the asrm opinion on pgt for conclusions and how we drew...

The ASRM Committee Opinion on PGT for Aneuploidy – Our Conclusions and How

We Drew Them

Alan Penzias, MDChair, Practice Committee

American Society for Reproductive Medicine

Development of US National Guidelines: An evidence‐based approach to fertility

treatment

Alan Penzias, MDChair, 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

Guideline

Committee Opinion

Guidance

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”

Fertil Steril 2018;109:429-36Published March 2018

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

Study type:RCT

Level of Evidence: 1


RCT, Level 1

Meta-analysis, Level 1

Case-Control, Level 2-2; 2-3

Cohort, Level 2-2; 2-3


Studies 1 - 46


Studies 692-735 !

Decision: Exclude

Rationale: Animal

Practical Limitations

1) Focused and Accessible2) Long enough to be useful3) Short enough to be useful

a) ESHRE guideline: 154 pagesb) Very comprehensivec) Few will read entire document

Practical Limitations

Focused and AccessibleASRM Guidelines: 5‐10 pagesQuestion and Answer formata. 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 DevelopmentOverview 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 article2. assigns it a level of evidence based on the type3. 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!!!

Fertil Steril 2018;109:429-36Published March 2018

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)


● 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


● 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


● 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


● 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 abnormalityo 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


● 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