Early detection of fetal abnormalities, especially chromosomal abnormalities, is an important step in controlling the quality of the birth population and achieving early treatment of fetal abnormalities. Ultrasonography, with its advantages of being noninvasive, reproducible, and reliable results, has become the most common means of screening for fetal anomalies. In addition to observing some visual anomalies such as cleft lip, hand and foot deformities, and anomalies caused by abnormal development of various systems, obstetric ultrasonography can also detect some phenomena that are considered to be normal variants. These sonographic manifestations are different from the normal fetal anatomy, but are not related to fetal growth retardation which increases the risk of perinatal or genetic disorders, but fetuses with these sonographic manifestations have an increased risk of haploinsufficiency. These ultrasound findings are known as “soft markers” of the fetus. The Canadian Maternity Association’s clinical practice guidelines of June 2005 state that every pregnant woman should receive a routine ultrasound examination at 16-20 weeks of gestation. In addition to the usual measurements, 8 soft fetal markers should be observed on obstetric ultrasound at 16-20 weeks of gestation. 5 of these (dorsal neck fold thickness, intestinal echogenicity, mild ventricular dilatation, focal intracardiac hyper-echogenicity and choroid plexus cyst) are associated with fetal haploinsufficiency and in some cases non-chromosomal abnormalities. The other 3 (single umbilical artery, enlarged Magna’s pouch and dilated renal pelvis) are often associated with non-chromosomal anomalies when present alone.
Ultrasonographic methods of fetal soft markers and their relationship with fetal haploid and non-chromosomal abnormalities are as follows.
1. thickness of the dorsal cervical fold (thickened nuchal fold).
Definition: The thickness of the nuchal fold is the thickness of the skin at the back of the fetal neck.
Measurement method: transverse section of the fetal head, showing the hyaline septum and posterior thalamus, the probe is angled backward to clearly show the cerebellum, and the distance between the lateral edge of the skull and the lateral edge of the skin is measured at the midline level.
The thickness of the dorsal cervical fold varies with the week of gestation. The accepted standard is greater than 5 mm at 16-18 weeks of gestation and more than 6 mm at 18-24 weeks of gestation. Dorsal cervical fold thickness measurement should not be confused with cervical hyaline layer thickness measurement, which is the measurement of the posterior fluid portion of the fetal neck at 11 to 14 weeks of gestation. A thickened dorsal cervical fold should be differentiated from a dorsal cervical hydrocystic tumor.
Association with fetal haploid anomalies: A dorsal neck fold greater than 6 mm in thickness is associated with a 17-fold increased risk of fetal Down’s syndrome compared to a normal fetus.
Association with fetal non-chromosomal anomalies: dorsal neck fold thickness is associated with monogenic anomalies such as Noonan syndrome, multiple pterygium syndrome, skeletal dysplasia and cardiac malformations. Isolated thickening of the nuchal dorsal fold suggests an increased risk of fetal haploinsufficiency and should be referred for fetal karyotype analysis. For fetuses of different gestational ages, the nuchal dorsal fold thickness index can be used, which is calculated as (nuchal dorsal fold thickness/biparietal diameter)′100 %. The sensitivity of fetal abnormalities is 50% and the specificity is 96% when the dorsal neck fold thickness index is >11.
2.Echogenic bowel definition: a homogeneous strong echogenic area of the fetal intestine with an echogenic intensity equal to or greater than the surrounding skeletal echo.
Examination method: Use £ 5MHz probe to scan, when considering intestinal echo enhancement, turn down the gain of the instrument and carefully compare with the surrounding skeletal echo to reduce false positives. Intestinal echo enhancement can be classified as focal or multifocal. Compared with the surrounding skeletal echo, its echo intensity can be classified into 3 levels: level 1 is weaker than the skeletal echo; level 2 is equal to the surrounding skeletal echo, and level 3: greater than the surrounding skeletal echo.
Relationship with fetal haploinsufficiency abnormalities: those with enhanced intestinal echo have an increased risk of trisomy 13, 18, 21 and sex chromosome abnormalities. In fetuses at 13-28 gestational weeks, the detection rate of enhanced intestinal canal echo is 0.6-2.4%. Echo enhancement of the intestinal canal alone is found in 9% of fetuses with haploid abnormalities.
