During the first trimester, the risk assessment for trisomy 21 includes determining the serum markers PAPP-A and free β-hCG [1]. In 1% of cases, the profile of these markers is considered atypical or low (PAPP-A or free hCGβ < 0.30 MoM) and this should prompt consideration of screening for other aneuploidies [2,3]. In France, a Non-Invasive Prenatal Testing (NIPT) is recommended for secondary screening, after combined first-trimester screening in cases of intermediate risk of trisomy 21, defined as a risk between 1/50 and 1/1000. Furthermore, in cases of low risk of trisomy 21 (< 1/1000) with a low serum marker profile, Center for Fetal Diagnosis and Treatment (CFDT) can recommend a NIPT [4,5]. The performance of NIPT has extensively described in the literature, particularly in women with a low serum marker profile (100% sensitivity, 100% specificity for trisomy 21) [6]. However, the Association des Cytogénéticiens de Langue Française (ACLF) specifies that when serum markers are collapsed (< 0.10 MoM), ultrasound remains the gold standard for detecting ultrasound signs suggestive of triploidy [7].

In the literature, a low PAPP-A profile (less than 0.30 MoM) may be associated with the presence of trisomy 21, trisomy 18, trisomy 16 or triploidy [8]. Similarly, a low free β-hCG profile (less than 0.30 MoM), raises suspicion of trisomy 18, which has a 100-fold increased risk, trisomy 16 or triploidy. The pathophysiology leading to the alteration of these markers is certainly linked to an anomaly in placental function, but this remains uncertain [9]. However, their association with possible aneuploidy makes them a good screening test. For this reason, atypical serum markers results should be referred to expert centers for appropriate management. In France, although not officially recommended, when a PAPP-A or free β-hCG result < 0.30 MoM is observed, an early morphological ultrasound at 18 weeks of gestational (WG) is widely practiced, in addition to the 2nd trimester ultrasound performed around 22 WG, to look for sonographic signs such as IUGR or malformations suggestive of aneuploidy. Nonetheless, it is not reimbursed. The evaluation of the contribution of early morphological ultrasound, in the context of a low profile of serum markers, has been carried out by studies published before the recommendation for the NIPT [2,8,10]. Since its introduction, early systematic morphological ultrasound in cases of atypical markers seems to have lost its interest for the detection of unbalanced chromosomal abnormalities. It would therefore only be relevant for anomalies not detected by NIPT, such as triploidy [11].

Based on all these observations, our study aimed to assess the value and contribution of systematic early morphological ultrasound as a supplementary screening tool to NIPT in a population of women who underwent atypical serum marker profiling during the first trimester of pregnancy and had either a low or intermediate risk of trisomy 21 (<1/50).