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Scientific Roundtable on the Prevention of Multiple Births

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					    Prevention of Multiple Births
     Associated with Infertility
  Treatments: Building a Canadian
            Framework

                              Report



                     November 17-18, 2009
                         Montréal QC




This report has been prepared by Leslie Jones Communications, conference
                               secretariat.
                                              Table of Contents
Introduction ..................................................................................................................... 1
       Welcoming Remarks ............................................................................................. 1
       Purpose, People, Process..................................................................................... 2

Part I: Multiple Births in Canada.................................................................................... 3
        Presentations: Setting the Stage........................................................................... 3
               History, Current Situation, Survey ............................................................. 3
               Multiple Births from ART in Canada .......................................................... 3
        Presentations: Current Opportunities and Challenges .......................................... 5
               Multiple Birth Outcomes ............................................................................ 5
               Emerging Technologies and Tools for Predicting Embryo Quality ............ 5

Part II: Multiple Births: International Perspectives ...................................................... 7
         Presentations: ....................................................................................................... 7
                Belgium...................................................................................................... 7
                United States ............................................................................................. 7
                United Kingdom ......................................................................................... 8
         Small Group Discussions: ..................................................................................... 9
                Application to the Canadian Context ......................................................... 9

Part III: Developing and Implementing a Canadian Framework ............................... 11
         Presentation: A Canadian Framework for Preventing Multiple Births
          Associated with ART ......................................................................................... 11
         Small Group Discussions: ................................................................................... 12
                Draft Objectives ....................................................................................... 12
                Implementation Challenges ..................................................................... 14

Closing ........................................................................................................................... 17
      Summary ............................................................................................................. 17
      Concluding Remarks ........................................................................................... 17


Appendices.................................................................................................................... 19
     Appendix I: Meeting Agenda ............................................................................... 19
     Appendix II: List of Participants ........................................................................... 20
     Appendix III: Draft Framework………………………………………………………..22

References……………………………………………………………………………………..29




                                                                                                                                    1
                                        Introduction
Approximately 75 researchers, clinicians, and other infertility experts from across
Canada and other parts of the world met in Montréal on November 17 and 18, 2009, for
a scientific roundtable on the development of a framework for the prevention of multiple
births in Canada associated with infertility treatments. 1

The meeting, hosted by the Canadian Fertility and Andrology Society (CFAS), the
Society of Obstetricians and Gynaecologists of Canada (SOGC), and Assisted
Human Reproduction Canada (AHRC), is part of an ongoing effort to develop
specific objectives and timelines for this framework and to support their
implementation across the country.

The objectives of the roundtable were to
   • update participants on research, trends, current guidelines, legislation, and
       policy development related to multiple births associated with infertility
       treatments in Canada and internationally,
   • facilitate agreement on a Canadian framework (including timelines and
       targets) for reducing the contribution of infertility treatments—both in vitro
       fertilization (IVF) and non-IVF—to the annual number of multiple births in
       Canada, and
   • continue to build a Canadian and international community of experts committed
       to preventing the number of multiple births associated with infertility treatments
       and educating clients about the risks involved.

The roundtable featured a number of presentations by invited speakers from Canada
and other parts of the world who offered domestic and international perspectives on
multiple births associated with assisted reproductive technologies (ART). 2 These
presentations and the background information provided in advance of the meeting
stimulated plenary discussion and group work focused on proposed objectives in the
draft framework and implementation opportunities and challenges.

The purpose of this report is to serve as a record of key observations, comments, and
general suggestions from participants at the meeting to assist with the next phases of
the framework’s development and implementation.

Welcoming Remarks
Dr. Francois Bissonnette, President of the CFAS, and Dr. David Young, Past-President
of the SOGC, thanked guests for coming and noted that both organizations were very

1
  It is understood that multiple births arising from fertility treatments cannot be fully prevented; the
aim is to address the issue in order to prevent where feasible.
2
  Terminology note: For the purposes of this document, “assisted reproductive technologies”
  (ART) refers to methods of procreation involving clinic procedures for the uniting of male and
  female gametes and subsequent embryo transfer (e.g., in vitro fertilization and intracytoplasmic
  sperm injection). “Assisted human reproduction” (AHR) refers to all methods of assisting
  procreation, including ovulatory drugs, intrauterine insemination, and clinic ART procedures
  such as in vitro fertilization.


                                                                                                      1
interested in learning about and supporting suggestions on how to prevent multiple births
in Canada.

Dr. John Collins, Chair of the AHRC Science Advisory Panel, took the podium to offer
welcoming remarks, which began with thanks to Steering Committee members for
planning the event. He said that while multiple births have always been fascinating to the
public, they come at a high price: prematurity is the single greatest cause of morbidity
and mortality in obstetrics, and low birthweight twins cost the health-care system about a
million dollars each over their lifetime. He called the roundtable an opportunity for the
leaders in this debate to lead change rather than have it imposed on them, noting that
although patient education is also necessary, support must come first from within the
profession and the clinical community itself.

Dr. Collins raised the point that, in comparison to other countries of similar economic
status, Canada has the third-best pregnancy success rates in ART but the second-
highest multiple birth rates. He said that while a shift in professional attitudes has
already taken place here at home, there were many lessons to be learned from countries
that had reduced their rates through embryo transfer policies and other means, and he
thanked the international guests in attendance for coming to share their
accomplishments.

Purpose, People, Process
Dr. Elinor Wilson, President and Chief Executive Officer of AHRC, said it was a pleasure
to work with the CFAS and SOGC to plan this roundtable. She thanked the CFAS for
devoting time and space during its own conference to this issue and welcomed members
of the AHRC Board of Directors who were in attendance, including Chair Dr. John
Hamm. She explained the role of the Steering Committee and noted that many of the
same debates its members had would likely also come up during roundtable
discussions, as this was a challenging subject.

Dr. Wilson said work has already started on patient education and a follow-up meeting
would be held next year with patient groups and organizations. She hoped the
deliberations over the next day and a half would provide input for that next step. She
thanked AHRC staff for their work on this initiative and speakers for their contributions.
She noted that the presence of Dr. Robert Rebar, Chief Executive Officer of the
American Society for Reproductive Medicine, was much appreciated because a close
working relationship between Canada and the US is essential given our porous border.
Before turning the floor over to facilitator Dorothy Strachan, she thanked participants for
their active engagement and collaboration and assured them that the outcomes of their
deliberations would be closely considered by the Steering Committee.

The facilitator reviewed the contents of the registration kit, including the meeting agenda
and objectives. She then summarized the meeting process, and explained that
participants would be assigned to specific tables for small-group discussions in order to
maximize the mix of ART professionals and regions of practice. To promote networking
and offer a sense of the wide range of experience in the room, each participant was then
asked to give a roll call introduction.




                                                                                              2
                    Part I: Multiple Births in Canada

Presentations: Setting the Stage
The roundtable opened with presentations on the history and current situation in Canada
with regard to multiple births associated with ART.

History, Current Situation, and Survey Results
- Dr. Jason Min, Ottawa Fertility Centre

Dr. Jason Min provided an historical overview of multiple birth rates in Canada, where
the natural rate of multiples was 1.8% prior to the birth of the first Canadian child
conceived of in IVF in 1982, and has since risen to about 3%. While some of this
increase is due to embryo transfer practices, a significant proportion is attributable to
non-IVF ovarian stimulation.

Dr. Min also highlighted the results of a web-based survey that was conducted of
Canadian clinics involved in ART. The latter suggests that there is strong clinical support
for the prevention of multiple births, and almost one-third of respondents felt that current
Canadian guidelines for embryo transfers are likely too liberal. While only half of the
clinics surveyed have an elective single embryo transfer (eSET) policy, most offer eSET
to at least 30% of their good prognosis patients. The survey also indicated that patient
pressure to ensure pregnancy, time or resources to devote to patient education,
decreased success rates, and suboptimal cryopreservation success may not be barriers
to eSET; however, competition among clinics and patients’ willingness to accept the risk
of multiples may be.

