Dipartimento di Medicina Clinica e Sperimentale
Corso di Laurea Specialistica in Medicina e Chirurgia
Tesi di Laurea
GESTATIONAL AGE AT SONOGRAPHIC DIAGNOSIS
OF CONGENITAL STRUCTURAL ANOMALIES
Candidato:
Alina Neamtu
Relatore:
Prof.ssa Francesca A. L. Strigini
INDEX
1.1 INTRODUCTION………...6
1.2 THE AIM OF THE STUDY………23
2. MATERIALS AND METHODS………...24
3. RESULTS………..……….27
4. DISCUSSION………31
5. BIBLIOGRAPHY………..39
SUMMARY
The fetal anatomy evaluation and the subsequent timely detection of congenital anomalies is usually included in the aims of second trimester ultrasound screening. However, some structural anomalies can be detected before or after this time period. A growing body of literature is dealing with first trimester diagnosis, often in the setting of the nuchal translucency screening programme for trisomy 21. On the other hand, the term ‘’ late- onset’’ anomalies had been used since almost 20 years to refer to anomalies only detectable in the third trimester.
The aim of the present study was to evaluate the gestational age when the diagnosis of fetal structural anomalies is performed in the unselected obstetric population. The pregnant women with a suspicion of fetal structural anomaly at routine prenatal sonography and those with an increased risk for fetal anomalies are referred to the tertiary unit of University of Pisa based on geographic criteria. Among those examined between January 2011 and December 2015, 203 cases of fetal structural anomalies were eligible for the study, on the basis of their confirmation after completion of the pregnancy.
In our series, the majority of congenital anomalies were diagnosed between 15 and 22 weeks’ gestation (69.5 %), with a significant lower proportion detected before 14 (11.3 %) and after 23 weeks’ gestation (19.2 %) (p< 0.0001). The majority (52.7 %) of fetuses were diagnosed with Central Nervous System or Urinary System anomaly, whereas CHDs were the third more represented anomalies, probably because our unit is not the referral center for diagnosis and treatment of the CHDs. Also among the cases diagnosed before 14 weeks, the majority were CNS or Urinary system anomalies, but the specific diagnoses (i.e. anencephaly or megacystis) were often different from those detected in the subsequent periods. On the other hand, 61.5 % of the anomalies diagnosed after 23 weeks’ gestation were late onset anomalies (i.e. achondroplasia or autosomal dominant polycystic kidney disease) or anomalies with variable onset according to the specific cause (e.g. hydrocephalus, effusion, etc.). A relevant cause of late diagnosis was a disadvantaged social condition of the mother (20.5 %), whereas medical errors or
4 gaps in the organization system were observed in a minority of cases (respectively, 10.3% and 7.7 %).
In the present study, at the end of diagnostic procedure, 40 anomalies were regarded as lethal (8 of them with a lethal chromosomal anomaly), whereas 75 were severe and 88 were moderate; the gestational age at diagnosis was significantly lower according to the increasing severity of the anomaly (p< 0.0001).
Also the pregnancy outcomes were significantly different according to the severity of the anomaly (p< 0.0001), as termination of the pregnancy was requested by 72.5 % of patients with a lethal fetal anomaly, 52.0 % of those with a severe anomaly and 8.0 % of those with a moderate anomaly. Among pregnancies intended to continue, the rate of intrauterine fetal death was higher for lethal anomalies (45.5 %) than for severe (17.1 %) and moderate (1.3 %) anomalies.
In conclusion, the accuracy of sonography in the diagnosis of fetal structural anomalies at different gestational ages may depend on a variety of factors: besides the resolution of the equipment used and the ability of the sonographic operators, the natural history of the specific anomaly and the organization of the sonographic network play an important and often unrecognized role.
5
Abbreviations
ACC = agenesis of corpus callosum AVC = atrioventricular canal
AWDs = abdominal wall defects CHDs = congenital heart defects CNS = Central Nervous System
EUROCAT = European Concerted Action on Congenital Anomalies and Twins ISUOG = International Society of Ultrasound in Obstetrics and Gynecology IUFD = Intrauterine fetal death
IUGR = Intrauterine growth restriction PCF = posterior cranial fossa
TOP = termination of pregnancy VSDs = ventricular septal defects
6
INTRODUCTION
Diagnostic ultrasound is a sophisticated electronic technology, which utilises pulses of high-frequency sound to produce an image. It is a noninvasive screening method that has been shown to be biologically safe in long-term studies (Brent, 1991; Merritt, 1992).
The Beginning
A major factor for the development of a procedure later offered to all pregnant women in the industrialised world was the innovative work of an obstetrician, Ian Donald, and an engineer, Tom Brown, at the Queen Mother’s Maternity Hospital in Glasgow. They developed an ultrasound machine, called the Diasonograph (Donald et al., 1958). This technology laid the ground for the most comprehensive changes in pregnancy care in our time.
The first screening program offering a systematic ultrasound examination to a large pregnant population was started in Malmoe, in 1973 and aimed to detect twins.
In the start, the examination was offered at assumed 28 weeks, and in 1976, the examination was moved to week 18 and was followed by an additional examination at week 31 (Grennertet al., 1978).
Next was thought to use the ultrasound in pregnancy routinely and the reason for that use was that adverse outcomes may also occur in pregnancies without clear risk factors. Assumptions have been made that routine ultrasound in all pregnancies will prove beneficial by enabling earlier detection and improved management of pregnancy complications. A disorder of the pregnancy, such as misinformation of the gestational age, placenta praevia, twins, anomalies, growth retardation, is not necessarily recognised by clinical means (Bennet, 1982; Bakketeig, 1982; Eik-Nes SH., 1993).
In the following years, official health authorities in a number of countries decided to introduce routine ultrasound scanning as an offer. In 1987, Iceland followed Norway by offering one scan at 18 weeks, Austria followed the German two-stage model (at weeks 18 and 32) in 1988, Germany then expanded its screening
7 procedure by adding an exam in week 10, in 1995, later moved to week 12. They now offer ultrasound scans at 12, 18 and 32 weeks. Switzerland introduced in 1996 an early scan at week 10 followed by an 18-week scan, recently changed to weeks 12 and 18. The UK Royal College of Obstetricians and Gynaecologists recommended routine scanning at 18 to 20 weeks in 1991, but the government did not mandate the official offer of an anomaly scan until 2003.
In Italy, three ultrasound examinations, one for each trimester of pregnancy, are offered free-of-charge since 1995 (Decree of the Ministry of Health n° 87 of 6 march 1995).
