REVIEWS AND COMMENTARY on recent literature in reproductive medicine and biology
The staff of THE REPRODUCTIVE TIMES here offers commentaries on recently published articles, primarily chosen for educational values—in the positive but also in the negative—for clinical purposes, and for their potential translational values to clinical medicine when addressing basic science in reproductive medicine and biology.
Ethics in reproductive medicine
With emphasis on NIPT, how much prenatal testing is ethical?
This is an increasingly relevant question and, of course, in principle also includes the testing of embryos. Molly McDonough, Associate Editor of Harvard Medicine, attempted to address it in interviewing Vardit Ravitsky, PhD, who is not only one of the world’s preeminent reproductive ethicists, but also a little over a year ago became the new President and CEO of the prestigious Hastings Center in Westchester. She also still holds a professorial appointment in bioethics at the University of Montreal, where she was a scholar before and is also a senior lecturer at Harvard Medical School and was able to speak from personal experience (1).
Vardit Ravitsky, Ph.D
What gave her the opportunity to address this issue from personal point of view was the fact that (at age 40) a routine screening test during her pregnancy revealed that she had a 1-in-40 chance that her child could be born with Down’s syndrome. In an interview published in the Harvard Medicine Magazine, the two discussed this experience within the context of ever more prenatal genetic testing, especially so-called NIPT (non-invasive prenatal testing).
Also speaking from personal experience, McDonough felt “empowered” by having the information that NIPT offered. But once she started thinking about the implications at a societal scale, things started “to feel more problematic.”
Ravitsky was very clear in her position when stating that, “it always must be about choices and knowledge and should not slip into the goal of eliminating certain types of conditions or even certain traits, syndromes, or types of people.” She went on, “what child to have should always remain a personal decision, free of societal pressures.”
Regarding NIPT, which basically very early in pregnancy uses the same technology to determine the fetuses’ DNA from maternal blood that is used in preimplantation genetic testing for aneuploidy (PGT-A) through a biopsy of the embryo, it, therefore, has similar unreliability built into its process as PGT-A. As Ravitsky noted, the context matters if the result of the test suggests that the pregnancy may be at high risk for a specific chromosomal abnormality, raising the question, what justifies more invasive follow-up testing with chorionic villous sampling (CVS) or amniocentesis?
She also pointed out that some diagnoses made by NIPT are, moreover, not even diseases, with ethicists still even disagreeing, “what to call them: conditions, traits, or disabilities?” And when it comes to disabilities, some rights advocates argue against including them.
The ethics of “serious” genetic conditions in reproduction
Related to the above-described interview, Ravitsky was also the senior author of a recent paper in the European Journal of Human Genetics which discussed reproductive decision-making when it comes to “serious” genetic conditions (2). The article notes that the definition of a genetic condition as “serious” has defined importance because the term is often used to define and/or delineate permissibility and access to new reproductive genomic technologies. The paper, however, also pointed out that the term also lacks clarity, leading to inconsistent use, and then tried to address this gap.
In the process, within the context of prenatal (and, though not mentioned, PGT-A) and reproductive genomic technologies they identified three areas of ‘tension:” (i) Clinical care and population health; (ii) The impact of designating something as ‘serious;” and (iii) the perception of quality of life. The first basically involves the issues discussed in above-described interview. Defining something as ‘serious,” is, of course, highly subjective and requires appropriate mindfulness and, regarding the issue of quality of life, it is important to note that the widely held notion that anybody affected by a “serious” genetic condition must have a poor quality of life has been proven incorrect.
The authors conclude that “the concept of seriousness in reproductive decision-making represents one of the most ethically complex uses of the term, as it influences not only prospective parents’ reproductive decisions and family planning, but also has a direct influence on societal decisions around who is born.”
Are we saving enough very premature babies?
A recent article by Liz Essley Whyte in the Wall Street Journal asked two questions: first, why most hospitals do not try to save very premature babies, even though babies—starting already approximately at 21-22 weeks gestational age—now demonstrate increasingly better odds of survival; second, if hospitals cannot do this, why don’t they inform parents that other hospitals can (3)?
As we discerned after listening to an interview she gave to a radio station regarding her article, she obviously meant well in writing it. But as unfortunately is so often the case, medicine is more complicated than lay people are able to understand, unless they are really willing and able to dig deep into a subject and that was definitely not the case here.
