Public funding for non‐invasive prenatal testing for fetal aneuploidy – It's time

Non-invasive prenatal testing with cell-free DNA (NIPT cfDNA) as a screening test for fetal aneuploidy (herein referred to as NIPT) was first provided commercially in Hong Kong and the United States (US) in 2011, and became available in Australia on a user-pays basis via international providers in 2012.1, 2 With performance metrics approaching those of traditional diagnostic karyotype testing, NIPT provides an opportunity to detect more cases of trisomy 21 (T21), and other fetal aneuploidies, with fewer invasive diagnostic procedures. Peak international bodies have endorsed NIPT as a primary or contingent screening tool for pregnancies at high probability of fetal T21 and the general obstetric population.3, 4 Despite this, so far NIPT has not been implemented into routine use in Australia, as there is no public or private health insurance funding for the test. Two articles in the current Journal describe aspects of the efficient and responsible integration of NIPT into the Australian healthcare setting. Rieder et al. present answers to some of the important clinical questions concerning NIPT for those providing obstetric care, including the use of clinically appropriate screening pathways.5 The paper has been written to complement the recently updated Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) position statement on Prenatal Screening for Fetal Aneuploidy.6 Hui et al. consider another aspect of the responsible use of NIPT, raising issues of public funding, equity and access.7 The latter publication uses population-based data to analyse prenatal diagnostic testing in the context of screening test indications for, and diagnostic yield of, invasive prenatal testing by socioeconomic status in the era of NIPT. Hui et al. demonstrate that significant disparities exist with women from the most advantaged regions having both the highest adjusted odds ratio of NIPT-indicated diagnostic testing and the largest diagnostic yield of invasive testing (31% compared to 14% among the most disadvantaged regions), suggesting that those from the most disadvantaged regions may be exposed more frequently to the iatrogenic risk of invasive diagnostic procedures. Both federal and state governments in Australia contribute funding for prenatal screening and diagnostic testing. The federal Medical Benefits Scheme (MBS) currently subsidises maternal serum screening (MSS) (since 1994) and combined first trimester screening (cFTS) (since 2004), as well as invasive prenatal diagnostic procedures and karyotyping undertaken in the private sector. Despite public funding, significant out-of-pocket costs can remain. A 2015 survey of the cost of cFTS in Western Australia (unpublished) revealed out-of-pocket costs of up to $230. The tests are part of routine clinical care whereby RANZCOG recommends all women are offered screening regardless of age, although anecdotally, some providers have interpreted the MBS reimbursement rules differently, and inform women that they are only eligible for a Medicare rebate if they are over the age of 35. Out-of-pocket costs may also be significant for patients accessing prenatal diagnosis. Invasive diagnostic testing and karyotyping attract an MBS rebate of almost $400, an amount comparable to the fee for NIPT. Due to the contentious nature of selective abortion, publicly funded prenatal aneuploidy testing is commonly justified by the value placed on ‘reproductive autonomy’ or choice for women.8 However, it is clear that a direct consequence of prenatal testing for T21 is abortion. This has the potential to decrease the live-born incidence of T21,8 the societal impact of which cannot be ignored, arguably providing the platform upon which publicly funded prenatal screening and diagnosis programs rely. Prenatal screening and diagnostic testing for T21 has had a significant impact on T21 births and terminations in Australia. In Western Australia between 1980 and 2013, invasive prenatal diagnostic tests as a percentage of live births declined and the live-born rate for T21 fell from 1.1 per 1000 in the pre-screening period (pre-1994) to 0.87 per 1000 in the period following the introduction of cFTS (2004). This was despite an almost threefold increase in the rate of fetal T21 over this time, attributable to increasing maternal age, with 4.7% of babies born to mothers over 35 years of age in 1980 increasing to 20% in 2013. In the absence of prenatal screening and diagnostic testing it is estimated that the birth rate for T21 would have doubled to 2.17 per 1000 in 2013.9 However, the uptake and impact of screening and diagnosis has been discriminatory, even with public funding. A study of T21 birth rates in Queensland reported a large fall in maternal age-adjusted rates of T21 births among women living in metropolitan areas — but not rural areas — and in women with private — but not public — obstetric care between 1990 and 2004.10 O'Leary et al. reported significant disparities in the provision and availability of prenatal screening services for T21 across Australia.11, 12 Participation ranged from 17% in the Northern Territory to 80% in South Australia. Another study13 reported similar discrepancies between Australian maternity hospitals and concluded that access to prenatal screening often depends on place of residence and the institution attended for prenatal care. As screening uptake is promoted as an informed choice, and not a routine test, variation in prenatal testing and outcomes could reflect differences in patient preferences. However, as with other health services, it is likely that barriers to accessing the service explain some of the variation. ‘Reproductive autonomy’ should be available to all women, not just those in privileged socio-demographic groups. Hui et al. make it clear that NIPT, in the absence of public funding, could further threaten ‘reproductive autonomy’ by magnifying pre-existing disparities, as only those women who can afford to access the test will do so.7 In 2015, Switzerland's national health system became the first to fund NIPT for women at increased probability of fetal trisomy.14 Large evaluation trials to assess the potential for public health system support