Features of chromosomal defects
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Features of chromosomal defects
The commonest chromosomal defects are trisomies 21, 18 or 13, Turner syndrome (45,X), 47,XXX, 47,XXY, 47,XYY and triploidy. In the first trimester, a common feature of many chromosomal defects is increased nuchal translucency thickness. In later pregnancy, each chromosomal defect has its own syndromal pattern of abnormalities.
Trisomy 21
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Trisomy 21 is associated with a tendency towards brachycephaly, mild ventriculomegaly, flattening of the face, nuchal edema, atrioventricular septal defects, duodenal atresia and echogenic bowel, mild hydronephrosis, shortening of the limbs, sandal gap and clinodactyly or mid-phalanx hypoplasia of the fifth finger.
Trisomy 18
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Trisomy 18 is associated with strawberry-shaped head, choroid plexus cysts, absent corpus callosum, Dandy–Walker complex, facial cleft, micrognathia, nuchal edema, heart defects, diaphragmatic hernia, esophageal atresia, exomphalos, renal defects, myelomeningocele, growth retardation and shortening of the limbs, radial aplasia, overlapping fingers and talipes or rocker bottom feet.
Trisomy 13
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In trisomy 13, common defects include holoprosencephaly and associated facial abnormalities, microcephaly, cardiac and renal abnormalities (often enlarged and echogenic kidneys), exomphalos and postaxial polydactyly.
Triploidy
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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 and the fetus demonstrates severe asymmetrical growth retardation. Commonly, there is mild ventriculomegaly, micrognathia, cardiac abnormalities, myelomeningocoele, syndactyly, and ‘hitch-hiker’ toe deformity.
Turner syndrome
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There are two types of this syndrome, the lethal and non-lethal types. The rate of intrauterine lethality between 12 and 40 weeks is about 75%. The lethal type of Turner syndrome presents with large nuchal cystic hygromata, generalized edema, mild pleural effusions and ascites, and cardiac abnormalities. The non-lethal type usually does not demonstrate any ultrasonographic abnormalities.
Sex chromosome abnormalities
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The main sex chromosome abnormalities, other than Turner syndrome, are 47,XXX, 47,XXY and 47,XYY. These are not associated with an increased prevalence of sonographically detectable defects.
RISK FOR CHROMOSOMAL DEFECTS
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Number of defects
Ultrasound studies have demonstrated that major chromosomal defects are often associated with multiple fetal abnormalities. The overall risk for chromosomal defects increases with the total number of abnormalities that are identified. It is therefore recommended that, when an abnormality/marker is detected at routine ultrasound examination, a thorough check is made for the other features of the chromosomal defect(s) known to be associated with that marker; should additional abnormalities be identified, the risk is dramatically increased.
Incidence of chromosomal defects in relation to number of sonographically detected abnormalities
(Nicolaides et al., Lancet 1992;340:704–7)
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Abnormalities
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n
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Chromosomal defects
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1
2
3
4
5
6
7
³ 8
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1128
490
220
115
53
40
16
24
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2%
11%
32%
52%
66%
63%
69%
92%
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Major defects
If the 18–23-week scan demonstrates major defects, it is advisable to offer fetal karyotyping even if these defects are apparently isolated. The prevalence of these defects is low and therefore the cost implications are small. If the defects are either lethal or they are associated with severe handicap, fetal karyotyping constitutes one of a series of investigations to determine the possible cause and therefore the risk of recurrence. Examples of these defects include hydrocephalus, holoprosencephaly, multicystic renal dysplasia and severe hydrops. In the case of isolated neural tube defects, there is controversy as to whether the risk for chromosomal defects is increased. Similarly, for skeletal dysplasias where the likely diagnosis is obvious by ultrasonography, it would probably be unnecessary to perform karyotyping. If the defect is potentially correctable by intrauterine or postnatal surgery, 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. Examples include facial cleft, diaphragmatic hernia, esophageal atresia, exomphalos and many of the cardiac defects. In the case of isolated gastroschisis or small bowel obstruction, there is no evidence of increased risk of trisomies.
Minor defects or markers
For apparently isolated abnormalities, there are large differences in the reported incidence of associated chromosomal defects. It is therefore uncertain whether, in such cases, karyotyping should be undertaken, especially for those abnormalities that have a high prevalence in the general population and for which the prognosis in the absence of a chromosomal defect is good. Since the incidence of chromosomal defects is associated with maternal age, it is possible that the wide range of results reported in the various studies is the mere consequence of differences in the maternal age distribution of the populations examined. In addition, since chromosomal abnormalities are associated with a high rate of intrauterine death, differences may arise from the fact that studies were undertaken at different stages of pregnancy. For example, to determine whether apparently isolated choroid plexus cysts at 20 weeks of gestation are associated with an increased risk for trisomy 18, it is essential to know the incidence of trisomy 18 at 20 weeks, based on the maternal age distribution of the population that is examined. Therefore, we propose that, in the calculation of risks for chromosomal defects, it is necessary to take into account ultrasound findings as well as the maternal age and the gestational age at the time of the scan .
