The consequences of implementing non-invasive prenatal testing in Dutch national health care: a cost-effectiveness analysis
European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 53 - 61
Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required.
A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results.
Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141).
NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.
Keywords: Prenatal screening, Non-invasive prenatal testing, Trisomy 21, Detection rate, Cost-effectiveness analysis.
Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for prenatal detection of fetal aneuploidy, , and . Clinical trials have proven its value in both high-risk and average-risk populations, showing high sensitivity and specificity for T21, , , , , , , and .
In the Netherlands, prenatal testing requires a permit under the Population Screening Act and is therefore highly regulated. As of April 2014, the government has provided a license for the pilot introduction of NIPT in Dutch health care. However, for a definitive implementation of NIPT, more information regarding the costs and consequences of the implementation of this novel technology in the national programme for prenatal screening is required.
This study uses decision-analytic modelling to determine outcomes, total costs, relative costs and cost-effectiveness of different strategies for prenatal screening and diagnosis of T21. It directly compares current clinical practice, i.e. first-trimester screening (FTS) by first-trimester combined testing (FCT) with invasive diagnostic testing only available for those women at high risk for fetal aneuploidy based on FTS, second-trimester ultrasonographic examination, maternal age or personal or family history, with the two most likely alternatives: implementing NIPT as an optional secondary screening test, to guide further testing for those women at high risk for fetal aneuploidy, and implementing NIPT as primary screening test, fully replacing conventional screening.
Materials and methods
A software package (TreeAge Pro 2009, TreeAge Inc., Williamstown, MA, USA) was used for the design and analysis of a decision-analytic model evaluating three strategies for prenatal screening and diagnosis of T21 from 10 weeks’ gestation until delivery. In the model three primary branches represent three pathways: (1) current clinical practice, (2) NIPT as optional secondary screening, or triage, test, and (3) NIPT as primary screening test (see Fig. 1 a and b).
The first branch represents current clinical practice. Prenatal tests currently available in Dutch health care are FTS by FCT and invasive diagnostic testing. Furthermore, at 20 weeks’ gestation all pregnant women are offered ultrasonographic examination of the fetus for detection of structural defects. Whenever a suspicion for fetal structural anomalies (including NT ≥ 3.5 mm) arises, women are referred for advanced ultrasound.
In current clinical practice, pregnant women aged ≤ 35 years have limited access to prenatal testing. They are routinely offered a second-trimester anomaly scan and FTS by FCT, but the latter is not reimbursed and in principal invasive diagnostic testing is only available for those who are screen-positive based on FCT (cut-off risk 1 in ≤ 200) or advanced ultrasound. Women of advanced maternal age (AMA), i.e. aged ≥ 36 years, and women with a personal or family history of numerical chromosomal abnormalities have full access to all available prenatal tests.
The second and third branch represent future prospects for the national programme for prenatal screening. It has already been decided that from January 2015 onwards, access to prenatal testing will no longer be differentiated by maternal age, i.e. women of AMA will have the same access as women aged ≤ 35 years in current clinical practice. In addition, in the second branch NIPT is added as an optional secondary screening test, meant to guide decision-making on whether or not to have invasive diagnostic testing performed. It is offered to those women at high risk for fetal aneuploidy based on FTS by FCT (cut-off risk 1 in ≤ 200) or a personal or family history of numerical chromosomal abnormalities. In the third branch NIPT is added as primary screening test, available for all pregnant women, completely replacing all components of the FCT.
In all strategies, pregnant women at high risk for fetal aneuploidy have the option of invasive diagnostic testing or not pursuing further testing. When invasive diagnostic testing is performed, fetal genotyping usually consists of QF-PCR analysis for the detection of (an)euploidies of chromosomes 13, 18, 21 and the sex chromosomes. In case of ultrasound anomalies and normal QF-PCR results, array analysis for detection of other genetic alterations is performed as well.
The invasive diagnostic procedure can lead to an iatrogenic miscarriage or be uncomplicated. A woman may opt for termination of pregnancy (TOP) when the diagnosis of fetal T21 is confirmed, or when an advanced ultrasound has confirmed the presence of fetal structural anomalies. A continued pregnancy can result in intra-uterine fetal demise (IUFD), stillbirth or live birth.