New clinical practice guidelines under development by the CFAS and SOGC will
promote eSET use for good prognosis patients (i.e., those under 35 years of age in their
first or second cycle who have two or more good quality embryos available for transfer).
The new guidelines will also promote eSET in good prognosis patients aged 36 to 37,
particularly when blastocysts are available, and in frozen-thawed embryo transfer cycles.

Multiple Births from ART in Canada
- Ms. Joanne Gunby, Canadian Assisted Reproductive Technologies Register

Ms. Joanne Gunby reported on multiple births resulting from ART procedures using data
from the Canadian ART Register (CARTR), which collects information from all Canadian
ART clinics. Whereas birth rates increased over the period from 2001 to 2007, multiple
birth rates decreased to 30% per birth in 2007, with most of the reduction in high-order
multiple births (1% in 2007). The four main predictors of birth and multiple births were
female age, number of embryos transferred, availability of surplus embryos for freezing,
and embryo transfer day. The interaction of these key factors produces different
probabilities of birth and multiple births. Canadian ART clinics have been adhering to
current embryo transfer guidelines in >85% of cycles, with excellent birth rates when the
number of embryos transferred was by choice; adherence to guidelines reduced triplet
births but not twin births. For cycles with additional embryos available, transferring fewer
than the recommended maximum number of embryos reduced the birth rate slightly but
resulted in a large decrease in multiple births, compared with transferring the maximum



                                                                                            3
    number. Use of eSET and elective double embryo transfer (eDET) have shown gradual
    increases since 2001 (representing 4% and 33%, respectively, of all embryo transfers in
    2008). Birth rates in women selected to receive eSET were similar to those in women
    who received eDET, within age groups.

    Plenary Discussion Points on the Current Situation in Canada:

        •   In Dr. Min’s presentation, the data on eSET refer to fresh embryos.
        •   Data are not collected on a national or regional level in Canada on intrauterine
            insemination (IUI). This is also an issue in the United States.
        •   In the United Kingdom and Europe, regulatory authorities have made it
            mandatory to report IUI.
        •   Of the 19,000 babies born through ART, almost half were not from singleton
            pregnancies. This is what is important, not just the percentage of multiple births.
        •   It is imperative to collect non-IVF data as well, because that information is not
            known.
        •   ART is currently an optional field in Ontario’s perinatal database, so one way to
            improve data would be to consider making it mandatory.
        •   Ontario’s perinatal surveillance system has brought together several information
            sources. It has recently been awarded registry status, and there is interest in
            converging with CARTR to make the data set even more complete.
        •   There are some limited data on monozygotic twinning from blastocysts, as
            CARTR has been collecting this information since 2007.
        •   Animal literature indicates the possibility of in vitro conditions impacting embryos
            and, in particular, causing imprinting disorders. British literature showed short
            time lags prior to transfer increases this risk in offspring. Whether this is
            translatable to humans is not known; however, further study is needed.
        •   There is even less information on cryopreserved embryos, and there is significant
            potential for damage resulting from freezing and thawing. The potential unknown
            effects of culture media also require further study.
        •   Some literature from Europe and elsewhere shows that babies from
            cryopreserved embryos are heavier than those from fresh embryos, which is
            surprising.
        •   It is amazing how little research has been done into culture conditions and how to
            optimize them and on the variability in culturing protocols from centre to centre.
        •   A balance between being too restrictive and too liberal needs to be stricken.
        •   According to CARTR, a significant proportion of twins come from 35-39 year old
            women, which is also the cohort more likely to have more than one embryo
            transferred at a time. Significant decreases in multiple births could be achieved
            by concentrating prevention efforts on this 35-39 year old cohort.
        •   If a frozen embryo transfer costs one-fifth that of regular IVF—then doing a single
            transfer and following up with frozen transfers may be cost effective.




Plenary discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.


                                                                                                   4
      Presentations: Current Opportunities and Challenges

      Multiple Birth Outcomes
      - Dr. Sarah McDonald, McMaster University

      Dr. McDonald spoke about multiple birth rates and multiple birth outcomes (both
      maternal and fetal) and touched on some of the limitations in Canadian data. She noted
      that multiples rates in Canada are increasing, that serious fetal risks are not rare, and
      that although maternal risks are still relatively rare, psychological risks (such as
      depression and high levels of stress) are not and have been neglected. Fetal risks
      include a three-fold increase in stillbirths for twins and six-fold for triplets, higher
      instances of preterm delivery (approximately 50% of twins and 100% of triplets), low
      birth weight (approximately 50% of twins and 94% of triplets), and a five-fold and 17-fold
      increase in cerebral palsy among twins and triplets, respectively. She noted that,
      compared to spontaneously conceived twins matched for other factors, IVF twins have
      small but significant increases in preterm delivery and low birthweight. Current gaps in
      our knowledge include lack of information on chorionicity in most large databases and
      rates and outcomes of multiples conceived through non-IVF ART.

      Emerging Technologies and Tools for Predicting Embryo Quality
      - Dr. Catherine Racowsky, Brigham and Women’s Hospital and Harvard
        Medical School

      Dr. Racowsky’s presentation focused on emerging technologies and tools for predicting
      embryo quality. She noted that ovarian stimulation results in retrieved eggs of diverse
      quality that typically give rise to a heterogeneous group of embryos. Better predictive
      techniques are needed because more embryos are typically created than should be
      transferred, and too many embryos continue to be transferred. Although principles for
      embryo selection give preference to non-invasive strategies because they pose less risk
      to the embryo, various invasive techniques have been evaluated, including biopsies on
      cleaved embryos for pre-implantation genetic screening and new strategies such as
      comparative genomic hybridization and microarray profiling with single nucleotide
      polymorphism analysis. Although it has its shortcomings, morphological assessment
      remains the first-line method of selection, and there is lots of promising work being done
      on other non-invasive techniques, such as follicular fluid analyses for cytokines and
      chemokines, granulosa cell gene expression, and assays of spent culture media. Further
      research is required, however, to verify reliability and improve sensitivity of these
      emerging technologies.

      Plenary Discussion Points on Current Opportunities and Challenges:

          •   Comparisons have not been made between the outcomes of singletons born
              from IVF and multiples born from IVF because the driving force in predicting the
              outcome of the latter is the fact that they are multiples.
          •   Embryo selection focuses on success in terms of whether pregnancy is achieved.
              Data on how the quality of the embryo relates to having a healthy baby are rare.
          •   The heterogeneity of oocytes corresponds to the heterogeneity of embryos, so if
              more than one embryo is transplanted that makes it very difficult to tell which one

Plenary discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.
                                                                                                     5
              was responsible for the pregnancy. Better registries and higher rates of eSET
              and eDET will eventually provide some answers.
          •   With respect to culture media, it is important to know if any are performing much
              better and if any are doing harm. Registries should be collecting that information.
          •   It would be helpful to know more about long-term psychological and behavioural
              problems that are increased in twins.
          •   On the maternal side, mothers of triplets showed emotional distance and
              psychological stress after the births of their children, and this persists beyond the
              children’s young age.
          •   There was a paper that showed that you could take a fairly mild stimulation
              protocol and get fewer eggs and embryos, but still wind up with the same number
              of useful embryos at the end of the day.
          •   Even in young women, one ends up with a large cohort of suboptimal embryos,
              so there are a lot of superfluous resources. That is not to say that some of these
              might not result in children; however, the tools are not yet available to identify
              embryos that are viable.
          •   The stimulation protocol is another important consideration.
          •   An analysis of data from studies of mild and conventional stimulation showed
              that, for mild stimulation, the optimal number of oocytes for maximum
              implementation was five. For conventional stimulation, it was 10. Eventually, the
              same number of pregnancies was achieved for both.
          •   Patients are the ones who put on the pressure to stimulate harder; this may be
              because they want more embryos to freeze.
          •   With in vitro maturation (IVM), an immature egg is taken from an unprimed ovary,
              put in culture, and stimulated to go through maturation. While this may be of
              some utility for some patients, the possible imprinting problems are a concern.
              The difficulty is in knowing whether imprinting effects are arising from the IVM,
              the infertility of the patient, or some other intervention in the lab.
          •   In terms of the long-term health of multiples, many studies of low birth weight
              babies have shown increased risk of learning disabilities, attention deficit,
              hyperactivity, etc. into adolescence.
          •   Before patients are educated, our colleagues have to be educated that multiples
              are not a desirable outcome. Professionals have to believe in eSET in order to
              explain its advantages to their patients.
          •   In some cases the issue may be that patients would prefer two babies to no
              baby.
          •   In Australia, there was a randomized controlled trial comparing eSET and eDET
              that was stopped early because when patients were properly informed about the
              risks, nobody chose DET. The most important element is to develop
              standardized information for patients about the risks of transferring two or more
              embryos.
          •   Another major issue is: who is paying for the treatment? Those who have to pay
              don’t want to have to undergo additional cycles because of the cost. In Australia,
              there is no limit on the number of cycles.
          •   As soon as there is a drop in the pregnancy success rate, people won’t go for it.
              It has to be demonstrated that the same amount of money spent on the treatment
              will result in the same chance of pregnancy.
          •   This issue can’t be addressed on the day of the embryo transfer; the patient has
              to be aware of it the day she enters the program.

