Which is the most cost-efficient paradigm of early screening for fetal congenital abnormalities?

Prenatal screening was introduced in The Netherlands in 2007. The program
included the Combined test, with ultrasound (US) measurement of nuchal
translucency (NT), performed between 11-13+6 weeks as screening for trisomy 21,
18 and 13, and the structural anomaly scan (SEO) at 18-21 weeks for the
detection of fetal structural anomalies. Since April 2017, non-invasive
prenatal testing (NIPT) has replaced the CT as first tier first-trimester
screening test. This is performed in a study setting (Trident 2 study) and is
financed, partly by the woman herself (Euro 175) and partly subsidized by the
government (the remaining Euro 500). As a consequence of offering NIPT to all
pregnant women, the CT is hardly performed anymore. This implies that the
nuchal translucency is no longer measured and information of fetal anatomy is
only obtained at 20 weeks. Even in case of severe fetal anomalies, such as
anencephaly, parents may only be informed at 20 weeks. The actual NIPT is
performed from 10 weeks gestation and the protocol suggests that an ultrasound
scan should be performed within one week of the NIPT for dating of the
pregnancy, by crown-rump-length (CRL) measurement of the fetus. Exclusion
criteria for NIPT are currently the presence of a fetal NT of * 3,5mm and/or
the presence of fetal structural anomalies. In such cases a more detailed kind
of genetic investigation (arrays CGH) is indicated, rather than NIPT, which
targets especially the three common trisomies 21,18 and 13 and only rather
large genetic aberrations. Unfortunately the chosen paradigm of first trimester
screening, in the Netherlands is not designed for a proper application of the
exclusion criteria, as the US scan prior to NIPT is performed too early (10
weeks), at a stage where both assessment of the NT thickness and exclusion of
structural anomalies warranting a more informative type of genetic
investigation, is not invariably possible. Moreover, performance of NIPT at
such an early gestational age increases the number of failed tests, owing to a
lower fetal fraction, which is dependent on gestational age. The prevalence of
failed test for a NIPT performed at 10-11 weeks is expected to be about 2-3%
and it decreases with increase in gestational age. When an inconclusive NIPT
result is obtained there are a number of options: 1) the test can be repeated,
or 2) the woman can choose for a CT, if still possible. In case the test fails
again (chance 30%) the woman can decide to undergo further investigations
(detailed scan or invasive procedure for karyotyping). The time required for
the whole process in these cases is experienced as stressful and frustrating by
both parents and caregivers. Another argument in favor of possibly postponing
the moment NIPT is carried out is the fact that in about 1-2% of cases the
pregnancy may demise between 10 weeks and 13 weeks.
The use of NIPT in all these cases (thickened NT, presence of structural
anomalies, test failure due to low fetal fraction and fetal demise) results in
unnecessary costs. This is relevant, given the high price of NIPT set at about
700-800 euro within the Trident 2 study.

This study is designed to identify the best performing screening strategy
within the options currently available in the Dutch prenatal screening program
by investigating whether postponement of the dating scan to 12-13 weeks and
NIPT thereafter could decrease the number of inconclusive NIPT results, reduce
costs and allow for full application of the exclusion criteria for NIPT.

This is a multicenter randomized-controlled trial.

Patients will be asked to participate into the study and, if consent is
obtained, they will be allocated to one of two different care models:
A) US scan at 10 weeks followed by NIPT (care as usual)
B) US scan at 12-13 weeks, followed by NIPT.

Both the ultrasound examination and NIPT provide no risk to the pregnant woman
or her child.