Assignment of probabilities
Probability estimates were derived from a systematic review of international literature (see Table 1 and Fig. 1 a and b), , , , , , , , , , , , , , , , , , , and .
|Proportion of women with advanced maternal age||0.164||0.08–0.24|||
|Risk of trisomy 21 in case maternal age is < 36 years||0.0019||0.001–0.005||, , and |
|Risk of trisomy 21 in case maternal age is ≥ 36 years||0.0116||0.005–0.02||, , and |
|Risk of iatrogenic miscarriage||0.0036||0.001–0.02|| and |
|Proportion of pregnancies terminated in case of trisomy 21||0.92||0.50–0.98|| and |
|Proportion of pregnancies terminated in case of ultrasound anomalies||0.45||0.20–0.80|||
|Risk of intra-uterine fetal demise||0.005||0.004–0.02|||
|Risk of intra-uterine fetal demise in case of trisomy 21||0.25||0.05–0.45|||
|Sensitivity FTS||0.9||0.75–0.95|| and |
|False-positive FTS in case maternal age is < 36 years||0.04||0.03–0.10|||
|False-positive FTS in case maternal age is ≥ 36 years||0.14||0.05–0.20|||
|NT ≥ 3.5 mm in case of screen-positive FTS without trisomy 21||0.078||0.00–0.20||Unpublished data|
|NT ≥ 3.5 mm in case of screen-positive FTS and trisomy 21||0.58||0.40–0.80|||
|Screen-positive second-trimester anomaly scan without trisomy 21||0.02||0.001–0.05|| and |
|Proportion confirmed by advanced ultrasound||0.9||0–1||Assumption|
|Screen-positive second-trimester anomaly scan in case of trisomy 21||0.24||0–0.5|||
|Proportion confirmed by advanced ultrasound||1||0–1||Assumption|
|Screen-positive advanced ultrasound in case NT ≥ 3.5 mm without trisomy 21||0.174||0.0–0.5|||
|Screen-positive advanced ultrasound in case NT ≥ 3.5 mm and trisomy 21||1||0–1||Assumption|
|Sensitivity NIPT||0.995||0.95–1.00||, , , , , , , and |
|False-positive NIPT||0.001||0–0.02||, , , , , , , and |
|See Fig. 1 a and b||a||a||, , , , and |
|Participation second-trimester anomaly scan||0.91||0.85–0.98|||
|Participation invasive PD, incl array, in case of ultrasound anomalies (incl NT ≥ 3.5 mm)||0.9||0–1||Assumption|
a Depending on strategy, maternal age group, participation other test options available, and results other test options available (where applicable).
Test characteristics, i.e. sensitivity and specificity, of the different prenatal tests were pooled. As invasive prenatal diagnosis is the gold standard for clinical decision-making these tests were modelled to be 100% sensitive and specific. Iatrogenic miscarriage rate was calculated by combining the miscarriage rates of chorionic villus sampling (0.5%) and amniocentesis (0.3%) with their share in the total number of invasive diagnostic procedures, 30% and 70%, respectively and .
Assumptions were made regarding test uptake after the introduction of NIPT in Dutch health care, based on studies evaluating women's expressed interest in NIPT and and recent publications on actual choices made following the implementation of NIPT in prenatal care and .
It is expected that with the introduction of NIPT, more pregnant women will choose prenatal testing than in current clinical practice, both because of the favourable characteristics of NIPT and the reduced need for invasive diagnostic testing. Just over half of pregnant women in the Netherlands currently declining prenatal screening or diagnosis for T21 indicated they would accept NIPT when available  . However, hypothetical interest tends to overestimate actual participation and . Therefore the total participation in the national programme for prenatal screening was assumed to rise to 60% of all pregnant women ≤ 35 years of age and 70% of all pregnant women aged ≥ 36 years.
When NIPT is discussed as an option to screen-positive women during high-risk counselling following an abnormal FTS result, 16% decline further testing, 65% have NIPT and 19% choose invasive diagnostic testing  . Of the women who accepted to have NIPT, 4.6% pursue invasive diagnostic testing despite receiving low-risk results for aneuploidy. When NIPT results indicate a high risk for aneuploidy, all patients accept invasive diagnostic testing for confirmation of results  .
