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Fair Inclusion of Pregnant Women in Clinical Research: A Systematic Review of Reported Reasons for Exclusion

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Clinical Research Involving Pregnant Women

Part of the book series: Research Ethics Forum ((REFF,volume 3))

Abstract

This empirical chapter provides a systematic review of literature relevant to the inclusion of pregnant women in clinical trials. In particular, it addresses barriers to fair inclusion identified within the literature. The 31 articles reviewed discuss the exclusion of pregnant women from clinical trials. Reasons given for such exclusion were grouped under several themes, including: foetal safety, collective memory or social controversies, liability, regulations, research ethics committee interpretations, research design, willingness to participate and consent. The discussion reviews arguments in the literature for how many of these barriers to fair inclusion can be surmounted. The authors find that barriers to fair inclusion of pregnant women in clinical research interact. While there are practical solutions for surmounting some barriers, others require further discussion.

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Notes

  1. 1.

    Because most of the articles originate from the United States where there are regulations, the term ‘regulations’ is used to refer to both regulations and guidelines except when there is specific reference to an identifiable guideline.

References

  • ACOG (American College of Obstetricians and Gynecologists). 2007. ACOG committee opinion no. 377: Research involving women. Obstetrics and Gynecology 110(3): 731–736 [At the time of writing, ACOG committee opinion no. 377 was in effect. It has since been withdrawn and replaced with American College of Obstetricians and Gynecologists. 2015. ACOG committee opinion no. 646: Ethical considerations for including women as research participants. Obstetrics and Gynecology 126: e100–e107].

    Google Scholar 

  • Alexander, D. 2011. Global health issues and US regulation 45 CFR 46 Subpart B. In ORWH workshop: Enrolling pregnant women: Issues in clinical research. An ORWH 20th Anniversary event, ed. ORWH, 57–61. Bethesda: National Institutes of Health.

    Google Scholar 

  • Allesee, L., and M. Gallagher. 2011. Pregnancy and protection: The ethics of limiting a pregnant woman’s participation in clinical trials. Journal of Clinical Research & Bioethics 2(108).

    Google Scholar 

  • Ballantyne, A., and W. Rogers. 2016. Pregnancy, vulnerability, and the risk of exploitation in clinical research. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 139–159. Cham: Springer.

    Google Scholar 

  • Barnett-Page, E., and J. Thomas. 2009. Methods for the synthesis of qualitative research: A critical review. BMC Medical Research Methodology 9: 59.

    Article  PubMed  PubMed Central  Google Scholar 

  • Battino, D. 2001. Trials in women. Epilepsy Research 45(1–3): 141–145.

    Article  CAS  PubMed  Google Scholar 

  • Baylis, F. 2010. Pregnant women deserve better. Nature 465: 689–690.

    Article  CAS  PubMed  Google Scholar 

  • Baylis, F., and C. Kaposy. 2010. Wanted: Inclusive guidelines for research involving pregnant women. Journal of Obstetrics and Gynaecology Canada 32(5): 473–476.

    Article  PubMed  Google Scholar 

  • Baylis, F., and R. MacQuarrie. 2016. Why physicians and women should want pregnant women included in clinical trials. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 17–31. Cham: Springer.

    Google Scholar 

  • Beran, R.G. 2006. The ethics of excluding women who become pregnant while participating in clinical trials of anti-epileptic medications. Seizure 15(8): 563–570.

    Article  PubMed  Google Scholar 

  • Binik, A., C. Weijer, and M. Sheehan. 2011. Minimal risk remains an open question. American Journal of Bioethics 11(6): 25–27.

    Article  PubMed  Google Scholar 

  • Blehar, M.C., C. Spong, C. Grady, S.F. Goldkind, L. Sahin, and J.A. Clayton. 2013. Enrolling pregnant women: Issues in clinical research. Women’s Health Issues: Official Publication of the Jacobs Institute of Women’s Health 23(1): e39–e45.

