Assisted Human Reproduction Research and Canada’s Contribution

1. Assisted Human Reproduction Research and Canada’s Contribution Joanne Gunby & John Collins McMaster University

2. Annual publications on assisted reproductive technology 2008 annualized from August 31

3. 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.

4. 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.

5. 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.

6. 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.

7. Databases searched • PubMed • MEDLINE • EMBASE • CINAHL • PsycINFO • Social Sciences Citation Index • Sociological Abstracts • SAGE: Nursing and Health Sciences, Psychology, and Sociology

8. The exploded MeSH term “Reproductive Techniques, Assisted“ includes Embryo TransferFertilization in VitroSperm Injections, Intracytoplasmic Oocyte Retrieval Gamete Intrafallopian TransferZygote Intrafallopian Transfer Sperm Retrieval Oocyte DonationOvulation InductionSuperovulationInsemination, ArtificialHeterologous, Homologous Posthumous Conception The MeSH term pre-implantation diagnosis was added.

9. Search terms for basic research Embryonic development Cell Lineage Embryo Implantation Embryo Implantation, Delayed Embryonic Induction Twinning, Monozygotic Embryo Culture Techniques Blastocyst Blastocyst Inner Cell Mass Trophoblasts Oogenesis Spermatogenesis Sperm Maturation Embryonic Stem Cells Nuclear Transfer Techniques

10. PsychINFO search terms Infertility Reproductive Technology Embryo Fertilization Ovulation

11. Social sciences search terms In Vitro Fertilization Assisted Reproduction Embryo Insemination Sperm Oocyte Preimplantation Diagnosis

12. Steps in the analysis • Compare Canada and the world • Assess for relevance to AHR (specificity) • Sensitivity of the search tools • Sort into human, animal, basic science

13. Canada and the world

14. 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

15. Specificity of the search tools Specificity is the number of articles considered relevant to AHR after individual review, divided by the total number of articles.

16. Sensitivity of the search tools • Sensitivity is the proportion of all truly Canadian AHR papers that was found by the search. • Numerator: the number of truly AHR articles by an individual author (as either first author or co-author) retrieved by our searches. • Denominator: the number of truly AHR articles in a PubMed search by author name.

17. Sensitivity

18. 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).

19. 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 Reference section of the Background paper.

20. 273 Clinical articles

21. 18 Canadian AHR RCTs

22. 95 human biomedical articles

23. 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

24. 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

25. 12 frequently published clinical authors

26. 18 frequently published basic science authors

27. Frequently published authors Canadians who published ten or more AHR papers Clinical 12 Basic science 18

28. 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 successful.

29. CIHR basic AHR research themes Some projects cover more than one topic.

30. Clinical CIHR AHR research themes *AHR is one of the prenatal determinants.

31. 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.

32. 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.

33. 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.

34. 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

35. 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.

36. 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.

37. 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.