Assignment of costs
The total cost of the national programme for prenatal screening and diagnosis of T21 was determined from a health care perspective, only taking screening and diagnostic costs into account. Total cost was based on the addition of the unit costs of all individual tests performed (see Table 2 ). As prenatal testing is highly regulated, unit costs of prenatal tests are determined by the Dutch Healthcare Authority, based on annual cost price calculations by national university medical centres, that include costs for general infrastructure, personnel, apparatus and materials. Unit costs consist of reimbursements made by health insurance companies as well as patients’ payments where applicable. Since the time horizon over which costs and outcomes are evaluated only covers the duration of pregnancy costs were not discounted.
|Unit||Cost (€) a|
|Second-trimester anomaly scan||158.91|
|Advanced anomaly scan||544.00|
|Invasive diagnostic testing||951.27b and c|
|Array analysis||775.82 b|
a Unit costs of prenatal tests are determined by the Dutch Healthcare Authority and based on annual cost price calculations by national university medical centres, that include costs for general infrastructure, personnel, apparatus and materials.
b An undifferentiated unit cost is determined for all methods of prenatal genotyping.
c The unit cost for invasive diagnostic testing consists of obtaining fetal material by chorionic villus sampling or amniocentesis (€175.45) and prenatal genotyping by QF-PCR (€775.82).
Data were analysed to obtain outcomes, total costs, relative costs and ICERs for the different strategies. Both absolute and incremental values were reported. Probabilities and costs were applied to a theoretical cohort of 180,000 pregnant women, representing the estimated annual number of pregnancies in the Netherlands.
Sensitivity analysis consisted of univariate analysis, varying different inputs of the model within feasible ranges (see Table 1 ) assuming all other variables to be fixed, and threshold analysis where applicable.
|Clinical practice, i.e. FTS by FCT||NIPT as (optional) secondary screening test||NIPT as primary screening test|
|Absolute value||Absolute value||Incremental value a||Absolute value||Incremental value a|
|No test b||0.000168||30 f||0.000109||20 f||−0.000059||−11 f||0.000109||20 f||−0.000059||−11 f|
|Trisomy 21 missed c||0.001398||252||0.001015||183||−0.000383||−69||0.000843||152||−0.000555||−100|
|Trisomy 21 suspected d||0.000290||52||0.000150||27||−0.000140||−25||0.000027||5||−0.000263||−47|
|Trisomy 21 diagnosed e||0.001635||294||0.002217||399||0.000582||105||0.002513||452||0.000878||158|
|TOP||0.001524||274 f||0.002052||369||0.000527||95||0.002315||417 f||0.000791||142 f|
|Live birth||0.001470||265 f||0.001073||193 f||−0.000397||−71 f||0.000875||157 f||−0.000595||−107 f|
|Live birth trisomy 21||0.001470||265||0.001073||193||−0.000397||−71||0.000875||157||−0.000595||−107|
|No test b||0.000126||23||0.000081||15||−0.000045||−8||0.000081||15||−0.000045||−8|
|Trisomy 21 missed c||0.001049||189||0.000761||137||−0.000288||−52||0.000632||114||−0.000416||−75|
|Trisomy 21 suspected d||0.000198||36||0.000098||18||−0.000099||−18||0.000011||2||−0.000187||−34|
|Trisomy 21 diagnosed e||0.000098||18||0.000133||24||0.000035||6||0.000150||27||0.000052||9|
|Iatrogenic miscarriage||0.000168||30 f||0.000094||17||−0.000074||−13||0.000064||12 f||−0.000104||−19 f|
a All incremental values are referenced to clinical practice.
b No test: no FCT/NIPT/second-trimester anomaly scan/invasive diagnostic testing performed.
c Trisomy 21 missed: false-negative FCT (clinical practice)/false-negative NIPT (NIPT as optional secondary screening test and NIPT as primary screening test)/false-negative second-trimester anomaly scan or advanced ultrasound.
d Trisomy 21 suspected: screen-positive FCT/NIPT/advanced ultrasound, without confirmation by invasive diagnostic testing.
e Trisomy 21 diagnosed: invasive diagnostic testing performed.
f Difference caused by rounding of probabilities.
