Currently, screening for trisomy (21,18 and 13) in Norway is based on a combination of blood tests and ultrasound (CUB) offered to all pregnant women 38 years of age or older. If the combined screening test indicates high risk, genetic verification via an invasive diagnostic test is offered either through chorionic villus sampling or amniocentesis. Non-Invasive Prenatal Testing (NIPT) measures the underlying genetic pathology of trisomies directly by analysing foetal genetic material in the maternal circulation (cell-free foetal DNA, cffDNA). Several commercial testing strategies are available using different sequencing techniques for screening of trisomy 21, 18 and 13.
We summarise research of diagnostic test accuracy of NIPT. In addition, we analyse health economic implications and highlight ethical consequences related to the national introduction of NIPT for detection of trisomy in pregnant women.
Based on the evidence it seems that:
• NIPT is a more accurate test for detecting trisomy than the CUB that is in use in Norway today.
• A program with NIPT as a secondary test after CUB will result in fewer invasive tests and be more expensive than the current screening in Norway.
• A program with NIPT as a primary test instead of CUB will also result in fewer invasive tests, but will be more expensive than both the current screening and if NIPT is used as secondary screening test.
• NIPT is a test that challenges the underlying rationale for why and how we as a community and health service want to organise the foetal diagnostic services in Norway.
Norwegian Knowledge Centre for the Health Services has been commissioned by “New methods” at our “Bestillerforum RHF” to perform a health technology assessment for diagnostic accuracy of Non-Invasive Prenatal Testing (NIPT) for detection of trisomy in the foetus, and clinical consequences of introducing the screening test. NIPT means mapping the genetic characteristics of the foetus using a blood sample from the pregnant woman.
Trisomy is a form of chromosomal abnormality which implies that an individual has three copies of one chromosome, instead of two as is the norm. There are different types of trisomies one can be born with; for the current test trisomy 21, 18 and 13 are in focus. Trisomy 21 (Down syndrome) is the most common one and occurs in one per 700-800 births in Norway. It is known that the probability of having a child with Down syndrome increases with the age of the mother. Trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) are both subgroups of very rare chromosome abnormalities with disabilities as a result. Trisomy 18 and trisomy 13 occur within fewer pregnancies than trisomy 21.
Different types of tests are available during pregnancy. A screening test shows if a pregnancy is at ‘increased risk’ of a birth defect. A screening test does not give a definite answer, but it does tell us which babies have an increased risk of having trisomy. A diagnostic test can identify a condition, and is very accurate.
Currently, screening for trisomy in Norway is based on a combination of blood tests and ultrasound (CUB) offered to all pregnant women 38 years of age or older. If the combined screening test indicates high risk, genetic verification via an invasive diagnostic test is offered either through chorionic villus sampling or amniocentesis. NIPT measures the underlying genetic pathology of trisomies directly, by analysing foetal genetic material in the maternal circulation (cell-free foetal DNA, cffDNA).
Diagnostic sensitivity and specificity are technical characteristics of a test, which specify the ability of the test to identify healthy and diseased individuals in a group. High sensitivity (close to 100%) means that the ability of the test to identify ill individuals is very good. High specificity (close to 100%) means that the ability of the test to verify healthy individuals is very good. It is therefore very important that a screening test for trisomies has both high sensitivity and high specificity. NIPT as a screening test implies the occurrence of both false positive and negative findings, and all positive screening tests need further diagnostic invasive tests to verify or reject the positive screening result from the NIPT. The risk of false negative screening tests is lower than for false positive screening tests, but is never nullified.
We conducted systematic literature searches for systematic reviews. Individual search strategies were designed for selected relevant databases. Search strategies were based on a combination of subject headings and text words for NIPT. Searches were limited to the period of 2010 to 2015. Two reviewers independently screened all identified records and critically appraised the selected publications. We investigated the outcomes diagnostic test accuracy, predictive values, likelihood ratio and inconclusive results, and compared the combined test with NIPT in a clinical setting.
Health economic evaluation
We performed a cost-effectiveness analysis (CEA) to estimate health economic consequences of introducing a screening program with NIPT for detection of trisomy. We considered the current practice involving combined tests (nuchal translucency combined with serum markers) as the base case scenario. In addition, we considered three alternative screening scenarios involving NIPT as both primary and secondary test. In all scenarios, invasive testing is offered to selected pregnant women following screening procedures. For each of the scenarios, we have calculated the following outcomes: number of correctly identified cases of trisomy 21, 18 and 13, number of undetected cases (false negative), number of invasive tests performed, total programme costs, costs per diagnosis and incremental costs per additional case of trisomy detected compared with current screening practice. The analyses are performed in a health care provider perspective, with a time perspective of one year.
