Faculty Bibliography

In a study conducted at the New York University Fertility Center, one of the scientific objectives is to investigate the relationship between the final pregnancy outcomes of participants receiving an in vitro fertilization (IVF) treatment and their beta-human chorionic gonadotrophin (beta-hCG) profiles. A common joint modeling approach to this objective is to use subject-specific normal random effects in a linear mixed model for longitudinal beta-hCG data as predictors in a model (e.g., logistic model) for the final pregnancy outcome. Empirical data exploration indicates that the observation times for longitudinal beta-hCG data may be informative and the distribution of random effects for longitudinal beta-hCG data may not be normally distributed. We propose to introduce a third model in the joint model for the informative beta-hCG observation times, and relax the normality distributional assumption of random effects using the semi-nonparametric (SNP) approach of Gallant and Nychka (1987) [8]. An EM algorithm is developed for parameter estimation. Extensive simulation designed to evaluate the proposed method indicates that ignoring either informative observation times or distributional assumption of the random effects would lead to invalid and/or inefficient inference. Applying our new approach to the data reveals some interesting findings the traditional approach failed to discover.

OBJECTIVE: To determine any beneficial effects of preimplantation genetic screening (PGS) of all chromosomes by array comparative genomic hybridization (aCGH), with either day 3 or blastocyst biopsy, for idiopathic recurrent pregnancy loss (RPL) patients compared with their expected loss rate. DESIGN: Case series report. SETTING: Multiple fertility centers. PATIENT(S): A total of 287 cycles of couples with idiopathic RPL (defined as two or more losses). INTERVENTION(S): PGS was done with day 3 biopsy (n = 193) or blastocyst biopsy (n = 94), followed by analysis with aCGH. MAIN OUTCOME MEASURE(S): Spontaneous abortion rate, euploidy rate. RESULT(S): A total of 2,282 embryos were analyzed, of which 35% were euploid and 60% were aneuploid. There were 181 embryo transfer cycles, of which 100 (55%) became pregnant with an implantation rate of 45% (136 sacs/299 replaced embryos) and 94 pregnancies (92%) were ongoing (past second trimester) or delivered. The miscarriage rate was found to be only 6.9% (7/102), compared with the expected rate of 33.5% in an RPL control population and 23.7% in an infertile control population. CONCLUSION(S): Current PGS results with aCGH indicate a significant decrease in the miscarriage rate of idiopathic RPL patients and high pregnancy rates. Furthermore, this suggests that idiopathic recurrent miscarriage is mostly caused by chromosomal abnormalities in embryos.

PURPOSE: To estimate the prevalence of chromosomally abnormal related miscarriages in an infertile population. METHODS: Retrospective analysis of cytogenetics obtained by chorionic villi harvesting of the first miscarriage cycle of infertile patients at our center from 2001-2010 were reviewed. Abnormal results were characterized as trisomy, monosomy X, structural, or other. Age, # of eggs, #2PN, # embryos transferred, day of transfer, and performance of intracytoplasmic sperm injection (ICSI) were recorded. RESULTS: In a study population of 299 patients with a mean age of 38.0 +/- 4.5 y, 276(92 %) patients had some form of assisted reproductive technologies (ART), and 244(82 %) had IVF. Of all results, 71.6 % had an abnormal karyotype. Patients with abnormal cytogenetics were older (38.6 +/- 4.1 vs. 36.3 +/- 4.9, p < 0.001), and more likely to have a day 3 transfer (age < 38 ( 20.7 %) vs. age 38 (46.3 %), p = <0.001) with more embryos transferred (3.0 +/- 1.2, vs. 2.3 +/- 0.9, p < 0.001). The performance of ICSI did not affect the rate of cytogenetically abnormal products of conception (ICSI 68.3 % vs. no ICSI 70.7 %). In comparing patients, monosomy X was more common in <38 y. Rates of trisomy, although not statistically significant, were higher in older patients. CONCLUSIONS: The classic associations between advancing age and chromosomal abnormalities, and younger age and monosomy X, are affirmed in our infertile population. There was no increase in chromosomal abnormalities in cycles where ICSI was performed. Older patients are more likely to have day 3 transfers and more embryos transferred. Our chromosomal abnormality rates are higher than classic estimates but comparable to recent studies. The limitation of this study was a lack in uniformity among practitioners in recommending all patients have a Dilation and Curettage (D&C) at time of diagnosis. Such information may serve to improve the counseling of patients after miscarriage.