    Article  Google Scholar 

  • Brandon, A.R., G. Shivakumar, S.J. Inrig, J.Z. Sadler, and S.J. Craddock Lee. 2014. Ethical challenges in designing, conducting, and reporting research to improve the mental health of pregnant women: The voices of investigators and IRB members. AJOB Empirical Bioethics 5(2): 25–43.

    Article  Google Scholar 

  • Briggs, G.G., and J.E. Polifka, K.L. Wisner, E. Gervais, R.K. Miller, A. Berard, et al. 2015. Should pregnant women be included in Phase IV clinical drug trials? American Journal of Obstetrics and Gynecology 231(6): 810–815.

    Google Scholar 

  • Cain, J., J. Lowell, L. Thorndyke, and R. Localio. 2000. Contraceptive requirements for clinical research. Obstetrics and Gynecology 95(6 Pt 1): 861–866.

    CAS  PubMed  Google Scholar 

  • Canada (Canadian Institutes of Health Research, Natural Sciences and Engineering Council of Canada, and Social Sciences and Humanities Research Council of Canada). 2014. Tri-Council Policy Statement: Ethical conduct for research involving humans (TCPS2). http://www.pre.ethics.gc.ca/pdf/eng/tcps2-2014/TCPS_2_FINAL_Web.pdf. Accessed 3 Oct 2016.

  • Chervenak, F.A., and L.B. McCullough. 2011. An ethically justified framework for clinical investigation to benefit pregnant and fetal patients. American Journal of Bioethics 11: 39–49.

    Article  PubMed  Google Scholar 

  • CIOMS (Council for International Organizations of Medical Sciences). 2002. International ethical guidelines for biomedical research involving human subjects. Geneva: World Health Organization. http://www.cioms.ch/publications/layout_guide2002.pdf. Accessed 3 Oct 2016.

  • Clayton, E.W. 1999. Liability exposure when offspring are injured because of their parents’ participation in clinical trials. In Women and health research: Ethical and legal issues of including women in clinical studies, volume 2, workshop and commissioned papers, eds. A.C. Mastroianni, R. Faden, and D. Federman, 103–112. Washington, DC: National Academies Press.

    Google Scholar 

  • DHHS (US Department of Health and Human Services). 2009. Code of Federal Regulations: Title 45, Part 46, Protection of Human Subjects. http://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html. Accessed 3 Oct 2016.

  • Ells, C., and C. Lyster. 2016. Research ethics review of drug trials targeting medical conditions of pregnant women. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 95–118. Cham: Springer.

    Google Scholar 

  • EMA (European Medicines Agency). 2005. Guideline of the exposure to medicinal products during pregnancy: Need for post-authorisation data. London. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011303.pdf. Accessed 17 June 2015.

  • Flannery, E., and S. Greenberg. 1999. Liability exposure for exclusion and inclusion of women as subjects in clinical studies. In Women and health research: Ethical and legal issues of including women in clinical studies, volume 2, workshop and commissioned papers, eds. A.C. Mastroianni, R. Faden, and D. Federman, 91–102. Washington, DC: National Academies Press.

    Google Scholar 

  • Foulkes, M.A., C. Grady, C.Y. Spong, A. Bates, and J.A. Clayton. 2011. Clinical research enrolling pregnant women: A workshop summary. Journal of Women’s Health 20(10): 1429–1432.

    Article  PubMed  PubMed Central  Google Scholar 

  • Frew, P.M., D.S. Saint-Victor, M.B. Isaacs, S. Kim, G.K. Swamy, J.S. Sheffield, et al. 2014. Recruitment and retention of pregnant women into clinical research trials: An overview of challenges, facilitators, and best practices. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 59(Suppl 7): S400–S407.

    Article  Google Scholar 

  • Godlovitch, G. 2003. Age discrimination in trials and treatment: Old dogs and new tricks. Monash Bioethics Review 22(3): 66–77.

    Article  PubMed  Google Scholar 

  • Goldkind, S.F., L. Sahin, and B. Gallauresi. 2010. Enrolling pregnant women in research – lessons from the H1N1 influenza pandemic. New England Journal of Medicine 362(24): 2241–2243.

