The ASRM Committee Opinion on PGT for Aneuploidy Our Conclusions and How We Drew Them Alan Penzias, MD Chair, Practice Committee American Society for Reproductive Medicine
Development of US National Guidelines: An evidence based approach to fertility treatment Alan Penzias, MD Chair, Practice Committee American Society for Reproductive Medicine
LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: State the difference between a Committee Opinion, Guidance Document and Guideline Discuss the challenges of document development Appreciate the transparency of the development process Customize treatment of individual patients incorporating ASRM evidence based documents
DISCLOSURE I have no disclosures related to this presentation
Vision of ASRM To be the nationally and internationally recognized leader for: Multidisciplinary information Education Advocacy and Standards in the field of reproductive medicine implementation of evidence based approaches to practice
WWW.ASRM.ORG
Committee Opinion Guidance Guideline
What Practice Committee Documents are NOT Textbooks of medicine Recipes that apply themselves to every clinical situation adherence to these clinical practice guidelines does not guarantee a successful or specific outcome do not override the healthcare professional's clinical judgment in diagnosis and treatment of particular patients
Published March 2018 Fertil Steril 2018;109:429-36
Important Details in the Boring Section!! Search: Medline Conducted: Sept 7, 2016 Time window: Human Studies published on/after June 1, 2014 40 search terms Subject headers Text 735 studies identified 96 studies included
The Published Literature is the foundation Does anyone ACTUALLY evaluate all 735 papers? YES!
The Literature Summary Spreadsheet Authors Title Journal Citation Abstract Level of Evidence: 1 Study type: RCT
The Literature Summary Spreadsheet RCT, Level 1 Meta-analysis, Level 1 Case-Control, Level 2-2; 2-3 Cohort, Level 2-2; 2-3
The Literature Summary Spreadsheet Studies 1-46
The Literature Summary Spreadsheet Rationale: Animal Decision: Exclude Studies 692-735!
Practical Limitations 1) Focused and Accessible 2) Long enough to be useful 3) Short enough to be useful a) ESHRE guideline: 154 pages b) Very comprehensive c) Few will read entire document
Practical Limitations Focused and Accessible ASRM Guidelines: 5 10 pages Question and Answer format a. What is the impact of leiomyomas on reproductive outcome? b. Does myomectomy improve fertility outcomes for women with intramural or subserosal fibroids? c. Does myomectomy impact the likelihood of pregnancy loss?
Some history for context 1. Based on systematic review of existing evidence 2. Developed by knowledgeable panel of experts 3. Consider important patient subgroups 4. Explicit and transparent process that minimized distortions and biases
Some history for context 5. Management of conflict of interest 6. Provide clear explanation of logical relationships between alternative care options 7. provide ratings of quality of evidence and strength of recommendations 8. Revise when important new evidence warrants change in recommendations
ASRM Guideline Development Overview of the ASRM Process
The Practice Committee Who are we? Member Representatives from: SART SREI SMRU SRBT SRS ACOG Patient Education Committee 3 Members at Large Consulting Epidemiologist ASRM President Elect ASRM Chief Scientific Officer ASRM CEO 2 ASRM Staff CHAIR
The Practice Committee
How is a guideline different from a committee opinion or guidance document? Guideline documents follows a rigorous process that is based on the standards set by the National Academy of Medicine Committee Opinions and Guidance Documents are evidence based but do not meet the stringent requirements of a guideline
Why wouldn t every document be a guideline? Not all topics are appropriate for a systematic review. In some cases, the literature is not yet available. Other topics don t lend themselves to a structured review of the literature and may be better addressed by a Committee Opinion or Guidance Document. Guidelines are very labor intensive. Each guideline takes between 12 18 months to conceive, develop, review, and publish.
