At present, the study of ultrasonographic soft markers (USMs) is relatively concentrated in the second trimester. However, reports regarding the first trimester are scarce. In our study, it was found that there were more USMs detected during the first trimester. Multiple USMs was associated with a greater probability of adverse pregnancy outcome occurred compared with single USM, which was consistent with the results of Shi et al. [11]. Moreover, the incidence of adverse pregnancy outcomes in fetuses with both USMs and structural abnormalities was significantly higher than those with isolated USM without structural malformations. Therefore, if the fetus had multiple USMs or USMs associated with structural abnormalities during the first trimester, more attention should be paid and the fetus should be comprehensively evaluated and counselled.
Our study demonstrated that increased NT thickness, absence/hypoplasia of the nasal bone, absent/reversed a-wave of ductus venosus, TR, CPC, EB and SUA were closely related to the adverse pregnancy outcomes (P < 0.05). Increased NT thickness was associated with the high risk of a series of congenital abnormalities, including structural malformations, genetic disorders, and developmental delays of the central nervous system [10]. In a recent large sample cohort, Hellmuth et al. [12] pointed out that with the NT thickness above 99th percentile, the risk of mental retardation and autism after birth in euploidy fetuses increased, however, with the NT thickness between 95th and 99th percentile, the risk of neurodevelopmental disorders did not increase. Bilardo et al.[13] introduced that increased NT thickness was a strong marker for adverse pregnancy outcome, such as miscarriage, intrauterine death, congenital heart defects (CHD), and numerous other structural malformations and genetic abnormalities. In our study, we found that the incidence of adverse pregnancy outcomes in fetuses with the NT thickness above 99th percentile was 30.14% (44/146), which was much higher than that with NT thickness between 95th and 99th percentile (6.56%, 21/320).
Absence/hypoplasia of the nasal bone was considered to be closely related to chromosomal abnormalities, such as trisomy 21, trisomy 18, trisomy 13 and Turner syndrome [5, 14]. In addition, the hypoplastic nasal bone also increased the risk of certain genetic syndromes caused by fetal pCNVs[15]. According to Zhang’s [14] study, even in fetuses with simple absence/hypoplasia, the genetic abnormality rate was 7.27% after prenatal chromosomal microarray analysis (CMA) diagnosis and an additional abnormality rate of 16.67% was found in further whole exome sequencing (WES) tests. In our study, it was reported that fetuses with absence/hypoplasia of the nasal bones frequently (31.81%) associated with chromosomal abnormalities and pCNVs.
Minnella et al. [4] emphasized the importance of the absent/reversed a-wave of ductus venosus for screening fetal heart defects during the first trimester. Similarly, Indian scholars Chhikara et al.[16] also pointed out that absent/reversed a-wave of ductus venosus was an excellent screening tool for cardiac defects and fetal death during the first trimester. Recently, Sun et al. [17] concluded that absent/reversed a-wave of ductus venosus was also accompanied by fetal chromosomal abnormalities and twin to twin transfusion syndrome (TTTS). In our study, 93 fetuses with absent/reversed a-wave of ductus venosus, 18 of which were complicated with cardiac structural malformations, with 17 ending in termination of pregnancy. Among these fetuses, 6 cases had genetic abnormalities, including 3 cases of trisomy 21, 1 case of trisomy 13, 1 case of pCNVs and 1 case of arr[hg19]Xp22.33p11.1(168,551 − 58,326,434)x1.
A meta-analysis suggested that TR, when detected in the first trimester, increased the risk of congenital heart diseases (CHD) in euploid fetuses [18]. Additionally, Wiechec et al. [19] noted that when TR was combined with other soft markers, it could be an excellent indicator for chromosomal abnormalities and CHD. Park et al. [20] reported that in the case of uteroplacental insufficiency in early pregnancy, due to the increase of placental resistance, the right ventricular afterload increases, which resulted in TR. This mild TR was associated with sex-specific low birth weight and borderline amniotic fluid index (AFI) before birth, but not with adverse pregnancy or perinatal outcomes due to placental insufficiency. However, in our study, TR was significantly associated with fetal adverse pregnancy outcomes. In particular for those fetuses with cardiac structural malformations, chromosomal abnormalities (trisomy 21, trisomy 13, anomaly of chromosome 17 and pCNVs) were reported.