Epidemiology and definitions
Major congenital malformations are reported in at least 2% of all fetuses and infants and have a major impact on perinatal and infant mortality and morbidity in infancy and childhood (EUROCAT, 2014).
A malformation is a structural defect that can be of various origin. Yagel and Achiron classified the congenital malformations as:
Primary: a morphological defect of an organ or large region of the body, resulting from an intrinsically abnormal developmental process
Secondary: represent accidental breakdowns or interference with previously normally formed structures.
They also stated that many Congenital Malformations should be regarded as developmental malformations.
Developmental fetal anomalies are classified in:
Malformations:
1. Growth deficiency- e.g. Achondroplasia (the molecular basis of this condition is a mutation of the FGFR, but the limited growth of the long bones is evident only at mid-trimester)
2. Excessive growth- e.g. rhabdomyoma, cardiac hypertrophy (excessive growth of cardiac muscle is always gradual and it may become apparent in the second or third trimester)
8 4. Delayed disappearance of normal structure- e.g. cervical blebs
Disruptions:
1. Mechanical- e.g. amniotic band syndrome 2. Vascular- e.g. terminal limb reduction
Deformations (usually caused in third trimester, e.g. in oligohydramnios) Sometimes early diagnosis is impossible because the organ involved in anomaly develops only later in pregnancy (Achiron and Yagel, 1998).
In the same time period, another author (Rottem, 1997) proposed a classification of fetal anomalies, based on their natural history, into four groups:
Class I: early-onset anomalies. These anomalies occur very early in pregnancy and could be detected during the first trimester of pregnancy provided that the resolution of the equipment is sufficient to image the defect (i.e. anencephaly, holoprosencephaly, facial cleft, osteogenesis imperfecta type II, dextrocardia, double collecting renal system).
Class II: transient conditions. Most of these conditions are the result of an abnormal accumulation or distribution of fluid in the fetal body involving the lymphatic, urinary or central nervous systems. Abnormal findings seen during an early scan may partially or completely resolve. (i.e. enlarged nuchal translucency, cystic hygromas, pericardial and pleural effusions, hydronephrosis).
Class III: anomalies with variable onset. These may occur at a different gestational age in different patients (i.e. hydrocephaly, diaphragmatic hernia, talipes equinovarus, obstructive uropathy, Dandy-Walker anomaly).
Class IV: late-onset anomalies. These either affect organs that develop late in pregnancy or they are manifested as the end of the natural history of anomalies occurring in early in pregnancy (i.e. microcephaly, lissencephaly, corpus callosum agenesis, arachnoid cysts).
In conclusion, undetected structural deformities belonging to Class III may be wrongly labelled as false negative where, in reality, is a simple consequence of the natural history of the condition.
9 The diagnosis of fetal malformations offers the possibility of therapeutic termination of pregnancy. In some countries, like Italy, the diagnosis must be completed within 23 weeks of gestational age, because after there is a possibility of survival of fetus outside the uterus. An antenatal diagnosis is also important for optimize the perinatal care and the best possible outcome for mother and fetus.
First-trimester ultrasound scan: goals and limitations
The aims of any early pregnancy ultrasound scan should be to determine viability, confirm an intrauterine pregnancy, establish gestational age accurately, detect multiples and describe chorionicity and amnionicity and, in health systems that offer first-trimester aneuploidy screening, measure the nuchal translucency thickness (NT). Before the noninvasive prenatal testing, which analyses cell-free fetal DNA circulating in maternal blood was developed, sonographic measurement of the fetal nuchal translucency thickness at 11 to 13 weeks of gestation in combination with maternal serum screening was the most effective method of screening for trisomy 21 (Snijders et al., 1998; Nicolaides, 2004); it still remains the most widely used screening for trisomy 21 in the general population.
An additional advantage of the routine first-trimester sonographic examination might be the early detection of a wide range of major fetal structural anomalies (Souka and Nicolaides, 1997; Weiszet al., 2005). Routine examination of the fetal head, anterior abdominal wall, and lower abdomen can be performed to rule out major fetal anomalies such as acrania, holoprosencephaly, omphalocele and megacystis (Sepulveda, 2011). According to some authors (Blaas, 2014) the time of detection of many structural abnormalities has moved from the second trimester to the first trimester and the detection rate at the end of the first trimester is steadily increasing with a significant amount of anomalies of the fetus being detected during the nuchal translucency screening programme.
Nevertheless, structural abnormalities occur, such as obstructions in the gastrointestinal tract and the urinary system, and hydrocephalus, which usually do not become visible before the second or even third trimester (Blaas, 2014).
10 Sometimes, early ultrasound screening might be more accurate than second-trimester ultrasonography for the detection of fetal anomalies associated with oligohydramnios or anhydramnios, resulting in poor examination of fetal anatomy. On the other hand, some false positive results are known to be possible in the first trimester, e. g. the fetal midgut is normally present in the base of the umbilical cord from approximately 8 weeks until 12 weeks of gestation, suggesting a false-positive diagnosis of omphalocele at this gestational age. (Snijders and Nicolaides, 1995). Moreover, the accuracy of early ultrasonography can be compromised by findings that resolve spontaneously throughout gestation. For example, small ventricular septal defects commonly undergo spontaneous closure during intrauterine life (Paladini, 2000), and hydronephrosis is regarded as transient anomaly in the first trimester (Sairam, 2001). Even if a systematic review (Rossi, 2013) concluded that ultrasound examination from 11 to 14 weeks of gestation can detect approximately half of fetal malformations, in a very large randomized study Saltvedt et al. reported that the antenatal detection rate of major fetal malformations at 12–14 weeks of gestation was lower than the detection rate at 15–22 weeks of gestation (38% and 47%, respectively) (Saltvedt, 2006).
Patients should be counselled that in some cases, the early diagnosis of most fetal malformations needs further confirmation in a later gestational period. The presence of associated anomalies appears to increase the accuracy of early ultrasonography, because early detection of fetal anomalies increased from 44% in fetuses with isolated malformations to 60% when fetuses were affected with multiple anomalies. The presence of maternal risk factors for fetal structural abnormalities also may influence the accuracy of early ultrasound examination. Therefore, the awareness of the ultrasonographer is higher when the a priori probability for anomalies is high (Rossi, 2013). The use of transvaginal technique also increases the successful examination of the fetal anatomy from 72% to 86% of cases and allows better visualization of the face, kidneys, and bladder (Souka, 2004). However, the reduced probe flexibility in obtaining different scanning plans limits the accuracy of transvaginal ultrasonography. A review shows that a
11 combination of both of the approaches may improve the visualization of fetal anatomy compared with either technique (Rossi, 2013).
