Introduction
Prenatal testing involves the use of a range of tests to screen and diagnose abnormalities in pregnancy. Prenatal “screening” is usually used to determine the risk of delivering a baby with an abnormality [
1]. Prenatal “diagnosis” techniques, such as amniocentesis and chorionic villus sampling (CVS), are then offered to confirm or reject a diagnosis of foetal abnormalities [
1]. Conditions that can be detected vary from developmental abnormalities, such as neural tube defects, to genetic disorders [
2]. Globally, one of the most common prenatal screening tests seeks to identify foetuses at risk of being born with Down’s syndrome (DS), but screening for other aneuploidies are often included as well [
3]. Down’s syndrome is the most common congenital cause of mental disability caused by a complete or partial third copy of Chromosome 21 [
4].
Prenatal screening technologies for DS and other aneuploidies have evolved significantly over the past several decades from determining risk, simply using maternal age, to the addition of serum protein markers and ultrasound scans to measure nuchal translucency (NT) [
5]. Screening programmes vary between countries [
6‐
8] but generally involve a first trimester triple or quadruple test comprising a combination of: two serum proteins, beta unit of human chorionic gonadotrophin (ß-hCG) and pregnancy-associated plasma protein A (PAPP-A) and NT measurement [
5]. However, these existing screening technologies exhibit negative characteristics such as a moderate risk of false-positive results (2–7%) [
9]. Furthermore, the diagnostic tests are invasive and pose the risk of complications to the mothers and their baby [
10]. According to the UK National Health Service Foetal Anomaly Screening Programme, the risk of miscarriage with invasive testing is 1–2% [
9,
11].
Non-invasive prenatal testing (NIPT) is a more recent test used to identify aneuploidies, which works by detecting cell-free foetal DNA in maternal plasma from a blood test [
12]. Clinical laboratories assess the likelihood of foetal aneuploidy by analysing cell-free DNA in maternal serum using various techniques, including shotgun massively parallel sequencing (s-MPS), targeted massively parallel sequencing (t-MPS) and single nucleotide polymorphism (SNP)-based approaches [
13].
NIPT has been suggested to be a clinically useful test; a systematic review and meta-analysis of clinical trials suggested the strategy to be highly accurate (99.7% sensitivity and almost 100% specificity) for the detection of DS in high to average risk populations [
14]. NIPT may also be used for detecting other aneuploidies but with much lower precision [
15]. NIPT cannot detect non-genetic abnormalities such as neural tube defects [
13]. The high accuracy of NIPT is a key advantage because the number of invasive diagnostic tests could potentially decrease [
10]. Furthermore, the test can be performed as early as at 10 weeks of pregnancy [
10]. For this reason, professional societies such as the International Society for Prenatal Diagnosis and the American College of Obstetricians and Gynaecologists (ACOG) recommend NIPT as an advanced screening test for women at high risk for foetal aneuploidy [
16,
17] and it is available in the private healthcare market.
The cost of NIPT varies greatly from several hundreds to thousands of US dollars and the high cost of testing may restrict its widespread use [
10]. The relative cost effectiveness of NIPT is likely to inform whether it will be used widely, especially in publicly funded health care systems. This is because the provision of funding for new interventions removes funding allocated to the existing programmes. Economic evaluations can be used to provide evidence as to whether the health gained by the patients who receive the new intervention is greater than the health lost by those individuals who forgo interventions in the healthcare system [
18]. A recent systematic review by Nshimyumukiza et al. (2018) identified economic evaluations of NIPT [
19]. The results of this review found that universal NIPT was not cost effective for publicly funded screening (when future costs of raising a child with disability were not considered), unless there is a substantial decrease in the direct cost of NIPT. However, many economic evaluations of NIPT recognised that the estimated costs may not be accurate and the authors of the review recommended that the design of future studies could be improved to include all relevant health outcomes and costs for the mother and infant [
20].
Such relevant costs and health outcomes should include the cost of information provision and the health impact resulting from the difficult choices faced by parents when receiving screening results [
21]. In a prospective cohort study from the UK, approximately one-third of parents (31%) with a confirmed positive NIPT result chose to continue their pregnancy, indicating a potential need for additional information to prepare for having a child with Down’s syndrome and not necessarily for decision making about termination of pregnancy [
15]. On the other hand, the majority of the women with a positive NIPT choose to terminate the pregnancy [
22]; therefore, it is important to explain the uncertainty around false-positive and false-negative results to parents clearly.