Shah [21], an Indian scholar, believed that most CPCs were normal benign mutations and 90% of them disappeared before the third trimester (28 weeks of gestation). To date, there is little literature available indicating that CPC itself might damage the fetal central nervous system or affect fetal cognitive or motor behavior [22]. When CPC was associated with other abnormalities, 2.1% of fetuses might be aneuploid, mostly trisomy 18[21]. Nevertheless, some other studies suggested that even simple or transient CPC was also relevant to fetal chromosomal aneuploidy[7]. In our study, 3 out of the 16 fetuses with CPC were terminated before 20 gestational weeks due to chromosomal abnormalities, resulting in the incidence of adverse pregnancy outcome was 18.75% (3/16). Therefore, the detection of fetal CPC during the first trimester should be on the alert.
A meta-analysis including 25 studies (1297 fetuses) revealed that EB was associated with various adverse pregnancy outcomes, including chromosomal abnormalities, cystic fibrosis, congenital infection, fetal growth restriction (FGR), and structural malformations mainly involving the gastrointestinal tract [23]. Our study also demonstrated a statistically significant correlation between EB and fetal adverse pregnancy outcome, the incidence of which was 38.46% (5/13). However, we did not specify the classification for the adverse pregnancy outcomes.
Zhao et al. [24] underlined that SUA could affect fetal blood circulation, resulting in premature birth, intrauterine growth retardation (IUGR), related fatal malformations and chromosomal abnormalities (mainly trisomy 18) and other adverse outcomes. Similarly, Murphy-Kaulbeck et al. [25] pointed out that SUA was a risk factor for adverse pregnancy outcomes. However, Van den Hof et al. [26] proposed that the chances of structural malformations and chromosomal abnormalities in fetuses with simple SUA were small, and most fetuses had good pregnancy outcomes. However, in our study, the correlation between SUA and adverse pregnancy outcomes was statistically significant. The incidence of adverse pregnancy outcomes in fetuses with SUA was 35.71% (10/28).
We also observed there was no significant correlation between EIF, mild PYE and fetal adverse pregnancy outcomes. Lorente et al. [27] argued that EIF could be used as a soft marker to identify high-risk population with Down syndrome (DS), but its sensitivity was low. The recent research found that EIF found in the first and second trimester did not indicate the increased risk of fetal chromosomal abnormalities, however, the persistence of EIF in late pregnancy was related to pCNVs and CHD after birth [6]. Our results were in line with most of the previous reports. Mild PYE was usually self-limited, yet in rare cases it could be an early manifestation of renal diseases and be associated with other structural malformations. Stefanovic[28] reported that majority of fetuses with mild PYE had normal pregnancy outcomes, which was in accordance with our result.
It is worth emphasizing that, of the 5841 fetuses with normal ultrasound findings during the first trimester, 87 cases (1.49%, 87/5841) had adverse pregnancy outcomes in our study. Due to the limited ultrasound accessment windom by ultrasound and the dynamic process of fetal development, some fetal abnormalities such as agenesis of the corpus callosum (ACC), achondroplasia reported later were not able to be detected in the first trimester[29]. FTS could not replace the routine mid-trimester fetal ultrasound scan and invasive prenatal diagnosis. For normal fetuses after FTS, the subsequent fetal routine ultrasound scan, fetal echocardiography and regular routine prenatal examination should still be completed.
As a retrospective study, the present study had some limitations. Firstly, the number of adverse outcomes in EB, CPC, mild PYE and SUA was small. Secondly, some aborted fetuses did not perform further genetic analysis, which limited the analysis of the results to a certain extent.