Assisted Human Reproduction Research

and Canada’s Contribution

Joanne Gunby
&
John Collins
McMaster University
 Annual publications on assisted
reproductive technology

2
2008 annualized from August 31
 Background

Canada does not have a catalogue of AHR-related

research.
Canada’s role in the world AHR literature is not
known.
Nevertheless, information on the current state of
AHR research in Canada is needed for future
planning.
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 Objective

This background paper aims to describe the volume

and scope of research in AHR in Canada and the
extent of Canada’s contribution to the world
literature.

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 Working definition of AHR

Assisted Human Reproduction includes:

 IVF, ICSI, in vitro maturation, oocyte donation,
embryo freezing, and PGD
ovulation induction, intrauterine insemination
(partner and donor)
fertility preservation
related psychological, social, and counseling
issues.
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 Further definitions
“Canadian” research publications comprise articles by
authors from Canadian institutions.
AHR-related research may be clinical (human or
animal) or basic science research related to gametes,
embryos, and implantation.
For the purpose of setting research priorities, the
relevant period is the eight years since 2000.

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 Databases searched

PubMed
MEDLINE
EMBASE
CINAHL
PsycINFO
Social Sciences Citation Index
Sociological Abstracts
SAGE: Nursing and Health Sciences, Psychology,
and Sociology
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The exploded MeSH term “Reproductive
Techniques, Assisted“ includes
Embryo Transfer Oocyte Donation
Fertilization in Vitro Ovulation Induction
Sperm Injections, Superovulation
Intracytoplasmic Insemination, Artificial
Oocyte Retrieval Heterologous,
Gamete Intrafallopian Transfer Homologous
Zygote Intrafallopian Transfer Posthumous Conception
Sperm Retrieval
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The MeSH term pre-implantation diagnosis was
added.
Search terms for basic research
Embryonic development Blastocyst
Cell Lineage Blastocyst Inner Cell Mass
Embryo Implantation Trophoblasts
Oogenesis
Embryo Implantation, Delayed
Spermatogenesis
Embryonic Induction Sperm Maturation
Twinning, Monozygotic Embryonic Stem Cells
Embryo Culture Techniques Nuclear Transfer
Techniques
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 PsychINFO search terms

Infertility
Reproductive Technology
Embryo
Fertilization
Ovulation

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 Social sciences search terms

In Vitro Fertilization
Assisted Reproduction
Embryo
Insemination
Sperm
Oocyte
Preimplantation Diagnosis
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 Steps in the analysis

1. Compare Canada and the world

2. Assess for relevance to AHR (specificity)
3. Sensitivity of the search tools
4. Sort into human, animal, basic science

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 Canada and the world
% from
Articles 2000-8 World Canada Canada
All AHR articles 15,425 489 3.17
Reviews 1,840 81 4.40
RCTs 710 18 2.54

All citations 2007 706,743 23,399 3.31

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 Comparisons: Canada and the world

The benchmark for Canadian AHR studies is 3.2%

Fewer Canadian AHR RCTs were reported (2.5%, p = 0.38)
More Canadian AHR reviews were reported (4.4%, p = 0.002)
Systematic reviews and/or meta-analyses:
101/1,840 (5.5%) of world AHR reviews
9 / 81 (11.1%) of Canadian AHR reviews

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 Specificity of the search tools

Truly AHR
Articles 2000-8 Canada (%)
All AHR articles 489 420 (86%)
Basic research 989 384 (38%)

Specificity is the number of articles considered relevant to AHR

after individual review, divided by the total number of articles.
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 Sensitivity of the search tools

1. Sensitivity is the proportion of all truly Canadian

AHR papers that was found by the search.
2. Numerator: the number of truly AHR articles by
an individual author (as either first author or co-
author) retrieved by our searches.
3. Denominator: the number of truly AHR articles
in a PubMed search by author name.

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 Sensitivity
Number of References
Retrieved by
Subject Author
Research Type Author Sensitivity
Search Search
Clinical 1 54 67 81%
2 34 45 76%
3 18 22 82%
Average 80%

Animal/Basic 1 32 44 73%
2 29 70 41%
3 25 33 76%
Average 63%
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 Impediments to sensitivity
The first author of the article was not from a Canadian
institution (although one or more of the co-authors was
Canadian).
The indexing terms for the article were not covered by our
search terms (clinical terms not searched included Oocytes;
Sperm; Embryo, Mammalian; and Infertility, Female).
The word “Canada” was not included in the Author
Affiliation field (most common in Canadian journals).

