The performance of FTS in our study
In recent years, different studies, based on different studied populations (high-risk and low-risk), different criteria for inclusion of malformations taken, and whether there are detailed standard protocols in scans, have reported large differences in the detection rate of fetal structural malformations in early pregnancy (13-88%), with an average detection rate of about 50%[8, 9]. The population in this study was a non-selective general population, using an established standard protocol for early anatomy screening, including all detectable structural malformations (regardless of chromosomal aberrations), and the detection rate of structural malformations in early pregnancy was 53.8% (64/119), which was in line with the average detection rate reported. A more recent study by Yimei Liao et al.[10] also reported a detection rate of 43.1% in the first trimester using a standardized anatomical protocol.
The performance of FTS varied in different studies. The sensitivity, specificity, PPV, and NPV of first trimester ultrasound in Fernando Felix Dulgheroff et al.’s[11] study was 14.06%, 98.65%, 39.13%, 94.90%, respectively. The corresponding values in our study were as following: 54.2%, 99.9%, 94.1%, and 99.3%, respectively. Despite the huge differences in sensitivity and PPV, there were high specificity and NPV in both studies, suggesting that FTS is a reliable method for confirming the normal results.
Early structural abnormalities detected in our study
A Syngelaki et al. [12] have divided fetal structural malformations into three groups according to the detection during early pregnancy: always detectable, never detectable, and sometimes detectable.
Acrania, ectopia cordis, alobar holoprosencephaly, exomphalos, gastroschisis, tricuspid or pulmonary atresia, pentalogy of Cantrell, and body-stalk anomaly can always be detectable in the first trimester in Syngelaki et al.’s study[12]. Ana Maria Vayna et al.[13] also detected all the cases of AVSD, right atrial isomerism, double-outlet right ventricle (DORV), megacystis, persistent cloaca, all the aplasia/hypoplasia of radius/ulna in their study with a small sample size. Our study detected all of alobar holoprosencephaly (Figure 1), encephalocele (Figure 2), exomphalos, hygroma, TOF, RAA, HLHS, AVSD, heterotaxy syndrome, megalocystiscases, limb reduction defects, severe short limb, and hemivertebrae cases. There were no cases of acrania, which may be ascribed to a previous ultrasound examination before the first trimester NT screening in our center. The detection rate of the Pentalogy of Cantrell and DORV was 50% (1/2) in our study. One case of Pentalogy of Cantrell in a twin pregnancy missed diagnosis prenatally because of the absence of ectopia cordis. One case of DORV was not proved until the mid-trimester in our study due to the poor image caused by the large body mass index (BMI) of the mother. The detection rate of some syndromes, such as caudal regression syndrome and Larsen syndrome also reached 100%.
The “sometimes detectable” group includes anomalies that can be potentially found depending on the expertise of the examiner, the instrument’s resolution, time of examination, presence or absence of detailed anatomy screening protocol, and whether detectable makers are implying certain malformations, such as TR for cardiac abnormalities. It is also worthy to note that the detection of malformations, especially those in the “sometimes detectable” group, improved as the standard protocol used for screening advanced. In our study, CLP, complex heart abnormalities, congenital diaphragmatic hernia (CDH), club foot, and multiple system defects all showed high detection rates(≥50%). We detected 71.4% (5/13) of CLP (figure 3) cases using the oblique coronal plane of the face, also known as the retronasal triangle plane (RNT). The RNT plane was of great value in detecting early cleft palate. De Robertis et al.[14]reported in a comparative study that the RNT plane was more sensitive compared to the maxillary gap (MG) in detecting cleft palate; but MG showed an additional diagnostic ability in secondary palate cleft. Compared with the detection rate of 30.4% and 34.6% for CLP reported by Liao and A Syngelaki[10, 12], the higher detection rate in our study might be due to both our small number of cases (5/7) and our strict standard operation of the RNT plane. We only got the RT plane when the palate was perpendicular to the ultrasound beam, avoiding the shadow of two frontal processes of the maxilla. Two cases of “cleft lip only” were found in the second trimester because it was tough to observe the soft tissues of the lip in early pregnancy only by two-dimensional imaging. A standard protocol for the fetal heart also showed great power in screening for congenital heart defects. In our study, the protocol contained the 4-chamber view, the LVOT view, and the 3VT view of the heart implemented with a combination of both two-dimensional and color flow imaging. Our center’s total detection rate for congenital heart defects was 57.1% (20/35). The four-chamber view detected all the AVSD (figure 4) and HLHS (figure 5) cases. Additionally, the 3VT view and the LVOT view detected all the TOF and RAA (figure 6) cases. We believed that the routine screening protocol for fetal heart used in the mid-trimester also fit the first-trimester, based on color flow imaging. Sifa Turan et al.[15]assessed the accuracy of early fetal heart assessment (EFHA) in excluding major congenital heart defects in a high-risk population, with a standardized protocol similar to ours, and found that EFHA with a standardized screening strategy had high positive and negative predictive value (98.6% and 99.6% respectively). J. N. Karim et al. [16]reported a pooled sensitivity of 55.80% (95% CI 45.87 – 65.50%) in non-high-risk pregnancies in their meta-analysis of first trimester ultrasound to detect fetal heart anomalies, and promote detailed structured anatomical assessment protocols for higher detection rate. It is suggested that the more detailed the screening protocol in early pregnancy, the higher the detection rate of structural malformations will be[17]. In our study, we detected one out of the two cases of CDH (Figure 8) by the presence of anechoic stomach in the thorax, while the other case was missed in the first trimester because of no apparent manifestation at that time, or maybe the hernia occurred later due to the increased abdominal pressure. In cases of suspicion of non-typical cases of CDH, Ravi Selvaraj Lakshmy et al.[18], reported that the upturned course of the superior mesenteric artery (SMA) could be a valuable sign in confirmation of CDH, which could be tried in further study for a higher detection rate. Though limb reductions were always easily detected in early pregnancy, deformities of the hands and feet were occasionally diagnosed. Ana Maria Vayna et al[13]. detected 75% ectrodactyly (3/4) in their study, and Yimei Liao et al.[10]detected none of the syndactyly cases (0/11) but 25% (6/24) of the polydactyly cases. In an earlier study of fetal limb abnormalities in the first trimester by Yi-Mei Liao et al.[19], they detected 1 out of 2 cases of syndactyly, but no cases of polydactyly (0/4). Two cases of polydactyly and one case of syndactyly were not detected in this study, probably because we focused on the presence or absence of the three segments of the limb and neglected to observe the morphology of the hand and foot.
