Volume 49, Issue 8 - Special Issue: Non-Invasive Prenatal Testing (NIPT) — Great Progress and Important Ethical and Legal Considerations; Issue Editor: Prof. Dr.med. Dr. hc.c.mult. Wolfgang Holzgreve, MBA, FACOG, FRCOG

In the Netherlands prenatal screening is offered as a mean to increase reproductive choices of couples. All women are counseled on the existing options by trained midwives. The government puts a great emphasis on informed choice and on womens’ opinions and reactions to screenings options. Since 2017 non-invasive prenatal testing (NIPT, cf-DNA) is offered as first tier screening for aneuploidies in the genome-wide (GW) variant at the cost of 175 Euro’s. Uptake is around 50%. This screenings offer is perceived as unconventional for the traditionally cautious Dutch system.

The most well-known goal of non-invasive prenatal testing (NIPT) is still to determine whether or not a fetus has trisomy 21. Since women often terminate the pregnancy upon a positive result, there is concern that the use of NIPT contributes to discrimination against persons with disabilities. If this concern is justified, it could have an impact on the wider social acceptability of existing testing practices and their potential further expansion. This paper demonstrates four different versions of the discrimination worry, indicates how international policy papers have reacted to them, and identifies the ethically most relevant feature of the concern.

Background Non-invasive prenatal testing (NIPT) has been available for almost 10 years. In many countries the test attracted considerable criticism from the start. While most critical comments in this context deal with the (alleged) problem of eugenic selection, I will concentrate on a somewhat broader issue. Content I will argue that NIPT clearly has the potential to increase reproductive autonomy and benefit expectant parents. However, NIPT can also put people in a situation that is morally overwhelming for them and from which there is no easy way out. In this sense, such tests can have a dilemma-generating effect. Summary and Outlook I will conclude that this can be adequately described by the term “moral ambivalence”.

There are a number of problems with the classification of prenatal screening as a form of ‘selective reproduction’ that has become an increasingly dominant classification scheme in the last decade. (1) Since the term ‘selection’ implies choosing one out of several (at least two), it misdescribes the decision to terminate a pregnancy. (2) Deciding whether to have this child is a decision taken within the relationships that constitute the pregnancy. (3) ‘Selection’ is a loaded term, connecting prenatal diagnosis to negative eugenics or to population genetics. (4) Deciding against the birth of a child who would suffer or would not be able to flourish is a decision taken within a negotiation of personal responsibilities and social constraints. The characterization of prenatal screening as selective reproduction is, in a very narrow way, defensible to reconstruct why prenatal screening is permissible in a liberal state and should not be banned, but it needs to be rejected as a general frame for understanding the substance of the ethical issues around prenatal diagnosis and screening. Ethics should rather attempt to create a respectful space of mutual understandings and reflect how women and couples, who are ultimately responsible for these decisions, perceive their responsibilities in care.

First mapping the main ethical issues surrounding prenatal testing, we then analyze which concerns are specific to non-invasive methods. Presupposing the privatization premise for reproductive autonomy in fundamentally liberal societies, we go on to specify common concerns about non-invasive prenatal testing (NIPT) covered by the term ‘routinization’, and conceptually unravel the frequently expressed worry of increasing ‘pressure’ to test and/or terminate affected pregnancies. We argue that mindful decision-making should be a key educational goal (not only) of NIPT counseling which could be achieved through stepwise disclosure. In addition, we identify indirect social pressure as the most plausible threat to reproductive freedom. While continuous efforts need to be made to prevent such pressure – not least by ensuring balanced availability of options –, restricting testing options, and thus freedom of choice, cannot be the answer to this concern. Lastly, we suggest abandoning the vague term ‘routinization’ and instead focusing on specified concerns to enable a fruitful debate.

By implementation of non-invasive prenatal testing (NIPT) for the diagnosis of Down syndrome (DS) in maternity care, an ethical debate is newly inflamed how to deal with this information. Fears of the consequences of an increased use of NIPT are justified with the same arguments when amniocentesis and preimplantation genetic diagnosis (PGD) were introduced decades ago. It can be expected that the prevalence of people with DS would significantly increase in Western societies as a result of the increasing age of pregnant women and the improved medical care for people with DS. The net effect as to whether an increasing uptake of NIPT will result in more abortions of fetuses with trisomy 21 cannot be reliably estimated. This holds true since more and more couples will use results of NIPT for information only, but will not opt for termination of pregnancy. Although parents love their children with DS, in a society where reproductive autonomy is seen as an achievement, access to NIPT cannot be limited. On this background, comprehensive and qualified pretest counseling is vital, also to avoid possible stigmatization of people with DS and as the resulting consequence to avoid feared deterioration in their living conditions, for which, however, there is no evidence to date. The personal view of a mother of a child with DS illustrates the complexity in dealing with NIPT, which does not allow simple answers and must be understood as a challenge for society as a whole.