In a prospective study on 45 191 pregnancies, undergoing prospective first trimester aneuploidy screening (Syngelaki, 2011), it has been concluded that major fetal abnormalities may be distinguished in relation to whether they can be detected at the 11–13 weeks scan.
Always detectable abnormalities Transverse sweeps through the head and
abdomen should identify all cases of body stalk anomaly, anencephaly, alobar holoprosencephaly (Sepulveda, 2004), exomphalos, gastroschisis and megacystis.
Undetectable abnormalities Certain fetal abnormalities are manifested only during
the second or third trimester of pregnancy and are therefore impossible to detect at 11–13 weeks. One such abnormality is microcephaly, in the absence of other brain defects, which is usually diagnosed after 30 weeks from the small measurement of the fetal head circumference. The corpus callosum normally develops at 14 – 19 weeks (Ren et al., 2006) and inevitably the diagnosis of agenesis of the corpus callosum cannot be made at 11 – 13 weeks. Similarly, ventriculomegaly secondary to congenital infection or brain hemorrhage will be manifested after the event, usually in the second or third trimesters.
Potentially detectable abnormalities For some abnormalities, such as facial cleft,
renal agenesis and multicystic kidneys, improved first trimester detection will be achieved if:
detailed examination of the relevant structure is included in the protocol;
the sonographers receive appropriate training for such examination, they are given extra time for the scan and resort to vaginal sonography more often than in current practice;
new techniques are described which facilitate the diagnosis of specific conditions, e. g. the assessment of the retronasal triangle is likely to facilitate the diagnosis of facial cleft (Sepulveda et al., 2010); high NT can unmask abnormalities such cardiac defects, diaphragmatic hernia, lethal skeletal dysplasia, more prevalent in the cases diagnosed in the first than in the second trimester.
12 For example, in the case of diaphragmatic hernia, increased NT, presumably due to venous congestion in the head and neck, would be observed only with the larger lesions and in cases where intrathoracic herniation of the abdominal viscera occurs in the first trimester, rather than later in pregnancy (Sebire et al., 1997).
Therefore, the performance for most abnormalities depends on their association with easily detectable markers and a policy decision as to the objectives of the scan (Syngelaki, 2011).
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The mid-trimester ultrasound scan
Whereas the main objectives of first trimester scan are usually regarded as others than diagnosis of fetal anomalies, the timely detection of major congenital anomalies is included in the aims of second trimester scan (ISUOG, 2011); it is performed between 18 and 22 weeks of gestation according to ISUOG guidelines and it evaluates:
number of fetuses (and chorionicity if multiple pregnancy)
presence of fetal cardiac activity
gestational age if the first-trimester ultrasound examination was not performed
placental localization.
The examination also includes to research/measure of the following structures: Head
biparietal diameter (BPD) and head circonference (HC) measure of the size of the trigone of the lateral ventricle measure of the transverse cerebellar diameter (TCD) visualization of the cavum septi pellucidi (CSP) visualization of the cisterna magna
visualization of the fetal orbits and lenses visualization of the upper lip
Spine
longitudinal scan of the spine Thorax
visualization of the lungs
heart activity present and cardiac situs four-chamber view of the heart
14
Abdomen
measure of the abdominal circonference stomach in normal position
visualization of the profile of abdominal wall kidneys and bladder
Limbs
visualization of the long bones of the arms and legs
visualization of the limb extremities present and normal relationships measure of the femur length
Amniotic fluid
the amniotic fluid volume assessment Placenta
localization Umbilical chord three-vessel present
The procedures offered at 12 weeks and 18 weeks do not compete with each other, but rather represent a natural sequence of collecting information from the developing fetus. Anyway, routine fetal examination at approximately 18 weeks remain the basis to obtain information about the developing fetus and its problems (Eik-nes, 2010).
In a prospective study, Schwa¨rzler et al. evaluated performing ultrasound screening for abnormalities at 18, 20, or 22 weeks. They found that the anomaly detection rate was no different at each of these gestational ages. Scans performed at 18 weeks of gestation, however, had a significantly increased chance of requiring a repeat examination caused by an incomplete anatomic scan. It seems that 20 to 22 weeks of gestation is the optimal time to perform an ultrasound for detection of fetal anomalies.
EVALUATION OF THE FETAL ANATOMY
Central nervous system (CNS) malformations: challenges in the ultrasound diagnosis
CNS malformations are some of the most common of all congenital abnormalities. The prevalence of congenital anomalies of the CNS varies among different studies, some of which suggest an incidence of about 3–5 per 1000 births (Garne, 2005). Ultrasound has been used as the main modality to diagnose fetal CNS anomalies. In recent years fetal magnetic resonance imaging (MRI) has emerged as a promising new technique that may add important information in selected cases (Griffiths et al., 2005), although its advantage over ultrasound remains debated (Malinger et al., 2004).
The appearance of the brain and spine changes throughout gestation. Basic examination is usually performed around 20 weeks of gestation, because even severe anomalies may be associated with only subtle findings in early gestation. The brain continues to develop in the second half of gestation and into the neonatal period. In the majority of late diagnoses, the cause is the late development of a specific, congenital or acquired pathology. Disorders of abnormal proliferation are usually expressed by an abnormal head circumference that may not be obvious until the last weeks of pregnancy or the first months postnatally and, therefore, may be missed by a second trimester ultrasound (Malinger, 2006). In addition, some cerebral lesions are not due to faulty embryological development but represent the consequence of acquired prenatal or perinatal insults, like intracranial hemorrhage, brain injury in the surviving fetus after the death of a monochorionic cotwin for example. Therefore, in patients who have a third trimester scan, assessment of the fetal CNS should be considered (Yinon, 2013), even if in late gestation visualization of the intracranial structures may be hampered by the ossification of the calvarium. However, even in countries where late termination is illegal, antenatal diagnosis of CNS anomalies may improve the neonatal outcome as some cases may require delivery at a tertiary center.
16 Transabdominal sonography is the technique of choice to investigate the fetal CNS during late first, second and third trimesters of gestation. The examination should include the evaluation of the fetal head and spine (ISUOG, 2007).
The fetal brain
Two axial planes permit visualization of the cerebral structures relevant to the anatomical integrity of the brain.: the transventricular plane and the transcerebellar plane. Structures that should be noted in the routine examination include the lateral ventricles, thalami, the cerebellum, cisterna magna, cavum septi pellucidi.
Head shape and brain texture should also be viewed.