“Never detectable” means the abnormalities cannot be found in early pregnancy, due to the late onset of some malformations or the late development of some organs. In our study, the “never detectable” group included: agenesis of corpus callosum (ACC), which could not be found because corpus callosum is not fully developed in the first trimester; arachnoid cyst, hydrocephalus, cardiac tumor, atrial septal defects (ASD), congenital chylothorax, congenital biliary atresia (CBA), and most of the genitourinary malformations, except for megalocystis, which may be ascribed to, on the one hand, their late-onset and manisfestation, and on the other hand, they were not apparent in the first trimester. Thus, a large proportion of these malformations were detected in later pregnancy, even postnatally. One case of sistus inversus missed diagnosis in the FTS may not be included in the “never detectable” group, because we thought it could be found when we reviewed the case.
For the central nervous system, since the corpus callosum and structures in the posterior fossa were not fully developed in the first trimester, deformities relating to such structures were conventionally considered never detectable. However, several indirect signs have been reported to predict ACC[20-23]and posterior fossa malformations[21, 22, 23] in early pregnancy. Also, different indicators have been explored for early suspicion of ventriculomegaly[24,25], which was always defined as an atrial diameter ≥10mm in the second trimester. Considering the gall bladder is usually seen in about 50% of fetuses by the 13th week of gestation and practically in all fetuses by the 14th week of gestation[26], attempts to evaluate the gall bladder as potential clues of CBA in early pregnancy worth trying, too. We found that the fetal kidneys are more readily visible on a coronal plane (figure 7) rather than on the transverse plane, especially when the gain of the ultrasound instrument was increased. However, finding the multicystic dysplastic kidney (MCDK) in the first trimester was still not possible. A similar situation was also found in recent studies[10, 12]. The diagnosis of pelvic kidney in early pregnancy is mainly impossible due to the small size of the kidney and the similarity of the echogenicity to the surrounding tissues. Evaluation of the urinary tract is difficult because the signs, such as the manifestations of cystic accumulation of fluid and decreased amniotic fluid volume, are not apparent in early pregnancy. In addition, the hydronephrosis and obstructive renal dysplasia found in our study were a gradual progression during the prenatal stage.
Twenty four cases with deformities missed diagnosis prenatally, covering several systems: the face (ear abnormalities), the heart(VSD and ASD), the genitourinary system (hypospadias and ambiguous genitalia), and the limbs and skeleton system (polydactyly, syndactyly, abnormalities of hand and foot joint, and hip dysplasia), as well as one case with multiple defects (coarctation of the aorta、pelvic kidney) and one case diagnosed Pierre Robin syndrome (PRS). Overall, none of these deformities were fatal, and most of the deformities can be surgically corrected with the exception of the case diagnosed Pierre Robin syndrome. Our review of the early images of this case revealed that we had missed the small mandible, a vital sign suggestive of PRS.
Four cases diagnosed VSD by FTS were proved to be normal in later pregnancy. There were two possibilities: the VSD did exist in the first trimester. However, the ventricle septum became intact in later pregnancy; the VSD was indeed misdiagnosed. Considering that the heart is tiny during early pregnancy, the artifacts of two-dimensional and color images, and the influence of fetal position, the diagnosis of VSD in early pregnancy should be cautious.
Relationship between fetal structural abnormalities and increased NT
It was known that increased NT is referred to NT thickness equal to or above the 95th percentile, and is related to a high risk of aneuploidies, including trisomy 13, 18, and 21 as well as triploidy or Turner syndrome[27-29], which were always associated with structural defects. Even in chromosomally normal fetuses, thickened NT can also be strongly associated with other fetal structural defects, particularly of the cardiovascular, gastrointestinal, or musculoskeletal systems, and a detailed anatomical assessment should be undertaken[30,31]. In our study, among the 452 fetuses with thickened NT, 48 (48/452 10.6%) showed structural malformations. The incidence of structural malformations is significantly higher in fetuses with thickened NT (10.6%) than those with normal NT (71/6924, 1.0%) (P< 0.01). Except for hygroma, which can also be considered as a type of NT thickening, congenital heart defects (CHD) had the highest incidence of NT thickening (14/35, 40%), followed by limbs and skeleton defects (5/13, 38.5%), central nervous system defects (2/6, 33.3%), and fetal syndromes (2/6, 33.3%). Multiple defects showed an even higher incidence of 58.5% (7/12). So increased NT could be a clue for further screening for structural malformations, and it may direct where to focus.
Several limitations of this study should also be highlighted. Firstly, this was a retrospective study with a moderate sample size. Secondly, all examinations were performed transabdominally instead of the combined use of transvaginal and transabdominal ultrasound, which may lead to a higher detection rate. In addition, a large proportion of pregnant women with fetal malformations underwent fetal genetic testing, and the relationship between malformations and genetics results may be studied in our further study.