Recent implementation of array genomic hybridization technology in prenatal diag- nostics may give rise to the diagnosis of genetic aberrations that may or may not be associated with the observed fetal ultrasound abnormalities. In these cases, certain postnatal prognoses cannot always be given.123-125 Micro-array testing is used usually after the exclusion of a fetal aneuploidy, to represent genome-wide screens for detect- ing sub-microscopic chromosomal deletions or duplications that are associated with serious fetal ultrasound abnormalities. The array test provides the possibility to reveal the deletion of a gene that is known to prevent cancer. Such a deletion significantly increases the lifetime risk of developing cancer. Genetic aberrations may come forward of which the clinical significance is as yet unclear, or family members may be diagnosed with a genetic abnormality that may have a negative effect on their (future) health.
Next-generation sequencing of cell-free fetal DNA in maternal plasma
Application of fetal cells and fetal cell-free genetic material in the maternal blood are two approaches currently being investigated. They are promising with regard to the rapid and reliable detection of fetal genetic abnormalities.126-130
1.4 the right to inform and to be informed about incidental findings and
ethical and policy dilemmas
While the novel molecularly targeted approaches focus on the diagnosis of specific genetic diseases, current discussions tend to focus on the possibility of full-scale testing using microarray-based techniques with a maximum of genetic information at an unequaled detection level. The use of these novel molecular genetic technologies for prenatal diagnoses gives rise to many ethical, social, and medico-legal problems and dilemmas.131,132 From the ethical point of view, the parents’ autonomous “right to know” versus “the right not to know” is of topical interest.133 In view of these new technological developments, it is relevant to examine the parents’ preference, i.e., whether women considered to be at high risk of having a child with Down syndrome who undergo invasive testing would opt for full-scale genetic testing for other disorders for which they do not have an a priori increased risk.
The right to be informed has been the basis of current laws and regulations “Everyone has the right to seek, receive and impart information”.134 The debate about patients’ right to be informed of their health status and treatment began in the mid-twentieth century in the United States, where these rights have now been consolidated and can still be considered an example for many countries in the world.135 In its Charter of Fundamental
Rights of the European Union of 2000, the European Union states that free and informed consent of the patient must be respected according to the procedures laid down by the law of each country. These codes refer to the Hippocratic Oath, which obliges physicians never to harm their patients.136,137 The right to information can be understood as an update of the Hippocratic obligation that refers to the relationship between physicians and patients. The patients’ right to information can be considered a result of mutual trust. In the case of an incidental finding in pregnancy with an uncertain prognosis, two patients are involved: the pregnant woman and the fetus. The benefits for each of them are unclear.
New communication technologies are both a risk and an opportunity. There is an increasingly important role for the Internet to provide additional medical information, aside from professional information. The access to and acquisition of large amounts of information has become an obvious right. The relevance of the acquired information varies for each person, and this applies to all kinds of genetic information. The Internet service can be critical in providing extended medical information, which should always be discussed with a professional.138
In view of the new technological developments in prenatal testing, the parental preference is an important factor.119,139,140 The question is whether women considered at high risk of having a child with Down syndrome and who undergo invasive testing would opt for full-scale genetic testing, even for disorders for which they do not have an a priori increased risk. It is not always easy to choose between full-scale testing using microarray-based techniques with a maximum of genetic information and molecularly targeted approaches that focus on the diagnoses of specific genetic diseases. Chromo- some abnormalities are associated with severe, moderate, or mild disease, although sometimes the clinical relevance is uncertain. Many women who undergo invasive prenatal tests are unaware of the possible adverse effects of an uncertain prognosis.141 Herein lies an important task for the professionals who are responsible for the pre-test counseling.
1.5 aim and outline of the thesis
AimThe aim of the thesis was to examine the value - in a positive or negative sense - of the incidental finding of a fetal sex chromosomal aneuploidy in invasive prenatal diagnostic procedures. The main study question was whether the incidental finding of a fetal sex chromosomal abnormality is a diagnostic gain or whether it should be omitted because of diagnostic damage.
Outline of the thesis
In order to answer the main study question, we have formulated some questions that are closer to the heart of the matter:
1. What are the attitudes of women in low-risk pregnancies towards full-scale genetic testing? Chapter 2 reports the answers.
2. What is known about the problems most often encountered by SCA-afflicted indi- viduals? What has recently been published in the medical literature about incidental prenatal findings of sex chromosomal aneuploidies and the postnatal phenotypes of these individuals? Chapter 3 reports a review of this selected literature and its conclusions.
3. What are the perspectives of parents who have been confronted with an unforeseen prenatal finding of a sex chromosome aneuploidy (full blown or mosaic) when they think about the events in retrospect? What were their reasons for continuing or terminating the pregnancy? Two qualitative interview studies were set up – one with parents who decided to continue the pregnancy and one with parents who decided to terminate the pregnancy. Chapters 4 and 5 present their responses. 4. What are the views of medical professionals who counsel the parents and treat SCA
individuals? These experts may decisively affect the parents’ considerations and decision-making, and they are involved in future medical policy changes. Chapter 6 reports the results of our qualitative interview study with several experts in this field.
During the study period, we had a scientific discussion with authors of a recently pub- lished review of factors that may influence the decision-making of parents confronted with a prenatal diagnosis of an SCA. Chapter 7 presents a letter to the editor of the journal Genetics in Medicine and the response of the authors to this letter.
The most important items that emerged for the literature study, as well as the results and conclusions of the three qualitative studies, have been assembled in a such way that they provide a practical answer to our main study question. Chapter 8 presents this material in relation to recent literature (General Discussion).