Cavum septi pellucidi may be altered with many cerebral lesions such as holoprosencephaly, agenesis of the corpus callosum, severe hydrocephaly and septo-optic dysplasia (Malinger et al., 2005). Absence of the cavum septum pellucidum may indicate an abnormality in midline structures of the brain including agenesis of the corpus callosum. The diagnostic issue of this condition is made even more challenging because, as recently reported, the cavum septi pellucidi may sometimes be ill defined or difficult to visualize (Malinger et al., 2012).
In the second half of gestation the depth of the cisterna magna is stable and should be 2 – 10 mm. Early in gestation the cerebellar vermis has not completely covered the fourth ventricle, and this may give the false impression of a defect of the vermis. In later pregnancy such a finding may raise the suspicion of a cerebellar abnormality but prior to 20 weeks’ gestation this is usually a normal finding (Bromley et al., 1994). Enlargement of the cisterna magna can indicate a potential Dandy-Walker malformation (Filly et al., 1989). Effacement of the cisterna magna is see in the Chiari II malformation, which is present in most cases of spina bifida. The ‘‘fruit’’ signs should also be sought during the fetal survey. Frontal bossing of the fetal skull seen in the axial plane is called the ''lemon'' sign. The cerebellum curves anteriorly and forms the ''banana'' sign.
Biometry is an essential part of the sonographic examination of the fetal head. In the second trimester and third trimester, a standard examination usually includes
17 the measurement of the biparietal diameter, head circumference and internal diameter of the atrium. Some also support measurement of the transverse cerebellar diameter and cisterna magna depth. Biparietal diameter and head circumference are commonly used for assessing fetal age and growth and may also be useful to identify some cerebral anomalies. Measurement of the atrium is recommended because several studies suggest that this is the most effective approach for assessing the integrity of the ventricular system (Cardoza et al., 1988), and ventriculomegaly is a frequent marker of abnormal cerebral development. The measurement is stable in the second and early third trimesters, with a mean diameter of 6–8mm (Pilu et al., 1989; Cardoza et al., 1988) and is considered normal when less than 10mm (Pilu et al. 1999; Kelly et al. 2001). Particularly at mid gestation a value of 10.0mm or greater should be considered suspicious. Measurement of the transverse diameter of the ventricular atrium at the level of the glomus of the choroid plexus, is currently favoured. This measurement is easily obtained and is reproducible (Pilu et al., 1999).
In a low risk pregnancy around mid-gestation, if the transventricular plane and the transcerebellar plane are satisfactorily obtained, the head measurements (head circumference in particular) are within normal limits for gestational age, the atrial width is less than 10.0mm and the cisterna magna width is between 2–10mm, many cerebral malformations are excluded, the risk of a CNS anomaly is exceedingly low and further examinations are not indicated (Filly et al., 1989).
The fetal spine
The examination of the fetal spine requires a meticulous scanning, and the results are heavily dependent upon the fetal position. The most frequent of the severe spinal abnormalities, open spina bifida, is usually associated with abnormal intracranial anatomy. However, a longitudinal section of the fetal spine should always be obtained because it may reveal other spinal malformations including vertebral abnormalities and sacral agenesis. Integrity of the neural canal is deduced by the regular disposition of the ossification centers of the spine and the presence of soft tissue covering the spine.
18
Examination of the fetal face (ISUOG, 2010):
A sagittal view of the face allows examination of the fetal profile to identify possible micrognathia or abnormalities of the fetal tongue. A coronal view including the nose and upper lip allows the diagnosis of a cleft lip.
19
Congenital Heart Disease (CHD): challenges in the ultrasound diagnosis
CHD is a leading cause of infant mortality, with an estimated incidence of about 4–13 per 1000 live births (van der Linde et al., 2011). The cardiac screening examination is performed optimally between 18 and 22 weeks of gestation. Some anomalies may be identified during the late first and early second trimesters of pregnancy, especially when increased nuchal translucency thickness is identified (Garne et al., 2001; Mc Brien et al., 2010).
Prenatal detection of CHD may improve the outcome of fetuses with specific types of cardiac lesions, but prenatal detection rates vary widely (Bonnet et al., 1999; Mahle et al., 2001; Franklin et al., 2002; Kaguelidou et al., 2008). Some of this variation can be attributed to differences in examiner experience, maternal obesity, transducer frequency, abdominal scars, gestational age, amniotic fluid volume and fetal position. In addition, only 10% of CHD cases occur in pregnancies with identifiable risk factors, such as fetal extracardiac malformations and this makes the detection of cardiac defects more difficult (Sharland, 2012). Continuous feedback-based training of healthcare professionals, a low threshold for echocardiography referrals and convenient access to fetal heart specialists are particularly important factors that can improve the effectiveness of a screening program (Yates, 2004). Suspected heart anomalies will require more comprehensive evaluation using fetal echocardiography.
According to ISUOG guidelines (ISUOG, 2006), situs abnormalities should be suspected when the fetal heart and/or stomach are not found on the left side. Abnormal axis increases the risk of a cardiac malformation and may also be associated with a chromosomal anomaly. Abnormal displacement of the heart from its normal anterior left position can be caused by a diaphragmatic hernia or a cystic adenomatoid malformation of the lung. Position abnormalities can also be secondary to fetal lung hypoplasia or agenesis, fetal gastroschisis and omphalocele. Normal heart rate and regular rhythm should be confirmed. Although mild ventricular disproportion can occur as a normal variant in the third trimester of pregnancy, clear right–left asymmetry in midgestation legitimates further
20 examination. Left-sided obstructive lesions, such as coarctation of the aorta and evolving hypoplastic left heart syndrome, are important causes of this disparity (Hornberger et al., 1995; Kirk et al., 1999).
The ventricular septum should be examined carefully for cardiac wall defects. Septal defects may be difficult to detect. However, in most cases these may undergo spontaneous closure in utero. Abnormal alignment of the atrioventricular valves can be a key sonographic finding for cardiac anomalies such as atrioventricular septal defect.
The inclusion of outflow tract views is more likely to identify conotruncal anomalies such as tetralogy of Fallot, transposition of the great arteries, double outlet right ventricle and truncus arteriosus.
Traditionally, anomalies in the cardiovascular system, e.g. small VSDs, are more difficult to examine by ultrasound, but the detection rate improves when a specialist in fetal echocardiography performs the heart examination (Tegnander et
al., 2006).
Abdomen
Initial evaluation of the abdomen should determine situs of the abdominal organs. The fetal stomach should be reliably visualized in the left upper quadrant after 14 weeks’ gestation. If not visualized, a repeat examination may be performed in 1 to 2 weeks. Persistent non visualization of the stomach may be associated with a number of abnormalities including esophageal atresia (McKenna et al., 1995). The fetal diaphragm should be imaged in the sagittal plane, making sure the stomach is in the abdominal cavity.
