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Netherlands Embarks on NIPT Evaluation Study; Next Steps on Implementation Expected in 2015

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NEW YORK (GenomeWeb) – The Netherlands is in the midst of a nationwide study of noninvasive prenatal testing to provide it with the scientific data needed to help decide whether and how to implement the test as part of the country's prenatal screening program.

At Cambridge Healthtech Institute's Advances in Prenatal Molecular Diagnostics meeting in Boston last week, Brigitte Faas, a clinical laboratory geneticist at the Department of Human Genetics at Radboud University Medical Centre in Nijmegen, provided an overview of the study and its goals, technologies used, and progress to date.

Under a Dutch population screening law, commercial NIPT providers are currently prohibited from offering their tests to women in the Netherlands, which has about 175,000 births per year. But interest in the test appears to be high: an unknown number of pregnant women who have been willing to cross borders and pay out of pocket have already received NIPT, particular in Belgium and Germany, where NIPT companies are allowed to offer the test.

Under the TRIDENT study, short for Trial by Dutch laboratories for the Evaluation of Non-Invasive Prenatal Testing, which launched April 1, women at elevated risk of a trisomy 21, 18, or 13 pregnancy – based on either the result of their combined first trimester screening test, cFTS, or because they already have a child with a trisomy, but not based on maternal age alone − are now eligible to receive NIPT. Uptake of the cFTS test, which has a sensitivity of about 85 percent, has been rather low: only about a quarter of all pregnant women, and about half of those over 36, opt for the test, Faas said.

The NIPT test under the TRIDENT study reports on the risk for trisomies 21, 18, and 13. Provided sufficient data, labs are allowed to report additional chromosomal aberrations, such as deletions. The test does not include sex chromosomal abnormalities and does not report the sex of the fetus.

Women receiving a positive NIPT result are counseled and are offered an invasive test to confirm the result, which is required if they opt to terminate the pregnancy.

The two-year study, which is funded by the Dutch government and will include at least 1,000 women, was conceived and is carried out by the country's NIPT consortium, a group of stakeholders in the field of prenatal care. Testing is offered through prenatal diagnostic units and is conducted by six of the eight clinical genetic laboratories of the Dutch University Medical Centers, which currently perform virtually all genetic testing in the country, under a temporary two-year license by the Dutch Ministry of Health.

To perform the test, the six laboratories use a variety of sequencing platforms, most of them from Illumina, including the Illumina HiSeq 2500, HiSeq 2000, and NextSeq 500, and the Life Technologies 5500xl Wildfire. Each lab has performed its own in-house validation of the test, and the groups use different analysis algorithms.

All testing is based on shotgun sequencing of DNA from the mother's blood and determining imbalances in the amount of DNA from certain chromosomes, rather than targeted sequencing.

Faas reported that her own laboratory at the Radboud University Medical Center switched its test in September from the Life Technologies 5500xl to the Illumina NextSeq 500 sequencing platform, mainly to decrease its turnaround time. Turnaround time with the 5500 xl ranged from 14 to 21 days, including four days of sample preparation and about a week of sequencing, which many clinicians considered too long. On the NextSeq, turnaround time has come down to five to seven days, including one day of sample prep and an 11-hour sequencing run, she said.

Some women receive their NIPT results fast: normal results in women with a relatively low risk are communicated via text messaging within half an hour of the completion of the test, Faas said.

Since the beginning of the study in April, the Radboud UMC laboratory has performed NIPT testing on about 370 samples, she reported, and has found evidence for chromosomal abnormalities, mostly the three trisomies, in a small percentage of them. Follow-up data that will be available after the birth of the children will help to evaluate the accuracy of the test results, in particular for the non-trisomy findings.

Overall, the TRIDENT study has enrolled more than 1,000 women for NIPT testing so far, exceeding its goal, according to Erik Sistermans, the project leader. The study will continue to enroll women, at least for the next year and a half of its duration.

Next steps on the possible implementation of NIPT are expected sometime next year. Sistermans, who is the head of genome diagnostics at the VU University Medical Center Amsterdam, told Clinical Sequencing News that he and his colleagues plan to advise the Ministry of Health as soon as the first study results are in next year to allow for ample planning time. "We cannot just stop [the study] after two years and then plan, that would be too late," he said.

Besides the study results, economic considerations will factor into whether, or how, NIPT will be implemented permanently in prenatal screening. Eventually, it will be up to politicians, not laboratories and clinicians, to decide, Sistermans said. "Our part is mainly to give them numbers, not where funding should come from."

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