|Outcome||Cost||Probability effect||Relative cost||Cost-effectiveness|
|Strategy||Absolute (€)||Incremental (€) a||Absolute||Incremental a||Absolute cost/effect (k€) b||ICER (k€) b|
|Trisomy 21 diagnosed|
|Clinical practice, i.e. FTS by FCT||257.09||0.001635||157|
|NIPT as (optional) secondary screening test||311.74||54.65||0.002217||0.000582||141||94|
|NIPT as primary screening test||660.94||403.85||0.002513||0.000878||263||460|
|Live birth trisomy 21|
|Clinical practice, i.e. FTS by FCT||257.09||0.001470|
|NIPT as (optional) secondary screening test||311.74||54.65||0.001073||−0.000397||137 c|
|NIPT as primary screening test||660.94||403.85||0.000875||−0.000595||678 c|
|Clinical practice, i.e. FTS by FCT||257.09||0.000168|
|NIPT as (optional) secondary screening test||311.74||54.65||0.000094||−0.000074||737 c|
|NIPT as primary screening test||660.94||403.85||0.000064||−0.000104||3875 c|
a All incremental values are referenced to clinical practice.
b For calculation of relative costs and cost-effectiveness the incremental values of outcomes ‘live birth trisomy 21’ and ‘iatrogenic miscarriage’ were inverted.
c Because of rounding relative costs and cost-effectiveness ratios cannot be precisely calculated from cost and effects presented in this table.
A strategy implementing NIPT as primary screening test is the most effective for all major outcomes, followed by the strategy adding NIPT as an optional secondary screening test. Implementing NIPT in Dutch national health care will increase the number of T21 cases diagnosed. When NIPT is added as an optional secondary screening test to guide further testing for those at high risk for fetal aneuploidy the detection rate of T21 will increase by 36% (from 46.8% to 63.5%). When NIPT is implemented as primary screening test the detection rate of T21 will increase by 54% (from 46.8% to 72.0%). Implementing NIPT will simultaneously lead to a decrease in the number of invasive diagnostic procedures, and therefore in the number of procedure-related miscarriages. As a result the average risk of an iatrogenic miscarriage decreases by 44% (from 0.0168% to 0.0094% per pregnant woman) when NIPT is used as triage test and 62% (from 0.0168% to 0.0064% per pregnant woman) when NIPT is used as primary screening test. Currently, 29 invasive diagnostic procedures are performed to diagnose one case of T21. This will decrease to 12:1 when NIPT is implemented as optional secondary screening test and 7:1 when implemented as primary screening test.
Although adhering to current clinical practice using conventional screening only is the least effective, it is also the least costly strategy. The total expected cost of the programme for prenatal screening and diagnosis of T21 will increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when NIPT is added as an optional secondary screening test, and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when implemented as primary screening test. However, implementing NIPT as triage test results in the lowest expected relative cost, at k€141 per case of T21 diagnosed.
As the sensitivity of the second-trimester anomaly scan to detect T21 increases, the added benefit of NIPT to the programme for prenatal screening and diagnosis becomes smaller. Whenp ≥ 0.48, the relative cost of implementing NIPT exceeds the relative cost of current clinical practice (see Fig. 2 a). When all other probabilities, such as the total participation in the national programme for prenatal screening by women aged ≤ 35 years and women aged ≥ 36 years after implementing NIPT, were varied within the given ranges, no changes in the order of the different strategies were seen. The strategy implementing NIPT as optional secondary screening test remained the strategy with the lowest cost per case of T21 diagnosed, followed by current clinical practice using conventional screening only (see Fig. 2 b and c).
The unit cost of NIPT largely influences the cost and cost-effectiveness of the different strategies for the programme for prenatal screening for and diagnosis of T21. At a unit price of €254 or less, implementing NIPT as primary screening test becomes the least costly, and therefore dominant, strategy (see Fig. 2 d).
This study shows that the implementation of NIPT in Dutch national health care would increase the detection rate of T21 cases. Furthermore the number of invasive diagnostic procedures would decrease, resulting in fewer iatrogenic miscarriages. These effects are evident when NIPT is added as an optional secondary screening test, and even stronger when NIPT is implemented as primary screening test. However, due to the costs associated with NIPT none of the strategies clearly dominated: current clinical practice is the least costly strategy, whereas the most effective strategy regarding detection rate and diagnosis to iatrogenic miscarriage rate is also the most expensive strategy. Implementing NIPT as triage test, to guide further testing for those at high risk for fetal aneuploidy, would lead to the lowest cost per case of T21 diagnosed. Implementing NIPT as primary screening option will only be feasible if the cost of this novel technique decreases dramatically.
