Safeguards to unfettered prenatal testing is necessary
8 MINUTE READ
“Look, there is one more baby inside!!!”
This was not an unusual way for many to diagnose twins about four decades ago.
Babies stillborn with serious abnormalities, or dying soon after birth due to missed congenital abnormalities, was not unusual. The focus in most countries was on saving the mother’s life. Averting maternal mortality and morbidity was urgent then and, although this is mostly assured now, reducing perinatal mortality to the lowest possible is now a priority1. The goal posts are rapidly changing – twins are diagnosed in early pregnancy and it is almost considered irresponsible if a baby is born without having genetic and phenotypic screening.
There is no doubt that the progress in science and technology has given us unprecedented opportunities in prenatal screening and diagnosis. Science and technology are a boon to mankind and, without a doubt, saves lives, e.g. emergency atrial septostomy for babies born with transposition of the great arteries and intact septum (a cause for immediate death of the newborn if not prenatally diagnosed).2 Most of us embrace science and technology without question – mobile phones, global positioning system (GPS) technology and air travel are a normal part of everyday life. Unfortunately, missile and drone warfare use the same technology to destroy lives.
“…while this information can be used for the beneficial treatment of the baby, it can also be used to make reproductive choices that may end in termination of the pregnancy.”
Similarly, none of us would have difficulty in accepting screening for antenatal abnormalities, especially the ones that cause perinatal mortality or severe morbidity in the child. However, while this information can be used for the beneficial treatment of the baby, it can also be used to make reproductive choices that may end in termination of the pregnancy.
Screening for Normality
In the twentieth century, screening tests became tools to detect individuals with risk factors for specific conditions, which could then be diagnosed by further costly and invasive tests. There has been a proliferation of screening tests over the years. The World Health Organisation (WHO) has observed a trend towards screening for more conditions, and that “many of these screening programmes are not based on available scientific evidence. Policy-makers, health professionals and the public are often unaware of the potential harm of screening and its cost and burden”.3
The notion of screening, not for specific conditions but for normality, is a shift that has occurred in the twenty-first century and is challenging. At the 18–20 week morphology scan we are not only looking for specific abnormalities but also looking for deviations from normality with the parents being reassured that “everything is normal” when this could be far from the truth. Parental and societal expectations place an enormous burden on health professionals to get it right every time. Many parents rightfully ask, “This is the 21st century, why do we not have the diagnosis or treatment for this condition?” On the one hand, screening individuals for recessive genetic conditions in high-risk groups is acceptable, on the other hand, screening the general population for hundreds of conditions is challenging and needs to be questioned.
Reproductive Genetic Carrier Screening
Recessive carrier screening has come to the forefront with the statement from Rachel Casella:“Why did we not know that we were carriers for SMA (spinal muscular atrophy)?”. This has resulted in 10,000 couples being tested (Mackenzie Mission) for the government to formulate a policy.4 The Obstetric and Gynaecology college guidelines have already recommended that all couples should be offered recessive carrier screening before or during the first trimester of pregnancy for specific conditions, or for the expanded screening for hundreds of conditions5. The complex interplay between the knowledge of the carrier state, the guilt of having passed it on, or the blaming of parents for bestowing it, along with the ethical dilemmas for reproductive choice is still to be fully comprehended.4 In addition to the college guidelines, it is likely that the Australian government will come out with a policy to implement this soon.
The triumvirate of ultrasound, fetal genome sequencing (non-invasively from maternal blood) and fetal magnetic resonance imaging (MRI) has armed us with powerful tools that were unthinkable in the last decade.
Non-Invasive Prenatal Testing
Non-Invasive Prenatal Testing (NIPT) from 10 weeks of gestation was initially advertised as a screening test for Down Syndrome, but is now offering whole genome sequencing for a fraction of the cost that was originally priced for the common trisomies. Using different platforms, laboratories can either target multiple specific conditions or sequence the whole genome to a resolution of 5 to 7 MB, picking up significant large deletions or duplications in the genome.
Often in the absence of structural abnormalities in the fetus, this demands further testing of the parents or counselling about the significance of the findings. This test, which is now freely available (although not covered by Medicare rebate), has inadequate pre-test counselling, with some laboratories offering pre- and post-test genetic counselling as needed. It is only a question of time before the resolution improves with many variations of unknown significance being reported.6 Moreover, if there are structural abnormalities, the testing is narrowed to check if this is genetic in nature. Many laboratories, both in Australia and overseas, offer sequencing of multiple gene panels with a turnaround time of only a few weeks.
“Projecting the knowledge that we have acquired from paediatric and adult populations backwards onto fetal medicine is fraught with danger.”
The area of prenatal genomic sequencing with the whole range of the variations is not fully understood. Projecting the knowledge that we have acquired from paediatric and adult populations backwards onto fetal medicine is fraught with danger. Testing in paediatric and adult populations is guided by clinical presentations. However, projecting the likely clinical consequences onto a fetus based on the findings of genomic sequencing is problematic. The time is not far off when we will be asked to test the fetus for functional disorders, including gene panels for autism spectrum disorders.7
In the absence of obvious structural abnormalities and our current inability to predict outcomes with certainty, it is not unreasonable to ask if this is not another form of screening for normality and not for specific conditions.
The latest ultrasound machines have improved resolution and powerful computational ability to give us images of the embryo/ fetus and increase our diagnostic capabilities. The nuchal translucency (NT) scan at 11-13 weeks of gestation is now often called the early anatomy scan, with numerous articles detailing the structural anomalies/abnormalities that can be picked up at that early gestation.8
The 20-week morphology scan is yet another routine scan where most abnormalities are expected to be picked up. Almost all the mothers I see voice their unspoken fear, “Is everything all right, Doctor?” I am still uncertain as to how best to answer this question. Most often I say that we have not been able to detect any obvious structural abnormality but that we are yet to devise a test that will assure us that “everything” is alright with the baby.9 Again, it appears more that we are screening for normality and not for specific abnormalities at the scan.