    Article  CAS  PubMed  Google Scholar 

  • Haas, D.M., B. Gallauresi, K. Shields, D. Zeitlin, S.M. Clark, M.F. Hebert, et al. 2011. Pharmacotherapy and pregnancy: Highlights from the third international conference for individualized pharmacotherapy in pregnancy. Clinical and Translational Science 4(3): 204–209.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurlimann, T., R. Stenne, V. Menuz, and B. Godard. 2011. Inclusion and exclusion in nutrigenetics clinical research: Ethical and scientific challenges. Journal of Nutrigenetics and Nutrigenomics 4(6): 322–343.

    Article  CAS  PubMed  Google Scholar 

  • Hurst, S.A. 2008. Vulnerability in research and health care: Describing the elephant in the room? Bioethics 22(4): 191–202.

    Article  PubMed  Google Scholar 

  • Hutson, J.R., F. Garcia-Bournissen, A. Davis, and G. Koren. 2011. The human placental perfusion model: A systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clinical Pharmacology and Therapeutics 90(1): 67–76.

    Article  CAS  PubMed  Google Scholar 

  • Kaposy, C. 2016. Presumptive inclusion and legitimate exclusion criteria. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 51–62. Cham: Springer.

    Google Scholar 

  • Kaposy, C., and L. Lafferty. 2012. Overcoming liability concerns in vaccine trials involving pregnant women. Accountability in Research 19(3): 156–174.

    PubMed  Google Scholar 

  • Kornblum, A. 1994. Trial and error: should pregnant women be research subjects? Environmental Health Perspective 102(9): 752–753.

    Google Scholar 

  • Kukla, R. 2016. Equipoise, uncertainty, and inductive risk in research involving pregnant women. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 179–196. Cham: Springer.

    Google Scholar 

  • Langston, L. 2016. Better safe than sorry: Risk, stigma, and research during pregnancy. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 33–50. Cham: Springer.

    Google Scholar 

  • Levine, R.J. 2011. IRB perspective on inclusion of pregnant women in clinical research. In ORWH workshop: Enrolling pregnant women: Issues in clinical research. An ORWH 20th Anniversary Event, ed. ORWH, 37–43. Bethesda: National Institutes of Health.

    Google Scholar 

  • Levine, C., R. Faden, C. Grady, D. Hammerschmidt, L. Eckenwiler, and J. Sugarman. 2004. The limitations of “vulnerability” as a protection for human research participants. The American Journal of Bioethics 4(3): 44–49.

    Article  PubMed  Google Scholar 

  • Little, M.O., A.D. Lyerly, and R.R. Faden. 2009. Pregnant women & medical research: A moral imperative. Bioethics Forum 2(2): 60–65.

    Google Scholar 

  • Luna, F. 2009. Elucidating the concept of vulnerability: Layers not labels. International Journal of Feminist Approaches to Bioethics 2(1): 121–139.

    Article  Google Scholar 

  • Luna, F., and S. van der Poel. 2013. Not the usual suspects: Addressing layers of vulnerability. Bioethics 27(6): 325–332.

    Article  PubMed  Google Scholar 

  • Lupattelli, A., O. Spigset, M.J. Twigg, K. Zagorodnikova, A.C. Mårdby, and M.E. Moretti. 2014. Medication use in pregnancy: A cross-sectional, multinational web-based study. BMJ Open 4(2): e004365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyerly, A.D. 2011. Direct benefit to pregnant women. In ORWH workshop: enrolling pregnant women: issues in clinical research. An ORWH 20th anniversary event, ed. ORWH, 57–61. Bethesda: National Institutes of Health.

    Google Scholar 

  • Lyerly, A.D., L.M. Mitchell, E.M. Armstrong, L.H. Harris, R. Kukla, M. Kuppermann, and M.O. Little. 2007. Risks, values, and decision making surrounding pregnancy. Obstetrics and Gynecology 109(4): 979–984.

