Research Publications

Driving Force behind CHR’s Clinical Success

CHR is a rare private fertility center that combines clinical fertility care with a robust clinical and laboratory research program. In over 30 years since its inception, CHR researchers have published hundreds of research papers, many in prestigious medical journals like Journal of the American Medical Association (JAMA) and New England Journal of Medicine (NEJM). CHR’s medical journal publications are listed below.

Some of CHR’s original research findings brought revolutionary new approaches to the field of reproductive endocrinology and infertility. Involvement of autoimmunity in endometriosis is one; the now-routine transvaginal egg retrieval is another; and the most recent example is the introduction of DHEA supplementation into the treatment of women with diminished ovarian reserve.

CHR’s focus has been the mechanism and treatment of diminished ovarian reserve for over a decade now, and many of our research publications are in this area. In the past few years, CHR has also expanded its laboratory research division significantly with 3 PhD-level scientists to conduct translational research in molecular biology and genetics. CHR’s Medical Director and Chief Scientist, Dr. Norbert Gleicher, emphasizes rigorous translational research because research is what drives innovation in fertility treatment at CHR, and our patients benefit directly from our research findings, which are “translated” into our clinical care program.

Infertility Clinical Trials

Clinical trials are considered the gold standard of research, and at any given time, CHR is likely to have more than one ongoing clinical trials. Some clinical trials recruit participants, while others may be open by invitation only.

Is Embryo Cryopreservation Causing Macrosomia-and What Else?

The number of embryos transferred during an IVF cycle is directly related to the high incidence of multiple births, which is the culprit of perinatal morbidity. Therefore, single fresh embryo transfer (ET) strategy, or freeze-all, followed by a single frozen-thawed embryo transfer (FET) cycle, may dramatically reduce the rate of multiple births, without compromising the cumulative live birth rates (LBRs). A literature review was conducted for all available evidences assessing obstetrics and perinatal outcomes associated with FET compared to fresh ET and natural conception. While studies comparing fresh and FET cycles in normal responders have yielded conflicting results for pregnancy rate, FET was associated with lower risk of prematurity and low birth weight and increased risk of large for gestational age (LGA) and/or macrosomic in singletons, when compared with fresh ET. Macrosomic/LGA births have a higher risk of fetal hypoxia, stillbirth, shoulder dystocia, perineal lacerations, cesarean section, postpartum hemorrhage and neonatal metabolic disturbances at birth. Nonetheless, it seems that other than higher risk of fetal macrosomia, there are additional obstetric complications associated with FET. The relative risk of hypertensive disorders in pregnancy, as well as perinatal mortality were also demonstrated to be increased in FET compared with singletons from fresh ET and natural conception. Therefore, when considering elective freeze-all policy, in addition to LBR and the risk of ovarian hyperstimulation syndrome, physicians should consider the aforementioned increased FET cycles' pregnancy complications, including LGA/ macrosomia, hypertensive disorders of pregnancy, as well as perinatal mortality.

Published in Frontiers in endocrinology https://pubmed.ncbi.nlm.nih.gov/32047479/

Citation Page #: 2020; 28;11:19.

Journal: Frontiers in endocrinology

Author Publication: Orvieto R, Kishenbaum M, Gleicher N.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32047479/

Date: 2020

Transiently increased risk of breast cancer after childbirth: implications for fertility treatments and surrogacy

Whereas longstanding dogma has purported that pregnancies protect women from breast cancer, a recent meta-analysis now mandates reconsideration since it reported an actual higher breast cancer risk for more than two decades after childbirth before the relative risk turns negative. Moreover, the risk of breast cancer appears higher for women having their first birth at an older age and with a family history and it is not reduced by breastfeeding. The process of obtaining informed consent for all fertility treatments, therefore, must make patients aware of the facts that every pregnancy, to a small degree, will increase the short-term breast cancer risk. This observation may be even more relevant in cases of surrogacy where women agree to conceive without deriving benefits of offspring from assuming the risk, thus creating a substantially different risk-benefit ratio. Consequently, it appears prudent for professional societies in the field to update recommendations regarding consent information for all fertility treatments but especially for treatments involving surrogacy.

Published in Human Reproduction https://pubmed.ncbi.nlm.nih.gov/32472674/

Citation Page #: 2020; 35(6):1253-1255.

Journal: Human Reproduction

Author Publication: Zeev B, Gleicher N, Adashi EY.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32472674/

Date: 2020

The PGS/PGT-A controversy in IVF addressed as a formal conflict resolution analysis

Purpose: To use conflict resolution analysis on the conflict between proponents and opponents of preimplantation genetic testing for aneuploidy (PGT-A), previously called preimplantation genetic screening (PGS).