What are the first steps of the guideline development process at ASRM? 1.Topic is selected by the ASRM Practice Committee Determines the questions to be asked and answered 2.Task force is empaneled Potential for conflict of interest is assessed for each member
How are members of the task force chosen? Epidemiologist: consultant engaged by ASRM Chair: member of the ASRM Practice Committee Members (3 4 clinicians at various levels of practice) can include: Clinician 10+ years in practice Clinician 5 10 years in practice Clinician 0 5 years in practice (may be a fellow) Past CREST scholar Other experts (mental health, genetics, laboratory, etc.) Ex officio: PC Chair, ASRM CEO and ASRM Staff
Then what? Search and assessment of literature ASRM staff designs and conducts a systematic literature search using identified keywords and builds a master spreadsheet of the search results. 1. identifies the type of each article 2. assigns it a level of evidence based on the type 3. culls low level evidence (case reports, small series, etc.) and off topic articles
The Workflow 12 to 18 months Task Force members assigned individual sections Task Force Chair assembles the sections, provides feedback, edits and sends first draft to the Practice committee (PC) PC reviews, provides feedback and sends draft back to Task Force for revision Revisions made, PC chair reviews and approves and sends to ASRM Members for Public Comment Public comments reviewed, document edited as needed then to ASRM Board of Directors (BoD) for review BoD provides comments, PC chair or Task Force make final revisions Final review by ASRM CEO and Scientific Director Publication in Fertility and Sterility and on ASRM website!!!
Published March 2018 Fertil Steril 2018;109:429-36
Use of PGT A Key Findings Clinical Outcomes in Favorable Prognosis Patients 3 RCTs (w/small sample sizes) Several retrospective cohort studies & Meta Analyses Significant limitations to these RCTs. randomization only for patients w/quality blastocysts, (good prognosis patients) Fresh transfer vs current practice in most clinics Bx d5/6 and vitrify for later FET US National ART Data analysis suggests: No improvement in Preg/Live Birth if aged 37 years Some improvement among women >37 years (21 needed to treat to accrue one addt l birth)
Use of PGT A Key Findings Retrospective studies: benefit up to age 43 yrs Potential bias because only good prognosis patients able to have biopsy would have been included in PGT A group Donor Oocytes No evidence of benefit eset retrospective study: PGT A to allow for eset while improving live birth
Use of PGT A Key Findings Recurrent Pregnancy Loss first trimester preg loss largely due to aneuploidy (biologic plausibility for PGT A) Existing studies can assist counseling regarding likelihood of successfully obtaining a euploid embryo The literature has not suggested an improved live birth rate using PGT A in RPL patients PGT A decreased miscarriage rates (7% vs 24%) D5 vs D6 Biopsy No differences reported
Use of PGT A Key Findings Thaw/Biopsy/Refreeze does not seem to significantly compromise IR, clinical pregnancy rate (CPR) or biochemical loss. Counsel that there may be fewer embryos available for transfer Neonatal and Early Childhood Outcomes Data reassuring thus far mostly from PGT M rather than PGT A PGT M vs. PGT A often inherently different in that most couples undergoing PGD do not have concomitant infertility Cost Effectiveness Hard to quantify intangible costs of preg loss and implant failure many studies don t include obstetric, neonatal and ongoing costs of disease/aneuploidy
Use of PGT A Key Findings Mosaicism Higher rates of mosaicism by NGS vs. acgh has cast doubt on the validity of a diagnosis of mosaicism o What % constitutes a true abnormality o Which specific chromosome mosaicism constitutes a problem more research needed to elucidate the mosaicism phenomenon current data does not exist to conclusively determine the superiority of any platform
Use of PGT A Key Findings Gaps in Knowledge / Call to Action for further research! cost effectiveness the role and effect of cryopreservation time to pregnancy utility in specific subgroups (e.g. recurrent loss, prior implantation failure, AMA) cumulative success rates over time total reproductive potential per intervention
Good Guidelines are not static Reviewed by PC every 5 years or sooner if new landmark data is published that would change recommendations The process is laborious but rewarding!!
Benefits of National Guidelines To Practicing Physicians: Summarizes the world literature and gives practical clinical guidance by answering discrete questions that are asked frequently To Patients: Guidelines are a starting point for discussion about their treatment Helps eliminate treatments that don t help or may harm To Society: Encourages progress that is evidence based and identifies areas where more research is needed Potential for overall improvement in quality of life through medical progress