Lean Beulen

The consequences of implementing non-invasive prenatal testing in Dutch national health care: a cost-effectiveness analysis

OBJECTIVE 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. STUDY DESIGN 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. 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). CONCLUSION NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.

Trial by Dutch laboratories for evaluation of non-invasive prenatal testing. Part II—women's perspectives†

To evaluate preferences and decision‐making among high‐risk pregnant women offered a choice between Non‐Invasive Prenatal Testing (NIPT), invasive testing or no further testing.

Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies

To evaluate the application of non‐invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing in pregnancies with abnormal ultrasound findings.

The effect of a decision aid on informed decision-making in the era of non-invasive prenatal testing: a randomised controlled trial

Early in pregnancy women and their partners face the complex decision on whether or not to participate in prenatal testing for fetal chromosomal abnormalities. Several studies show that the majority of pregnant women currently do not make informed decisions regarding prenatal testing. As the range of prenatal tests is expanding due to the development of new techniques such as non-invasive prenatal testing (NIPT), autonomous reproductive decision-making is increasingly challenging. In this study, a randomised controlled trial was conducted to evaluate the effect of a web-based multimedia decision aid on decision-making regarding prenatal testing. The decision aid provided both written and audiovisual information on prenatal tests currently available, that is, prenatal screening by first-trimester combined testing, NIPT and invasive diagnostic testing through chorionic villus sampling or amniocentesis. Furthermore, it contained values clarification exercises encouraging pregnant women to reflect on the potential harms and benefits of having prenatal tests performed. The use of the decision aid improved informed decision-making regarding prenatal testing. Of pregnant women allocated to the intervention group (n=130) 82.3% made an informed choice compared with 66.4% of women in the control group (n=131), P=0.004. As the vast majority of pregnant women made decisions consistent with their attitudes towards having prenatal testing performed, this improvement in informed decision-making could be attributed mainly to an increase in decision-relevant knowledge. This study shows that the implementation of a web-based multimedia decision aid directly facilitates the ultimate goal of prenatal testing for fetal chromosomal abnormalities, which is enabling informed autonomous reproductive choice.

Reliable noninvasive prenatal testing by massively parallel sequencing of circulating cell-free DNA from maternal plasma processed up to 24 h after venipuncture

OBJECTIVES Circulating cell-free fetal DNA (ccffDNA) in maternal plasma is an attractive source for noninvasive prenatal testing (NIPT). The amount of total cell-free DNA significantly increases 24h after venipuncture, leading to a relative decrease of the ccffDNA fraction in the blood sample. In this study, we evaluated the downstream effects of extended processing times on the reliability of aneuploidy detection by massively parallel sequencing (MPS). DESIGN AND METHODS Whole blood from pregnant women carrying normal and trisomy 21 (T21) fetuses was collected in regular EDTA anti-coagulated tubes and processed within 6h, 24 and 48h after venipuncture. Samples of all three different time points were further analyzed by MPS using Z-score calculation and the percentage of ccffDNA based on X-chromosome reads. RESULTS Both T21 samples were correctly identified as such at all time-points. However, after 48h, a higher deviation in Z-scores was noticed. Even though the percentage of ccffDNA in a plasma sample has been shown previously to significantly decrease 24h after venipuncture, the percentages based on MPS results did not show a significant decrease after 6, 24 or 48h. CONCLUSIONS The quality and quantity of ccffDNA extracted from plasma samples processed up to 24h after venipuncture are sufficiently high for reliable downstream NIPT analysis by MPS. Furthermore, we show that it is important to determine the percentage of ccffDNA in the fraction of the sample that is actually used for NIPT, as downstream procedures might influence the fetal or maternal fraction.

Implementation of whole genome massively parallel sequencing for noninvasive prenatal testing in laboratories

Noninvasive prenatal testing (NIPT) for fetal aneuploidies using cell-free fetal DNA in maternal plasma has revolutionized the field of prenatal care and methods using massively parallel sequencing are now being implemented almost worldwide. Substantial progress has been made from initially testing for (an)euploidies of chromosomes 13, 18 and 21, to testing for sex chromosome (an)euploidies, additional autosomal aneuploidies as well as partial deletions and duplications genome-wide. Although NIPT is associated with significantly reduced risks for the fetus in comparison to existing invasive prenatal diagnostic methods, it presents several implementation challenges. Here, we review key issues potentially influencing NIPT and illustrate them using both data from literature and in-house data.

Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: results of the TRIDENT study

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (<p10), which was severe (<p2.3) in six cases.ConclusionGenome-wide NIPS in pregnancies at risk for trisomy 21, 18, or 13, reveals a chromosomal aberration other than trisomy 21, 18 or 13 in about one-third of the abnormal cases. The majority involves a fetal or placental chromosome aberration with clinical relevance for pregnancy management.

Validation of two-channel sequencing-by-synthesis for noninvasive prenatal testing of fetal whole and partial chromosome aberrations.

To validate Illuminas two‐channel NextSeq 500 sequencing system for noninvasive prenatal testing (NIPT) of fetal whole chromosome and partial aberrations.

Experiences of high-risk pregnant women who were offered a choice between non-invasive prenatal testing, invasive testing or no follow-up test

OBJECTIVES: Sequencing of cell-free fetal DNA from maternal plasma, also known as non-invasive prenatal testing (NIPT), has enabled accurate prenatal diagnosis of aneuploidy. This approach is gaining clinical acceptance, as it significantly reduces the necessity of invasive diagnostic procedures such as amniocentesis that carry a significant risk of fetal loss. Recent studies have demonstrated the potential for NIPT to detect subchromosomal abnormalities. We investigated whether NIPT using semiconductor sequencing could reliably detect subchromosomal deletions and duplications in a large population of women carrying high-risk fetuses. METHODS: We applied a sliding window method to reduce required sequencing depth. First, we demonstrated that increasing concentration of abnormal DNA as well as increasing number of sequencing reads improved detection of chromosomal abnormalities. We then analyzed plasma from 1456 pregnant women to develop a method to predict the fraction of fetal DNA based on the size distribution of DNA fragments (r = 0.818, p<2.2e 16, linear regression model). Finally, we collected plasma from 938 of pregnant women having a fetus with structural abnormalities detected on ultrasound who also underwent amniocentesis, chorionic villous sampling, or umbilical cord blood sampling. We sequenced these samples using from 3M up to 15M reads to detect subchromosomal abnormalities, in parallel with array comparative genomic hybridization performed on each invasively-derived sample as a comparison. RESULTS: In total, 100% (57/57) instances of aneuploidy and 36/40 (90%) of samples with subchromosomal abnormalities greater than 5MB in size were detected using only 3 million (3 M) reads, while 5M reads was required to detect two more samples subchromosomal abnormalities greater than 5MB in size and 12/19 samples with chromosomal abnormalities between 1.5 and 5 MB. While increasing sequencing depth up to 15M reads increased accuracy for larger deletions/duplications, 88.1% (52/59) abnormalities larger than 1.5M could be detected using this method, while 5 abnormalities under 1.5MB were not reliably detected. CONCLUSIONS: This study demonstrates the viability of NIPT using semiconductor sequencing to accurately detect subchromosomal abnormalities greater than 1.5MB in a high-risk population. 1–2 Feasibility of noninvasive prenatal testing for common fetal aneuploidies in maternal serum with low levels circulating fetal cell-free DNA fraction