The Initial Diagnosis
History
Fetal growth and birth weight are determined not only by a genetic basis, but also from placental and maternal factors extrinsic to the fetus. Thus, it is imperative at the first consultation to take a detailed history (Figure 3.1) from the patient and partner, including family history if available. In this context, of importance are smoking, exposure to viral infections (working with children, veterinary work), previous pregnancy history, hypertension, or other maternal illnesses. The father’s history may be relevant, for example, in autosomal-dominant conditions such as Russell-Silver Syndrome, and Advanced paternal age is of significance if skeletal dysplasias are considered as a differential of growth restriction.
Figure 3.1 History at the first consultation.
The conventional definition of fetal growth restriction (FGR) referred to in this chapter uses an estimated fetal weight (EFW) or abdominal circumference (AC) below the 10th percentile in the presence of abnormal umbilical artery Doppler [1] (see Chapter 3).
The diagnosis of true FGR is furthermore supported by the observation of reduced growth velocity over serial scans with fetal biometry crossing percentiles indicating fetal deviation from its original genetic growth potential. FGR is classically caused by uteroplacental impairment, confirmed by typical abnormal functional parameters such as increased uterine artery Doppler PI with notching and reduced amniotic fluid.
However, especially at the initial suspicion of FGR, the underlying cause of the growth impairment is not always obvious. A number of differential diagnoses should be taken into consideration and systematically excluded to ensure the management of the pregnancy is determined by the actual underlying cause of fetal “smallness” (Table 3.1). Identifying the cause of growth restriction allows appropriate parental counseling and enables informed parental decision making. This is particularly important in cases of growth restriction caused by structural malformations or aneuploidy. Management of the pregnancy according to the specific cause of FGR safeguards optimal timing of delivery and improves fetal prognosis. Moreover, the possible coexistence of more than one cause of FGR should be anticipated and taken into consideration for an individualized care plan. When ultrasound examination suggests fetal growth restriction (FGR), the investigation for causality and management depends on the gestation (Table 3.2) and other features on ultrasound (Table 3.3). The diagnosis of placental fetal growth restriction is particularly crucial as the correct management and timing of delivery can alter outcome and improve prognosis.
Table 3.1 Differential diagnoses of FGR
| Uteroplacental impairment (FGR) |
| Small for gestational age (SGA) |
| Isolated structural malformations |
| Genetic-chromosomal cause |
| Infection (TORCH) |
Table 3.2 Likely cause of growth restriction per trimester
| Trimester of diagnosis | First | Second | Third |
|---|---|---|---|
| Likely cause of growth restriction | Genetic/chromosomal | Genetic/chromosomal | Uteroplacental growth restriction |
| Uteroplacental growth restriction | Genetic | ||
| Infection | Infection |
Table 3.3 SGA and its associations
| Uteroplacental Fetal Growth Restriction | Structural | Chromosomal/genetic | Infection | |
|---|---|---|---|---|
| General | Oligohydramnios | Congenital heart disease | Abnormal limb position | Hydrops Fetalis |
| Placental calcification | E.g., Tetralogy of Fallot | Nuchal thickening | ||
| Central Nervous System | Neural tube defects | Ventriculomegaly | Ventriculomegaly | |
| Agenesis of the corpus callosum | calcification | |||
| Dandy-Walker Malformation | ||||
| Cardiovascular system | Relative cardiomegaly | Atrio-ventricular septal defect | Pericardial effusion | |
| Thickened interventricular septum and right-sided heart dominance | Ventricular septal defect | Poor cardiac contractility | ||
| Tetralogy of Fallot | ||||
| Gastrointestinal system | Echogenic bowel | Abdominal wall defects e.g., Gastroschisis, exomphalos | Echogenic bowel | Hepatomegaly |
| Echogenicity and calcification of the liver |
This chapter focuses on the differential diagnosis of the fetus that is small for gestational age, including those that have true growth restriction primarily caused by abnormal placentation. It will consider the constitutional small-for-gestational-age fetus (SGA), which, while still at risk of increased perinatal morbidity, faces an overall better prognosis while also being a variant of normal. Rarely, an isolated structural malformation can lead to growth restriction and warrants involvement of paediatric surgical expertise for management guidance and treatment planning.
If a chromosomal or genetic condition is considered, this is important for diagnosis, dependent on parental wishes, with invasive testing or tests after birth. Subsequent management may include further support and advice for care after birth (including palliation) or termination of pregnancy.