Association with maternal age and gestation
The risk for trisomies increases with maternal age and decreases with gestation; the rate of intrauterine lethality between 12 weeks and 40 weeks is about 30% for trisomy 21, and 80% for trisomies 18 and 13.
Risk of trisomy 21
(Snijders et al. Ultrasound Obstet Gynecol 1999;13:167–70)
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Maternal age (years)
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Gestational age
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10 weeks
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12 weeks
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14 weeks
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16 weeks
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20 weeks
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40 weeks
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20
25
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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1/983
1/870
1/576
1/500
1/424
1/352
1/287
1/229
1/180
1/140
1/108
1/82
1/62
1/47
1/35
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Turner syndrome is usually due to loss of the paternal X chromosome and, consequently, the frequency of conception of 45,X embryos, unlike that of trisomies, is unrelated to maternal age. The prevalence is about 1 per 1500 at 12 weeks, 1 per 3000 at 20 weeks and 1 per 4000 at 40 weeks. For the other sex chromosome abnormalities (47,XXX, 47,XXY and 47,XYY), there is no significant change with maternal age and, since the rate of intrauterine lethality is not higher than in chromosomally normal fetuses, the overall prevalence (about 1 per 500) does not decrease with gestation. Polyploidy affects about 2% of recognized conceptions but it is highly lethal and it is very rarely observed in live births; the prevalence at 12 and 20 weeks is about 1 per 2000 and 1 per 250 000, respectively.
Type of defect
If there are minor defects, the risk for trisomy 21 is calculated by multiplying the background (maternal age- and gestation-related risk) by a factor depending on the specific defect. For the following conditions, there are sufficient data in the literature to estimate the risk factors.
Type of defect
If there are minor defects, the risk for trisomy 21 is calculated by multiplying the background (maternal age- and gestation-related risk) by a factor depending on the specific defect. For the following conditions, there are sufficient data in the literature to estimate the risk factors.
Nuchal edema or fold more than 6 mm
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Hyperechogenic bowel
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This is the second-trimester form of nuchal translucency. It is found in about 0.5% of fetuses and it may be of no pathological significance. However, it is sometimes associated with chromosomal defects, cardiac anomalies, infection or genetic syndromes. For isolated nuchal edema, the risk for trisomy 21 may be ten-times the background risk.
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This is found in about 0.5% of fetuses and is usually of no pathological significance. The commonest cause is intra-amniotic bleeding, but occasionally it may be a marker of cystic fibrosis or chromosomal defects. For isolated hyperechogenic bowel, the risk for trisomy 21 may be seven-times the background risk.
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Short femur
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Echogenic foci in the heart
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If the femur is below the 5th centile and all other measurements are normal, the baby is likely to be normal but rather short. Rarely, this is a sign of dwarfism. Occasionally, it may be a marker of chromosomal defects. On the basis of existing studies, short femur is found four-times as commonly in trisomy 21 fetuses compared to normal fetuses. However, there is some evidence that isolated short femur may not be more common in trisomic than normal fetuses.
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These are found in about 4% of pregnancies and they are usually of no pathological significance. However, they are sometimes associated with cardiac defects and chromosomal abnormalities. For isolated hyperechogenic foci, the risk for trisomy 21 may be three-times the background risk.
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Choroid plexus cysts
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Mild hydronephrosis
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These are found in about 1–2% of pregnancies and they are usually of no pathological significance. When other defects are present, there is a high risk of chromosomal defects, usually trisomy 18 but occasionally trisomy 21. For isolated choroid plexus cysts, the risk for trisomy 18 and trisomy 21 is 1.5-times the background risk.
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This is found in about 1–2% of pregnancies and is usually of no pathological significance. When other abnormalities are present, there is a high risk of chromosomal defects, usually trisomy 21. For isolated mild hydronephrosis, the risk for trisomy 21 is 1.5-times the background risk.
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Examination of cerebral ventricles, choroid plexuses, mid-brain, posterior fossa (cerebellum and cisterna magna), and measurement of the anterior and posterior horns of the lateral ventricles.
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BPD Plane - Transverse view
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Transverse Cerebellar Diameter Plane - Transverse view
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ABNORMALITIES OF THE AMNIOTIC FLUID VOLUME
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Amniotic fluid is produced by fetal urination but in the first 16 weeks of gestation additional sources include the placenta, amniotic membranes, umbilical cord and fetal skin. Removal of amniotic fluid is by fetal swallowing. Ultrasonographically, the diagnosis of polyhydramnios or oligohydramnios is made when there is excessive or virtual absence of echo-free spaces around the fetus.
OLIGOHYDRAMNIOS
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Oligohydramnios means reduced amniotic fluid and anhydramnios means absence of amniotic fluid.
Prevalence:
Oligohydramnios in the second trimester is found in about 1 per 500 pregnancies.
Etiology:
Oligohydramnios in the second trimester is usually the result of
preterm premature rupture of the membranes,
uteroplacental insufficiency and urinary tract malformations
bilateral renal agenesis,
multicystic or polycystic kidneys,
or urethral obstruction.
