Improving the safety of fetal therapy trials and studies

Lynn Bush and Katie Ellis
Co-Chairs, Genetic Counseling, Ethics, and Patient Education Special Interest Group

After a long COVID-driven absence from being together in person, the ISPD 2022 Counseling-Ethics-Education SIG breakfast opened with our word cloud to engage the hybrid ISPD community. Interdisciplinary panelists for the session, The Certainty of Uncertainty: Considerations and Conversations in the Context of Screening, Diagnosis and Therapy, were co-chairs Lynn Bush, PhD, MS Bioethics, MA and Katie Ellis, FHGSA, GDipHEd, MSc along with invited guest speakers Alireza Haghighi, MD, DPhil, FACMG and Alireza (“Shami”) A. Shamshirsaz, MD, FACOG. Lively discussion ensued on a variety of topics!

Many felt it would be easier if guidelines were reviewed and updated in a more timely manner to help with patient interactions.

Another major theme was the complexity around what options can be offered to patients at their practice, state, or country. This was highlighted by the overturning of Roe v. Wade that very day but also encompassed availability of technology such as exome or genome sequencing or fetal therapy or pre-implantation genetic diagnosis. Attendees reported these issues made consultations more complex but agreed they advise their patients about technologies or services available elsewhere (even in another country), if their patient wishes to and can avail themselves of that. All present who voiced their perspective stated this was ethically the right practice.

Invited geneticist, panelist Alireza Highighi, shared aspects of an endeavor he directs (for which Lynn is bioethics collaborator). He explains: “Genetic screening is a type of public health program that is systematically offered to a specified population to identify members at high risk for genetic disease and provide them with opportunities for potential preventive and early treatment care, and information for reproductive decision making. Ensuring these potential preventive and therapeutic benefits while minimizing the potential risks and unintended harms depend upon implementing the optimal screening program, appropriate recruitment methods, education, and counseling programs, and a host of additional factors specific to the testing program contemplated. We, at the Harvard International Center for Genetic Disease (iCGD), are working on design and implementation of an affordable, clinical-grade, pan-ethnic genetic screening program at population-scale. This program will simultaneously conduct four classes of screens for genetic conditions: (i) prenatal carrier screening, (ii) newborn screening, (iii) pre-symptomatic screening for actionable diseases in adults and children, and (iv) pharmacogenomic screening. We will initially pilot this program in a few carefully selected countries in partnership with their Ministries of Health. In addition, this program includes comprehensive training to educate local physicians and healthcare providers on the diverse aspects of population genetic screening. We welcome collaborations with clinicians and investigators from around the world."

Alireza can be contacted at Lynn can be reached at regarding many of the issues she raised, such as the complexity of ethical considerations and the imperative for respect of individuals, communities, regional governance — with cultural sensitivity — as we strive to make equitable access a reality for more individuals.

On this topic, our invited MFM surgeon panelist, “Shami” Shamshirsaz, provided historical context by highlighting successful implementation of early screening efforts for beta thalassemia in Tehran. He links the importance of screening to diagnosis not only for identification but ultimately to provide for treatment options as the field evolves. The potential challenges and opportunities arising with innovative fetal diagnostic technologies and therapies increasingly necessitates ethical nuances with decision making and counseling, and particularly in light of uncertainty with risk and phenotypic variation and a lens towards issues of ableness and disability. This provided much discussion from participants around equity of access and ensuring patient-centered care.

Katie Ellis detailed Mackenzie’s Mission, a 3-year research study investigating how reproductive carrier screening should be provided as a National screening program in Australia. The study was named after Mackenzie Casella who died with Spinal Muscular Atrophy (SMA) at 7 months. Her parents lobbied the Government stating they had not been warned of the high carrier rate of SMA nor that there was an easily available test that would have identified them as carriers and given reproductive choices. They wanted carrier screening to be routinely and freely available to all couples if they chose. Approximately 8,000 couples were recruited by Health Care Providers (HCP) from all over Australia and screened for 750 (autosomal recessive and x-linked recessive) severe, childhood onset disorders. The couple receives a high or low chance result; the individual’s results are not released in the study. Extensive variables are being examined including couples’ feelings about the screening, ethical and psychological impacts, health economics and resources the system and HCP's needs if they are to offer and deliver screening in the future. The study is complete, and results are likely to be published in the near future. This research project evoked rich discussion among the ISPD attendees as we tried to capture diverse perspectives from varying regions. One aspect emerged particularly controversial. Upon learning that “individual’s results are not released in the study,” some attendees expressed concern and questioned the ethical justification of not sharing “serious” and/or “actionable” findings even if the screening is within the parameters of a research setting.

On another note, we would like to alert ISPD members of the Community options within ISPD. Under each Special Interest Group is a Community tab option. You can log in and start a discussion topic. There will be links and additional resources added to the library over time. This could be a great support during these uncertain times!

In addition, we provide, below, a brief selection of relevant publications we thought might be of interest:

Several ethics-related articles by authors familiar to many ISPD members appear in a recent AJOB issue with international commentary to the linked target article:

Bayefsky MJ, Berkman BE. Implementing Expanded Prenatal Genetic Testing: Should Parents Have Access to Any and All Fetal Genetic Information? Am J Bioeth. 2022 Feb;22(2):4-22. doi: 10.1080/15265161.2020.1867933. PMID: 33459580.

  • Berens N, Wasserman D. Restricting Access, Stigmatizing Disability? 25-27.
  • Callahan KP, Feudtner C. Genetic Testing Is Messier in Practice than in Theory: Lessons from Neonatology. 37-39.
  • Esquerda M, Lorenzo D, Torralba F. Certainties and Uncertainties in Genetic Information: Good Ethics Starts with Good Data. 48-50.
  • Dive L, Newson AJ, Holmes I, Deans Z, MacKay K. Intertwined Interests in Expanded Prenatal Genetic Testing: The State's Role in Facilitating Equitable Access. 45-47
  • Kleiderman E, Rahimzadeh V, Knoppers B, Roy MC, Laberge AM, Ravitsky V. The Serious Factor in Expanded Prenatal Genetic Testing. 23-25.
  • Michie M, Allyse MA. What Really Matters Now in Prenatal Genetics. 31-33.

Delatycki, MB,  Alkuraya, F,  Archibald, A, et al.  International perspectives on the implementation of reproductive carrier screening. Prenatal Diagnosis.  2020; 40: 301– 310.

Brown, E. M., Grinzaid, K. A., Ali, N., Mehta, N., & Hardy, M. W. (2022). Evaluating the experiences of individuals with personal health risks identified through expanded carrier screening. Journal of Genetic Counseling, 31, 59 8 – 6 07.
This study provides insights into the experiences of individuals identified as having personal health risks via expanded carrier screening and highlights practical pre-test counselling suggestions to potentially improve the patient experience. The study found receiving PHR information was useful to patients and was used afterwards by the majority.

Hammond J, Klapwijk JE, Hill M, et al. Parental experiences of uncertainty following an abnormal fetal anomaly scan: Insights using Han’s taxonomy of uncertainty. J Genet Couns. 2021;30:198–210.
This study interviewed parents from the UK and the Netherlands to analyze their experiences of uncertainty after their ultrasound indicated fetal concerns. Several recommendations are outlined for the healthcare professional to assist in minimizing uncertainty and help patients deal with uncertainty.

We look forward to continuing our conversations throughout the year and in Edinburgh.