If infection is suspected due to maternal history and/or ultrasound features, this will allow more focused counseling with the option of termination if the fetus is severely affected, and, in some infections, treatment may improve fetal prognosis.
The time of diagnosis and hence the onset of growth restriction, early or late in pregnancy, is an important factor in determining the differential diagnoses of FGR. Early-onset severe FGR may be diagnosed from 20 weeks’ gestation onward and is usually associated with substantial perinatal mortality, neonatal morbidity, prematurity, and long-term postnatal disease (see Chapter 22). Diagnoses may, apart from uteroplacental impairment (FGR), include the constitutionally small-for-gestational-age (SGA) fetus, placental damage, genetic-chromosomal cause, infection, and, rarely, structural abnormalities (Figure 3.2).
Figure 3.2 Investigation flow chart for FGR.
Fetal “smallness” diagnosed in later gestation is much more common (see Chapter 23) and is usually associated with lower mortality compared to early-onset growth restriction, but still faces significant perinatal morbidity and the risk of late stillbirth. Differential diagnoses of causes here include primarily SGA, the constitutionally small baby, and, less often, a true late presentation of FGR fetus with uteroplacental insufficiency of a milder phenotype (Figure 3.3). Rarely fetal congenital malformation, genetic-chromosomal causes, or infections are the cause of late-onset FGR.
Figure 3.3 Growth charts and fetal arterial Doppler patterns typically observed in the constitutional SGA fetus. Note the growth along the percentiles and normal Doppler values.
Structural abnormalities may be either associated with or cause FGR through different mechanisms depending on the type of abnormality; for example, a fetal heart defect may limit perfusion to the rest of the fetal body; an abdominal wall defect with herniated viscera leads to the abdominal circumference appearing smaller than expected.
Constitutionally Small-for-Gestational-Age (SGA) Fetuses
The term small for gestational age (SGA) describes those fetuses that are small and normal. Usually the 10th percentile is chosen as the arbitrary cut-off for abdominal circumference or estimated fetal weight, defining those below the 10th percentile as SGA. They represent a population of mostly (70%) constitutionally small babies with normal growth trajectory [2] and without underlying pathology (normal uteroplacental Doppler; Figure 3.3 and Table 3.4). Smallness may be associated with maternal ethnicity, parity, or BMI [3].
Table 3.4 USS features of SGA fetus
| First Trimester Screening | Anatomy | Amniotic Fluid Volume | Uteroplacental Doppler | Growth along Percentiles |
|---|---|---|---|---|
| Low risk | Normal | Normal | Normal | Forward |
| Symmetrical |
The percentiles used to plot fetal growth are derived from reference ranges constructed from observed fetal dimensions on ultrasound. These percentile charts have been criticized as they may not reflect heterogeneous populations nor allow for ethnical differences in growth. Different strategies have been invented to improve percentile charts: In the recent “Intergrowth 21” project, data were prospectively collected to create new descriptive percentile charts of normal fetal growth. Here the growth measurements have been collected in eight geographically diverse but “optimally” healthy populations [4]. While describing fetal growth in a healthy population of similar characteristics (weight, height, etc.), it is not clear how these data relate to “normal” populations.
Reflecting that different maternal characteristics influencing growth may not necessarily represent pathological growth, customized growth charts have been created to respect ethnical diversity and individual growth potential [5]. The “Gestation Network” (www.gestation.net), for example, provides tools for assessment of fetal growth by defining each pregnancy’s growth potential with a “Gestation-Related Optimal Weight” (GROW) software. The validity of this approach remains to be proven.
Naturally, the diagnosis of an SGA fetus can be concluded only after longitudinal assessment of growth. Nevertheless, it has to be remembered that as there are no definite thresholds to distinguish normal growth from pathological and restricted growth, no specific cut-off will define a totally abnormal or normal population correctly [6].
Placental Fetal Growth Restriction
Typically, a fetus growth restricted secondary to placental insufficiency is said to exhibit an asymmetrical pattern of growth restriction, but mixed patterns of fetal growth are possible. In very early FGR, symmetrical fetal growth is frequently seen, for example, with all parameters below the 3rd percentile. The defining characteristic in addition to fetal growth is raised umbilical and/or uterine artery Doppler impedance (Figure 3.4 and Table 3.5).
Figure 3.4 Growth charts for HC, FL, and AC typically observed in placental fetal growth restriction, with the Doppler parameters shown at the final scan.