The umbilical cord insertion into the anterior abdominal wall should be documented along with the integrity of the adjacent abdominal wall.
The urinary tract
The fetal kidneys are visualized as hypoechoic, paraspinal structures that frequently have an echogenic central renal pelvis. The kidneys should be examined for any intrarenal cysts or echogenicity, which may suggest renal dysplasia. In
21 addition, adjacent cystic structures, which might indicate a duplicated collecting system, should be noted.
The most commonly seen abnormality is renal pyelectasis. Controversy has existed on how to manage fetuses when pyelectasis is seen in the second trimester. A common approach has been to repeat the examination in the third trimester and only if the measurement is greater than or equal to 7 mm is postnatal follow-up recommended.
Renal anomalies often cause difficulties because of oligohydramnios (Akgun et
al., 2014).
The fetal bladder should also be examined. If distended, abnormalities of the kidneys and possible dilation of the ureters should be sought. Also, the volume of amniotic fluid should be evaluated. Abnormalities in the shape of the bladder may be an indicator of a cloacal abnormality.
Extremities
Although the femur is the only bone routinely measured for biometry, all of the fetal long bones should be imaged and examined for morphology to screen for skeletal dysplasias.
In addition, both hands and feet should be documented. The axis of the foot in relation to the tibula-fibula should also be imaged to rule out a clubfoot anomaly.
Umbilical cord
The fetal umbilical cord should be imaged to determine the number of vessels. A single umbilical artery is seen in approximately 1% of pregnancies. The finding of a two-vessel umbilical cord is an indication for a detailed ultrasound to rule out other abnormalities and for a fetal echocardiogram.
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The routine third trimester ultrasound scan: is justified?
The utility of third trimester sonographic examination in the general population is still questioned (Bricker et al., 2015). Its main aim is to evaluate fetal growth. However, in a prospective study between 1998 and 2008, from Manegold, an additional 15 % structural abnormalities were found in the third trimester, mainly abnormalities of the urogenital system, but also anomalies of the cardiovascular system, the gastrointestinal system and the central nervous system. These findings may be relevant for perinatal management and postnatal follow-up. Therefore, when a third trimester scan is performed it may allow for the detection of fetal anomalies, which can be undetectable or difficult to detect in the second trimester scan. In a previous study, it was found that as many as 11.5% of CNS anomalies were diagnosed during the third trimester, following a normal second trimester examination (Malinger et al., 2002).
Throughout the years of ultrasound diagnostics, detection of anomalies by ultrasound has improved due to the increasing expertise of sonographers and the higher quality of the ultrasound equipment (Levi, 2002). There is a clear correlation between ultrasound and autopsy findings, which is continuously improving. However, there is reason to continue the practice of validation to ensure the safety of the diagnostic process because there is a trend towards an earlier termination of pregnancy. However, for various reasons, including fetal position, maternal body mass index, amniotic fluid volume, image resolution, or operator’s experience, between 0.4 and 82.8% of congenital anomalies depending on their type still escape prenatal ultrasound detection.
Therefore, it is important to make clear to the patient that ultrasound has its limitations. The patient must realize that not all malformations can be detected (Goldberg, 2004).
23
THE AIM OF THE STUDY
The aim of the present study was to evaluate the gestational age when the diagnosis of fetal structural anomalies is performed in the unselected obstetric population. At odds with other studies, performed in a research setting of repeated examinations of the same fetuses by trained sonographers following research protocols, in the present study the fetuses were consecutively enrolled as they were referred to our tertiary scan center from the general population. Therefore, we did not evaluate the accuracy of sonography in an optimal setting, but the different causes, which can affect the diagnostic process.
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MATERIALS AND METHODS
The present study was performed in the tertiary referral unit for prenatal sonography of the University of Pisa (Division of Obstetrics and Gynaecology) between January 2011 and December 2015. Even if doctors and patients can choose the referral centre to which rely, roughly one third of the pregnant population of the Tuscany Region of Italy are referred to the University of Pisa based on the geographic proximity to the local hospital.
All consecutive cases of prenatal diagnosis of structural anomalies, provided that they were confirmed after completion of the pregnancy, were included in the study. Therefore, the borderline abnormal findings that disappeared throughout or after completion of the pregnancy were excluded from this data collection.
In Italy, prenatal ultrasound screening includes three ultrasound examinations: one in the first trimester between 11 and 13 weeks of gestation, a second in the second trimester between 19 and 21 weeks, and a third in the third trimester between 30 and 34 weeks, according to the guidelines of the Italian Society of Ultrasound in Obstetrics and Gynecology (SIEOG, 2015).
The second trimester ultrasound examination is the standard of care for fetal anatomical evaluation.
The pregnant women of the present study were referred at our tertiary unit because of a suspicion of congenital malformation at routine prenatal sonography screening or because of an increased risk for fetal anomalies (e.g. familiarity for polycystic kidney disease, maternal illnesses like diabetes mellitus, previous fetus with structural anomaly).
After completion of the fetal anatomy assessment and confirmation of a fetal structural anomaly, further information regarding associated abnormalities or genetic syndromes were looked for, by means of genetic counselling, fetal echocardiography, magnetic resonance imaging (MRI).
Patients that chose to continue the pregnancy underwent serial ultrasound examinations, on average every two weeks depending on what expected on the possible trend of the anomaly diagnosed.
25 To categorize the different gestational age at diagnosis of the structural fetal anomalies, the cases were divided in 3 groups: diagnoses performed before 14 weeks, between 15 and 22, and after 23 weeks of gestation.
Fourteen weeks has become the conventional limit for first trimester scan because the screening for fetal trisomy 21, by measurement of the nuchal translucency, can be performed up to 13 weeks plus 6 days. As the Italian law allows the mother to choose termination of pregnancy up to the gestational age at which the fetus can be viable outside the uterus, 22 weeks were regarded as the upper limit of timely performed second trimester scan.
In cases of late diagnosis, we checked the reasons why the diagnosis was made after 23 weeks of gestation and classified them as: late-onset anomalies (Rottem, 1997; Achiron et al. 1998); a disadvantaged social condition which hampered the patient from looking for medical assistance in pregnancy; mistake of the sanitary system in fixing the correct appointment for the second trimester scan; and medical error in diagnosing the anomaly in previous ultrasound examinations.
