Making the most of uncertainty: Treasuring exceptions in prenatal diagnosis

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Highlights

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    Prenatal genetic testing became a new source for genetic variants of interest to clinicians and geneticists after 1990.

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    Chorionic villus sampling (CVS) and prenatal microarray altered providers' expectations about the value of uncertain results.

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    CVS and microarray were presented as better prenatal tests because they occasionally made new diagnoses possible.

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    Providers were confident that present uncertainty would improve the scope and accuracy of prenatal diagnosis in the future.

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    “Training for certainty” in medical education led prenatal providers to approach uncertainty as puzzles that would be solved.

Abstract

Throughout the 20th century, human genetics research was driven by the identification of new variants. As pioneering geneticist William Bateson put it, novel variants were “exceptions” to “treasure”. With the rise of human chromosomal analysis in the postwar period, the identification of genetic variants became increasingly significant to clinical and prenatal diagnosis. Human geneticists had long sought a broader sampling of human genetic variation, from a largely “normal” population. The expansion of prenatal diagnosis in the late 20th century offered a new resource for identifying novel genetic variants. In the prenatal diagnostic setting however, many of the exceptions to be treasured were of uncertain clinical significance, which raised anxiety among parents. In the early 1990s, providers reported that specific uncertain results from chorionic villus sampling (CVS) facilitated prenatal diagnoses that were not previously possible. Based on this, some prenatal diagnostic providers began to embrace uncertainty, when properly managed to reduce anxiety, rather than prevent it. The potential to produce uncertainty in prenatal diagnosis grew with whole genome microarray in the 2000s. Rather than outcomes to avoid, or accept as inevitable, providers presented uncertain results as starting points for research to improve the scope prenatal diagnosis, and bring future certainty.

Section snippets

Training for certainty

Ambiguous or unanticipated findings are common in all areas of medical diagnosis. Results often straddle the border between two or more categories, making it difficult for physicians to provide or agree upon a diagnosis (Bowker & Star, 1999). Testing may also result in “incidentalomas”, unexpected findings that have different or broader health implications for a patient than initially anticipated (Wolf et al., 2008). Scholars have long been interested in how uncertainty is interpreted and

Ambiguity in the prenatal context

During the 1970s and early-1980s, prenatal chromosomal samples were derived from second trimester amniocentesis. Laboratory results were reported around the 20th week of pregnancy, giving women a very short window of time in which to make a decision about abortion after a positive diagnosis. In the mid-1980s, new approaches shifted the point at which screening and diagnosis could begin into the first trimester. This sometimes resulted in an earlier definitive answer. In other instances, testing

False positive or false negative?

Dagmar Kalousek, one of the first medical geneticists to report the increased incidence of mosaicism in CVS was less confident than some of her colleagues that confined placental mosaicism was clinically benign. In her early studies of mosaicism detected by CVS, she noted variability in outcomes: in some instances, these fetus experienced severe intrauterine growth retardation. Interested in the cause of this variation, Kalousek began to ponder the mechanism by which confined placental

CVS as the better test

While some clinicians and geneticists were concerned about the uncertainty arising from confined placental mosaicism and uniparental disomy in CVS, others interpreted these findings more optimistically. When the link between a mosaic CVS result and the potential for disease causing UPD was established, some providers responded by pointing to the greater prevalence of mosaicism in fetal samples as an advantage of CVS, rather than a problematic complication. A 1995 report from the Centers for

The rise of prenatal microarray

The completion of the Human Genome Project in 2000 led, over the coming years, to a significant expansion in the scope and resolution of genetic diagnosis. Human geneticists had, since the 1950s, approached the study of human chromosomes as a form of whole genome analysis (de Chadarevian, 2010). Various efforts by cytogeneticists to improve the resolution of chromosomal examination over the coming decades facilitated the identification of increasingly subtle forms of genetic variation. After

Debating the value of more

Reports of the prenatal application of DNA microarray immediately raised concerns about the potential implications of expanded testing. In 2007, Philadelphia bioethicist Evelyn Shuster argued that prenatal microarray represented a “roadblock for life” (Shuster, 2007, 526). Looking at the history of prenatal diagnosis, Shuster noted that decisions about testing had previously been made one disorder at a time, with a primary focus on Down syndrome and specific inherited conditions. Microarray, on

Conclusions

The uptake and scope of prenatal genetic diagnosis expanded significantly between the 1980s and 2010s. Scholars have highlighted many of the forces driving this trend including the desire to prevent Down syndrome and inherited disorders, the introduction of non-invasive screening options, and increased social focus on individual genetic risk and responsibility (Cowan, 2008, Lindee, 2005, Löwy, 2014a, Löwy, 2014b, Markens, 2013, Remennick, 2006, Resta, 2002, Stern, 2012, Williams et al., 2002).

Acknowledgments

I would like to thank Robin Wolfe Scheffler and Stephen T. Casper for their comments on early drafts of this paper, which contributed significantly to its framing and development. I am grateful to those who took the time to be interviewed as part of this project. This research was partially funded by a generous Dissertation Research Fellowship from the University of Pennsylvania.

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