of NIPT, have been or are currently being conducted in the Netherlands (TRIDENT study),15 the United Kingdom (UK) (RAPID trial)16 and Canada (PEGASUS trial).17 In the UK, the National Health Service accepted a submission to implement NIPT based on the results of the RAPID trial with a plan to begin a national contingent screening program in 2018. Wales has been the first of the UK nations to implement the program, with screening introduced in April this year. In Germany, authorities will make a decision regarding public funding of NIPT for fetal trisomy in August 2019 following evaluation of the evidence and consultation with stakeholders and industry professionals.18 Economic evaluation undertaken from a public health system perspective using a horizon of the duration of pregnancy have recommended the use of NIPT as a contingent screen, with varying definitions of increased probability in the US,19, 20 the UK,21 the Netherlands,22 Belgium23 and Canada.24 The cost of introducing universal (or primary) screening with NIPT testing into a public healthcare system appears to be prohibitive. Thus far, Australian cost-effectiveness analyses have reached similar conclusions.25, 26 Our modelling estimates that a contingent model with a high probability cut-off of one in 50 (for invasive testing) and an intermediate probability cut-off of one in 1000 (for NIPT) would detect 90.4% of T21 cases. Reducing the intermediate cut off to one in 300 decreases the detection rate to 81.7%, no higher than current cFTS screening practices. The estimated cost of the one in 1000 intermediate probability cut-off model is $53 453 per diagnosis,26 similar to the current cFTS model ($51 876 per diagnosis) with an incremental cost-effective ratio of $68 927. Furthermore, the estimated number of invasive tests per diagnosis and fetal losses per 1000 would fall from 14.2 to 4.33 and 85 to 20, respectively.26 The high probability cut-off directing women toward invasive testing rather than NIPT has a negligible impact on cost, but a significant impact on fetal loss. However, any reduction in fetal loss has to be weighed against the benefit of identifying rare chromosomal anomalies, most common among the highest probability pregnancies. As such, and in reference to a study by Lindquist et al.27 Rieder et al. recommend women with a probability greater than one in 100 ‘be more strongly advised to consider diagnostic testing’.5 The decision to have diagnostic testing rather than NIPT in this group of women will ultimately depend on a woman's individual circumstances, clinical indicators and preferences. Given the performance metrics and cost-effectiveness of NIPT, it is inevitable that some form of public funding will be introduced for NIPT in Australia. The question is: what will a publicly funded screening model for NIPT look like? A submission for public funding of NIPT has been put forward to the Australian Medical Services Advisory Committee (MSAC). The submission advances two potential funding models, one in which universal screening would be eligible for subsidised NIPT, and an alternative contingent screening model, in which only woman with pregnancies at high probability as identified through cFTS or MSS would be eligible — using the traditional greater than one in 300 cut-off to define high probability.28 As identified by Rieder et al., these screening approaches are both clinically appropriate; however for some women — depending on the funding model adopted — this may be at their own cost. As described, Australian economic evaluation has shown various contingent models to be cost-effective. However, the total cost of screening is also a consideration. Australian economic evaluations have been based on hypothetical analysis and assumptions regarding the uptake of NIPT and prenatal testing. Women's choices, and therefore uptake and health system cost, are likely to be impacted by out-of-pocket costs and the way in which risk groups are defined within a new screening model. Given this uncertainty, where there are budgetary constraints, a stepped approach to the integration of publicly funded NIPT may be the best way forward. At a minimum, NIPT should initially be subsidised for those pregnancies with a cFTS probability result of greater than one in 300, as presented in the MSAC application. However, while this would reduce fetal loss rates, it fails to take advantage of the superior detection rate of NIPT. Ultimately, public funding should support a model with a more sensitive definition of increased probability to enable the detection of more cases of fetal T21. Since NIPT became available in Australia, the body of evidence has informed the development of clinical guidelines as to the responsible integration of NIPT into screening pathways, locally and internationally. Economic evaluation has shown NIPT to be cost-effective, with the potential to improve the detection rate of fetal T21. Given this strong platform, and the evidence that there is already socioeconomic disparity in the use of NIPT in Australia, it is clearly time for NIPT to receive public funding. However, while public subsidy is essential to mitigate disparate access to prenatal screening, as with other health services, it is not the panacea, and patients are likely to continue to experience out-of-pocket costs and other barriers to access. Ensuing that women from the most disadvantaged sectors of society can also access these services is paramount. While our discussion has focused on the most common trisomies, particularly T21, NIPT is also commonly used — but with lower specificity — for sex chromosome abnormalities, and is available — but with limited evidence — for a number of other conditions.5 NIPT cfDNA can also be used for the diagnosis of some single gene disorders and fetal rhesus D determination, with scope for many other applications.29 As technology advances, and where evidence becomes available supporting clinical application, the role of NIPT cfDNA in obstetric pathways should continue to evolve. For any application, consideration must be given to costs and benefits, equity, ethics and social and service delivery challenges before integration into the public health system.29

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