Prospective observations study protocol to investigate cost-effectiveness of various prenatal test strategies after the introduction of noninvasive prenatal testing

Aneuploidy is defined as a numerical abnormality of chromosomes and is reported to have an incidence of 1 out of 160 live births [1]. Prenatal diagnosis of aneuploidy is crucial, since it is associated with an increased perinatal morbidity and mortality. In addition, the presence of fetal aneuploidy can affect decision making in fetal treatment, screening, and method of delivery.

Several strategies are currently available for the identification of fetal aneuploidy [2]. Invasive test includes chorionic villi sampling, amniocentesis, and cordocentesis, and is usually indicated for high-risk pregnant women in order to diagnose aneuploidy. The procedure-related risk of this invasive test amounts to 1/300–1/500 within two weeks [3, 4], which restricts this tests from being universally used in low-risk pregnancies. In addition, such an invasive test requires highly trained professionals for the diagnostic procedure. The conventional non-invasive screening tests include maternal serum screening with biochemical markers or ultrasound examination, such as the measurement of fetal nuchal translucency (NT). Among the non-invasive screening methods, triple test and quad test have the accuracy rate of 61–70% and 74–81%, respectively in diagnosing Down syndrome, with the false positive rate of 5% [2, 5]. At 12-week pregnancy, using maternal blood markers, namely, PAPP-A and free beta-hCG, has only 79–87% accuracy rate, with 5% false positive rate [5]. Recently, integrated test involving maternal serum test combined with sonographic results through the first to mid-trimester pregnancy has been introduced, with limited detection rate of 94–96% [5].

Another method introduced in the USA in 2011 and now widely used in 60 different countries is analyzing fetal cell-free DNA in maternal blood sample which is called as NIPT (non-invasive prenatal testing). In recent guidelines, the NIPT is indicated mainly in high-risk pregnant women [6] and shows the highest sensitivity (> 99%) with low false positive rate (<= 0.15%) for the detection of Down syndrome in high-risk pregnancies [7‐12].

Due to this low false positive rate, it is assumed that the implementation of NIPT as a screening method may reduce the number of invasive fetal tests. In the study of Larion et al., NIPT’s high detection rate reduces undue invasive prenatal screening tests [13], therefore reducing fetal mortality rate caused by conventional invasive tests.

In terms of cost effectiveness, the decreased number of invasive tests may result in a similar or lowered cost in the overall detection of Down syndrome, as compared to other screening or diagnostic methods. NIPT is expensive, with the associated cost ranging from $795 to $2900 depending on the country; However, the high accuracy rate of NIPT has a value in reducing invasive prenatal tests [1, 13]. These conflicting points (high cost and a value in reduction of invasive test) raise the questions about the cost effectiveness of NIPT in both high-risk and low-risk pregnant women. However, the advantage may be more critical in high-risk pregnancies, although clinical application of NIPT to all pregnant women may not be economically practical.

In the literature, there have been several studies on the cost effectiveness of NIPT (Table 1). Most studies are based on theoretical economic analysis, especially in high-risk pregnancies [14‐17]. In England, prospective observational study has been conducted and showed that NIPT decreased invasive tests with same detection rate [18]. This England study was the first study on the effectiveness of NIPT in real world situation than in theoretical model, but this study did not included low risk women (included women with aneuploidy risk of at least 1/1000).

To determine this issue, we aimed to evaluate the cost effectiveness of different prenatal test strategies for the identification of fetal aneuploidy, including NIPT, in real clinical setting in both low risk and high risk pregnancies.

In this study, we will try to find out which method is more cost-effective for detection of fetal aneuploidy, including NIPT.

NIPT is expensive ranging from $795 to 2900 depending on countries in the literature, and the NIPT cost in Korea is between 550,000 and 800,000 KRW. However, the high accuracy rate of NIPT has a value in reducing invasive prenatal tests [1, 13]. These conflicting points (high cost and a value in reduction of invasive test) raised the questions on the cost-effectiveness of NIPT in both high-risk and low-risk pregnant women. In the literature, there have been several studies on the cost-effectiveness of NIPT (Table 1). The NIPT has been shown to be cost-effective, especially in high risk patients. However, the cost-effectiveness of NIPT in low risk women has not been well determined. In addition, these previous studies are mostly based on theoretical economic analysis and clinical data in a ‘real-world situation’ has not been well evaluated. Lastly, the cost-effectiveness analysis in Korean population seems to be important, because the mean age of Korean pregnant women was higher than other countries (such as USA and England) and old age itself can be a high risk factor [19].

To our knowledge, this study will be the first study which evaluated the cost effectiveness of NIPT in low risk pregnancies in reality. In addition, this will be the first study determining the impact of NIPT in twin pregnancies.

The results of this study are expected to have a significant impact on improving national health, and related policies (Table 2). First, on national health level, prenatal screening guidelines would reduce unnecessary invasive tests and result related abortion. Secondly, prenatal screening costs would be reduced. Third, more effective government policies would be made for prenatal care and gathering evidence for improving low birth rates. Finally, this would be basis of effective prenatal screening.