OBJECTIVE: To determine if patients, less than 40 years of age with or without day 5 cryopreservation (d5 cryo), compromise their pregnancy rate (PR) by choosing an eSBT. DESIGN: Retrospective analysis SETTING: University IVF center PATIENTS: 2,203 non-donor fresh IVF cycles in women <40 years of age from January 2004 to January 2010. INTERVENTIONS: None MAIN OUTCOME MEASURE(S): Eggs retrieved, Embryos cryopreserved, Implantation Rates, Clinical Pregnancy Rates, Live Birth Rates, Spontaneous Abortion Rates RESULTS: Pregnancy outcomes in women <40 years with or without d5 cryo were compared according to whether patients underwent an eSBT versus a 2BT in non-donor fresh IVF cycles. Overall, eSBT was associated with elimination of twinning while maintaining a high clinical pregnancy rate in both groups with d5 cryo (75 % eSBT versus 72 % 2BT) and groups without d5 cryo (48 % eSBT versus 56 % 2BT). CONCLUSIONS: In this study, patients <40 years of age have eliminated twinning by electively choosing to transfer a single blastocyst without compromising their PR if embryos are available for d5 cryo, and suffer only a non-statistically significant drop in their PR if there are no embryos available for d5 cryo in exchange for the benefit of eliminating the obstetrical risk of twinning.

Human embryonic stem cells (hESCs) have the potential to revolutionize many biomedical fields ranging from basic research to disease modeling, regenerative medicine, drug discovery and toxicity testing. A multitude of hESC lines have been derived worldwide since the first five lines by Thomson and colleagues 13 years ago, but many of these are poorly characterized, unavailable or do not represent desired traits, thus making them unsuitable for application purposes. In order to provide the scientific community with better options, we have derived twelve new hESC lines at New York University from discard genetically normal and abnormal embryos using the latest techniques. We examined the genetic status of the NYUES lines in detail as well as their molecular and cellular features and DNA fingerprinting profile. Furthermore, we differentiated our hESCs into the tissues most affected by a specific condition or into clinically desired cell types. To our knowledge, a number of characteristics of our hESCs have not previously been reported, e.g. mutation for alpha thalassemia X-linked mental retardation syndrome, linkage to conditions with a genetic component such as asthma or poor sperm morphology and novel combinations of ethnic backgrounds. Importantly, all of our undifferentiated euploid female lines tested to date did not show X chromosome inactivation, believed to result in superior potency. We continue to derive new hESC lines and add them to the NIH registry and other registries. This should facilitate the use of our hESCs and lead to advancements for patient-benefitting applications

Fluorescent in-situ hybridization (FISH) for preimplantation genetic diagnosis (PGD) of structural chromosome abnormalities has limitations, including carrier testing, inconclusive results and limited aneuploidy screening. Array comparative genome hybridization (CGH) was used in PGD cases for translocations. Unbalances could be identified if three fragments were detectable. Smallest detectable fragments were approximately 6 Mbp and approximately 5 Mbp for blastomeres and trophectoderm, respectively. Cases in which three or more fragments were detectable by array CGH underwent PGD by FISH and concordance was obtained in 53/54 (98.1%). The error rate for array CGH was 1.9% (1/54). Of 402 embryos analysed, 81 were normal or balanced, 92 unbalanced but euploid, 123 unbalanced and aneuploid and 106 balanced but aneuploid. FISH with additional probes to detect other aneuploidies would have missed 28 abnormal embryos in the reciprocal group and 10 in the Robertsonian group. PGD cases (926) were retrospectively reviewed for reciprocal translocations performed by FISH to identify which could have been analysed by array CGH. This study validates array CGH in PGD for translocations and shows that it can identify all embryos with unbalanced reciprocal and Robertsonian translocations. Array CGH is a better approach than FISH since it allows simultaneous screening of all chromosomes for aneuploidy.

Superovulation procedures and assisted reproductive technologies (ART) have provided the means for significant improvement in infertility care. Although generally safe, these procedures are associated with complications that, albeit rare, can have significant morbidity. Complications from superovulation include ovarian hyperstimulation syndrome, thromboembolism, and adnexal torsion. Complications from oocyte retrieval include infection, bleeding, bowel injury, and anesthetic complications. Early pregnancy complications from in vitro fertilization include multiple gestations, ectopic pregnancy, and heterotopic pregnancy. Stimulation, retrieval, and transfer techniques can be modified to minimize these risks and prevent complications. Further research in the field is needed to continue to improve the safety of superovulation and ART.

PURPOSE: We determined whether the use of intracytoplasmic sperm injection in couples who previously underwent intracytoplasmic sperm injection cycles elsewhere could be decreased without compromising the pregnancy rate. MATERIALS AND METHODS: At our university in vitro fertilization-embryo transfer center we retrospectively analyzed the records of 149 fresh, in vitro fertilization-embryo transfer cycles in patients who underwent intracytoplasmic sperm injection elsewhere and subsequent fertilization by insemination only (all insemination group) or half insemination and half intracytoplasmic sperm injection at our center. We compared fertilization, implantation, clinical pregnancy and live birth rates. RESULTS: The fertilization rate was 74% and 73% for the all insemination and the half intracytoplasmic sperm injection groups, respectively. In the latter group 69% of inseminated and 78% of intracytoplasmic sperm injected oocytes were fertilized. No cycle showed complete fertilization failure. No statistically significant difference in the live birth rate was found between the 2 groups. CONCLUSIONS: More stringent criteria for intracytoplasmic sperm injection do not compromise the clinical outcome and reasonable fertilization can be achieved whether or not intracytoplasmic sperm injection is performed. Thus, although intracytoplasmic sperm injection is one of the greatest advances in our field, it is overused and should only be done for clinically proven indications