Plenary discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.
                                                                                                     6
      Part II: Multiple Births: International Perspectives

Presentations

Belgium
- Dr. André van Steirteghem, Vrije Universiteit Brussel

Dr. van Steirteghem provided participants with a history and overview of Belgium’s
embryo transfer practices from 1992 to 2002 and the changes in single and multiple
delivery rates. During this period, the number of triple embryo transfers decreased by
nearly half, while the number of double embryo transfers increased by about a third.
Although the number of triplets and twins born dropped by a small percentage as a
result, the still-significant number of twin births (about 30%) resulted in a strict embryo
transfer policy being launched in 2003. The policy includes reimbursement for laboratory
procedures for a maximum of six cycles for patients under 43, with strict conditions on
the number of embryos transferred. Since that time, the number of cycles in Belgium has
increased, most likely due to both the reimbursement and the need to register in order to
receive it. Multiple deliveries have decreased to a point where close to 90% of all
deliveries are now singletons. Less flexibility would result in an even further decrease.
Future priorities include the need to
    • monitor the outcome of freezing,
    • make the monitoring of non-ART procedures mandatory (new legislation requires
         all ovarian stimulations to be registered, as well),
    • closely monitor the slight increase in the twinning rate in recent years,
    • ensure that non-ART activity (e.g., IUI, controlled ovarian stimulation without
         ART) is registered by the ART centres, and
    • have non-ART clinicians register with a licensed ART clinic and report on their
         activities.

United States
- Dr. Anuja Dokras, Penn Fertility Centre

Dr. Anuja Dokras gave an overview of multiple births from ART from a US perspective,
focusing on data collection on ART outcomes and American Society for Reproductive
Medicine (ASRM) / Society for Assisted Reproductive Technologies (SART) guidelines
on embryo transfer, which have been in existence since 1998. Although these guidelines
(which have been revised over the years) have dramatically decreased triplet pregnancy
rates, twin rates have remained at about 30%. Pregnancy success rates have increased
despite there being fewer embryos transferred.

To determine why twin rates are still high, the University of Iowa surveyed ART patients
and found that more than 30% wanted multiple pregnancies; however, after being
informed about the risks, this dropped to 14%. Patients were also less likely to opt for
eSET if they were told there was a drop in the pregnancy rate. A program at University
of Iowa offering eSET to good prognosis patients has had good results. In comparison to
the national average, where eSET represented 4.5% and 2.6% of cycles among ART
patients aged 35 and under and 36-37, respectively, the rates for study group members
in the same age brackets were 38.5% and 26%. The national average for live births with
twins was 32.9% and 28.4%, while the Iowa group average was 9.1% and 18.2%. Other


                                                                                         7
    studies have provided additional evidence that in good prognosis patients, pregnancy
    rates are only marginally higher for eDET compared to eSET.

    United Kingdom
    - Dr. Tony Rutherford, Leeds Reproductive Medicine Unit

    Dr. Tony Rutherford discussed multiple births associated with ART in the UK, where the
    Human Fertilisation and Embryology Authority (HFEA) began limiting embryo transfers
    to a maximum of two for women 40 and under (except under exceptional circumstances)
    in 2001 and imposed this limit without exception in 2004. Although this reduced the
    triplet rate, the twin rate stayed about the same until a strategy was announced in 2007
    to reduce it to 10% over a number of years. This strategy, launched in 2008, has four
    key components: a multi-stakeholder group, funding from the Department of Health, a
    website for patients (One at a Time), and best practice guidelines, including an algorithm
    and an embryo grading system.

    A predictive modelling study was also launched to estimate the potential outcomes for
    DET and eSET in the same patient given various embryo and uterine grading
    parameters. Lessons learned so far are that eSET will not be adopted overnight and
    may require an overall patient cost package that also includes a subsequent first frozen
    embryo transfer; funding problems need to be addressed; doctors and nurses have to be
    educated and brought on board; and significant decreases (below 19%) are unlikely to
    be achieved through a voluntary program.

    Plenary Discussion Points on International Perspectives:

        •   There are no data to indicate whether reproductive tourists who come to Belgium
            (and are self-funded) have a higher number of embryo transfers or a higher rate
            of multiple pregnancy because the data in the Belgian registry are focused on
            Belgian patients. Experience would suggest that these patients have had a
            higher number of cycles in different centres, so the number of embryos replaced
            may be higher but would not exceed three. There might also be a slightly higher
            multiple pregnancy rate.
        •   It would be helpful to define success and report on it as a “healthy, full-term
            infant” so it is attached to what the pregnancy outcome is supposed to be.
        •   Patients choosing a clinic look at the websites and the pregnancy rate. If there
            was some indication of the rate of healthy, full-term births, that would lower the
            incidence of clinics transferring more embryos just to keep pregnancy rates up.
        •   The International Committee Monitoring ART (ICMART) has made the same
            suggestion—that “success” should not be used because as long as that is the
            emphasis, people will compare clinics. This is difficult to implement when there is
            competition; however, we have to start focusing on live births.
        •   In the UK, live birth rates/cycles started and live birth rate/embryo transfer are
            now collected.
        •   Clinics have started publishing success rates in ranges, with the HFEA national
            average in the middle.
        •   In Belgium, during discussions held prior to the new law coming into effect, some
            health economic studies showed substantial savings to neonatal care intensive
            units if multiple pregnancies were prevented. That money is now going toward
            better reimbursement.

Plenary discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.
                                                                                                   8
          •   There may be immediate savings in neonatal care; however, savings for many
              will be life-long. More work has to be done in Canada of convincing governments
              that this will be a cost-neutral improvement to the healthcare system.
          •   Health care is regulated at the national level and paid for at the provincial level,
              so this is a complex issue. Cost savings are not only in health care but also in
              areas like social services and tax collection, as it is hard to work and take care of
              multiples at the same time.
          •   The real issue is that, regardless of funding, this is the practice of medicine, and
              the focus should be on intending to do no harm. We have a conflict between the
              patient’s wishes and the public health good—perhaps we should be considering
              the latter more strongly.
          •   From a medical perspective, the priority should be on reducing morbidity. But
              from a health policy perspective, it is essential for decision-makers to have
              quantifiable information about economic impacts because they are responsible
              for ensuring that programs have maximum effect. In Quebec, for example, where
              they will likely be covering three cycles, the number of cycles could increase
              significantly, so the percentage of multiples would stay about the same.
          •   In Belgium, registration of AHR has just started. The difficulty is that these
              practices are not limited to clinics.
          •   The UK collects data on IUI under the Donor Material Act.
          •   It would be very helpful to report the percentage of low birth weight babies. This
              could be an objective measure for consideration in comparing clinics.
          •   There are many complex health issues associated with AHR across Canada. A
              national strategy will require cooperation between the federal and
              provincial/territorial health ministers.