A few other economic evaluations of the implementation of NIPT in clinical care have recently been published. However, these studies focused on NIPT being utilised in a high-risk population only  , did not include current practice using conventional screening methods as a comparator  , or did not include second-trimester ultrasonographic examination in their model, , , and . Due to these differences in methods used, results cannot be compared. This study is the first to include second-trimester ultrasonographic examination in the model developed, thereby completely reflecting all tests available in the Dutch national programme for prenatal screening and diagnosis. As second-trimester ultrasonographic examination leads to detection of structural anomalies, invasive diagnostic testing, resulting in possible iatrogenic miscarriage or diagnosis of fetal T21, one cannot accurately evaluate the consequences of implementing NIPT without including second-trimester ultrasonographic examination in the model.
Cost-effectiveness of implementing a novel technology is usually established by comparing the incremental cost-effectiveness ratio against a designated threshold, e.g. cost per case of T21 diagnosed. However, the Dutch national programme for prenatal screening is aimed at facilitating informed, reproductive choice, rather than prevention of costs associated with T21 live births. As the value of information cannot be expressed in monetary units, no such threshold was used when estimating costs and consequences of different screening strategies. For the same reason only direct screening and diagnostic costs were considered in the analysis, whereas costs associated with outcomes such as procedure-related miscarriage and T21 live births were not taken into account. This approach is tentative, detrimental to implementing NIPT, so is not expected to have biased results towards implementation of this new prenatal test.
As anticipated, the decision analysis is limited by the evidence available. Although most input variables could be retrieved directly from international literature, some assumptions had to be made, especially regarding women's preferences and test participation following introduction of NIPT in national health care. Total participation in prenatal screening and diagnosis is expected to rise, mainly due to the favourable characteristics of NIPT. However, actual participation depends on other factors as well, such as societal attitudes towards screening and diagnosis for T21, counsellors’ and patients’ knowledge and understanding of test options available and reimbursement policies.
The structure and input of the decision-analytic economic model were primarily focused on Dutch national health care. To accurately assess results for other countries’ programmes for prenatal screening and diagnosis input variables should be adjusted to reflect their national maternal age distribution, organisation of prenatal care and risk cut-offs. However, sensitivity analysis showed the model to be robust over a wide range of values for most variables.
When health care resources are limited, decision-analytic economic modelling can be used to guide resource allocation under conditions of uncertainty  . As this model shows that adhering to current clinical practice using conventional screening only would be the least costly strategy, decision-makers might be inclined to refrain from implementing NIPT in national health care. However, the benefits of this novel technology should not be underestimated. Non-invasive testing provides women interested in prenatal testing for T21 with an easy to understand, highly accurate and safe option. Its implementation would therefore directly facilitate the ultimate goal of the national programme for prenatal screening and diagnosis, which is informed, autonomous reproductive choice.
Implementing NIPT would lead to a higher detection rate and fewer live births of children affected by T21. Research has shown that the per-capita incremental direct medical and nonmedical cost of T21 is approximately €250,000. When indirect costs due to morbidity and mortality are also considered the total lifetime cost of T21 is approximately €715,000  . Thus, any investments in this novel technology would in fact be outweighed by a concurrent decrease in health care and societal costs associated with T21.
With future advances in technology, costs of NIPT might decrease, making its implementation as primary screening test feasible. When NIPT would fully replace conventional screening, ultrasonographic NT measurement would no longer be needed for the detection of fetal aneuploidy. However, as it has been proven to be a valuable tool for the early detection of structural anomalies  , future research is necessary to determine whether early sonographic examination should remain part of prenatal care.
Since the introduction of NIPT would lead to an increased T21 detection rate, associated with a decrease in invasive diagnostic procedures performed, and therefore reduced iatrogenic miscarriage rate, and a decrease in costs per case of T21 detected, NIPT should be implemented in Dutch national health care. As implementation as primary screening test is not yet feasible, mainly due to the cost of this novel technique, NIPT should be implemented as optional screening test for those pregnancies complicated by a high risk for fetal T21.
Disclosure of interests
Contribution to authorship
L.B. designed the decision-analytic model, performed the analysis, interpreted the results and wrote the first draft of this report. J.P.C.G., B.H.F., I.F. and J.M.G.v V. participated in study design, interpretation of results, and manuscript preparation. M.N.B. had overall responsibility for the project, working closely with L.B. in all aspects of the study. All authors approved the final version of the paper.
NIPT should be implemented in prenatal care as an optional secondary screening test for those pregnancies complicated by a high risk for trisomy 21.
This study was financially supported by the Foundation for Prenatal Screening in the Nijmegen Region.
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a Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands
b Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
c Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
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