    Article  PubMed  Google Scholar 

  • Lyerly, A.D., M.O. Little, and R.R. Faden. 2008. The second wave: Toward responsible inclusion of pregnant women in research. International Journal of Feminist Approaches to Bioethics 1(2): 5–22.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lyerly, A.D., M.O. Little, and R.R. Faden. 2011. Reframing the framework: Toward fair inclusion of pregnant women as participants in research. American Journal of Bioethics 11(5): 50–52.

    Article  PubMed  Google Scholar 

  • Macklin, R. 1990. Maternal-fetal conflict: An ethical analysis. Women’s Health Issues 1(1): 28–30.

    Article  CAS  PubMed  Google Scholar 

  • Macklin, R. 2003. Bioethics, vulnerability and protection. Bioethics 17(5–6): 472–486.

    Article  PubMed  Google Scholar 

  • Macklin, R. 2010. The art of medicine: Enrolling pregnant women in biomedical research. Lancet 375: 632–633.

    Article  PubMed  Google Scholar 

  • Madan, A., S. Tracy, R. Reid, and A. Henry. 2014. Recruitment difficulties in obstetric trials: A case study and review. The Australian & New Zealand Journal of Obstetrics & Gynaecology 54(6): 546–552.

    Article  Google Scholar 

  • Mariner, W.K. 1999. Compensation for Research Injuries. In Women and health research: Ethical and legal issues of including women in clinical studies: Volume 2: Workshop and commissioned papers, eds. A. Matroianni, R. Faden, and D. Federman. Washington, DC: National Academies Press.

    Google Scholar 

  • Mastroianni, A.C., R. Faden, and D. Federman (eds.). 1999. Women and health research: Ethical and legal issues of including women in clinical studies, volume 2, workshop and commissioned papers. Washington, DC: National Academies Press.

    Google Scholar 

  • McCullough, L.B., and F.A. Chervenak. 2011. The fetus as a patient and the ethics of human subjects research: Response to commentaries on “An ethically justified framework for clinical investigation to benefit pregnant and fetal patients.”. American Journal of Bioethics 11(5): W3–W7.

    Article  PubMed  Google Scholar 

  • Merkatz, R.B. 1998. Inclusion of women in clinical trials: A historical overview of scientific, ethical, and legal issues. Journal of Obstetric, Gynecologic, and Neonatal Nursing 27(1): 78–84.

    Article  CAS  PubMed  Google Scholar 

  • Merton, V. 1993. The exclusion of pregnant, pregnable, and once-pregnable people (a.k.a. women) from biomedical research. American Journal of Law and Medicine 19(4): 369–451.

    CAS  PubMed  Google Scholar 

  • Moher, D., A. Liberati, J. Tetzlaff, D.G. Altman, and The PRISMA Group. 2009. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Medicine 6(7): e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  • Myren, M., T. Mose, L. Mathiesen, and L.E. Knudsen. 2007. The human placenta – An alternative for studying foetal exposure. Toxicology in Vitro 21(7): 1332–1340.

    Article  CAS  PubMed  Google Scholar 

  • Noah, B.A. 2014. The inclusion of pregnant women in clinical research. St. Louis University Journal of Health Law and Policy 7: 353–388.

    Google Scholar 

  • ORWH (United States. Department of Health and Human Services, Public Health Service, National Institutes of Health, Office of Research on Women’s Health). 2011. Enrolling pregnant women: Issues in clinical research. Bethesda: National Institutes of Health.

    Google Scholar 

  • Sahin, L. 2011. The FDA perspective on the ethical barriers of conducting research in pregnant women. AJOB Primary Research 2(1): 13–14.

    Article  Google Scholar 

  • Schonfeld, T., and B. Gordon. 2005. Contraception in research: A policy suggestion. IRB 27(2): 15–20.

    Article  PubMed  Google Scholar 

  • Schroeder, D., and E. Gefenas. 2009. Vulnerability: Too vague and too broad? Cambridge Quarterly of Healthcare Ethics 18(2): 113–121.