The risk of cystic fibrosis, congenital infection, intra-amniotic hemorrhage, congenital intestinal malformation and other perinatal complications such as intrauterine growth retardation is increased in fetuses with enhanced intestinal echogenicity, with the incidence of cystic fibrosis being approximately 2%. The most common cause of enhanced gut echo is fetal infection (cytomegalovirus, herpes virus, small cell virus, rubella virus, varicella virus, and toxoplasmosis virus). The next most common causes are intra-amniotic hemorrhage (often due to amniotic intervention or placental rupture) and congenital intestinal malformations, especially upper gastrointestinal malformations. Fetal ascites and dilatation of the intestinal canal are often seen with echogenic enhancement of the intestinal canal. The fetal intestinal canal should be examined for other anatomical structures, growth, placental position and fetal chromosomes, and fetal DNA should be checked when available.
3.Definition of mild ventriculomegaly: the ventricle diameter is 10mm-15mm.
Normal value: The normal value of fetal ventricular diameter is 7.6±0.6mm.
Measurement method: measured at the level of the thalamic nucleus in the transverse cranial section, slightly below the standard section for measuring the biparietal diameter. The measuring scale is placed at the edge of the intraventricular space, perpendicular to the long axis of the ventricle, near the posterior edge of the choroid plexus. Far-field ventricles should be measured to avoid near-field artifacts.
Relationship to fetal haploinsufficiency: When mild ventricular dilatation is present alone, the incidence of fetal haploinsufficiency is approximately 3.8%. In fetuses with trisomy 21, unilateral mild ventricular dilatation is detected on ultrasound at 16-20 weeks of gestation in about 1.4% of cases.
The relationship with fetal non-chromosomal abnormalities: ventricular dilatation is the most common ultrasound abnormality in fetal neurological anomalies. It can be due to cerebral hypoplasia or degeneration, vascular anomalies or obstruction of the ventricular system. Between 10% and 36% of children diagnosed with ventricular dilatation before birth have neurological developmental abnormalities. In chromosomally normal fetuses, approximately 0.15% have unilateral mild ventricular dilatation. The prognosis is better for unilateral simple ventricular dilatation.
When mild ventricular dilatation is detected, the fetus should be examined for congenital infection and amniocentesis for fetal karyotype. Ultrasound should also be performed to examine other fetal structures, including the heart. Since some neurological abnormalities are potential, the fetus with mild ventricular dilatation should be followed up after birth to rule out related abnormalities.
4.Echogenic intracardiac focus EICF (intracardiac strong echo)
Definition: Focal echogenic area of enhanced echogenicity in the papillary muscle of the fetal ventricle, with an echogenic intensity similar to that of the skeletal echo. It may occur in one or both ventricles.
Methods: The scan is usually performed with a standard four-chamber heart view, with a probe frequency of less than 5 HMz and appropriate gain reduction. Compared to the surrounding bone tissue, the intracardiac focal strong echoes can be classified into three levels: primary, lower than the bone tissue echoes; secondary, equal to the bone tissue echoes; and tertiary, stronger than the bone tissue echoes.
The relationship with fetal haploid abnormalities: single focal strong echoes in the left ventricle are more common, and the likelihood of fetal haploid abnormalities is only 0-1.8, while multiple or significant focal strong echoes in the right ventricle and both ventricles have an increased risk of fetal haploid abnormalities, and fetal chromosome histotyping should be performed when available.
The relationship with fetal non-chromosomal anomalies: intracardiac focal strong echoes are not associated with fetal congenital cardiac anomalies and other non-chromosomal anomalies. It is more frequently seen in Asians than in centenarians. If only focal intracardiac echoes are found and there are no other positive findings, they should be recorded in the ultrasound report and no further investigations (e.g. echocardiography) are necessary. The incidence of chromosomal abnormalities in fetuses with focal intracardiac echogenicity is about 1/600 when the maternal age is older than 31 years.
5, choroid plexus cysts (choroid plexus cysts) definition: choroid plexus cysts are small, scattered cysts greater than 3 mm in diameter found by ultrasonography in the lateral ventricular choroid plexus in developing fetuses at 14-24 weeks of gestational age.
Measurement: measured at the level of the lateral ventricle in the transverse section of the fetal head. During the examination, attention should be paid to the observation of the bilateral choroid plexus and to the need to exclude ultrasound artifacts in the observation of near-field choroid plexus cysts in the ventricles.
Relationship to fetal haploinsufficiency: choroid plexus cysts occur in 1% of mid-pregnancy fetuses. The incidence is 50% in fetuses with trisomy 18. 10% of fetuses with trisomy 18 have choroid plexus cysts as the only ultrasound abnormality, but the size, distribution and number of cysts are not related to the risk of trisomy 18. An increased risk of trisomy 21 has also been reported in fetuses with choroid plexus cysts.