      Small Group Discussions: Application to the Canadian Context
      Participants were assigned seating in small groups to maximize the mix of clinicians,
      embryologists, and other AHR-related professions representing different clinics across
      Canada. They were asked, from their perspectives, which approaches to preventing
      ART-related multiple births that have been taken in other countries would work in
      Canada. Their responses are summarized as follows:

      Elective Single Embryo Transfer

          •   Take advantage of the existing trend toward eSET.
          •   Amortize the cost of eSET to include the cost of an additional cycle of frozen
              embryo transfer (FET) if needed.
          •   Have centres adopt a pricing increase for all IVF cycles to account for the frozen
              cycle.




Plenary discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.



                                                                                                     9
    Funding
        •   Link funding to limitations on the number of embryos transferred.
        •   Consider directed funding payments from the federal government to the
            provinces for ART treatments, with consideration given to savings for reduced
            lifetime costs due to decreased multiple pregnancies.
        •   Tie funding to regulation.

    Patient Education
        •   Teach patients about the risks of multiple births and they will make the right
            decision.
        •   Create a standardized national document for use in all clinics to inform patients
            about the risks and lifetime costs of multiple births, and have the patient sign a
            form indicating that she has read and understood it.
        •   Use innovative and effective means to reach patients (e.g., One at a Time
            website, prognostic tables).
        •   Make preconception information on reproductive health available to young adults.
        •   Develop a national strategy for patient education that utilizes expert information
            and engages practitioners in the process.
        •   Produce educational pamphlets on the subject.

    Professional Consensus
        •   Develop a professional consensus on this issue: uptake by IVF directors could be
            followed by physician education programs.
        •   Ensure consistent messaging from the entire health care team.
        •   Obtain consensus on what constitutes successful IVF.

    Registration
        •   Implement mandatory, comprehensive registration of non-IVF fertility treatments.
        •   Implement mandatory cycle registration.

    Regulation
        •   Impose and enforce strict regulations on embryo transfers.
        •   Connect regulations to licensing.
        •   Phase-in targets, allowing some flexibility in terms of how they are achieved.
        •   Establish national guidelines for reducing the number of embryos transferred,
            and emphasize eSET.

    Reporting
        •   Enforce audited, mandatory reporting of all IVF and non-IVF treatments and
            outcomes, including the use of gonadotropins.
        •   Make gonadotropin prescription reporting mandatory (as with narcotics and
            sedatives).
        •   Collect data on the composition of culture media.

    Research
        •   Conduct more research on how to determine the best quality embryo for transfer.

Discussion points represent the opinions expressed by one or more of the participants, and have not
been verified for this report.
                                                                                                  10
              Part III: Developing a Canadian Framework

  Presentation
  A Canadian Framework for the Prevention of Multiple Births from ART
  - Dr. Al Yuzpe, Co-Director of The Genesis Fertility Centre and member of the
  Multiple Births Framework Subcommittee and Multiple Births Steering Committee

  Dr. Yuzpe took the opportunity to thank the organizations involved for providing the
  impetus for the roundtable, adding that this collaboration is evidence that Canada plans
  to move forward and follow the glowing examples presented by the international
  speakers. He then provided a brief overview of the five draft objectives of the framework,
  three of which would be the topic of small-group discussions. He said that actions to
  address these objectives fall under three pillars: professional education, patient
  education, and data collection and analysis. Dr. Yuzpe noted several major
  considerations in these areas: the level to which multiple births could reasonably be
  prevented; the training needs of clinicians and embryologists; the information needs of
  patients; the additional data needed to track implementation and support a national
  research program; and challenges that could impede the development or implementation
  of individualized plans to prevent multiple births.

  Dr. Yuzpe emphasized that the final framework must be flexible, achievable, realistic,
  and evidence-based. The draft document will be finalized by the Steering Committee
  based on input from this roundtable and will then be presented to the CFAS, SOGC, IVF
  and Laboratory Director special interest groups and others for support in its
  implementation. Workshops and educational initiatives will be organized, as necessary,
  to address needs and deficiencies identified by the framework.

  Plenary Discussion Points:

      •   Twin pregnancies don’t always have a bad outcome. We have simply come to
          the point where we want to prevent twin births, and that needs to be done
          gradually.
      •   Patients are not represented at this roundtable, but we have to keep their
          autonomy in mind.
      •   Patient groups and patients themselves will be added to future roundtables: their
          voices need to be heard.
      •   Without funding, there will likely be a decrease of higher-order multiple
          percentages from IVF and an increase from non-IVF AHR because IVF isn’t the
          only offender—it is just the only one tracking data. Many multiple pregnancies
          and a large proportion of higher-order multiples are from superovulation and IUI,
          and we need to monitor that.
      •   Nobody has raised the issue of conflict of interest and the fact that a paid service
          is provided. Funding would relieve that conflict, but without it the interest of the
          medical community is the same as the patients’ in terms of pregnancy success,
          although that of the community also includes maintaining a successful business.
      •   In the US, the publication of clinic-specific data that promote “shopping around”
          based on pregnancy rates has been a problem.


Plenary discussion points represent the opinions expressed by one or more of the participants, and
have not been verified for this report.
                                                                                                11
        •   Randomized controlled trials may not be the best evidence. In one trial where
            eSET was forced on everyone, it did not do well. Clinical judgment is a really
            powerful tool for deciding which patients are appropriate candidates for eSET.
        •   The bigger issue is social policy. The best way to prevent multiple births is to
            prevent patients from requiring AHR. The question is how to provide financial
            compensation to encourage couples to have children earlier.
        •   It would be a mistake to implement mandatory, regulated embryo transfer
            requirements across the board, because clinics vary hugely in terms of their
            performance. Clinics that already have low pregnancy rates would get even
            worse. Leaving clinics to decide how to achieve targets is a better option.
        •   In the UK, licensure is tied to the number of embryos transferred. Targets have
            been set, and as long as clinics fall below them there’s no penalty. That way, it’s
            clinics that have higher multiple birth rates that are affected.
        •   Natural cycle IVF did not come up in the Steering Committee discussions;
            however, this is another area for discussion.
        •   The regulations written for these activities are covered by criminal law, so they
            will have to be very precise. Frameworks and guidelines can be aspirational but
            legislation and regulations that carry the risk of criminal prosecution cannot.

    Small Group Discussions: Draft Objectives
    Participants broke into small groups to discuss and comment on the extent to which they
    agreed with the first three of the five objectives in the draft framework. They then
    presented the results of their discussions in plenary, as summarized below.

    Objective 1: Decrease the twin rate per clinic to 25% by 2012 and to 15%
     by 2015

    There was overall agreement on this objective, although one table suggested that
    targets could be lower (20% and 10%), while another suggested that 20% was a more
    realistic target rate for 2015. Most agreed that the targets should be assessed every one
    or two years to determine whether they should be adjusted. People agreed that the way
    CARTR groups women aged 35-39 together should be changed so that data are
    collected for 36-37 year olds and 38-39 year olds separately—if not by each individual
    year—due to the considerable variation in the prognosis from one year to the next. The
    same age-breakdowns were suggested for women 40 and over. It was also noted that
    the issue of clinical competition needs to be addressed.

    Groups identified the following as necessary to achieve this objective:

        •   Consensus on the definition of a “good prognosis” patient, based on scientific
            evidence and multiple factors (e.g., age, embryo quality, previous cycles)
        •   Standardized criteria for embryo quality resulting in better embryo selection
        •   Expansion of “good prognosis” patients to 37 and under, rather than 35 and
            under
        •   A good embryo freezing program
        •   Mandatory reporting of non-IVF treatments and outcomes, with follow-up and
            corrective action
        •   Promotion of eSET among “best prognosis” patients first

Discussion points represent the opinions expressed by one or more of the participants, and have not
been verified for this report.
                                                                                                  12
      •   Patient education
      •   Physician education
      •   Stricter guidelines as to when to suggest eSET to patients
      •   Professional consensus
      •   Restrictions on the number of embryos transferred
      •   More research on epigenetics and blastocyst transfer
      •   Better lab techniques
      •   Promotion of minimal stimulation
      •   Ongoing quality improvement at all levels
      •   Funding
      •   Guidelines/standards of practice
      •   More blastocyst transfer
      •   More information on the risks of selective reductions

  Objective 2: Increase the use of eSET to ≥50% of good prognosis patients
   by 2012

  Most tables either agreed with this objective or said they could live with it. Those who
  disagreed felt the target rate was too high given that the current rate of eSET in Canada
  is around 4% and particularly since most good prognosis patients might experience a
  30% decrease in pregnancy rates in comparison to a DET. Others suggested that the
  rate of eSET for good prognosis patients should be 80% or higher. The question of what
  to do if a patient refuses eSET was also raised.

