In the Netherlands, invasive prenatal diagnosis is offered to all women who are considered to be at increased risk for Down's syndrome. Until recently, the vast majority of invasive tests was done for advanced maternal age. More recently, a nationwide screening program for Down's syndrome using first trimester serum testing combined with ultrasonographic nuchal translucency measurement was introduced [1, 2]. A positive result of this combination test or maternal age (36 years or older) represent 80% of the indications for the invasive diagnostic procedures (amniocentesis and chorionic villus sampling). We have seen a still continuing shift of maternal age-based karyotyping towards prenatal screening based testing.
Traditional karyotyping (TKT) is considered the gold standard for invasive prenatal diagnosis (PND) [2, 3]. TKT is able to detect a range of numerical and structural chromosomal abnormalities with considerable accuracy (99.4–99.8%) and reliability[3, 4]. However, TKT also has several disadvantages: it is labour intensive and the costs are high. Furthermore, obtaining results from karyotyping takes 2–3 weeks, and this waiting time places a significant emotional burden on women and their partners. Moreover, the extensive detection capacity of TKT can be perceived as a disadvantage due to the detection of abnormalities with unclear or mild clinical relevance. These results can cause patient anxiety, emotional dilemmas concerning the continuation of pregnancy and, albeit rare, unnecessary pregnancy terminations .
Due to these disadvantages, TKT has been challenged as a reference test. In 2002, a molecular PCR-based technique, MLPA (multiplex ligation-dependent probe amplification) became available to detect foetal aneuploidies in amniotic fluid cells. In preclinical laboratory studies, MLPA has been a robust test in detecting the most common chromosomal aneuploidies, namely trisomy 21, 13, 18 and sex chromosome abnormalities [7–9]. Compared to TKT, MLPA has several potential advantages: the result is available in 2–4 days instead of 3 weeks, the technique requires only 2 ml of amniotic fluid instead of 16–20 ml, and the technique is considerably less labour-intensive and is suitable for high-throughput testing [8–10].
In the Netherlands, like other western countries, there is an ongoing debate whether rapid molecular tests should be used as a stand-alone diagnostic tool instead of karyotyping in prenatal diagnosis for certain indications[5, 11–15]. To strengthen the debate and to supply it with evidence, we designed a clinical prospective cohort study in which MLPA is compared independently to TKT for the two main referral indications; advanced maternal age and increased risk following prenatal screening tests. The aim is to estimate diagnostic accuracy for the detection of trisomies 21, 18,13 and sex chromosome abnormalities, as well as the reduction in waiting time for the prospective parents, maternal quality of life, women's preferences, the relevance of 'unexpected findings' and costs.