To simplify the data analysis, the anomalies were assigned to be a part of an organ system. EUROCAT grouping system was used for this purpose. (EUROCAT website, 2014 version). EUROCAT is the major registry in Europe, used for the epidemiological surveillance of birth defects. The allocation to one of the EUROCAT subgroup was made according to the main anomaly detected at our first abnormal scan and this is why the chromosomal anomalies did not constitute a subgroup in the present study.
Pregnancy outcome and postnatal follow-up were obtained from the obstetric and neonatal hospital records, or from the patients themselves with special pre-printed forms or telephone interviews.
Pathological examination was performed in cases that had an intrauterine fetal death, elective termination of pregnancy or neonatal death.
At the end of the diagnostic procedure, the detected lesions were distinguished on the basis of the severity of the anomaly:
-lethal, when it does not exist an efficient treatment and the expected survival of liveborns is not longer than a few months (e.g. anencephalus, trisomy 18);
26 -severe, when the anomaly causes a severe neuropsychiatric disability, or when multiple malformations are present in the same fetus, or when the malformation can be treated with a high surgical risk (e.g. AVC) or without the possibility to recover the lost function;
-moderate, when it may allow for a normal quality of life, with or without surgical intervention; if surgery is required, the surgical risk is moderate or low.
In all cases, a complete structural ultrasound evaluation was performed by a consultant in maternal fetal medicine. The used ultrasound machine was Voluson E8 ultrasound scanner (GE Healthcare, Milwaukee, WI).
For the treatment of the data and the statistics analyses a commercially available software was used (JMP). The different rate of diagnoses between groups was evaluated by the squared chi test.
27
RESULTS
During the study period, 203 pregnant women with fetal structural anomalies detected by prenatal sonography were eligible for the study.
Table I shows our study cases of structural congenital anomalies grouped according to the EUROCAT grouping system.
Although a significantly (p< 0.0001) higher proportion of fetal anomalies (141: 69.5%) were diagnosed between 15 and 23 weeks of gestation, 11.3 % cases were diagnosed before 14 weeks of gestation and 19.2 % after 23 weeks of gestation.
Fifteen fetuses had a chromosomal anomaly associated to the structural anomaly detected by ultrasound examination (Table II). Less than half of them (7/ 15) had a trisomy 21; all trisomy 21 cases were diagnosed after 14 weeks of gestation. On the contrary, 1 out of 6 fetuses with trisomy 18 and those with trisomy 13 and triploidy had fetal anomalies which enabled sonographic diagnosis before the 14th week.
The majority of fetuses (107: 52,7 %) were diagnosed with a Central Nervous System or Urinary System anomaly. The gestational age at the diagnosis of the fetal anomaly varied with the EUROCAT subgroup (Table I).
Also among the cases diagnosed before 14 weeks, the majority were CNS (n=8) or Urinary system (n=6) anomalies. However, the frequency of specific anomalies within these systems were different before 14 weeks and in the subsequent periods. In particular, all cases of anencephaly (n=4) were diagnosed before 14 weeks of gestation, as well as all cases of megacystis (n=5). No case of CHDs, Oro-facial clefts, Musculoskeletal, Digestive, Genital and Respiratory anomalies were diagnosed before 14 weeks of gestation in this series.
On the other end of the spectrum, the majority of Genital anomalies (4 out of 5) were diagnosed after 23 weeks of gestation, and were represented by ovarian cysts in female fetuses. Also among Musculoskeletal anomalies, a high proportion (33.3 %, 3 out of 9) of cases were diagnosed after 23 weeks of gestation, namely, all 3 cases of achondroplasia present in this study. In fact, most of the anomalies
28 diagnosed after 23 weeks of gestation (24/39: 61.5 %) in our series were late- onset anomalies or anomalies which can occur or manifest with sonographic signs at any gestational age o even after birth (e.g. hydrocephalus, effusions, posterior urethral valve).
On the other hand, 20.5 % of structural fetal anomalies were diagnosed after 23 weeks of gestation because of a disadvantaged social condition of the mother which hampered her from looking for medical assistance in pregnancy. Only a minority of late diagnosis were linked to medical errors in making diagnosis at the ultrasound mid- trimester scan (n=4, 10.3 %) and to errors of the sanitary system in offering the appointment for mid- trimester scan (out of the time interval advised by the guidelines) (n=3, 7.7 %) (Table III).
Table IV shows the distribution of anomalies according to the EUROCAT grouping system and the severity of the anomaly.
Forty (19.7 %) anomalies were regarded as lethal (8 of them because of a lethal chromosomal anomaly; Table II), whereas 75 (37.0 %) were severe and 88 (43.3 %) were moderate. As expected, the severity of the anomaly was significantly associated with the EUROCAT subgroup (p < 0.0001), with subgroups characterized by a high incidence of lethal anomalies (66.8 % in the subgroup of the ‘’other anomalies’’; 31.8 % in the subgroup of the CHDs), and others including only severe or moderate cases (e.g. the subgroups of the Digestive system anomalies, Genital system anomalies and Oro-facial clefts).
However, in some subgroups the number of cases was too low for the statistical analysis, because of the rarity of the anomaly or the difficulty of the prenatal diagnosis.
The gestational age period at diagnosis was significantly different (p < 0.0001) according to the severity of the anomaly. (Table V)
The majority of lethal malformations were diagnosed before 23 weeks of gestation (87.5 %), with many (42.5 %) diagnosed before 14 weeks; only 5 (12,5%) cases of lethal anomalies were diagnosed after 23 weeks of gestation, because in 1 case
29 the patient had an incorrect appointment for the ultrasound mid-trimester scan (spina bifida) and 4 cases were late-onset or variable- onset anomalies (i. e. 2 cases of bilateral polycystic kidney and 2 cases of hydrops).
On the other side, 21.3 % of the severe anomalies and 20.4 % of the moderate anomalies were diagnosed after 23 weeks of gestation, with a few cases diagnosed in the first trimester of pregnancy, namely 1 moderate anomaly (cystic hygroma) and 5 severe anomalies (2 limb reduction defects, 1 hydrocephalus, 1 spina bifida and 1 abdominal wall defect).
Of the 16 (21.3 %) severe fetal malformations diagnosed after 23 weeks, 8 were late onset anomalies, 6 cases were patients in a disadvantaged social condition, 1 patient had an incorrect appointment for the ultrasound mid- trimester scan and 1 case of misdiagnosis (p < 0.0001).
Also pregnancy outcomes were significantly different according to the severity of the anomaly (p< 0.0001) (Table VI). Two patients of our series had unknown pregnancy outcome.