Methods: Considered in conflict analysis a case study, we reviewed the English literature based on key-word searches at www.pubmed.com and www.google.com, and interviewed professional opinion leaders and other actor-representatives. This analysis was the product of a mandated externship by L.M. at the Foundation for Reproductive Medicine (FRM), as part of the Master of Science Program in Negotiations and Conflict Resolution at Columbia University, New York, NY.

Results: Initially a typical difference of opinion, conflict evolved after proponents rejected studies that failed to confirm expected benefits, and authors felt demeaned by their criticism. Becoming "destructive," the conflict evolved according to Glasl's escalation model stages. Proponents became continuous attractors. Unable to produce validations for PGT-A, proponents moved goal posts through 3 stages (PGS 1.0-PGS 3.0). Ultimately concurring that pregnancy and live birth rates are unaffected, they started claiming new benefits.

Conclusions: The FRM underwrote this study as a starting tool for a conflict resolution process. A consensus building conference of stakeholders appears as of this point to represent the most promising potential intervention. The goal of such a conference should be sustainable consensus about clinical utilization of PGS/PGT-A in IVF, based on transparent and validated criteria. A potential date for such a conference is set for 2020.

Published in the Journal of Assisted Reproduction and Genetics https://pubmed.ncbi.nlm.nih.gov/32219600/

Citation Page #: 2020; 37(3):677-687

Journal: Journal of Assisted Reproduction and Genetics

Author Publication: Mochizuki L, Gleicher N.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32219600/

Date: 2020

Not even noninvasive cell-free DNA can rescue preimplantation genetic testing

No abstract available

Citation Page #: 2019;116(44):21976-21977

Journal: Proceedings of the National Academy of Sciences of the United States of America

Author Publication: Gleicher N, Barad DH.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/31575738/

Date: 2019

Why is use of donor eggs not viewed as treatment failure? A call for improvements in treatments with autologous oocytes

Based on national registry reports, after age 42, the number of IVF cycles utilizing autologous oocytes is very small; after age 43, autologous oocyte use in US IVF cycles is almost non-existent. We here argue that the in vitro fertilization (IVF) field has created a self-fulfilling prophecy by basically abandoning the utilization of autologous oocytes after ages 42-43 years. This not only resulted in almost no IVF cycles with autologous oocytes being performed but also in abandonment of research that could lead to improvements in IVF outcomes in older women when using autologous oocytes. As a consequence, IVF has largely stagnated in this area. We further argue that third-party oocyte donation in clinical IVF should be considered a treatment failure, as it requires patients to choose a second rather than a first-choice treatment. Such a redesignation of third-party egg donation would not only be appropriate but could lead to necessary changes in physician attitudes, considering that women almost exclusively prefer to conceive with their autologous oocytes.

Published in the Journal of Assisted Reproduction and Genetics https://pubmed.ncbi.nlm.nih.gov/32504304/

Citation Page #: 2020; 37(7):1583-1588.

Journal: Journal of Assisted Reproduction and Genetics

Author Publication: Gleicher, N, Barad, DH, Adashi, EY.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32504304/

Date: 2020

Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women: a pilot study

Purpose: Increased serum C-protein (CRP) levels reduce fecundity in healthy eumenorrheic women with 1-2 pregnancy losses. Subclinical systemic inflammation may impede maternal immune tolerance toward the fetal semi-allograft, compromising implantation and early embryonic development. Some miscarriages with normal karyotypes could, therefore, be caused by inflammation. Whether pre-pregnancy CRP relates to karyotypes of spontaneously aborted products of conception (POCs) was investigated.

Methods: A study cohort of 100 infertile women with missed abortions who underwent vacuum aspirations followed by cytogenetic analysis of their products of conception tissue was evaluated at an academically affiliated fertility center. Since a normal female fetus cannot be differentiated from maternal cell contamination (MCC) in conventional chromosomal analyses, POC testing was performed by chromosomal microarray analysis. MCC cases and incomplete data were excluded. Associations of elevated CRP with first trimester pregnancy loss in the presence of a normal fetal karyotype were investigated.

Results: Mean patients' age was 39.9 ± 5.8 years; they demonstrated a BMI of 23.9 ± 4.6 kg/m2 and antiMullerian hormone (AMH) of 1.7 ± 2.4 ng/mL; 21.3% were parous, 19.1% reported no prior pregnancy losses, 36.2% 1-2 and 6.4% = 3 losses. Karyotypes were normal in 34% and abnormal in 66%. Adjusted for BMI, women with elevated CRP were more likely to experience euploid pregnancy loss (p = 0.03). This relationship persisted when controlled for female age and AMH.

Conclusions: Women with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.

Published in the Archives of gynecology and obstetrics https://pubmed.ncbi.nlm.nih.gov/32107607/

Citation Page #: 2020;301(3):831-836.