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 Types of research

After individual assessment for relevance to AHR,

the total number of Canadian AHR articles was 856
273 (32%) clinical research
95 (11%) human biomedical research
488 (57%) animal/basic research

All articles are listed, by research type and category, in the

19 Reference section of the Background paper.
 273 Clinical articles
Category Number
In vitro fertilization 61

Ovulation induction/Intrauterine insem’n 42

Ethics/law 37
Consequences of ART 32
Intracytoplasmic sperm injection 24
In vitro maturation 20
Psychology/counselling 20
Pre-implantation genetic diagnosis 12
Health systems 12
Fertility preservation 8
Embryo freezing 3
20 Therapeutic donor insemination 2
 18 Canadian AHR RCTs
Nine IVF trials Overall effectiveness

IV-IgG pre-treatment
IVF vs ICSI (2)
Assisted hatching
Embryo transfer catheters
Analgesia for oocyte retrieval
Ovarian stimulation protocol (2)
Five IUI trials Timing of IUI
Bed rest after IUI
Ovarian stimulation protocol (3)
Two IVM trials In vitro maturation methods (2)

Two OI trials Low dose FSH

21 rhCG
 95 human biomedical articles

Category Number

Embryonic Stem Cells 23

Sperm 20
Embryos 19
Implantation 19
Oocytes 14

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 488 animal/basic articles
Number of titles which included the words
“embryo” 179
“sperm” 82
“oocyte” 65
“implantation” 55
“nuclear transfer” 17
60 titles mentioned “stem cells” or the
paper was published in a stem cell journal
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 Other topics of basic research articles

oogenesis, spermatogenesis, fertilization

preimplantation embryonic development
implantation, early pregnancy loss
manipulation of gonadal tissue
environmental toxins and embryo development

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 12 frequently published clinical authors
Included
Author Institution
articles
Tan, SL McGill University 53
Casper, RF University of Toronto 34
Buckett, WM McGill University 18
Chian, RC McGill University 18
Daya, S McMaster University 15
Tulandi, T McGill University 15
Mitwally, MF University of Toronto 14
Ma, S UBC 14
Ao, A McGill University 13
Child, TJ McGill University 11
Leader, A University of Ottawa 10
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Baylis, F Dalhousie University 10
 18 frequently published basic science authors
Author Institution # of articles
King, WA University of Guelph 32
Sirard, MA Laval University 29
Watson, AJ University of Western Ontario 25

Rossant, J University of Toronto 21

Mapletoft, RJ University of Saskatchewan 21

Smith, LC University of Montreal 19

Robaire, B McGill University 16
Kastelic, JP Agriculture Canada 15
Sullivan, R Laval University 12
Trasler, JM McGill University 12
Karatzas, CN McGill University 11
Martinez, MF University of Saskatchewan 11

Rancourt, DE University of Calgary 11

Hales, BF McGill University 10
Lazaris, A McGill University 10
Robert, C Laval University 10
26 Wang, B Nexia Biotechnologies 10
Zandstra, PW University of Toronto 10
 Frequently published authors

Canadians who published ten or more AHR

papers
Clinical 12
Basic science 18

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 CIHR funding for AHR research

79 new or renewed grants for AHR research since 2000

49 different Canadian principal investigators
total funding more than $39,000,000
majority of topics are basic science related to AHR

The available data do not reveal whether reproductive

clinicians have not submitted requests to fund RCTs in
AHR or whether such applications have not been
28 successful.
 CIHR basic AHR research themes
Topic Projects

human biomedical research 34

basic research in animal models 39

oocytes or oogenesis 17
sperm or spermatogenesis 26
fertilization 7
embryos 15
implantation 12
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Some projects cover more than one topic.
 Clinical CIHR AHR research themes
oocyte health
training program in women’s reproductive health

genetic abnormalities after AHR procedures (2)

qualitative study on altruistic oocyte donation

prenatal determinants of perinatal health outcomes*

30 *AHR is one of the prenatal determinants.

 Cautions to readers

Citation counts are only a proxy for research

activity.
There are too many world AHR citations to
validate.
Sensitivity and specificity vary by topic.
Identifying missing topics is subjective.

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 Assessment of the findings

AHR research in Canada reflects a broad

spectrum of topics that are relevant to the
clinical and basic science of AHR. Ethics,
law, and counselling topics are well-
represented.

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 Basic AHR research
Biomedical AHR research reflects current AHR
research interests, including stem cell research
(60 citations) and somatic cell nuclear transfer
(17 citations).
Basic AHR research in Canada is distributed
among more centres and authors than clinical
research.

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 Clinical AHR research

Some current clinical interests were missing from

the Canadian AHR citation database
patient preferences for # of embryos to transfer
mild ovarian stimulation
embryo selection methods

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 Balance of basic and clinical research
Clinical research: 32% of 856
Human biomedical research citations 11%
Animal/basic research citations 57%

The balance appears to be appropriate, given that the

novel insights from basic research are not
necessarily meant to have a clinical application.

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 Promising AHR techniques
Oocyte and embryo vitrification: in danger of
being applied without formal evaluation.
PGD: ten of the twelve citations were from a
single centre.
PGS: while FISH is not an effective means of
selecting embryos (ten RCTs), we found only two
farm animal studies of genomics or proteomics for
this purpose.
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 Canada’s role in world AHR research

Canada outperforms the world in reviews and the

proportion of systematic reviews is two-fold higher
than expected.
Canada underperforms the world in the publication
of randomized controlled trials.
This does not reflect insufficient personnel, as the
skills required are usually gained from the same
training that gives rise to performance of systematic
reviews and meta-analyses.
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