    Article  PubMed  Google Scholar 

  • Second Wave Initiative. 2009. The Second Wave Initiative: Toward the responsible inclusion of pregnant women in medical research. http://secondwaveinitiative.org/. Accessed 17 June 2015.

  • Second Wave Initiative. 2016. http://secondwaveinitiative.org/. Accessed 7 Apr 2016.

  • Shields, K.E., and A.D. Lyerly. 2013. Exclusion of pregnant women from industry-sponsored clinical trials. Obstetrics and Gynecology 122(5): 1077–1081.

    Article  PubMed  Google Scholar 

  • Strech, D., and N. Sofaer. 2012. How to write a systematic review of reasons. Journal of Medical Ethics 38(2): 121–126.

    Article  PubMed  Google Scholar 

  • Strong, C. 2011. Minimal risk in research involving pregnant women and fetuses. The Journal of Law, Medicine & Ethics 39(3): 529–538.

    Article  Google Scholar 

  • Swan, S.H. 2000. Intrauterine exposure to diethylstilbestrol: Long-term effects in humans. APMIS 108(12): 793–804.

    Article  CAS  PubMed  Google Scholar 

  • Tan, K.S., and N.C. Thomson. 2000. Asthma in pregnancy. American Journal of Medicine 109(9): 727–733.

    Article  CAS  PubMed  Google Scholar 

  • Theiler, R.N. 2009. Evidence-based antimicrobial therapy in pregnancy: Long overdue. Clinical Pharmacology and Therapeutics 86(3): 237–238.

    Article  CAS  PubMed  Google Scholar 

  • Van der Graaf, R., R.H.H. Groenwold, S. Kalkman, D.E. Grobbee, and J.J.M. van Delden. 2013. From justifying inclusion to justifying exclusion of study populations: Strengths and limitations. World Medical Journal 59(5): 192–197.

    Google Scholar 

  • Westreich, D., M. Rosenberg, S. Schwartz, and G. Swamy. 2013. Representation of women and pregnant women in HIV research: A limited systematic review. PloS One 8(8): e73398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wild, V., and N. Biller-Andorno. 2016. Pregnant women’s views about participation in clinical research. In Clinical research involving pregnant women, eds. F. Baylis and A. Ballantyne, 119–136. Cham: Springer.

    Google Scholar 

  • World Medical Association. 2013. WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/. Accessed 3 Oct 2016.

  • Zajicek, A., and G.P. Giacoia. 2007. Obstetric clinical pharmacology: Coming of age. Clinical Pharmacology and Therapeutics 81(4): 481–482.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Julius Center for Health Sciences and Primary Care, Department of Medical Humanities, University Medical Center Utrecht, Utrecht, The Netherlands

    Indira S. E. van der Zande MA, MSc, Rieke van der Graaf PhD & Johannes J. M. van Delden MD, PhD

  2. Julius Center for Health Sciences and Primary Care, Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Joyce L. Browne MD, MSc

Authors
  1. Indira S. E. van der Zande MA, MSc
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  2. Rieke van der Graaf PhD
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  3. Joyce L. Browne MD, MSc
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  4. Johannes J. M. van Delden MD, PhD
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Corresponding author

Correspondence to Indira S. E. van der Zande MA, MSc .

Editor information

Editors and Affiliations

  1. Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

    Françoise Baylis

  2. University of Otago, Wellington, New Zealand

    Angela Ballantyne

Appendix

Appendix

Table 5.1 Searches
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Table 5.2 PRISMA 2009 flow diagram
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Table 5.3 Summary of papers selected for the review
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Table 5.4 Overview of reported reasons for exclusion
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Table 5.5 Grouping of reported reasons for exclusion
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van der Zande, I.S.E., van der Graaf, R., Browne, J.L., van Delden, J.J.M. (2016). Fair Inclusion of Pregnant Women in Clinical Research: A Systematic Review of Reported Reasons for Exclusion. In: Baylis, F., Ballantyne, A. (eds) Clinical Research Involving Pregnant Women. Research Ethics Forum, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-26512-4_5

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