Journal: Archives of gynecology and obstetrics

Author Publication: Weghofer A, Barad DH, Darmon SK, Kushnir VA, Albertini DF, Gleicher N.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32107607/

Date: 2020

Preimplantation genetic testing for aneuploidy (PGT-A)-finally revealed

The hypothesis that elimination of aneuploid embryos prior to transfer into the uterus will improve in vitro fertilization (IVF) cycle outcomes has permeated IVF under various synonyms since the 1990s. Under most recent terminology called preimplantation genetic testing (PGT-A), the procedure, though never able to prove its clinical utility, has in the U.S. in many IVF centers become a routine add-on to IVF over the last 4-5 years. Meant to determine whether human embryos are to be transferred or disposed of, PGT-A was never validated and/or approved by a regulatory body, including the U.S. Food and Drug Administration (FDA), or found effective in improving IVF outcomes by an authoritative professional organization like the American Society for Reproductive Medicine (ASRM) or the European Society for Reproductive Medicine and Embryology (ESHRE). We here argue that PGT-A, as currently clinically applied, does not improve IVF outcomes and, indeed, may have the opposite effect in selected patient subpopulations. Though standard ethical clinical practice mandates prior validation studies before clinical introduction of new diagnostic tests and/or treatments, the responsibility to assess PGT-A, paradoxically, has primary fallen on the basic science community, which in recent years convincingly demonstrated that the PGT-A hypothesis for biological, mathematical and technical reasons, simply, cannot work. We, therefore, conclude that PGT-A should not be offered to patients except within experimental study frameworks and should be considered contraindicated in women with small embryo numbers, including older women and younger women with low functional ovarian reserve.

Published in the Journal of Assisted Reproduction and Genetics https://pubmed.ncbi.nlm.nih.gov/32008181/

Citation Page #: 2020; 37(3):669-672.

Journal: Journal of Assisted Reproduction and Genetics

Author Publication: Orvieto R, Gleicher N.

Publication Link: https://pubmed.ncbi.nlm.nih.gov/32008181/

Date: 2020

Worldwide decline of IVF birth rates and its probable causes.

Published in Human Reproduction Open.

With steadily improving pregnancy and live birth rates, IVF over approximately the first two and a half decades evolved into a highly successful treatment for female and male infertility, reaching peak live birth rates by 2001-2002. Plateauing rates, thereafter, actually started declining in most regions of the world. We here report worldwide IVF live birth rates between 2004 and 2016, defined as live births per fresh IVF/ICSI cycle started, and how the introduction of certain practice add-ons in timing was associated with changes in these live birth rates. We also attempted to define how rapid worldwide 'industrialization' (transition from a private practice model to an investor-driven industry) and 'commoditization' in IVF practice (primary competitive emphasis on revenue rather than IVF outcomes) affected IVF outcomes. The data presented here are based on published regional registry data from governments and/or specialty societies, covering the USA, Canada, the UK, Australia/New Zealand (combined), Latin America (as a block) and Japan. Changes in live birth rates were associated with introduction of new IVF practices, including mild stimulation, elective single embryo transfer (eSET), PGS (now renamed preimplantation genetic testing for aneuploidy), all-freeze cycles and embryo banking. Profound negative associations were observed with mild stimulation, extended embryo culture to blastocyst and eSET in Japan, Australia/New Zealand and Canada but to milder degrees also elsewhere. Effects of 'industrialization' suggested rising utilization of add-ons ('commoditization'), increased IVF costs, reduced live birth rates and poorer patient satisfaction. Over the past decade and a half, IVF, therefore, has increasingly disappointed outcome expectations. Remarkably, neither the profession nor the public have paid attention to this development which, therefore, also has gone unexplained. It now urgently calls for evidence-based explanations.

Citation Page #: 2019(3):hoz017.

Journal: Human Reproduction Open

Author Publication: Gleicher N, Kushnir VA, Barad DH.

Publication Link: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31406934/

Date: 2019

Not even noninvasive cell-free DNA can rescue preimplantation genetic testing.

Published in the Proceedings of the National Academy of Sciences.

The latest iteration of PGS/PGT-A analyzes the media in which the embryos spent some time in the lab developing and looks for aneuploidy (chromosomal abnormality) in the embryos. This new testing method circumvents the need to remove cells from the embryos to analyze, but it still comes with all the problems of false positives. Full text available from the link.

Citation Page #: Epub ahead of print

Journal: Proceedings of the National Academy of Sciences

Author Publication: Gleicher N, Barad DH.

Publication Link: https://www.pnas.org/content/early/2019/09/30/1911710116.long

Date: 2019

Reduced RNA expression of the FMR1 gene in women

Citation Page #: 13(12):e0209309.

Journal: PLoS ONE

Author Publication: Wang Q, Barad DH, Darmon SK, Kushnir VA, Wu YG, Lazzaroni-Tealdi E, Zhang L, Albertini DF, Gleicher N.

Publication Link: http://dx.plos.org/10.1371/journal.pone.0209309

Date: 2018

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