Determining Best Practices in ART: A call for new ideas

July 12, 2012Carole No Comments »

(Originally published in Journal of Clinical Embryology, Spring 2012)

Assisted Reproductive Technology (ART) is a curious blend of medical practice and scientific technical expertise. Unlike much of medical practice, fertility treatment involves not only the patient’s body and physician’s expertise but also the skills of laboratory technicians to produce healthy embryos. As embryologists readily acknowledge, there are almost as many clinic-specific variations on in vitro fertilization protocols as there are IVF programs (436 programs reported to the CDC in 2008). With so much variation, how can the field determine best practices and evolve to benefit patients?

Best practices in IVF are frequently based more on anecdotal consensus, oral histories, or how clinicians and technicians were taught rather than robust scientific evidence. Unlike other medical fields, technical advances in ART have largely come about as a by-product of direct patient care, rather than from evidence based research. Arguably, patients have largely funded IVF “research” by seeking fertility treatments. Patients’ success or failure in cycles informed our medical and laboratory techniques going forward. IVF techniques have not historically been subject to scientific validation via peer-reviewed publicly funded research.

Federal funding of embryo research (or the lack thereof) has been a topic of heated debate since before the first IVF baby was born. “Embryo and stem cell research in the United States: history and politics”, by D.C. Wertz provides an overview of 30 years of politics and its effect on embryo research. In 1973, the same year that the Roe vs. Wade decision made abortion legal, the Department of Health and Human Services placed a moratorium on research on living embryos. In the next year, Congress put a temporary ban on federal funding of IVF research and infertility and also created the National Commission for the Protection of Human Subjects of Biomedical and Behavorial Research to determine ethical guidelines for fetal and embryo research. The Commission extended the existing protections of human research subjects to embryos and created an Ethics Advisory Board (EAB) to review research protocols involving embryos. The temporary moratorium on federal funding of IVF research was lifted by DHHS in 1975 but no research was actually funded. In 1978, the first IVF baby is born in Great Britain. In 1979, the EAB approved funding on embryo research up to 14 days of development but DHHS rejects this recommendation and the EAB is dissolved due to lack of funding. Because the law required EAB approval for funding, dissolution of the EAB effectively removed any mechanism to approve embryo research protocols and receive federal funding.

The focus of embryo research moved away from IVF in 1978 due to the emerging public interest in embryonic stem cell therapy. DHHS refused to fund a Parkinson’s disease study using fetal cells, arguing that approval of the study would encourage abortion. The same year NIH created the Human Fetal Tissue Transplantation Research Panel which voted on whether to approve funding for embryo and fetal research.

DHHS extended the moratorium on federal funding of embryo research, citing the opinion of some of the panel members that research funding would encourage abortion. The stem cell research debate continued to heat up in the nineties with patient advocacy organizations suing DHHS to lift the moratorium on embryo research. In the years following, stem cell funding continued to be controversial and any thought to funding translational research for better IVF outcomes was forgotten. Interestingly, several states (for example, California and Connecticut) have created state sponsored stem cell research initiatives within their state. Although no similar state initiatives to fund IVF research have been created, concerns about the use of IVF embryos continue today. Candidate Newt Gingrich recently promised social conservatives that he would create an ethics panel to look into the regulation of IVF due to concerns over the production and fate of excess embryos from IVF (ASRM Bulletin).

As a result of thirty years of political turmoil, research on embryos and IVF in the US has largely been driven out of the public sphere and into the private sector, entirely supported by commercial interests and individual clinics. Arguably, private sector funding is better than no funding but private sector funding of IVF research and the resultant data are often viewed with more skepticism due to perceived bias or self-promotion.

Given that rigorous federally funded translational research is unlikely, what mechanisms are available to identify effective techniques and determine best clinical practices in ART? How can embryologists identify best practices for the technical procedures that we use every day?

Embryologists, eager to determine best practices tend to turn to each other for anecdotal information and advice. One platform for this exchange between peers is Embryomail, a moderated discussion group for research scientists and clinical embryologists and andrologists. Recent topics on Embryo Mail included sperm selection, oocyte vitrification, incubator problems, and shipping of specimens internationally. Discussions can become heated and sometimes more heat than light is generated regarding best practices. In 2010, I started a blog for patients called Fertility Lab Insider ( in which I answer patient questions about what happens behind the lab door. I receive questions daily from patients on lab topics because these questions are not typically addressed in depth in most clinics and patients want to know about their embryos. What has surprised me is not the patients’ interest in lab topics but also that embryologists and physicians read the blog. I have fielded emails from clinicians looking for experts in air quality or freezing or FDA regulations, to name a few. Obviously, there is an unmet need for determination of best practices that has not been met by existing venues for peer discussion.