Diagnosis:
The diagnosis of oligohydramnios is usually made subjectively.
Quantitative criteria include:
(a) the largest single pocket of amniotic fluid being 1 cm or less, or
(b) amniotic fluid index (the sum of the vertical measurements of the largest pockets of amniotic fluid in the four quadrants of the uterus) of 5 cm.
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Anecoic areas simulating pockets of amniotic fluid
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Color Doppler energy at the umbilical cord
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In the absence of the "acoustic window" normally provided by the amniotic fluid, and the "undesirable" postures often adopted by these fetuses, confident exclusion of a fetal defects may be impossible. Nevertheless, the detection of a dilated bladder in urethral obstruction and enlarged echogenic or multicystic kidneys in renal disease should be relatively easy. The main difficulty is in the differential diagnosis of renal agenesis. In cases of preterm prelabor rupture of the membranes, detailed questioning of the mother may reveal a history of chronic leakage of amniotic fluid. Furthermore, in uteroplacental insufficiency, Doppler blood flow studies will often demonstrate high impedance to flow in the placental circulation and redistribution in the fetal circulation. In the remaining cases, intraamniotic instillation of normal saline may help improve ultrasonographic examination and lead to the diagnosis of fetal abnormalities like renal agenesis.
Prognosis:
Bilateral renal agenesis, multicystic or polycystic kidneys are lethal abnormalities, usually in the neonatal period due to pulmonary hypoplasia. Preterm rupture of membranes at 20 weeks or earlier is associated with a poor prognosis; about 40% miscarry within five days of membrane rupture due to chorioamnionitis and in the remaining 60% of pregnancies more than 50% of neonates die due to pulmonary hypoplasia. Uteroplacental insufficiency resulting in oligohydramnios at 18-22 weeks is very severe and the most likely outcome is intrauterine death.
POLYHYDRAMNIOS
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Polyhydramnios means increased or excessive amniotic fluid volume.
Prevalence:
Polyhydramnios in the second trimester is found in about 1 per 200 pregnancies.
Etiology:
There are essentially two major causes of polyhydramnios;
reduced fetal swallowing or absorption of amniotic fluid and increased fetal urination.
Reduced fetal swallowing may be due to
craniospinal defects (such as anencephaly),
facial tumors,
gastrointestinal obstruction (such as esophageal atresia, duodenal atresia and small bowel obstruction),
compressive pulmonary disorders (such as pleural effusions, diaphragmatic hernia or cystic adenomatoid malformation of the lungs),
narrow thoracic cage (due to skeletal dysplasias),
and fetal akinesia deformation sequence (due neuromascular impairment of fetal swallowing).
Increased fetal urination is observed in maternal diabetes mellitus and maternal uremia (increased glucose and urea cause osmotic diuresis),
hyperdynamic fetal circulation due to fetal anemia (due to red cell isoimmunization or congenital infection) or
fetal and placental tumors or cutaneous arteriovenous malformations (such as sacrococcygeal teratoma, placental chorioangioma), twin-to twin transfusion syndrome.
Diagnosis:
The diagnosis of polyhydramnios is usually made subjectively. Quantitatively, polyhydramnios is defined an amniotic fluid index (the sum of the vertical measurements of the largest pockets of amniotic fluid in the four quadrants of the uterus) of 20 cm or more. Alternatively, the vertical measurement of the largest single pocket of amniotic fluid free of fetal parts is used to classify polyhydramnios into mild (8-11 cm), moderate (12-15 cm) and severe (16 cm or more). Although 80% of cases with mild polyhydramnios are considered to be idiopathic, in the majority of cases with moderate or severe polyhydramnios there are maternal or fetal disorders. In most cases polyhydramnios develops late in the second or in the third trimester of pregnancy. Acute polyhydramnios at 18-24 weeks is mainly seen in association with twin-twin transfusion syndrome. Testing for maternal diabetes, detailed sonographic examination for anomalies, and fetal karyotyping should constitute the cornerstones of the diagnostic protocol in the investigation of these cases.
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Moderate polyhydramnios
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Polyhydramnios - Diaphragmatic Hernia
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Prenatal therapy:
The aim is to reduce the risk of very premature delivery and the maternal discomfort that often accompanies severe polyhydramnios. Treatment will obviously depend on the diagnosis, and will include better glycemic control of maternal diabetes mellitus, antiarrhythmic medication for fetal hydrops due to dysrrhythmias, thoraco-amniotic shunting for fetal pulmonary cysts or pleural effusions. For the other cases, polyhydramnios may be treated by repeated amniocenteses every few days and drainage of large volumes of amniotic fluid. However, the procedure itself may precipitate premature labour. An alternative and effective method of treatment is maternal administration of indomethacin; however, this drug may cause fetal ductal constriction and close monitoring by serial fetal echocardiographic studies is necessary. In twin-twin transfusion syndrome, presenting with acute polyhydramnios at 18-22 weeks of gestation endocopic laser occlusion of placental anastomoses or serial amniodrainage may be carried out.
Prognosis:
This depends on the cause of polyhydramnios.
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