Essley Whyte correctly noted that some neonatal intensive care units (NICUs), indeed, are getting better and better in achieving good survival of very immature infants starting at roughly 21-22 weeks. These units in the U.S. are so-called Level IV NICUs and are located in regional perinatal centers and are referral centers for so-called level III NICUs which are equipped to manage critically ill newborns who need intensive care but do not have the ability to provide level IV services (see table below).
In short, like with all medical care, not all hospitals can provide all of it. If a higher level of care is required, the patient (in this case the baby) is transferred to an appropriate provider who offers a higher level of care. The truth, therefore, is not, as the article appears to suggest, that “most hospitals don’t try,” but that most hospitals are not expected to try. The real question is also not whether the parents are told that other hospitals are offering such highly specialized care but, whether hospitals are fulfilling their obligation within perinatal networks to transfer the patient (in this case the baby) to an appropriate level NICU if the baby’s needs exceed the hospital’s capabilities. And hospital usually do this rather automatically in all medical specialties.
One difference from many other medical specialties, however, is that the occurrence of a very premature deliveries cannot always be predicted. In a majority of cases it, indeed, will occur unexpectedly, with the patient ending up in the closest and not necessarily best hospital for her situation.
And then there is another crucially important point the science reporter for the WSJ apparently did not understand. In her interview, when asked whether other countries did better than the U.S., she described Japan and Sweden as especially successful with survival rates in the high-50% range. But that means that in the high 40% range babies do not survive. She also noted that surviving babies may have mild learning disabilities, but many surviving babies may, indeed, end up with quite severe lifelong disabilities, and nobody can at 21-22 weeks with accuracy predict which baby will survive, or survive with only mild or with severe disabilities. The treatment offered to parents of such very premature infants, therefore, often must be considered “experimental,” and, therefore, requires their specific consent.
In short, another rather superficial article critical of medical care, maybe meaning well, but essentially just trying to be provocative by falsely accusing hospitals of “not even trying” to save very immature babies.
The ethics of working with embryo models
We have in these pages on several prior occasions pointed out the increasing use in human embryo research of stem cell-derived human embryo models. Nature magazine—we believe also rather superficially and quite uncharacteristically for this highest-ranked science journal—described this effort recently as “uncharted ethical territory (4).” The author, Smriti Felicitas Mallapaty, an Asia reporter for Nature News, should know better because this subject has become highly “charted” territory, maybe even too charted, as some scientists working in the field would say. Interestingly, Mallapatty correctly quoted in her article such a scientist making the point that, aside of the fact that so many different embryo models have by now been reported, none of them has led to “scientific discoveries of any societal value.”
This is important because she also correctly pointed out that ethical issues would become relevant only once one of the embryo models could be viewed as becoming “equivalent” to a human embryo; and that appears still miles away. It appears to us, therefore, that the very visible drive by many toward regulation of embryo models, also demonstrated in publication of the recent “code of practice” for human embryo models grown from stem cells organized by Cambridge Reproduction (4) may turn out to be more hindrance than benefit for the field but it, most definitely, cannot any longer be described as “uncharted territory.” One can also only hope that Roger Sturmey, a professor of reproductive medicine in the UK, was correct in suggesting, also in Nature, that the above-noted code of practice aims to ensure ethical research, while demonstrating enough flexibility to allow for progress in a rapidly moving field. As he also noted to establish unified limits to all types of embryo models would seem impractical (5).
Two steps forward, one step backwards in improving research integrity
Science magazine recently reported that the Office of Research Integrity (yes, there is such a thing!) in its first regulatory overhaul in 20 years is taking “modest steps toward greater transparency (6).” What this means according to the article is that the U.S. agency responsible for investigating research misconduct by federally funded biomedical scientists (where has this agency been for the last 20 years?) has actually dropped “controversial proposals” intended to speed up investigations and increase transparency.
The agency apparently “listened to concerns expressed by attorneys representing several major research institutions.” One wonders whether that is a good omen?
References
1. McDonough M. Harvard Medicine Magazine 2024; https://magazine.hms.harvard.edu/articles.ethics-prenatal-genetic-testing
2. Kleiderman et al., Europ J Hum Genet 2024; https://doi.org/10.1038/s41431-024-01681-0
3. Essley Whyte L. Wall Street Journal. August 7, 2024. https://www.wsj.com/health/healthcare/premature-babies-hospitals-pregnancy-fa1f091f
4. Mallapaty S. Nature 2024; 633:269-271
5. Cambridge Reproduction July 2024. https://www.repro.cam.ac.uk/scbemcode/governance-stem-cell-based-embryo-models-g-scbem-project
6. Sturmey R. Nature 2024;632:639. Mervis J. Science 2024;385(6715