The vast majority (90.9 %) of patients whose fetus had a moderate anomaly delivered at term a liveborn baby, even if 1 (1.1 %) fetus, diagnosed with unilateral renal agenesis, died in utero at 30 weeks of gestation because of fetal hydrops, and 7 patients (8.0 %) elected to terminate their pregnancy (3 cases of oro-facial clefts, 1 case of cystic hygroma, 1 case hydrocephalus, 1 case of agenesis of corpus callosum and 1 case of PCF anomaly, i. e. cerebellar vermis hypoplasia).
On the contrary, termination of pregnancy was requested by the majority of patients with a lethal fetal anomaly (72.5 %); among the pregnancies not terminated, 5 (12.5 %) fetuses were stillborn (2 cases of fetal hydrops, 2 cases of lethal chromosomal abnormalities and 1 case of limb reduction defect). The remaining 6 (15.0 %) were liveborn and died afterwards:
two fetuses were delivered because of the choice of the mother to continue the pregnancy despite the diagnosis was made before 23 weeks of gestation: 1 case of holoprosencephaly (trisomy 18) and the other one of bilateral polycystic kidney with renal failure;
30
one fetus had a diagnosis of club foot at mid- trimester ultrasound scan, but at 29 weeks of gestation his condition was complicated by fetal hydrops and preterm labour;
the remaining 3 fetuses were diagnosed after 23 weeks of gestation, beyond the time limit for TOP in Italy: 2 cases had a bilateral polycystic kidney and 1 case had hydrops.
Among pregnancies with fetal severe anomalies, the outcome was intermediate: 52.0 % terminations, 39.8 % livebirths and 8.2 % stillbirths. The difference among the groups was statistically significant (p < 0.0001).
31
DISCUSSION
In the present study, the anomalies diagnosed by obstetric sonography were distributed in EUROCAT subgroups in proportions slightly different from those observed in the general population. In fact, in the general population the most common anomalies are CHDs (van der Linde et al., 2011), followed by CNS anomalies (Garne et al., 2005) and Urinary system anomalies (Song et al., 2011). On the contrary, in our series, CNS anomalies and Urinary system anomalies were the first and the second more represented subgroups, whereas CHDs were the third subgroup in order of frequency. This can depend on the fact that our unit is not a referral center for diagnosis and treatment of CHDs.
As cases of postnatal diagnosis were not included in the present study, the overall sensitivity of fetal sonography was not evaluated. From the registries of congenital anomalies, it is well known that sensitivity also depends on the completeness of postnatal ascertainment. In fact, when the ascertainment is limited to the period preceding the hospital discharge of the newborn, many cases are not included and sensitivity of prenatal sonography may be reported falsely high.
The ultrasound examinations were performed according to the guidelines of Italian Society of Ultrasound in Obstetrics and Gynecology; anyway, these are similar to most international guidelines, such as those of the International Society of Ultrasound in Obstetrics and Gynecology. The latter requires that the second trimester scan should be performed between 18 and 22 weeks of gestation, while in Italy the advised gestational age is more restricted (19 to 21 weeks’ gestation).
In the present study, the majority of congenital anomalies were diagnosed between 15 and 22 weeks’ gestation, with a significant lower proportion detected before 14 and after 23 weeks’ gestation (p< 0.0001). This observation is consistent with several studies (Carvalho et al., 2002; Saltvedt et al., 2006; Eik-Nes, 2010) showing that the highest detection rate of anomalies can be reached if the ultrasound fetal screening is performed in the second trimester of pregnancy.
32 The search for fetal anomalies is not regarded as an aim of the first trimester sonography, and no research project was established in the sanitary system on first trimester detection of fetal anomalies. In spite of this, more than 10 % of fetal anomalies were detected before 14 weeks’ gestation. Some of them were detected on the basis of the routine measurements involved in the screening for trisomy 21 based on nuchal translucency (cystic hygroma and fetal growth restriction). Other anomalies are evident even if not formally searched for, such as anenchephalus, megacystis and body- stalk anomaly: taken together, these anomalies represented the majority of the cases diagnosed before 14 weeks. It has been proposed that scans enabling the evaluation of this abnormal structures should be included in all sonographies performed at 11-14 weeks’ gestation (Syngelaki, 2011). Other anomalies such as holoprosencephaly, severe early hydrocephalus, severe dysplastic kidneys or limb reduction defects can be identified by early sonography if the fetus is in an appropriate position and the body habitus of the mother is favourable (Goldberg, 2004; Dashe et al., 2009).
However, it is difficult to conceive that the diagnosis of anomalies such as spina bifida or polydactyly have occurred by chance without a specific intention of the sonographer to evaluate fetal anatomy in the first trimester (Sepulveda et al., 2011). The knowledge that in research settings some diagnoses can be achieved, may have prompted the sonographers to try getting more information than advised by the guidelines. Anyway, this should not be used in medical litigations, because the sensitivity of obstetric ultrasound at these early gestational age is not yet known. For example, focused sonographic examination of the fetal spine is not part of the first-trimester scanning protocol because of the poor ossification and size of the fetal spine at this gestational age, which hinders the appropriate examination (De Biasio et al., 2002; Vignolo et al., 2005). Consequently, fetal spinal abnormalities diagnosed in the first trimester are usually severe, like the case in our series, that was at higher level of the spine and more extended than the most common cases of sacral defects involving only a few vertebrae.
Although the absence of a focused ultrasonography may be the reason why, in our study, no case of certain anomalies was diagnosed before 14 weeks, the natural
33 history of fetal malformations plays a very important role in the timing of their diagnosis. The manifestation of structural defects in the second trimester represents an important limitation of early ultrasonography. For example, the earliest reported gestation for the diagnosis of sequestration and cystic adenomatoid malformation is 16 weeks (Cavoretto et al., 2008), presumably because the production of pulmonary fluid and its retention within the lung resulting in detectable hyperechogenicity occurs after the onset of the canalicular phase of lung development at 16 weeks; also in our series, all cases of cystic adenomatous malformation of lung were recognised after 15 weeks’ gestation (Syngelaki, 2011).
Similarly, almost all cases of spina bifida were diagnosed between 15 and 22 weeks’ gestation, when its indirect signs (lemon sign, effaced cisterna magna, and small cerebellum) become visible (D’ Addario et al., 2008), and can prompt to a more detailed examination of the fetal spine. Equally, all cases of duodenal atresia and bowel obstruction were detected in the second half of pregnancy by their manifestations of polyhydramnios and double bubble appearance at sonography, that occur only when the amount of swallowed amniotic fluid exceeds the absorptive capacity of the stomach or the bowel and this usually happen after 20 weeks (Syngelaki, 2011).