The relationship with fetal non-chromosomal abnormalities: In chromosomally normal fetuses, choroid plexus cysts are not associated with other fetal malformations and postnatal development.
6, single umbilical artery (single umbilicalartery) definition: there is only one umbilical artery in the fetal umbilical cord and around the bladder, and the other umbilical artery is absent.
Examination method: Umbilical artery can be observed in longitudinal or transverse section of the umbilical cord, where the umbilical artery enters the fetal abdominal wall, or on both sides of the bladder where the umbilical artery originates from the iliac vessels.
Relationship with fetal haploinsufficiency anomalies: Simple single umbilical artery is not associated with fetal haploinsufficiency anomalies.
Association with fetal non-chromosomal anomalies: associated with fetal renal dysplasia, cardiac malformations and low birth weight. When a fetus is found to have a single umbilical artery, other anatomical structures should be carefully examined, ultrasonically evaluated and followed up to observe fetal growth and development. Combined malformations or soft indicators of chromosomal anomalies should be seen and fetal chromosomal examination should be done.
7.Magna sac enlargement (enlarged cisterna magna).
Definition: The distance between the cerebellar pool and the anterior-posterior diameter of the medial aspect of the skull is measured at an angle of 15 degrees from the caudal end of the transverse section of the fetal head probe to the midline of the brain, and when the anterior-posterior diameter is greater than 10 mm, the bursa magna is enlarged.
(Measurement method: take a transverse section of the fetal head, the caudal end of the probe to the posterior cranial midline at an angle of 15 degrees, and measure the distance between the cerebellar pool and the anterior-posterior distance before the medial skull). In normal fetuses, the measurement value is 5 mm ± 3 mm, but it should be noted that when the sound beam is further angled towards the posterior cranial concavity or in long head shape, the measurement value is often large and false positives occur.
The association of Magna bursa enlargement with fetal haploid abnormalities, especially trisomy 18, has been reported. The association with haploid abnormalities is greatest especially when the lateral ventricles are not dilated but other abnormalities are present. Isolated Magna bursa enlargement is not strongly associated with chromosomal abnormalities. There are no prospective, large sample studies available on the significance of this marker.
Association with fetal non-chromosomal anomalies: Magna bursa enlargement is commonly associated with other anatomical anomalies (arachnoid cysts, Dandy Walker malformations and Dandy Walker variants) or syndromes (e.g. oro-facial-digital syndrome, Mecker-Gruber syndrome and DiGeorge syndrome). In the presence of an enlarged Magna bursa, the rest of the fetus should be carefully examined to exclude other abnormalities or intrauterine growth retardation or abnormal amniotic fluid volume. The fetal chromosome histotype is not necessary if the Magna sac is enlarged and no other abnormalities coexist, but can be followed up by ultrasound or other imaging methods (e.g. MRI). Vergani found that the incidence of fetuses with trisomy 21 was 18.2%, compared with only 2% in the normal group, based on the criterion of ≥4mm between 14 and 22 weeks of gestation.
Measurement: The maximum anteroposterior diameter is measured in a transverse section at the level of the fetal renal pelvis. The normal measurement is <5 mm.
Association with fetal haploinsufficiency abnormalities: In fetuses at 16-26 weeks of gestation, the incidence of unilateral renal pelvis dilatation is found to be approximately 0.7%. In fetuses with Down’s syndrome, ultrasonography reveals only mild renal pelvis dilatation in 2% of cases.
Association with fetal non-chromosomal abnormalities: In fetuses without other positive signs, the risk of Down’s syndrome is 1.5 times higher in fetuses with mild pelvic dilatation alone than in those with pre-existing levels. If the dilated renal pelvis is >10 mm in diameter, congenital hydronephrosis should be considered and should be followed up for observation. >5 mm should be followed until late gestation and neonatal renal ultrasound should be performed if necessary. In low-risk pregnancies, the incidence of unilateral mild renal pelvis dilatation fetal haploinsufficiency is low, but congenital hydronephrosis should be followed up with ultrasound because of the high incidence of congenital hydronephrosis.
Other.
Subclavian artery vagal: 25 times the risk rate of trisomy 21 compared to the original level.
Femoral shortening: risk rate of trisomy 21 is 2.5 times the original level.
Positive fetal ultrasound soft markers are helpful in screening out fetuses with haploid abnormalities and non-chromosomal abnormalities at high risk for further clinical examination or follow-up observation for early detection of fetal abnormalities. The test is simple and easy to perform, and can be performed with a 2D grayscale ultrasound machine with good resolution and a well-trained ultrasonographer. However, this test is not yet common in obstetric ultrasound in China.