Fetal MRI has added an additional modality of imaging and has been made affordable with a Medicare rebate allowed for specific indications. Fetal MRI, especially of the fetal brain has added to the prenatal diagnostic capabilities and the ability to counsel parents about postnatal outcomes.10 However, this has also brought about diagnostic and counselling dilemmas with findings of uncertain significance, particularly when they are isolated. We do not have sufficient information to be able to predict outcomes, and in fact the outcomes may be completely within normal limits. The screening for normality continues, with parents often left in the dilemma that arises from ‘full disclosure’ of the results: as the resolution of the images improve, we see more detail and any deviation from ‘normality’ is reported.
Altar of Science and Technology
We worship at the altar of science and technology, our new gods. My concern is that we set ourselves up for failure with the inability to counsel parents adequately about the array of tests available, the varying sensitivities, specificities, and positive predictive value of the tests. The uncertainties that the results raise (even in situations where most of the results are normal) if a genetic variation of unknown significance is detected; or a gene that makes a child susceptible to a disorder; or an adult-onset gene with varying penetrance and expression; brings complexity to the situation. Attachment disorders and overprotective behaviour towards children born with abnormal test results have been described. However, the inability to cope with uncertainty sometimes moves parents towards a decision they would never have otherwise contemplated. In the prenatal context where the fetus is not attributed legal protection, the possibility of uncertainty resulting in the termination of pregnancy is real.
GuardRails Around Science and Technology
Screening for normality as a notion needs to be debated and challenged at various levels, whether it is in structural anatomy or in genomic sequencing. Testing for functional and behavioural disorders as well as adult-onset illnesses needs to be widely debated. Technological development, laboratories, shareholders, powerful lobbies, and patient autonomy will drive much of the decision-making, both in the choice of the tests requested and in the decisions made after the tests. Great responsibility rests on us as health professionals and on the policy-makers as to how science and technology are applied in the prenatal situation.
“Great responsibility rests on us as health professionals and on the policy-makers as to how science and technology are applied in the prenatal situation.”
From the very beginning, it is recorded that we desired knowledge – to define good and evil and become like God (Gen 3:1-6). Given the creation mandate to “be fruitful and increase in number, fill the earth and subdue it. Rule over the earth…” (Gen 1:28) the right acquisition and proper use of knowledge is essential. Using science and technology as tools is part of the creativity bestowed on us at Creation, as beings made in the image of God (Gen 1:26-27).
Though some Christian groups may prohibit medical treatment and surgery, progress in health care is mostly accepted as part of the creation mandate and provision from God. However, we need to be aware that all of science and technology is also part of the fallen world and we will need discernment as to its use and application (Rom 8:20-22).
The use of science and technology with the proliferation of screening tests, without the concomitant application of ethical and moral boundaries is irresponsible. Urgent safeguards to unfettered prenatal testing of both genomic and structural anatomy is necessary.
Dr Joseph Thomas Dr Joseph Thomas trained at the Christian Medical College, Vellore, India. He worked in several charitable mission hospitals in India before moving to Adelaide SA, and training in Maternal Fetal Medicine. He has been working at the Mater Mothers Hospital, Brisbane QLD, as a specialist in Obstetrics and Maternal Fetal Medicine since 2008. He completed a Masters from Regent College (Vancouver) in Leadership, Theology and Society.
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- Gulmezoglu AM, Lawrie TA, Hezelgrave N, Oladapo OT, Souza JP, Gielen M, et al. Interventions to Reduce Maternal and Newborn Morbidity and Mortality. In: Black RE, Laxminarayan R, Temmerman M, Walker N, editors. Reproductive, Maternal, Newborn, and Child Health: Disease Control Priorities, Third Edition (Volume 2). Washington (DC)2016.
- Stockley EL, Singh A, Desai T, Ewer AK. Can fetal echocardiograms reliably predict the need for urgent balloon atrial septostomy in transposition of the great arteries? Arch Dis Child. 2019;104(11):1114-6.
- WHO. Screening programmes: a short guide Increase effectiveness, maximize benefits and minimize harm 2020 [Available from: https://apps.who.int/iris/bitstream/handle/10665/330829/9789289054782-eng.pdf.
- Dive L, Newson AJ. Ethical issues in reproductive genetic carrier screening. Med J Aust. 2021;214(4):165-7 e1.
- RANZCOG. Genetic carrier screening 2019 [Available from: https://ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Genetic-carrier-screening(C-Obs-63)New-March-2019_1.pdf?ext=.pdf.
- Thomas J, Harraway. J, Kirchhoffer. D. Non-invasive prenatal testing: clinical utility and ethical concerns about recent advances. Med J Aust. 2021( 214(4)):168-70.
- El-Fishawy P, State MW. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr Clin North Am. 2010;33(1):83-105.
- Bardi F, Bakker M, Kenkhuis MJA, Ranchor AV, Bakker MK, Elvan A, et al. Psychological outcomes, knowledge and preferences of pregnant women on first-trimester screening for fetal structural abnormalities: A prospective cohort study. PLoS One. 2021;16(1):e0245938.
- Diulgheroff FF, Peixoto AB, Petrini CG, Caldas T, Ramos DR, Magalhaes FO, et al. Fetal structural anomalies diagnosed during the first, second and third trimesters of pregnancy using ultrasonography: a retrospective cohort study. Sao Paulo Med J. 2019;137(5):391-400.
- Pugash D, Brugger PC, Bettelheim D, Prayer D. Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis. Eur J Radiol. 2008;68(2):214-26.