  The groups identified many of the same needs as they did for Objective 1. Others
  included the following:

      •   A shared national algorithm, tailored by individual clinics to determine the
          minimum number of embryos to transfer in order to maintain a good live birth rate
      •   More research on variations between Day 3 and Day 5 transfers
      •   Legislation that sets criteria for when to offer eSET (i.e. patient criteria)
      •   The ability for labs to successfully culture blastocysts and reliably predict good
          quality embryos
      •   The inclusion of frozen embryo transfer in the fresh cycle package

  Objective 3: Eliminate higher-order multiple pregnancies by 2015

  Participants agreed that the wording of this objective should be changed from “multiple
  pregnancies” to “multiple births”. While most tables agreed with the target date for
  elimination, it was recognized that reducing the rate to zero was not possible and that
  “near zero” (e.g., 0.5%) should be the target, particularly since older women often have
  three or four embryos transferred. One group also suggested that the objective be split
  into two parts: one specific to IVF ART, with a target date of 2012; and the other specific
  to non-IVF ART, with a target of 2015.

  Potential barriers identified included the fact that higher-order multiples could not be
  prevented through infertility treatment unless IUI with superovulation was reduced. This
  raised the issue of needing to increase access to IVF. It was also noted that centres with
  low sophistication in statistical analysis could have problems analyzing their own data.
Discussion points represent the opinions expressed by one or more of the participants, and have not
been verified for this report.
                                                                                                13
  These groups identified many of the same needs as they did for objectives 1 and 2.
  Others included the following:

      •   Specific training/qualifications for gonadotropin use
      •   Ongoing monitoring for efficacy and complications
      •   Mandatory counselling by clinics on issues relating to prevention of multiple
          births
      •   Flexibility for clinics to achieve targets using their own strategies
      •   Centre-specific data for analysis, validation, and quality assurance
      •   Clinical performance reviews

  During the break, Dr. Christopher Newton played a few minutes of an interactive DVD
  that was originally developed in 2008 to explain the risks and benefits of various options
  for embryo transfers to potential IVF patients. He noted that he had received funding to
  distribute the video and assess its efficacy over the next year and invited clinics to share
  the video with their patients and provide him with feedback on its usefulness to patients
  and staff. Copies of this DVD were provided to all participants.

  Small Group Discussions: Implementation Challenges
  Participants were re-assigned to a second table based on maximizing the mix of
  professionals and regions represented during discussions and asked to look at
  implementation challenges related to one of four topics related to multiple births: data
  collection and analysis; non-IVF AHR; patient education; and professionals. They were
  then asked to suggest actions to tackle these challenges. Their responses are
  summarized as follows:

  Data Collection and Analysis

  Challenge: To get more timely, accurate, and detailed data than are currently available
  (e.g., age-specific, culture media, perinatal outcome).
  Actions:
      • Improve data entry and standardize variables.
      • Link CARTR to live birth outcomes.
      • Obtain funding for data collection development.

  Challenge: Achieve consensus on definitions (e.g., good prognosis patient, good quality
  embryo), mandate data reporting and validation, and capture use of non-IVF ovarian
  stimulation.
  Actions:
      • Encourage obligatory data collection and validation for IVF and non-IVF
         gonadotropin treatment.
      • Reach consensus on the definition of a good prognosis patient.
      • Develop a standardized approach to embryo assessment across clinics.




Discussion points represent the opinions expressed by one or more of the participants, and have not
been verified for this report.
                                                                                                14
Challenge: To get comprehensive data in real time and act on it.
Actions:
   • Collect and monitor/enforce all relevant data (e.g., ovulation induction, pregnancy
      outcomes including selective reduction).
   • Link CARTR to other outcome databases.
   • Validate data and act on them.
   • Attempt to obtain funding for these efforts.

Plenary Discussion Points:

    •   It may be necessary to involve a privacy expert in future discussions about
        linking patient information databases.
    •   A prospective consent form should be developed to permit the use of collected
        data and link it to other databases. Many templates exist in other areas of health.
    •   CARTR’s data are not currently validated. In the US, a percentage of all cycles
        and programs are validated each year at random (about 10% of clinics and about
        30 cycles each). There have been very few errors, and most of those have been
        related to recording.
    •   Lag time in data collection is an issue in the US as well, because science
        changes quickly but government agencies like to maintain the status quo and
        collect the same data year after year.

Non-IVF AHR

Challenge: To decrease multiple birth rates for non-IVF stimulation cycles.
Actions:
   • Collect non-IVF data (e.g., age, diagnosis, number of previous cycles, medication
      used, size and number of follicles triggered, outcome of cycle) using a CARTR-
      like mechanism.
   • Establish national guidelines on when to cancel or convert cycles to IVF.
   • Establish medication protocols for ovulation induction or superovulation.
   • Improve access to the full range of fertility treatments and ensure that an
      individual’s personal finances are not an obstacle to quality of care.
   • Require both IVF and non-IVF care providers to report on gonadotropin use and
      outcomes, possibly through mandatory registration. Procedure costs could be
      increased slightly to cover the cost of data collection.

Patient Education

Challenge: To increase patients’ knowledge and awareness of the risks of multiple
births.
Actions:
    • Develop educational tools at the national and provincial and territorial levels.
    • Promote lobbying by patient groups for government funding.
    • Improve and expand the counseling of patients within clinics.

Challenge: To develop an effective process that all clinicians will buy into and that will
inform patients and encourage them to opt for a strategy that minimizes the risk of
multiple births.

Discussion points represent the opinions expressed by one or more of the participants, and have
not been verified for this report.
                                                                                             15
  Actions:
     • Begin educating patients on their initial visits to a clinic.
     • Conduct a mandatory review of risks prior to treatment.
     • Implement a standardized national program of patient education.
     • Obtain funding for education and research undertaken on strategies and tools for
        in-clinic decision making.

  Challenge: To change public perceptions about the optimal outcomes of ART.
  Actions:
     • Form interdisciplinary groups to develop and evaluate standardized educational
        materials that address ethnic and cultural differences.
     • Disseminate standardized material to all stakeholders (e.g., media, patient
        associations, schools).
     • Find the resources to develop and update materials on an ongoing basis.

  Professionals

  Challenge: To demonstrate to all IVF/ART professionals that the cumulative pregnancy
  rate is comparable for DET and eSET.
  Actions:
      • Educate all professionals in order to maximize acceptance and success.
      • Increase transparency of success/live birth.
      • Standardize embryo quality assessment parameters.
      • Formulate algorithm guidelines for selection of good prognosis patients for eSET.
      • Promote interdisciplinary regulation/self-regulation of eSET guidelines and clinic
           accreditation.

  Challenges: To implement eSET and prevent twinning by all involved professionals; to
  achieve consensus on algorithms for selecting and transferring top-quality embryos; to
  achieve good implantation rates across the country; and to monitor adherence in a
  competitive environment.
  Actions:
     • Educate all professionals about the risks of multiples and how to reach targets.
     • Set fixed goals for acceptable twin rates.
     • Develop multi-centre collaborative studies aimed at identifying and evaluating
         markers of top-quality embryos.

  Challenges: To ensure the wholehearted, comprehensive endorsement of the
  framework by all relevant professionals and all stakeholders; to overcome the
  competitive spirit; and to support this shift through education and research funding.
  Actions:
      • Embark on a comprehensive educational/social marketing campaign.
      • Arrange a series of educational meetings/rolling workshops geared toward
        patients, professionals, government, and media
      • Establish a website like the UK’s One at a Time.
      • Improve frozen embryo programs.
      • Encourage the CIHR to make the funding of research on embryo grading and
        embryo culture a priority.


