The 11-14 weeks scan - KH Nicolaides, NJ Sebire, RJM Snijders, AP Souka

Chapter 2

SECOND TRIMESTER ULTRASONOGRAPHY

In the second trimester scan, as in the first trimester, each chromosomal defect has its own syndromal pattern of detectable abnormalities (Table 1) (Snijders and Nicolaides 1996, Nicolaides et al 1992). It is therefore recommended that, when a defect/marker is detected at routine ultrasound examination, a thorough check is made for the other features of the chromosomal abnormality known to be associated with that marker; should additional defects be identified, the risk is dramatically increased. In the case of apparently isolated defects, the decision of whether to carry out an invasive test depends on the type of defect.

Table 1. Common chromosomal abnormalities in fetuses with sonographic defects

Second trimester scan: phenotypic expression of chromosomal defects

• Trisomy 21 is associated with nasal hypoplasia, increased nuchal fold thickness, cardiac defects, intracardiac echogenic foci, duodenal atresia and echogenic bowel, mild hydronephrosis, shortening of the femur and more so of the humerus, sandal gap and clinodactyly or mid-phalanx hypoplasia of the fifth finger.
• Trisomy 18 is associated with strawberry-shaped head, choroid plexus cysts, absent corpus callosum, enlarged cisterna magna, facial cleft, micrognathia, nuchal edema, heart defects, diaphragmatic hernia, esophageal atresia, exomphalos, usually with bowel only in the sac, single umbilical artery, renal defects, echogenic bowel, myelomeningocoele, growth restriction and shortening of the limbs, radial aplasia, overlapping fingers and talipes or rocker bottom feet.
• Trisomy 13 is associated with holoprosencephaly, microcephaly, facial abnormalities, cardiac and renal abnormalities with often enlarged and echogenic kidneys, exomphalos and post axial polydactyly.
• Triploidy where the extra set of chromosomes is paternally derived is associated with a molar placenta and the pregnancy rarely persists beyond 20 weeks. When there is a double maternal chromosome contribution, the pregnancy may persist into the third trimester. The placenta is of normal consistency but thin and the fetus demonstrates severe asymmetrical growth restriction. Commonly there is mild ventriculomegaly, micrognathia, cardiac abnormalities, myelomeningocoele, syndactyly, and 'hitch-hiker' toe deformity.
• Turner syndrome is associated with large nuchal cystic hygromas, generalised edema, mild pleural effusions and ascites, cardiac abnormalities and horseshoe kidneys, which are suspected by the ultrasonographic appearance of bilateral mild hydronephrosis.
  

Ventriculomegaly

The birth prevalence of ventriculomegaly is about 1 per 1,000. Causes include chromosomal and genetic defects, intrauterine haemorrhage or infection but in many cases no clear-cut aetiology is identified. The overall prevalence of chromosomal defects in fetal ventriculomegaly is about 10% and the commonest chromosomal defects are trisomies 21, 18, 13 and triploidy. The prevalence of chromosomal defects is higher in those with mild to moderate, rather than severe ventriculomegaly.

Holoprosencephaly

The birth prevalence of holoprosencephaly is about 1 per 10,000. Although in many cases the cause is a chromosomal defect or a genetic disorder in the majority of cases the etiology is unknown. The overall prevalence of chromosomal defects in fetal holoprosencephaly is about 30% and the commonest chromosomal defects are trisomies 13 and 18. Holoprosencephaly is commonly associated with a wide variety of mid-facial abnormalities but the incidence of chromosomal defects in only increased in fetuses with holoprosencephaly and extrafacial defects but not in those where the holoprosencephaly is either isolated or it is associated with facial abnormalities only.

Choroid plexus cysts

These are found in approximately 2% of fetuses at 16-24 weeks of gestation but in more than 95% of cases they resolve by 28 weeks and are of no pathological significance. There is an association between choroid plexus cysts and chromosomal defects, particularly trisomy 18. However, the vast majority of fetuses with trisomy 18 have multiple other defects and therefore, the detection of fetal choroid plexus cysts should stimulate the sonographer to search for the other features of trisomy 18. If the cysts are apparently isolated the risk for trisomy 18 is only marginally increased.

Dandy-Walker complex

This refers to a spectrum of abnormalities of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the cisterna magna. The condition is classified into Dandy-Walker malformation (complete or partial agenesis of the cerebellar vermis and enlarged posterior fossa), Dandy-Walker variant (partial agenesis of the cerebellar vermis without enlargement of the posterior fossa and mega-cisterna magna (normal vermis and fourth ventricle). The birth prevalence of Dandy-Walker malformation is about 1 per 30,000. Causes include chromosomal defects, more than 50 genetic syndromes, congenital infection or teratogens such as warfarin, but it can also be an isolated finding. The overall prevalence of chromosomal defects is about 40%, usually trisomies 18 or 13 and triploidy.