Table 3.5 USS features of placental fetal growth restriction
| First Trimester Screening | Anatomy | Amniotic Fluid Volume | Doppler (in order of severity) | Growth along Centiles |
|---|---|---|---|---|
| Low PAPP-A [7,8] | Echogenic bowel | Oligohydramnios | Uterine Artery: Notches, may be unilateral or bilateral [10,11]. Raised impedance (pulsatility index: PI). | Small AC (asymmetrical) |
| Low b-hcg [9] | Can be used as a screening tool | But can be symmetrical | ||
| Umbilical Artery: Raised PI >95th centile Absent or Reversed End-Diastolic Flow [12,13] | Short long bones may be the initial sign in the third trimester. | |||
| Middle Cerebral Artery: reduced PI <5th percentile [14] | ||||
| Ductus Venosus: Deepening in the “a” wave toward baseline or reversed “a” wave reflects a decrease in forward flow during atrial systole [15] |
In early preterm FGR, that is generally considered to be less than 32/40, progressive abnormalities in the ductus venosus Doppler are used to time delivery [1,16] (unless the CTG becomes abnormal, in which case delivery is mandated), as it is shown to have a better association with subsequent neurodevelopmental outcome than that based on umbilical Doppler abnormality alone [17,18]. Beyond this gestation, a combination of CTG, umbilical artery, and middle cerebral artery Doppler is normally used for timing of delivery.
After 34 weeks, major aberrations in umbilical artery flow velocity waveforms are rare due in part to the high flow through the umbilical circulation. Absent umbilical arterial diastolic flow (AEDF) occurs when 60–70% of the villous vascular tree is damaged [19], eventually leading to reversed end-diastolic flow (REDF), hence this is highly unusual.
Isolated Structural Malformations
One quarter of all infants with congenital structural malformations will have FGR, and there is increased risk of FGR with increasing number of malformations [20] (Table 3.6).
Table 3.6 USS features of genetic syndromes
| First Trimester Screening | Anatomy | Amniotic Fluid Volume | Fetal-Placental Doppler | Growth along Percentiles |
|---|---|---|---|---|
| May be normal or high risk on nuchal translucency and/or biochemistry | May be normal, specific or non-specific abnormalities | Normal or increased | Often normal | Symmetrical reduction in growth |
Cardiac Anomalies
In the “The Baltimore-Washington Infant Study,” fetuses with cardiac anomalies were found to be approximately 100–200g lighter than unaffected babies at the same gestation [21,22]. The causation between growth restriction and cardiac abnormalities is unclear, but proposed mechanisms include embryos with intrinsic growth disturbances may be at increased risk of developmental errors during cardiogenesis [23]. Alternatively, fetal circulatory patterns in the presence of specific cardiovascular malformations may be incompatible with optimal fetal growth [24].
Abdominal Wall Defects
Seventy percent of fetuses affected by gastroschisis are growth restricted [25]; the exact cause is unknown. It is simplistic to assume that fetal growth is restricted simply because of the reduced AC from herniated abdominal viscera. The mechanism could be due to underlying hypoxia [26] evidenced by raised umbilical artery pulsatility index, but could also be due to increased protein loss from the exposed viscera [27].
Neural Tube Defects
A fetus affected with a neural tube defect is 2.6 times more likely to also be born with a birthweight <10th percentile (aOR 2.6, 95% confidence interval [CI] 1.8 to 3.9) [28].
Chromosomal Aberrations
There is a strong association between FGR, chromosome aberrations, and congenital malformations that significantly increases perinatal morbidity [29]. Abnormal fetal karyotype is responsible for approximately 20% of all FGR fetuses, and the percentage is substantially higher if growth failure is detected before 26 weeks’ gestation [30]. Confined placental mosaicism is more common in placentas of FGR fetuses compared with those from appropriately grown fetuses [31].
Trisomy 21
Trisomy 21, also known as Down syndrome, named after John Langdon Down, initially described the associated pattern of congenital abnormalities. The incidence increases with advancing maternal age; 95% of cases are caused by non-disjunction of chromosome 21 during maternal meiosis, resulting in an extra chromosome 21, and the remaining 5% are due to Robertsonian translocation or mosaicism with a recurrence risk of 1% and 25%, respectively.
Fifty percent of affected fetuses do not show any evidence of minor or major abnormalities on scan. The major abnormalities associated with this condition in the other half are cardiac (50%) and gastrointestinal (30%). Cardiac abnormalities include atrioventricular septal defects and ventricular septal defects. Gastrointestinal abnormalities include duodenal atresia and esophageal atresia. Short femur and humerus can be seen. Soft markers are often observed at USS and are used to modify pre-invasive risk analysis of Down syndrome diagnosis. These include hypoplasia of the nasal bone, right aberrant subclavian artery, and thickened nuchal fold.
