For more than a decade, couples at risk for Huntington's disease have had the option to conceive an unaffected child by utilizing the reproductive process of preimplantation genetic diagnosis (PGD). If PGD became common practice in HD, it could eliminate the majority of disease for the next generation. So if PGD has the potential to mostly "wipe out" HD for the next generation, why is it so rarely utilized?
What is PGD? First carried out in 1990, PGD is the procedure that does genetic testing of an embryo created by combining egg cells and sperm cells outside of the mother's body. The process begins with ovary stimulation (by self injection of hormone medications) so that multiple eggs are produced. Subsequently mature eggs are surgically removed during a procedure performed in the doctor's office. Then in vitro fertilization (IVF) is done by injecting each egg with sperm. Resultant embryos are grown for 5 days and a few cells are removed from each for gene analysis. Embryos that test negative for the disease gene are frozen, then subsequently implanted into the mother's uterus, most often after one or two menstrual cycles.
What is PGD with non-disclosure? In this PGD situation clinic staff follow procedures to prevent disclosure of gene status to those at risk for HD who have chosen not to test. Though non-disclosure practice is discouraged in Europe, the U.S. appears to have greater respect for the individual's right "not to know" gene status.
It could be said that by discouraging non-disclosure PGD, the Europeans are in effect limiting PGD access to fewer than 10% of individuals with premanifest HD. This seems a counterproductive policy if the goal is to prevent HD in the next generation.
Rates of PGD use in HD are low: How rarely is PGD used in HD? The only published studies suggest that it is very low -- even in countries where PGD for HD is covered by national health insurance. Utilization from 1995-2008 was only 0.7% in France, 1.7% in Belgium, and 1.2% in the Netherlands [Van Rij MC 2012]. Though there are no studies or reports from North America where PGD is often not covered by insurance, the rates are likely not much higher. Why so low?
Barriers for using PGD for HD
- Lack of Awareness/Lack of Education: Though no studies specific to HD have been done, it is likely that the vast majority of HD couples have never been given education or received counseling about PGD. In fact in a study done among internal medicine physicians, more than 90% could not explain the procedure to patients [Klitzman R 2013]. It is doubtful that neurologists would be much better. What about HD specialists? Though it is unknown how many have ever talked about PGD with their patients, it has not been an education topic prominently discussed in either the Huntington Study Group (HSG) or European Network of Huntington's Disease (EHDN) meetings. Though it is recommended that reproductive options be discussed during genetic testing counseling for HD [de Die-Smulders CE 2013], it is unclear how often this is done. Even if done for every person undergoing genetic counseling for HD, such education would reach only the minority of those at risk for the disease.
- Financial Burden: Cost is in the range of $20,000 per procedure. Unfortunately for many at risk couples more than 1 cycle is needed, particularly if the mother is older than 35 years of age where 3 (or more) cycles may be needed. Only fifteen states in the U.S. have mandates for even partial coverage for PGD. A few progressive large company employers including Google, Microsoft, and Amazon provide substantial PGD benefits, but most employers do not. However, it isn't just financial burden limiting PGD; even in those countries where PGD is covered by national insurance, at least as reported in the earlier study, fewer than 2% of couples utilized this option.
- Lack of Access/Geographical Location: PGD is offered only in large urban areas. Because the entire procedure requires frequent visits for monitoring, multiple trips must be made to the center, making it more difficult for those who must travel long distances.
- Psychological and Physical Stress of the Procedure: PGD "takes over your life" during the weeks required for all the steps related to the procedure, although studies suggest that there are no long-term adverse consequences for those who achieve a successful pregnancy using PGD [Karatas JC 2010].
- Religious/Ethical Reasons: It is not known how many at risk HD couples choose not to have PGD for religious or ethical reasons.
- Acceptance or Denial of Risk for the Next Generation: Reproductive decisions are very complex and may be subject to emotional and unconscious psychological processes, so it is likely that a published study of reproductive decision-making in those who had children while knowing of risk for HD [Quaid KA 2010] was oversimplified. However, important themes reported are that many couples (1) "accepted" risk to children citing hope and a belief that treatment or cure for HD might occur in their childrens' lifetimes, or they felt optimism about their ability to care for a spouse and children if HD occurred. (2) Others "denied" risk believing they would escape HD, and others minimized risk. It should be remembered that at the time of this study, PGD was not as readily available; however it is likely that similar thinking contributes to lower use of PGD in the present generation.
Author's comments: PGD is underutilized. HD doctors and HD societies do not readily increase awareness or provide adequate education. And there are geographic and financial barriers. However -- it is past time for more support and better application of PGD as a voluntary means of preventing HD in the next generation. The experts tend to agree, as is argued in a recent Nature Reviews Neurology article [Tur-Kaspa I 2014], "It is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology."
Authors of this article cite several societies for reproductive health and genetics who recommend and have guidelines for counseling of all family members afflicted by genetic disease. However, as of now, no neurological societies, including those for HD have done so. PGD has been around for more than two decades. Admittedly a sensitive topic, it is high time for the clinicians in our community to increase awareness and to provide more education to HD families.
Addendum: After this HDDW article was published, a excellent two article summary has been published on ALZFORUM, a web based site for the Alzheimer's community. Dr. Jeff Carroll from HDBuzz is quoted in the second article.
Van Rij MC, De Rademaeker M, Moutou C, Dreesen JC, De Rycke M, Liebaers I, Geraedts JP, De Die-Smulders CE, Viville S; BruMaStra PGD working group. Preimplantation genetic diagnosis (PGD) for Huntington's disease: the experience of three European centres. Eur J Hum Genet. 2012 Apr;20(4):368-75. doi: 10.1038/ejhg.2011.202. Epub 2011 Nov 9. PubMed abstract
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Quaid KA, Swenson MM, Sims SL, Harrison JM, Moskowitz C, Stepanov N, Suter GW, Westphal BJ; Huntington Study Group PHAROS Investigators and Coordinators. What were you thinking?: individuals at risk for Huntington Disease talk about having children. J Genet Couns. 2010 Dec;19(6):606-17. doi: 10.1007/s10897-010-9312-2. Epub 2010 Aug 24. PubMed abstract
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