Discussion points represent the opinions expressed by one or more of the participants, and have not
been verified for this report.
                                                                                                16
                                       Closing
Summary
Dr. Collins summarized the meeting by highlighting the key needs identified by one or
more participants during the roundtable discussions and urged participants, where
appropriate, to take action by recognizing them and adopting the three pillars as outlined
below.

Data Collection and Analysis

   •   Better predictors of outcomes
   •   More data on the long-term risks of multiple births
   •   Data on the risks of selective reduction
   •   Reporting of both IVF and non-IVF AHR outcomes

Patient Education

   •   Better availability of information for patients
   •   Clinicians who have confidence in eSET is necessary to provide meaningful
       advice to patients
   •   Education modules as a starting point for AHR
   •   Family-friendly education to encourage people to have children earlier

Professional Education

   •   Definitions of appropriate terminology, including “good prognosis patient”
   •   Improve public health while respecting patients’ decisions
   •   Leadership from the medical practice to ensure that regulations are sensitive to
       patients’ needs
   •   Buy-in from medical practitioners

Dr. Collins cautioned that the prevention of multiples may not be offset by funding, as
reimbursement for AHR cycles may decrease the number of twins per cycle but increase
the number of cycles, which could result in the same number of ART twins. He noted
general agreement by the group not to necessarily wait for legislation or approved
guidelines to embark on these efforts, but rather demonstrate clinical and scientific
leadership now.

Concluding Remarks
Dr. Hamm wrapped up by thanking the speakers and participants for taking time out of
their schedules to talk about these important issues. He also thanked the facilitator for
keeping the discussion on track, the Steering Committee for arranging the session, and
the CFAS, SOGC, and AHRC for their collaboration. He noted that what was discussed
over the course of the two days pointed toward clear direction for future activities. Those
gathered here today could be the solution by sharing responsibility for preventing
multiple births and taking these discussions back to their organizations. Dr. Hamm



                                                                                         17
closed by reiterating AHRC’s commitment to working with professional associations in
order to prevent multiple births due to infertility treatments.




                                                                                       18
         Appendices

         Appendix I: Meeting Agenda

                     Tuesday, November 17, 2009: Hilton Garden Inn
             Welcome
1600
             Dr. Francois Bissonnette (President, CFAS),
             Dr. Scott Farrell (Past President, SOGC),
             Dr. John Collins (Chair, AHRC Science Advisory Panel)
             Part I: Purpose, People, Process
1615
             Dr. Elinor Wilson, President and CEO, Assisted Human Reproduction Canada
             Dorothy Strachan, Facilitator
             Part II: Multiple Births in Canada
1645
             Setting the Stage:
                      Dr. Jason Min – History, Current Situation, Survey
                      Ms. Joanne Gunby – Multiple Births from ART in Canada
                      Q&A
             Current Opportunities and Challenges:
                      Dr. Sarah McDonald – Multiple Birth Outcomes
                      Dr. Catherine Racowsky – Emerging Technologies and Tools for Predicting Embryo
             Quality
                      Q&A
                   Wednesday, November 18, 2009: Hilton Bonaventure
            Part III — Multiple Births: International Perspectives
0800
            Belgium: Dr. André van Steirteghem
            United States: Dr. Anuja Dokras
            United Kingdom: Dr. Tony Rutherford
0910        Table discussions: Application to the Canadian context
0930        Plenary summary
            Part IV — Developing a Canadian Framework
1010
             Presented by Dr. Al Yuzpe on Behalf of the Framework Working Group (Dr. Cal Greene, Dr.
                Ed Hughes, Dr. Al Yuzpe)
            Part V — Implementing a Canadian Framework
1300
            Small group and plenary discussion/agreement
Working Break
1445        Summary and Next Steps
            Dr. John Collins
            Dr. John Hamm
1500        Adjournment
1520        Steering Committee meeting (30 minutes)




                                                                                           19
Appendix II: List of Participants
*Member of Multiple Births Roundtable Steering Committee

Antaki, Roland—Clinician, CHUM (Montréal)
Balakier, Hanna—Embryologist, CReATe (Toronto)
Baylis, Françoise—AHRC Board of Directors
Belisle, Francine—Nursing, McGill (Montréal)
Belisle, Serge—Clinician, CHUM (Montréal)
Bing, Yinzhong—Embryologist, Conceptia (Moncton)
Bissonnette, François—Clinician, OVO (Montréal)*
Case, Allison—Clinician, ARTUS (Saskatoon)
Cheung, Anthony—Clinician, UBC (Vancouver)
Claman, Paul—Clinician, Ottawa Fertility (Ottawa)
Collins, John—Clinician and Chair, AHRC Science Advisory Panel (Mahone Bay)*
Cook, Jocelynn—AHRC Chief Science Advisor (Ottawa)
Cowan, Lisa—Embryologist, Victoria Fertility (Victoria)
Del Valle, Alfonso—Clinician, TIRM (Toronto)
Desrosiers, Pascal—Embryologist, PROCREA (Québec City)
Di Berardino, Toni—Embryologist, Mount Sinai (Toronto)
Dokras, Anuja—Clinician, Penn Fertility (Philadelphia)
Feyles, Valter—Clinician, LHSC (London)
Fleetham, Judy—Embryologist, UCalgary (Calgary)
Forestell, Martha—Ontario Ministry of Health (Toronto)
Fraser, William—Epidemiologist, Ste-Justine (Montréal)
Greenblatt, Ellen—Clinician, Mount Sinai (Toronto)
Greene, Cal—Clinician, UCalgary (Calgary)*
Gunby, Joanne—CARTR (Hamilton)
Gysler, Mathias—Clinician, ISIS (Mississauga)
Haase, Jean—AHRC Policy Analyst (London)
Hamilton, Linda—Embryologist, IWK (Halifax)
Hamm, John—Chair, AHRC Board of Directors
Havelock, Jon—Clinician, Pacific Centre (Burnaby)
Jamal, Wael—Clinician, OVO (Montréal)
Janes-Kelley, Selikke—Alberta Perinatal Health Program (Calgary)
Karnis, Megan—Clinician, Hamilton Health Sciences (Hamilton)
Kredentser, Jeremy—Clinician, Heartland Fertility (Winnipeg)
Kuznyetsova, Iryna—Emryologist, TIRM (Toronto)
Lachgar, Hanane—Embryologist, Montréal Fertility (Montréal)
Laskin, Carl—Clinician, LifeQuest (Toronto)
Leader, Art—Clinician, Ottawa Fertility (Ottawa)
Léveillé, Marie-Claude—Embryologist, Ottawa Fertility (Ottawa)*
Librach, Cliff—Clinician, CReATe (Toronto)
Lo, Jonathan—Embryologist, Genesis Fertility (Vancouver)
MacDonald, Josée—Embryologist, IWK (Halifax)
Mahutte, Neal—Clinician, Montréal Fertility (Montréal)
Mainland, Lynn—AHRC Senior Policy Advisor (Vancouver)
McDonald, Sarah—Clinician, Hamilton Health Sciences (Hamilton)
Meriano, Jim—Embryologist, LifeQuest (Toronto)
Michael, Essam—Clinician, Astra Fertility (Mississauga)