We included two systematic reviews of high methodological quality, one from Sweden and one from the UK. The systematic reviews included results from 31 and 52 primary studies respectively, and we chose to present the results from both overviews. Only one of the reviews compare NIPT with current practice.
The diagnostic accuracy of NIPT for trisomy 21 is very good, with a high sensitivity (0.970) and high specificity (0.998). In a high risk population, the summarised positive predictive value is also high (above 0.91). In Norway, about 60 000 children are born every year. Of these pregnancies, approximately 4 000 are classified as high risk population and are offered prenatal diagnosis.
By introducing a program of routine screening with NIPT for trisomies in high risk population, 32 foetuses (95% CI 31-32) per 1,000 pregnant women tested will be classified correctly with trisomy 21 and 965 (95% CI 961- 965) correctly without trisomy 21 every year. One foetus (95% CI 1-2) will likely be wrongly classified as without trisomy although it has trisomy 21 (false negative), while two foetuses (95% CI 2-6) will be erroneously classified with trisomy 21 (false positive) per 1 000 pregnant woman tested. Since trisomy 18 and 13 are more seldom than trisomy 21, there will be fewer correctly detected cases of trisomy 18 and 13. However, there will be relatively more cases of false positive test response, because the diagnostic accuracy of NIPT is somewhat weaker for trisomy 18 and considerably weaker for trisomy 13 compared to trisomy 21.
In a Norwegian setting, if NIPT replaces the current combined test, 0-3 more foetuses will be classified correctly with trisomy per 1000 pregnancies in a high risk population. Around 40 fewer foetuses (95% CI 36-43) per 1,000 will be classified as positive with the test, even if they do not have trisomy 21 (false positive). Under the current practice with CUB these would have been referred to invasive testing, and NIPT would therefore result in fewer invasive tests.
The number of invasive diagnostic tests is considerably reduced in all alternative scenarios involving NIPT screening, compared with current practice. The scenario with NIPT as a secondary screening test for pregnant women, with trisomy risk equal to or higher than 1: 250 following CUB, is both less effective in terms of fewer cases of trisomy detected, while being more expensive than the current screening practice.
The scenario with NIPT as a secondary screening test, offered to the intermediate risk group of pregnant women (risk lower than 1: 100 and equal to or greater than 1: 1000 following combined tests) is more expensive and more effective than the current CUB screening. Cost per additionally detected case of trisomy is about 196,000 Norwegian kroner.
The scenario with NIPT as the primary screening test is the most effective and most expensive screening programme. Costs per additionally detected case of trisomy is approximately 4.4 million Norwegian kroner compared to the most efficient alternative (scenario with NIPT as a secondary screening test offered to the intermediate risk population of pregnant women).
Cost results should be interpreted cautiously due to considerable uncertainty about NIPT-costs and feasibility.
NIPT raises several important ethical questions. The fact that NIPT is a simple screening test that provides a relatively good test result, may lead to that it is considered as a routine part of antenatal care, instead of an offer which pregnant woman can accept or not. Good information is required on what kind of answers this screening test can provide, and what consequences a positive test result may have (need for invasive diagnostic test to conform or reject a positive NIPT screening test).
Despite high diagnostic accuracy, the included systematic reviews highlight that NIPT is not suitable as a diagnostic test for the three types of trisomy. In most countries, before the pregnant woman decides whether to terminate a pregnancy or not on the basis of a trisomia foetus, an invasive diagnostic test is recommended. A special feature of NIPT is that the test is not only a new prenatal screening test, but also a test that forces one to reconsider why and how we as a community and health service want to organise the foetal diagnostic services in Norway. The socioeconomic consequences of more women wishing (and undergoing) NIPT as primary screening for trisomies, as compared to today’s CUB screening offered to high risk pregnancies in Norway, are uncertain and not addressed in our report.
NIPT is a new screening test that may be used to identify a high-risk group that should be referred to further diagnostic investigation for confirmation or rejection of the screening findings, using invasive procedures. The sensitivity and specificity of NIPT for trisomy is high, but not 100%, and therefore the included systematic reviews do not recommend it as a replacement for an invasive diagnostic test, neither in the high risk population or the general population of pregnant women. The test performance is good, and far better than the current CUB screening test for both trisomy 21 and trisomy 18, with a good detection rate and a low rate of false positive cases. Both the number of detected cases of trisomy and costs will be affected by the placement of NIPT in the screening program. The number of invasive tests is considerably reduced in all alternative health economic scenarios involving NIPT compared with current CUB screening practice. The scenario with NIPT as a secondary screening test, offered to the intermediate risk group of pregnant women more effective than the current CUB screening.