Vitrification is one topic in which consensus on best practices would be highly beneficial. Although vitrification is becoming the preferred method for cryopreservation there is no consensus on best media, best container, or best protocol to use for vitrification. This lack of consensus can create real harm when patients move vitrified specimens between laboratories. The receiving lab may not have the specific technical expertise to properly warm the specimen or may mishandle it, causing a premature thaw and loss of viability. Some programs have gone so far as to discourage patients from shipping specimens between labs.

Survey of best practices in top-performing clinics may provide one answer to determining best practices. Bradley J. Van Voorhis, MD and his colleagues demonstrated this approach in their paper, “What do consistently high-performing in vitro fertilization programs in the US do?” Voorhis surveyed the practices of 10 programs consistently ranked in the top 25 IVF clinics reporting results to CDC in 2005 and 2006. Singleton delivery rate per cycle was the main criteria used to identify the best programs. Clinics chosen to receive the survey had an average live birth rate per cycle in 2006 of 52% compared to 39% for all reporting programs. The authors noted that the live birth per cycle outcomes for all programs reporting in 2007 ranged from a low of 9% to over 50%.

The original article was mostly devoted to the clinician side of the IVF cycle reviewing best practices for stimulation protocols, measuring ovarian response, performing anesthesia, egg retrieval and embryo transfer. IVF lab best practices were summarized in supplemental information in an erratum published on-line in Fertility and Sterility, volume 95, Issue 6, Page e23, May 2011.

A brief review of some of their lab findings reveals areas that are ripe for discussion among lab technicians. Common andrology lab best practices included an evaluation of the male partner’s semen parameters including sperm concentration, motility and morphology (80% of surveyed programs used Tygerberg Strict Criteria). Sperm antibody testing and /or DNA integrity tests were used by less than half of the programs. Most programs (80%) use some testing criteria to prescribe ICSI; only one program used ICSI on all mature eggs in all patients. Criteria used to perform ICSI included sperm morphology with cut-off ranging from less than 2 to 8% normal forms to order ICSI. The concentration of progressively motile sperm in the neat sample and total motile sperm in the post wash specimen were additional criteria used by programs to prescribe ICSI.

Common embryology lab best practices included consensus on timing for the denuding of oocytes that occurred on average 38.5 hours after the hCG trigger with a range of 36.5-40 hours. ICSI was performed on average at 39.7 hours after trigger with a range of 38-42 hours. Culture system for conventional insemination varied with 60% of programs inseminating in microdrops and 40% in an open culture system (e.g. in organ culture dishes or Nunc wells). Motile sperm concentrations used for insemination ranged from 50,000 to 150,000 motile sperm/mL. Group culture of embryos was employed by 90% of top clinics. Assisted Hatching, either via acid Tyrodes or laser, was used by 90% of the programs surveyed but the criteria for using AH varied widely. Most programs performed embryo transfer on either day 3 or 5, but some transferred as early as day 2 and as late as day 6.

Even without a negative control (practices of worst 12 clinics?), identifying top programs and finding similarities among these clinics should be a more powerful tool for identifying best practices than traditional single program reports.

Although ASRM publishes practice guidelines for reproductive medicine, these guidelines are primarily focused on physician medical practices, not technical protocols. Identifying best programs and conducting annual surveys may be a role more appropriate for the Society for Assisted Reproductive Technology (SART). SART already collects research data from reporting programs that are not specifically required to fulfill the CDC reporting requirement under federal law. SART already has access to program outcomes. Would SART consider using the annual database to identify top programs and administer surveys regarding best practices?

How do you think we should identify best practices in the ART field? How does your program make decisions about best practices and when and how to implement technique changes? Would you welcome more internet based tools to communicate within the ART community about best practices?

DC Wertz “Embryo and stem cell research in the United States: history and politics”, Gene Therapy, Volume 9, Number 11, Pages 674-678.

Gingrich Calls for Commission to Study Ethics of In Vitro Fertilization, ASRM Bulletin, Volume 14, Number 7, January 30, 2012.

Bradley J. Van Voorhis, Amy Sparks, Mika Thomas and Eric S. Surrey “What do consistently high-performing in vitro fertilization programs in the US do? Fertil Steril. 2010 Sep;94(4):1346-9. Epub 2010 Aug 2. Supplemental material published online in erratum Fertility and Sterility, volume 95, Issue 6, Page e23, May 2011.

© 2012, Carole. All rights reserved.

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