                                                                               20
Min, Jason—Embryologist, Ottawa Fertility (Ottawa)*
Moore, Charlotte—Ontario Ministry of Health (Toronto)
Mutch, Jeaneil—Embryologist, ARTUS (Saskatoon)
Neal, Michael—Embryologist, Hamilton Health Services (Hamilton)
Newton, Christopher—Psychologist, LHSC (London)
Patrick, Lindsay—AHRC Science Advisor (Ottawa)
Pejcic-Karapetrovic, Branka—Health Canada (Ottawa)
Phillips, Simon—Embryologist, OVO (Montréal)
Raciocot, Marie-Hélène—Clinician, CHUM (Montréal)
Racowsky, Catherine—Embryologist, Brigham and Women’s (Boston)
Rebar, Robert—ASRM Executive Director (Birmingham)
Robichaud, Alfred—Clinician, Conceptia (Moncton)
Rutherford, Anthony—Clinician, Leeds Reproductive Medicine (Leeds)
Ryll, Irene—AHRC Board of Directors (Edmonton)
Sheridan, Heather—Embryologist, Markham Fertility (Markham)
Sirard, Marc- André—Veterinary Research (Laval)
Soliman, Samuel—Clinician, NewLife (Brampton)
Son, Young Weon—Embryologist, McGill (Montréal)
St. Michel, Pierre—Clinician, PROCREA (Montréal)
Tan, SL—Clinician, McGill (Montréal)
Tekpetey, Francis—Embryologist, LHSC (London)
Tough, Suzanne—Child Development Centre (Calgary)
Van Steirteghem, André—Clinician, Brussels Free University (Brussels)
Villeneuve, Marc—Clinician, PROCREA (Québec City)
Virro, Michael—Clinician, Markham Fertility (Markham)
Wang, Bin—Embryologist, NewLife (Brampton)
Wilson, Elinor—AHRC President and CEO (Ottawa)
Young, David—Clinician, IWK (Halifax)*
Yuzpe, Al—Clinician, Genesis Fertility (Vancouver)*

Steering Committee members not in attendance:

Farrell, Scott
Han, Victor
Hughes, Edward

Facilitator:
Strachan, Dorothy—Strachan-Tomlinson (Ottawa)

Recorder:
Jones, Leslie—Leslie Jones Communications (Carleton Place)




                                                                        21
Appendix III: Draft Framework for the Prevention of Multiple
Births Associated with Infertility Treatments

Development of country-wide objectives for minimizing Canada’s multiple birth rate is an
ongoing effort, requiring regular input and continual adaptation on the part of all involved.
A Canadian framework outlines objectives, timelines and three primary pillars to support
implementation: professional education, patient education, and data collection and
analysis.

During this initial phase, the Canadian Fertility and Andrology Society (CFAS), Society of
Obstetricians and Gynaecologists of Canada (SOGC) and Assisted Human
Reproduction Canada (AHRC) are working together to develop these objectives and
timelines and support their implementation across the country. Stakeholders such as
patients and counsellors will provide critical input during the next phase of framework
development.

This draft framework has been created in order to provide a basis for roundtable
discussion of Canadian objectives for prevention of multiple births attributable to ART.
It is not intended for use outside of this context.

This document is presented on behalf of the Multiple Births Roundtable Steering
Committee.


Why a Framework?

       1. Multi-fetal gestations pose significant risks to maternal and fetal health: (1) 3
             a. Low birth weight (LBW), neonatal morbidity and mortality, and long-
                  term developmental deficits are all increased in children of multi-fetal
                  pregnancies.
             b. Pre-eclampsia, heart disease and diabetes all increase in mothers of
                  multi-fetal pregnancies.

       2. Canada’s multiple birth rates are among the highest when compared to
          countries with a GNP over $20,000 per capita and more than 2,000 in vitro
          fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles (See Table,
          p.9):
               a. Canada’s elective single embryo transfer (eSET) rate in 2006 was
                   2.8%. (2)
               b. Canada’s multiple birth rate rose from 1.8% in 1981 to 3.0% in 2008,
                   an increase attributable to the introduction and spread of assisted
                   reproductive technology use (ART). (3)
               c. Over 30% of IVF/ICSI treatments in Canada result in multiple births.
                   (2)

       3. Pre-transfer assessment of ART embryos may become a more reliable
          predictor of embryo implantation:

3
    See end-notes for references.


                                                                                           22
               a. Combinations of molecular and morphological assessment are non-
                  invasive techniques in cases with no expected genetic anomalies. (4,
                  5)
               b. Improved pre-implantation genetic methods may provide reliable
                  genetic testing with minimized damage to the embryo. (6-8)
               c. Both day 5-6 transfer and cryopreservation of embryos enable more
                  time for informed decision-making. (9, 10)

        4. There is a public financial burden associated with multiple births:
              a. The majority of multiple gestation infants are born prematurely,
                  therefore requiring additional neonatal care; the average gestational
                  age at delivery for twins is 35 weeks, and for triplets, 31 weeks. (3)
              b. Complications of pregnancy during labour and delivery; antenatal
                  complications; and disorders related to short gestation and low birth
                  weight account for $1.1 billion dollars in Canadian health care
                  spending each year. (11)
              c. The long-term health care and indirect support costs related to
                  children born preterm are significant, e.g., direct and indirect costs
                  associated with cerebral palsy are $382 million per year in Canada.
                  (12)


Objectives for Prevention of Multiple Births Associated with
Infertility Treatments
Based on the above rationale, discussions among working group members and the
results of the Multiple Births Roundtable participant survey, the following objectives for a
Canadian framework are suggested:

   1.   Decrease the twin rate per clinic to 25% by 2012 and 15% by 2015.
   2.   Increase the use of eSET to ≥50% of good prognosis patients by 2012.
   3.   Eliminate higher-order multiple pregnancies by 2015.
   4.   Develop and implement country-wide educational tools for patients.
   5.   Develop and implement training workshops and innovative practice updates
        among Canadian ART professionals.

Actions taken in countries such as Sweden, Belgium, and the United Kingdom to
address objectives successfully include:

        Achieving consensus among professional and patient groups on shared
        objectives (13-16)
        Creating a clinic-specific plan to meet framework objectives (17-19)
        Providing partial or complete funding for cycles that meet objectives (20)
        Focusing on shared decision-making with patients and professionals (13, 21)
        Focusing first on patients with good prognosis (e.g. <37 years old, first cycle,
        more than one top quality embryo available) (13)
        Having electronic or print information available to the patient (before an
        appointment) explaining risks of multiple births (14, 21)



                                                                                           23
       Regularly self-auditing clinical practice and laboratory techniques (17, 18)
       Regularly self-auditing success in achieving objectives (18)


Pillars to Support an Adaptable Canadian Framework
Three key pillars support implementation of these objectives:

   •   Professional Education
   •   Patient Education
   •   Data Collection and Analysis

Pillar 1: Professional Education
Given that:

       Consensus is incomplete on best clinical and laboratory practices among ART
       professionals within Canada
       SET and frozen embryo transfer (FET) have lower pregnancy success rates in
       Canada than double embryo transfer (DET) (2)
       eSET comprises only 2.8% of all embryo transfers in Canada (2)
       Embryo assessment is a multifaceted and evolving science (4, 22, 23)
       Prognosis for each patient is individual and variable
       Physicians outside of fertility centres who include infertility treatment in their
       practices are not currently engaged in reporting data or collaborating on the
       development and implementation of a country-wide framework
       Countries with rates of pregnancy >25-30% and decreasing rates of multiple
       births vary with respect to availability of public funding for ART (24-26),

Questions this framework needs to address include:

   •   What are reasonable levels to which multiple birth rates can be decreased with
       present knowledge and technology?

In the period 2001-2005, twin rates in the United States and Canada remained stable at
~29% of ART births, while countries such as Sweden and Belgium decreased their twin
rates by more than 50% (to 6.1% and 12.7% respectively)(2, 26, 27)

   •   What training and/or standards for clinicians and embryologists are required to
       maintain leading-edge care for Canadians?