Pre-test counselling alongside NIPT is recommended by several published guidelines [
13]. Pre-test counselling should ensure that informed consent is gained from the parent which requires the provision of accurate information about screening, its advantages and limitations. The education of patients currently undergoing NIPT does not meet these standards for informed consent consistently. A survey of American women who had experienced NIPT found that most appeared satisfied with their understanding of NIPT and the testing process, yet they may not have appreciated the limitations of this screening method fully [
13].
Alternatively, NIPT may help to reduce the anxiety that parents experience during the screening process. A questionnaire study conducted with Finnish women in 1998 found that women believed that serum screening was more associated with finding diseases or abnormalities than with the ultrasound, and that the main reason for screening was for reassurance. However, the sample was also found to have limited knowledge regarding the sensitivity of the screening tests and the risks associated with diagnostic tests [
23]. Furthermore, as the uptake of NIPT increases, it is important that routine use does not hinder parental informed consent and autonomous choice as has been argued to occur in the provision of some newborn bloodspot screening programmes [
13,
24].
A previous systematic review of economic evaluations of newborn bloodspot screening programmes and technologies found that few studies included the cost of providing information about testing or the health impact of not providing this information [
21]. Only five studies included a cost of information provision, which while small for each patient (ranging from GBP £0.40 to EUR €5.41) would sum up to significant levels given the large number of babies that receive screening. Potential health disutilities arising from poor information provision occurred when parents received false-positive results and ranged from 0.0005 to 0.0125 quality-adjusted life years lost. While these values are relatively small, it is arguable that parents going through prenatal screening for aneuploidy are likely to experience larger levels of anxiety due to the potential consequences of the test.
The aim of this systematic review was to identify the extent to which economic evaluations of NIPT have accounted for the need to provide information for parents alongside testing and the associated costs and health outcomes of information provision.
Discussion
This systematic review identified 12 economic evaluations of NIPT testing for aneuploidies. However, despite the need for informed consent, the difficult decisions that may have to be made by parents when receiving test results, and the inherent complexity of the testing process itself, only few of the evaluations have accounted for the need for, and impact of, information provision. Receiving positive or false-positive results from screening has been shown to significantly increase parental anxiety [
40]. Providing information may come at a financial cost to the health service but is likely to provide benefits in reducing the anxiety that parents experience during screening for aneuploidies. Furthermore, it is possible that effective information provision may increase the uptake of a potentially cost effective intervention, thereby increasing the total health benefit to society.
Omitting the cost of information provision alongside NIPT screening may result in an overestimate of relative cost effectiveness of the intervention. Four (33%) of the studies in this review included a cost for information provision, which was commonly quantified as the cost of an additional visit to a clinician for counselling on the receipt of positive results. One study also considered the cost of counselling in their sensitivity analyses [
3]. The costs of information provision ranged from AUS $36.30 to $200 in Australia to US $40 to $247 in the USA. While these values are small for an individual, the size of the population eligible to receive testing means that the total cost of information provision will be high. For example, WHO estimated that between 3000 and 5000 children are born with Down’s syndrome each year in the USA. Given the estimates for the cost of counselling in the USA, this could mean an additional cost between $120,000 and $1,235,000 per year. These figures are in addition to the cost of counselling provided to families who later decide to terminate the pregnancy. A study conducted in the state of Massachusetts in 2016 suggested that around 49% may decide to terminate the pregnancy, meaning that the cost of counselling could range from US $344,898 to $2,520,408 annually across the USA, although termination rates are likely to differ by state [
41]. These approximations also omit counselling for parents with positive results for other aneuploidies such as Edward’s syndrome and Patau’s syndrome.
While the cost of counselling on receipt of NIPT results may be a significant omission from many economic evaluations, a more serious issue may be the omission of costs related to information provision prior to the screening process to all expectant parents. Such information is critical in allowing parents to make an informed decision about whether or not to take part in screening for aneuploidies and in preparing parents for the potentially difficult decisions that may arise from screening. None of the studies identified in this review included such a cost. While the cost of providing information about NIPT screening to individual sets of parents may be small, all expectant parents who have access to screening should have access to this information.
