preimplantation genetic diagnosis (PGD) can provide genetic information on embryos obtained through in vitro fertilization (IVF), allowing implantation of embryos identified as unaffected with a given genetic or chromosomal disorder. With the availability of increasingly sophisticated genetic testing, its use has advanced from the selection of female embryos for the prevention of X-linked genetic diseases to testing for single gene disorders via PCR. Recently, PGD has also been used in the setting of assisted reproductive technology to select for chromosomally normal embryos in an effort to increase the rates of implantation and successful pregnancy. As the number of patients undergoing IVF increases, the indications for its use broadens, and more mutations underlying genetic disorders are identified, PGD is becoming more widespread. As this evolution continues, recognition of the limitations of PGD, as well as ethical concerns regarding use and misuse of this technology, need to be considered by patients, clinicians, and policy makers.

Embryo selection with preimplantation chromosomal screening in patients with recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a multifactorial disorder which is often challenging for both patients and providers. Guidelines for the evaluation and treatment of patients with RPL include screening for uterine abnormalities, parental chromosomes, and antiphospholipid antibodies, but approximately half of RPL patients remain unexplained. The current recommendation for patients with unexplained RPL is expectant management which offers most patients a 60 to 80% success rate over time. Genetic imbalances in the embryo, including inherited unbalanced translocations and de novo aneuploidy, are frequent causes of miscarriage. Preimplantation genetic screening (PGS) has been proposed as an effective method for selecting viable embryos for transfer that may result lower risk of miscarriage for patients with unexplained RPL and carriers of balanced translocations. The current evidence examining the use of in vitro fertilization with PGS in patients with RPL reveals variable results, due to differences in technologies used and variable patient populations. Newer approaches, which include blastocyst biopsy and the ability to screen for all 24 chromosomes, show the most promise in reducing miscarriage rates. Studies that identify which patients are most likely to benefit from PGS and include live birth rates per initiated cycles are needed before universally recommending this treatment to couples with RPL.

Oocyte retrieval versus conversion to intrauterine insemination in patients with poor response to gonadotropin therapy.

We compared cycle characteristics and outcomes for planned in vitro fertilization cycles with five or fewer developing follicles that proceeded to retrieval (n = 170) with those that converted to intrauterine insemination (IUI) (n = 50). The risk of no embryo transfer was 24% in cycles that proceeded to retrieval. Live birth rate per cycle started was similar for IUI (6%) compared with retrieval (7%).