Facial cleft

Cleft lip and/or palate is found in approximately 1 per 800 live births, and both genetic and environmental factors are implicated in their causation. Postnatally, chromosomal defects are found in less than 1% of babies with facial cleft. However, in prenatal series the prevalence is about 40%, most commonly trisomies 13 and 18. This apparent discrepancy is because in the prenatal studies the populations examined are pre-selected and include many fetuses with multiple other defects.

Micrognathia

The birth prevalence of micrognathia is about 1 per 1,000. This is a non-specific finding in a wide range of genetic syndromes and chromosomal defects, mainly trisomy 18 and triploidy. In two studies reporting on fetal micrognathia the prevalence of chromosomal defects was about 60% but all fetuses had additional malformations and/or growth restriction.

Nasal hypoplasia

Sonographic studies at 15-24 weeks of gestation reported that about 65% of trisomy 21 fetuses have nasal bone hypoplasia, defined by a nasal bone that is not visible or with a length of less than 2.5 mm Sonek and Nicolaides 2002, Cicero et al 2003). In chromosomally normal fetuses, the prevalence of nasal hypoplasia is related to the ethnic origin of the mothers, being less than 1% in Caucasians and up to 10% in African-Caribbeans. It is premature to speculate on the precise detection rates that could be achieved in the second trimester by a combination of maternal age, serum biochemistry and ultrasound examination for the fetal nasal bone and other sonographic markers. Nevertheless, on the basis of currently available data, nasal hypoplasia is likely to be the single most sensitive and specific second trimester marker of trisomy 21.

Diaphragmatic hernia

The birth prevalence of diaphragmatic hernia is about 1 per 3,000 and the condition is usually sporadic. The prevalence of chromosomal defects, mainly trisomy 18, is about 20%.

Cardiac abnormalities

Abnormalities of the heart and great arteries are found in 4-7 per 1,000 live births and in about 30 per 1,000 stillbirths. The etiology of heart defects is heterogeneous and probably depends on the interplay of multiple genetic and environmental factors. Heart defects are found in more than 90% of fetuses with trisomy 18 or 13, 50% of those with trisomy 21, and 40% of those with Turner syndrome, deletions or partial trisomies involving a variety of chromosomes. Prenatal studies of ultrasonographically detectable fetal cardiac abnormalities, have reported chromosomal defects in about 25% of cases. The commonest defects were trisomies 21, 18, 13 and Turner syndrome.

Exomphalos

The birth prevalence of exomphalos is about 1 in 4,000. The condition is usually sporadic but in some cases there may be an associated genetic syndrome. Chromosomal defects, mainly trisomies 18 and 13, are found in about 30% of cases at mid-gestation and in 15% of neonates. The prevalence of chromosomal abnormalities is four-times higher when the exomphalos sac contains only bowel than in cases where the liver is included.

Esophageal atresia

The birth prevalence of esophageal atresia is about 1 in 3,000. In 90% of cases there is an associated tracheoesophageal fistula. The condition is sporadic. Chromosomal defects are found in 3-4% of affected neonates. Prenatally, chromosomal defects, mainly trisomy 18, are found in about 20% of cases.

Duodenal atresia

The birth prevalence of duodenal atresia or stenosis is about 1 in 5,000. In most cases the condition is sporadic, although in some cases there is an autosomal recessive pattern of inheritance. Trisomy 21 is found in about 40% of cases.

Urinary tract abnormalities

Prenatal studies have established that urinary tract defects are commonly found in many chromosomal defects. The risk for chromosomal defects is similar for fetuses with unilateral or bilateral involvement, different types of renal abnormalities, urethral or ureteric obstruction, and oligohydramnios or normal/reduced amniotic fluid volume. However, the prevalence of chromosomal defects in females is double that in males. The pattern of chromosomal defects, and consequently that of associated malformations, is related to the different types of renal abnormalities. Thus, in mild hydronephrosis, the commonest chromosomal defect is trisomy 21, whereas in moderate/severe hydronephrosis, multicystic kidneys, or renal agenesis the commonest defects are trisomies 18 and 13.

Abnormalities of extremities

Trisomies 21, 18, triploidy and Turner syndrome are associated with relative shortening of the long bones. Syndactyly is associated with triploidy, clinodactyly and sandal gap with trisomy 21, polydactyly with trisomy 13, overlapping fingers, rocker bottom feet and talipes with trisomy 18.

Fetal growth restriction

Low birth weight is a common feature of many chromosomal defects, but the prevalence of chromosomal defects in small for gestational age neonates is only about 1%. However, data derived from postnatal studies underestimate the association between chromosomal defects and growth restriction, since many pregnancies with chromosomally abnormal fetuses result in spontaneous abortion or intrauterine death. The commonest chromosomal defects associated with growth restriction are triploidy and trisomy 18. The highest prevalence of chromosomal defects is found in those cases where in addition to the growth restriction there are fetal structural abnormalities, the amniotic fluid volume is normal or increased and in the group with normal Doppler flow velocity waveforms from both uterine and umbilical arteries. Therefore, growth restriction due to chromosomal defects presents differently from growth restriction due to placental insufficiency, which is characterized by reduced amniotic fluid volume and increased impedance to flow in the uterine and/or umbilical arteries with redistribution in the fetal circulation.