A previous systematic review of the inclusion of information provision in economic evaluations of newborn screening programmes found that this cost could be as high as €5.41 (2002 prices, approximately US $7.04 in 2018 prices) and a micro-costing study conducted in the UK estimated that the expected cost per set of parents could be £17.65 (2014 prices, US $24.81 in 2018 prices) [
21,
24,
42]. It is arguable that the decisions resulting from positive screening results from NIPT testing, terminating or continuing a pregnancy, may be more difficult than those arising from NBS screening and that more information may be required for the parent(s) to make informed decisions. Therefore, by omitting the provision of such information, the cost of NIPT may be underestimated.
Failing to provide effective information about NIPT screening may result in higher anxiety for the parent(s) when receiving test results. No studies linked the provision of information for NIPT testing to levels of parental quality of life. The low number of studies accounting for the impact of test results on parental HRQoL is likely a result of the use of cost effectiveness analysis in the majority of these studies which measure outcomes in natural units.
Two studies did include disutilities for parents that received distressing results. Kaimal et al. [
36] conducted a time-trade-off study to elicit utility values for different health states pertaining to the receipt of test results. These values highlighted the significant impact that results can have on parents and the implications of uncertain results arising during the screening and diagnostic process. Similarly, Ohno et al. [
16] included disutilities for false-positive and false-negative results with the latter assumed to have a significant lifelong impact on the parents.
However, by including such utility values for both the intervention and comparator, the relative cost effectiveness of NIPT, which reduces the risks of uncertain results, may improve. The cost effectiveness of NIPT could also be affected by the perceived accuracy of the test which could mean that parents make decisions about the pregnancy without receiving invasive but confirmatory diagnostic tests. Kaimal et al. [
36] raised the prospect of NIPT testing being used after multiple marker testing as a diagnostic itself and utility values for the outcomes associated with this strategy were higher than the more reliable but riskier invasive diagnostic testing strategy. If NIPT screening is deemed to be a cost effective use of resources, then failing to provide adequate information about testing may lead to a sub-optimal uptake of the intervention and missed potential societal health gains. While some studies in this review included uptake in their economic models, none linked this to the quality of information provision as part of the screening programme. Alternative methodological approaches such as discrete choice experiments may be useful to determine what information parents would like to receive about NIPT screening and how they would like this to be delivered [
43,
44].
There may be challenges in quantifying utility, particularly when it is related to non-health costs or benefits, for example, the intrinsic “value of knowing” associated with a true test result [
45]. It might therefore be useful for economic analyses to include data derived from alternative valuation methods such as discrete choice experiments (DCEs) or contingent valuation studies. DCEs have been used to understand the preferences of women and healthcare professionals for NIPT and understand how they balance the associated benefits and risks. DCE data have also been used to predict the probability of a participant choosing NIPT in different scenarios. As studies in this systematic review often assumed participation rates, the results of a DCE could be used in a model-based economic evaluation for both utility and uptake parameters.
This systematic review had some limitations. Only decision-analytic models and not trials were included in this review. It is therefore possible that some trials of NIPT testing which included the cost of information provision and its impact were excluded from the review. However, the authors are only aware of one such trial and the complex nature of NIPT testing mean that decision-analytic models are a more practical vehicle to compare all relevant testing strategies in a cost effectiveness analysis [
29]. This review also only looked at information provision alongside NIPT testing; expanding the review to all economic evaluations of screening for aneuploidies may have identified cost and disutility estimates for information provision alongside other technologies which may have been useful for researchers seeking to include such input parameters in future economic evaluations.
Including these additional costs and outcomes in economic evaluations of NIPT testing is critical to gain an accurate estimate of the cost effectiveness of this clinically useful but costly intervention. This is particularly important when screening for aneuploidies, as information provision is essential to ensure that parents make an informed choice about screening. However, few economic evaluations identified in this systematic review accounted for such costs and outcomes which may lead to inaccurate estimates of the cost effectiveness of NIPT. These findings may be symptomatic of a wider failure in health economics to account for such service delivery costs [
46].
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