The severity of the condition in terms of neurodevelopmental and motor delay can vary greatly from mild mental and motor delay to severe neurodevelopmental and motor delay. It was traditionally thought that Down syndrome babies were affected with fetal growth restriction [32], however, a recent paper by Morris and colleagues suggests that babies affected by T21 have similar growth potentials until 38 weeks of pregnancy [33], thus it is appropriate to use the UK-WHO birth weight charts up to this point. Thereafter birth weight is below that of unaffected babies (on average 159–304g for boys, 86–239g for girls), and thus it should be plotted on the UK Down syndrome growth chart.
Trisomy 18
Trisomy 18 is also known as Edwards syndrome. More than 99% of cases are of non-disjunction resulting in an additional chromosome 18. Very rarely, it can be the result of gonadal mosaicism, which explains the 1% empirical risk of recurrence. It is associated with high rates (70%) of intrauterine demise and a survival birth rate of only 5%, with 90% mortality within 6 months.
A wide range of anomalies may be seen on ultrasound and include cardiac, central nervous system, gastrointestinal, and urinary tract abnormalities. Early-onset symmetrical FGR is observed (Figure 3.5), and soft markers such as enlarged nuchal translucency and choroid plexus cysts may also be seen. In 2003, of a series of 38 patients with T18, 63% of fetuses exhibited fetal growth restriction [34].
Figure 3.5 Growth and Doppler findings typically seen in a Trisomy 18 fetus. Note FGR in this fetus with abnormal uterine and middle cerebral artery Doppler. The neonate survived for 3 days after birth.
Trisomy 13, also known as Pataus syndrome, is the least common autosomal trisomy to occur, affecting 1 in 12,500 births. The majority of cases are again due to non-disjunction (75%), with the remaining due to Robertsonian translocation. Only 2.5% of fetuses will reach term, and 3% survive at 6 months of life. Early-onset FGR is observed typically in the first trimester [35], but FGR is not a specific feature of T13 (unlike T18), only affecting 10% of the cases [36]. Major congenital abnormalities involving the cardiac, urinary tract, and central nervous system with craniofacial abnormalities are particularly evident (cleft, microphthalmia). Enlarged nuchal translucency is often how initial diagnosis occurs in the first trimester.
Triploidy is extremely rare, with an incidence of 1 in 2,500–5,000 births. It is due to a complete extra set of chromosomes (69), which can be of maternal or paternal origin and is not associated with advancing maternal age. The majority of triploidy is due to 69XXY with the remaining mainly due to 69XXX and only a few due to 69XYY. The majority miscarry in the first trimester, but of those that do survive, early-onset FGR is seen (often extremely asymmetrical), and thus most cases result in an intrauterine death by 20 weeks or survival of only a few hours after birth. Other features that may be seen on ultrasound include CNS abnormalities such as Dandy-Walker variant, congenital heart disease, syndactyly, and molar changes in the placenta accompanied with high b-hcg (diandric-paternal origin) or low hCG (digynaenic-maternal origin).
Genetic Causes
Russell-Silver Syndrome, with an estimated incidence of 1 in 7,000 [37], is an imprinting disorder characterized by severe FGR. Half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain; 10% have maternal uniparental disomy of chromosome 7 [38].
Typical facial appearances are frontal bossing and triangular-shaped face with marked body asymmetry as the head circumference is maintained [39]. Café au lait spots and fifth-finger clinodactyly may also be seen, and postnatally patients can exhibit speech and neurodevelopmental delay [40].
Cornelia de Lange (also called Brachmann-de Lange Syndrome) is an example of a multisystem malformation syndrome associated with growth restriction. In 50–60% of cases, a mutation is found in the NIPBL gene located at 5p13.2 encoding components of the cohesin complex [41]. The remaining 5–10% of cases are x-linked mutations related to the cohesin complex but found on other chromosomes. On ultrasound, FGR is seen with polyhydramnios. Upper limb abnormalities can be detected, including oligosyndactyly and radial aplasia. The typical facial appearances are often diagnosed postnatally, but with the help of 3D imaging may now be possible to visualize in utero. These include anteverted nares with a long philtrum, prognathism, micrognathia, and prefrontal edema. This condition can also be associated with congenital diaphragmatic hernia and heart disease. Postnatally, these babies have a poor outcome with severe neurodevelopmental delay and failure to thrive.