Some examples for clinicians include:

       Increased availability of continuing medical education (CME) accredited
       workshops
       Increased availability of online seminars and clinical updates
       Increased educational resources from professional organizations
       Recognition of reproductive endocrinology and immunology (REI) as a clinical
       specialty in Canada


                                                                                            24
Some examples for embryologists include:

       Professional degree or training program in Embyrology in Canada
       Development of reliable grading and prediction algorithms
       Increased availability of professional update workshops
       Increased availability of standardized training for new staff
       Increased education and support from professional organizations

Pillar 2: Patient Education
Given that:

       There is widespread positive public perception of multiple birth families (21, 28,
       29)
       There are substantial medical, social and economic risks associated with multiple
       gestations for the mother, the children, and the family (30)
       Patients and families are largely unaware of the psychosocial impacts associated
       with multiple births, including economic strain, increased divorce rates, inability to
       provide adequate care or services for a disabled child, depression, stress, sleep
       deprivation, and higher risk of infant mortality (30-32)
       Patients and families are largely unaware of the risks to children born of multiple
       births, including increased risk of cerebral palsy, birth defects, learning
       disabilities, developmental delays, perinatal death, organ development
       complications, as well as decreases in long-term health and well-being (31, 33,
       34)
       Patients are largely unaware of the maternal risks associated with multiple births,
       including increased risk of gestational diabetes, pre-eclampsia, post-partum
       hemorrhage, hypertension, post-partum depression as well as adversity due to
       increased weight gain, time away from work, stress, nausea, fatigue, depression
       and travel to tertiary care (30, 33)
       There are substantial economic and medical burdens to the health care system
       associated with multiple gestations (31, 35-38)
       It is not widely known that eSET is only recommended for patients with good
       prognosis (14, 21),

Questions this framework needs to address include:

   •   What information do patients need in order to make informed choices with their
       practitioners given the risks associated with multiple births?

Actions taken in countries such as Sweden, Belgium and the United Kingdom to address
objectives successfully include:

       Clinic implementation of financial incentive to choose eSET + FET rather than
       immediate DET (19, 21)
       Provision of individualized counselling for patients insistent on MET with
       documentation of counselling and education attempts (18)




                                                                                          25
       Creation of multimedia programs for patient self-exploration and education
       available in a format suitable for waiting rooms or home computer
       Creation of similar outreach and education programs to the United Kingdom’s
       “One Child at a Time” initiative (14)

Pillar 3: Data Collection and Analysis
Given that:

       A country-wide consensus on embryo grading and patient prognostic parameters
       must evolve in response to improvements in research and technology (19, 21,
       22)
       Current data collection is voluntary and inaccessible outside of clinic membership
       Health reporting information will become mandatory and publicly available over
       the next few years
       International data indicate periodic self-auditing within clinics is necessary to
       maintain a valid and updated picture of objectives achievement (17, 18)
       Regulation of ART services in Canada will be implemented over the next few
       years,

Questions this framework needs to address include:

   •   Which additions to current clinical data parameters are essential to track
       successful framework implementation?

   •   Which additions to current clinical data parameters would facilitate epidemiologic
       research, e.g. on cross-border care or confounding factors in fertility treatment
       success?

Actions taken in countries such as Sweden, Belgium and the United Kingdom to address
objectives successfully include:

       Expanding reporting requirements to include ovarian stimulation and IUI
       procedures (15, 17)
       Linking national databases to allow follow-up of children born of ART (17, 19)
       Periodic reviewing and revision of reported parameters in order to eliminate
       outdated information, streamline data collected, and add new categories of
       interest (e.g. chorionicity, fertility history, country of residence, hormone levels)
       (17, 18)
       Utilization of standardized, automated reporting measures assessed by a federal
       epidemiology centre (17)

What challenges impede the development and implementation of individualized plans to
minimize multiple births associated with infertility?

Challenges identified in other countries include: (21, 39)

       Financial inability to provide cryopreservation for second cycle with FET




                                                                                          26
Inability to properly communicate with patients the risks associated with multiple
births
Lack of negative experience with twins due to limited follow-up experience
(e.g. prenatal/antenatal complications)
Lack of prognostic models for SET success
Lack of scientifically-proven equivalency between eSET+FET and DET
Loss of patient to another clinic due to variations in clinic protocols
Technical inability to provide cryopreservation for second cycle with FET




                                                                                 27
Countries reporting data, with GDPpc >$20,000 and >2000 IVF+ICSI cycles per year (2005 laws and data shown)
                                                                                         Embryos Transferred (%)




                         IVF and ICSI




                                                                                                                                                                                    Triplet Birth
                                        (IVF+ICSI)




                                                                                         Gov't pays?




                                                                                                                                                                       Twin Birth
                                                                                                                                                          /Cycle (%)
                                                                                                                                                          Preg. Rate
                                                             Required?




                                                                                                       ET policy




                                                                                                                                                Mean ET
                                                                          Penalties




                                                                                                                                                                        Rate (%)



                                                                                                                                                                                     Rate (%)
         Country




                                                              License
                            Cycles


                                          cpmpy



                                                     Rules




                                                                                                                                         4+
                                                                                                                    1


                                                                                                                           2


                                                                                                                                  3
     Australia #        25,643          1272         S/G     Y/N                       Partial         1-2         48.2   49.8   1.9    n/a    1.54       24.00        13.70        0.30
      Belgium           15,185          1457          S       N           N           Complete         SET         48.0   43.3   7.3    1.4    1.62       22.22*       12.70        0.50
      Canada             8,195           254          S                                Partial         AR          11.0   57.0   23.0   9.0    2.40       32.10        29.40        1.40
   Czech Republic        3,790           371          S        N          N            Partial          3           n/a    n/a    n/a   n/a    1.80       33.82         n/a          n/a
     Denmark             9,541          1757          S        N          F            Partial         SET         32.6   62.8    4.5    0     1.72        26.10       20.70        0.40

      Finland           4,731           901          S                                 Partial         SET         49.7   50.0    0.3     0    1.51       24.63        11.50        0.20
       France           55,526          918          S         Y           Y          Complete         NS          17.5   59.1   18.7    4.7   1.92       22.10        20.50        0.50
      Germany           38,380          464          S         Y           N           Partial          3          11.5   65.5   22.9     0    2.11       27.23        20.90        0.90
       Greece           8,300           746          S         Y         C/F/L        Complete         AR          13.3   21.9   49.7   15.0   2.66       31.30        24.80        1.30
       Ireland          2,330           562          G                                  No             NS          8.7    79.5   11.7    0.2   2.03       26.06        24.70        0.40

       Italy            33,203           572         S         N          F/L          Partial          3          18.7   30.9   50.4    0     2.32       18.76        21.60        2.70
    Netherlands         14,995           920         S         Y           L           Partial         NS           n/a    n/a    n/a   n/a     n/a       24.32         n/a          n/a
   New Zealand #         2,352           584         S         N          C/F          Partial         SET         48.2   49.8    1.9   n/a    1.54        24.00       13.70        0.30
     Norway              5,067          1097         S         Y         C/F/L         Partial         SET         42.8   56.7    0.5    0     1.58       26.18        16.80        0.50
     Portugal            3,235           308         S                                Complete         AR          15.6   65.7   18.0   0.8    2.04       28.98*       21.70        1.20

       Slovenia          2,225        1131       S     Y        F       Complete       3     30.0     58.0    11.9      0     1.82    27.03 18.90 0.40
         Spain          26,739         621       S     Y        Y        Partial       3     14.4     53.9    31.7      0     2.17    31.79 26.60 1.00
        Sweden           9,415        1041       S     Y        L       Complete     SET     69.4     30.6     0.0      0     1.31    27.98 6.10  0.00
      Switzerland        3,466         478       S     Y       C/F         No          3     12.4     61.3    24.0      0     2.12    24.25 19.60 1.00
   United Kingdom       31,858         534       S     Y      C/F/L      Partial       2      9.9     85.3    4.8       0     1.95    25.93 25.50 0.50
     United States      92,405         310      G                          No         1-5     9.3     43.4    29.4    17.8    2.70    34.00 29.60 2.40
Rules                                S= statute, G=guidelines
Penalties                            C= criminal code, F=fee, L=license withdrawal, N=none specified, Y=yes, but unspecified
ET policy                            NS=not specified, AR=age-related, SET=single embryo transfer when possible (all are case-dependent)
Sources: CDC and SART 2005 (USA), CARTR 2005 (Canada, published 2009), ANZARD 2005 (Aus/NZ, published 2007), EIM 2005 (EU, published 2007), IFFS
Surveillance 2007 (regulations), CIA Factbook (GDP information)
#Australia and New Zealand data pooled by ANZARD, *pregnancies per aspiration (clinical pregnancy per cycle not available)


                                                                                                                                                                                    28
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