The procedures of prenatal and preimplantation diagnostics are discussed critically again and again in our community. In addition to the permanently controversial issues of embryo protection and abortion, considerations that discrimination on the basis of disability could occur with problematic consequences also for already born people with disabilities and their relatives now play a central role.

Experimental and clinical studies suggest that prenatal experiences may influence health trajectories up to adulthood and high age. According to the hypothesis of developmental origins of health and disease exposure of pregnant women to stress, nutritional challenges, infection, violence, or war may “program” risks for diseases in later life. Stress and anxieties can exist or be provoked in parents after fertility treatment, after information or diagnosis of fetal abnormalities and demand simultaneous caring concepts to support the parents. In vulnerable groups, it is therefore important to increase the stress resilience to avoid harmful consequences for the growing child. “Enriched environment” defines a key paradigm to decipher how interactions between genes and environment change the structure and function of the brain. The regulation of the fetal hippocampal neurogenesis and morphology during pregnancy is one example of this complex interaction. Animal experiments have demonstrated that an enriched environment can revert consequences of stress in the offspring during critical periods of brain plasticity. Epigenetic markers of stress or wellbeing during pregnancy might even be diagnosed by fragments of placental DNA in the maternal circulation that show characteristic methylation patterns. The development of fetal senses further illustrates how external stimulation may impact individual preferences. Here, we therefore not only discuss how maternal stress influences cognitive development and resilience, but also design possibilities of non-invasive interventions for both mothers and children summarized and evaluated in the light of their potential to improve the health of future generations.

Non-invasive prenatal testing (NIPT) is often erroneously received as a diagnostic procedure due to its high discriminatory power in the field of fetal trisomy 21 diagnosis (wording: “NIPT replaces amniocentesis”). Already a look at the methodology of NIPT (statistical gene dose comparison of a primarily maternofetal DNA mixture information at selected sites of the genome) easily reveals that NIPT cannot match the gold standard offered by cytogenetic and molecular genetic analysis procedures from the matrix of the entire human genome (origin: vital fetal cells), neither in diagnostic breadth nor in diagnostic depth. In fact, NIPT in fetal medicine in its current stage of development is a selective genetic search procedure, which can be applied in primary (without indication) or secondary (indication-related) screening. Thus, NIPT competes with established search procedures for this field. Here, the combined nuchal translucency (NT) test according to Nicolaides has become the worldwide standard since 2000. The strength of this procedure is its broad predictive power: NT addresses not only the area of genetics, but also the statistically 10 times more frequent structural fetal defects. Thus, NIPT and NT have large overlaps with each other in the field of classical cytogenetics, with slightly different weighting in the fine consideration. However, NIPT without a systematic accompanying ultrasound examination would mean a step back to the prenatal care level of the 1980s. In this respect, additional fine ultrasound should always be required in the professional application of NIPT. NIPT can thus complement NT in wide areas, but not completely replace it.

Reproductive genetic screening has introduced the possibility for pregnant women to learn, during the pregnancy or sometimes earlier, about the likelihood of their baby being affected with certain genetic conditions. As medicine progresses, the options afforded by this early information have expanded. This has led to a shifting paradigm in prenatal screening, wherein the early knowledge is seen as useful not solely for its inherent value to the pregnant woman, but also as enabling an expansion of conditions whose identification may allow early intervention and clinical impact. This article discusses this paradigm against the backdrop of prenatal genetic screening that is available today.

New genomic laboratory technology namely microarrays and high throughput sequencing (HTS) as well as a steady progress in sonographic image capture and processing have changed the practice of prenatal diagnosis during the last decade fundamentally. Pregnancies at high risk for common trisomies are reliably identified by non-invasive prenatal testing (NIPT) and expert sonography has greatly improved the assessment of the fetal phenotype. Preconceptional comprehensive carrier screening using HTS is available for all parents, if they should wish to do so. A definite fetal diagnosis, however, will still require invasive testing for most conditions. Chromosomal microarrays (CMA) have greatly enhanced the resolution in the detection of chromosome anomalies and other causal copy number variations (CNV). Gene panel or whole exome sequencing (WES) is becoming the routine follow up of many anomalies detected by ultrasound after CNVs have been excluded. The benefits and limitations of the various screening as well as diagnostic options are perceived as complex by many who find it challenging to cope with the need for immediate choices. The communication of facts to ensure an informed decision making is obviously a growing challenge with the advent of the new genomic testing options. This contribution provides an overview of the current practice and policies in Switzerland.

During the last decade a number of innovative treatments including gene therapies have been approved for the treatment of monogenic inherited diseases. For some neuromuscular diseases these approaches have dramatically changed the course of the disease. For others relevant challenges still remain and require disease specific approaches to overcome difficulties related to the immune response and the efficient transduction of target cells. This review provides an overview of the current development status of mutation specific treatments for neuromuscular diseases and concludes with on outlook on future developments and perspectives.