22q11.2 deletion, which includes DiGeorge and other syndromes such as craniofacial and velocardiofacial syndrome, is the most common microdeletion syndrome reported. It can be inherited as an autosomal dominant trait, but can also arise de novo. The major causative gene is TBX1, part of the T-box protein family of genes. These babies are most commonly affected by congenital cardiac abnormalities (75%) such as Tetralogy of Fallot, but can also have other associated sonographic findings, including thymic hypoplasia and renal anomalies. Chen and colleagues found that in 3 out of the 27 fetuses affected with growth restriction but normal karyotype, 22q11 microdeletion was detected (11%) [42]. FGR in this cohort is associated with poor prognosis leading to intrauterine death or early postnatal death [43].
Skeletal Dysplasia
Skeletal dysplasias are broadly classified into two main forms; lethal and nonlethal.
Lethal skeletal dysplasias are usually identified early in gestation by 16 weeks and almost universally by 20 weeks. The extreme shortening of the bones and abnormality of the ribs, head, and skeleton means that there is very rarely a diagnostic confusion with early-onset fetal growth restriction (Table 3.7). These are, however, described briefly:
Table 3.7 Comparison of ultrasound features of skeletal dysplasias with fetal growth restriction
| Ultrasound Features | Anatomy | Amniotic Fluid Volume | Uterine/Umbilical Artery Doppler | Growth along Percentiles |
|---|---|---|---|---|
| Skeletal dysplasia | Small chest circumference | Increased | Normal | Particularly short long bones, including humerus |
| Abnormal mineralization of the long bones | ||||
| Angulation | ||||
| Fractures | ||||
| Fetal growth restriction | Bone structure appears normal | Decreased | Abnormal | Asymmetrical growth restriction: may present with isolated reduced femur length |
| Initially in the third trimester, FL<3rd centile may be the first feature |
Thanatophoric dysplasia is a condition that is lethal neonatally. It is caused by a new dominant mutation in fibroblast growth factor receptor gene 3 (FGFR3 gene) [44] and associated with increased paternal age. It can be diagnosed with invasive testing. There are two main subtypes. Type I classically shows curved femurs that are thought to look like telephone receivers [45], and Type II shows straight femurs and a cloverleaf skull [46].
Osteogenesis imperfecta is often recognized in the second trimester and is associated with bowing and shortening of the limbs. Decreased mineralization of the bones may be seen with decreased skull echogenicity. In type II, which causes the majority of defects, it is due to a defect in the synthesis of collagen type 1. This is a very severe form and usually results in perinatal lethality, whereas fetuses affected with Type III often survive.
The recurrence risk is quoted to be as high as 5% to 7% if secondary to collagen type 1 defects occur due to the high incidence of gonadal mosaicism. Non-invasive prenatal diagnosis (NIPD) is an option in a subsequent pregnancy if mutation in the previous fetus is identified in collagen 1.
Achondrogenesis is an autosomal recessive condition with a 25% risk of recurrence. Two types exist. Type 1 is due to a defect in the SLC26A2 recessive gene that causes severe bone shortening. Type 2 causes severe micromelia with poor mineralization of the long bones, spiky metaphyseal spurs, and absent vertebral bodies; this is due to a new dominant mutation in collagen type 2.
A less common diagnosis that must be considered is campomelic dysplasia, with an incidence of 0.05 to 1.6 per 10,000 live births. This distinct skeletal dysplasia is characterized by bowing of the long bones of the lower extremity, phenotypic sex reversal, flat face, micrognathia, and cleft palate, as well as associated renal and cardiac abnormalities. It is caused by a mutation in the SOX 9 gene, essential transcription factor in chondrogenesis found on chromosome 17.
Nonlethal
The nonlethal forms of skeletal dysplasia are usually diagnosed in the second or third trimester. Achondroplasia is the most common form. It is an autosomal dominant condition with a high new mutation rate of approximately 80%. The majority of cases are due to one of two mutations in the FGFR3 gene (>98%) and rarely present before 24 weeks. It is associated with increased paternal age. Recurrence risk is extremely small at <1%. On ultrasound, typically rhizomelic short limbs are seen with short fingers known as the trident hand. There is relative macrocephaly with frontal bossing and a depressed nasal bridge. A normal trunk is observed with a wide angle at the proximal femur. Polyhydramnios is often observed (Figure 3.6).