Major defects

If the second trimester scan demonstrates major defects, it is advisable to offer fetal karyotyping, even if these defects are apparently isolated. The prevalence of such defects is low and therefore the cost implications are small. If the defects are either lethal or they are associated with severe handicap, such as holoprosencephaly, fetal karyotyping constitutes one of a series of investigations to determine the possible cause and thus the risk of recurrence. If the defect is potentially correctable by intrauterine or postnatal surgery, such as diaphragmatic hernia, it may be logical to exclude an underlying chromosomal abnormality – especially because, for many of these conditions, the usual abnormality is trisomy 18 or 13.

Minor defects or soft markers

Minor fetal defects or soft markers are common and they are not usually associated with any handicap, unless there is an underlying chromosomal abnormality. Routine karyotyping of all pregnancies with these markers would have major implications, both in terms of miscarriage and in economic costs. It is best to base counseling on an individual estimated risk for a chromosomal abnormality, rather than the arbitrary advice that invasive testing is recommended because the risk is ‘high’. The estimated risk can be derived by multiplying the a priori risk (based on maternal age, gestational age, history of previously affected pregnancies and, where appropriate, the results of previous screening by NT and/or biochemistry in the current pregnancy) by the likelihood ratio of the specific defect.

The best estimates of both the positive and negative likelihood ratios for each of the common markers of trisomy 21 are given in Table 10 (Nyberg et al 2001; Bromley et al 2002, Nicolaides 2003). Major or minor defects are found in about 75% of fetuses with trisomy 21 and in 10-15% of chromosomally normal fetuses. On the basis of these data the likelihood ratio for trisomy 21 if there is no detectable defect or marker is 0.30. In each case the likelihood ratio is derived by dividing the incidence of a given marker in trisomy 21 pregnancies by its incidence in chromosomally normal pregnancies. For example, an intracardiac echogenic focus is found in 28.2% of trisomy 21 fetuses and in 4.4% chromosomally normal fetuses, resulting in a positive likelihood ratio of 6.41 (28.2 / 4.4) and a negative likelihood ratio of 0.75 (71.8 / 95.6). Consequently, the finding of an echogenic focus increases the background risk by a factor of 6.41, but at the same time absence of this marker should reduce the risk by 25%.

The same logic applies to each one of the six markers in Table 2. Thus, in a 25 year old woman undergoing an ultrasound scan at 20 weeks of gestation the a priori risk is about 1 in 1,000. If the scan demonstrates an intracardiac echogenic focus, but the nuchal fold is not increased, the humerus and femur are not short and there is no hydronephrosis, hyperechogenic bowel or major defect, the combined likelihood ratio should be 1.1 (6.41x0.67x0.68x0.62x0.85x0.87x0.79) and consequently her risk remains at about 1 in 1,000. The same is true if the only abnormal finding is mild hydronephrosis (likelihood ratio of 1). In contrast, if the fetus is found to have both an intracardiac echogenic focus and mild hydronephrosis but no other defects the combined likelihood ratio should be 8.42 (6.41x6.77x0.67x0.68x0.62x0.87x0.79) and consequently the risk is increased from 1 in 1,000 to 1 in 119.

There are no data on the interrelation between these second-trimester ultrasound markers and fetal NT or maternal serum free β-hCG or PAPP-A at 11–14 weeks. However, there is no obvious physiological reason for such an interrelation and it is therefore reasonable to assume that they are independent. Consequently, in estimating the risk in a pregnancy with a marker, it is logical to take into account the results of previous screening tests. For example, in a 32-year-old woman at 20 weeks of gestation (background risk of 1 in 507), who had an 11–14 week assessment by NT measurement that resulted in a 7-fold reduction in risk (to 1 in 3,549), after the diagnosis of isolated echogenic bowel at the 20-week scan, the estimated risk would increase by a factor of three to 1 in 1,183. However, for the same ultrasound finding in the absence of prior NT screening the risk would increase from 1 in 507 to 1 in 169.

There are some exceptions to this process of sequential screening, which assumes independence between the findings of different screening results. The findings of nuchal edema or a cardiac defect at the mid-trimester scan cannot be considered independently of NT screening at 11–14 weeks.

Table 2. Incidence of major and minor defects or markers in the second trimester scan in trisomy 21 and chromosomally normal fetuses in the combined data of two major series. From these data the positive and negative likelihood ratios (with 95% confidence interval) for each marker can be calculated. In the last column is the likelihood ratio for each marker found in isolation.

LR = Likelihood ratio