Most of the Congenital Heart Defects, in the present study, were diagnosed between 15 and 22 weeks, consistent with a cohort study from van Velzen, showing that the prenatal detection rate of severe CHD in an unselected population may be significantly increased if thoroughly national screening programme are organised, with more than 90% of the prenatal diagnoses made before 24 weeks of gestation. A formal assessment of the four-chamber view and the outflow tracts is in fact part of the ultrasound second trimester screening, and in our series 21 out of 22 prenatal diagnoses of CHD were performed at the second trimester examination provided by the national protocol. However, it is well known that normal appearance of cardiac anatomy at any time of pregnancy does not exclude heart defects that may develop with advancing gestational age and can be detected later in pregnancy or even postnatally (Smrcek, 2006).
34 Finally, most of the urinary tract dilatations due to pyeloureteral junction stenosis, ureteric stenosis or vescicoureteric reflux, unlike those from urethral obstruction presenting as megacystis detectable in the first trimester, are not apparent until the second or third trimesters because the rate of fetal urine production is too low to result in retention within the upper urinary tract. The same would be true for fetal tumors like the 2 cases of sacrococcygeal teratoma of the present study, which often develop after the first trimester (Syngelaki, 2011).
As for late diagnoses, most of the anomalies diagnosed after 23 weeks of gestation have a recognised late onset (Rottem, 1997). All cases of ovarian cysts, in this study, were diagnosed after 23 weeks’ gestation, as expected from the natural course of this anomaly. In fact, maturation of the hypothalamus–pituitary–ovary axis commences from the 29th week of gestation under elevated levels of feto-placental estrogen and an immature hypothalamus–pituitary–ovarian feedback is thought to be responsible for gonadal hyperstimulation in premature fetuses (Shimada et al., 2008). Also all cases of achondroplasia were diagnosed after 23 weeks of gestation, when usually becomes apparent the limited growth of the long bones (Shramm, 2009), at variance with other skeletal dysplasia (thanatophoric dysplasia, achondrogenesis, etc.), which can receive an early diagnosis because the signs of affected skeleton, like hypomineralised skull, small chest with evidence of fractured ribs and short long bones, become evident even in the second or late first trimester. In addition, increased NT or hydrops were observed frequently associated with serious skeletal dysplasia presenting in early pregnancy, that may induce the sonographer to measure at minimum the femur length in the attempt to diagnose the anomaly (Khadil, 2011).
Other anomalies detected in the third trimester may have variable onset. In fact, in our series, cases of fetal hydrops, urinary tract dilatation, posterior urethral valve, hydrocephalus were diagnosed both before and after 23 weeks of gestation. The causes of these anomalies are multiple, and can impact on the fetal anatomy in different periods. For instance, dilatation of the fetal cerebral ventricles (hydrocephaly) is common to several pathological entities: aqueductal stenosis,
35 Chiari II malformation, Dandy–Walker complex, agenesis of the corpus callosum and in these cases the diagnosis may be achieved by the second trimester ultrasound examination (D' Addario, 2007). On the contrary, apparently isolated hydrocephaly has a natural history that lead to diagnosis late in the second trimester (Kennelly et al., 2009). Maternal infections and trauma to the mother during pregnancy have also been highlighted as risk factors for congenital hydrocephalus that can manifest at any gestational age or even after birth (Strigini et al., 2001; Kalyvas et al., 2016).
Another anomaly which was detected at different gestational age was polycystic kidney disease. Cases of polycystic kidney disease were diagnosed not only in the second and third trimester, but also in the first trimester of pregnancy. This can be linked to the specific diagnosis of polycystic kidney (autosomal dominant or autosomal recessive), but also to the phenotypic variability of this disease, with cases in the same family that can become clinically evident before or after birth (Roume et al., 2004).
Even if in the present study most of the anomalies diagnosed after 23 weeks’ gestation were late- onset or variable- onset anomalies (n=24), there are cases detected late because of other causes. In particular, in 8 cases, a disadvantaged social condition of the pregnant woman prevented her from seeking obstetric assistance, and therefore she did not undergo the mid-trimester ultrasound scan provided by the sanitary system. In a few cases (n=3) the sanitary system offered an incorrect appointment for the ultrasound examination (later than advised by the guidelines) or there was a medical error in the second trimester scan (n=4). In our study we considered the late diagnosis of ACC as a consequence of medical error. However, other studies showed that in a significant proportion of cases, most of the indirect signs of ACC are either absent or barely visible at the time of the mid-trimester ultrasound examination, and become more evident after 24 weeks of gestation; therefore, ACC may escape recognition at the time of the mid-trimester anomaly scan (Paladini et al., 2013).
36 In conclusion, unlike the common belief, our study shows that medical error is a rare cause of late diagnosis; on the other hand, other preventable causes are linked to the inability of the sanitary system to appropriately reach all pregnant women. However, even in an ideally perfect sanitary organization, some cases will remain undetected in early pregnancy because of their natural history.
Fifteen fetuses had a chromosomal anomaly beyond the structural anomaly detected at ultrasound examination (Table II). Almost all were diagnosed before 23 weeks’ gestation with only 2 cases detected later (namely, 1 case of trisomy 21 with duodenal stenosis because of the disadvantaged condition of the mother that delayed the ultrasound examination; and 1 case of trisomy 18 with spina bifida, diagnosed late because of an incorrect appointment for the ultrasound midtrimester scan). Among the chromosomal anomalies, trisomy 21, which is at birth much more common than other aneuploides, represented less than half of the cases included in the present series. This may reflect the high intrauterine lethality of trisomy 13, 18, and triploidy (also observed in our series); in fact, it is well known that their prevalence is higher at earlier gestational ages. Moreover, structural anomalies are more frequent in trisomies other than trisomy 21, making them more common in sonographic series than in series based on invasive prenatal diagnosis.
Timely prenatal diagnosis of lethal or severe malformations may offer benefit to the couple by giving them the possibility to terminate the pregnancy or alternatively by making it possible to prepare themselves for the birth of the ill baby. In the present study, a high proportion of fetuses with a lethal malformation were diagnosed before 23 weeks’ gestation, with many of them diagnosed even before 14 weeks. An early diagnosis may be more likely if the fetus has a gross malformation, such as anencephaly, megacystis, body-stalk anomaly, etc. On the other hand, in our study 5 cases of lethal anomalies remained undiagnosed by the mid- trimester scan. This was linked to a lethal genetic disease characterised by late phenotypic manifestations (2 cases of polycystic kidney disease) or an acquired condition that may occur at any gestational age (2 cases of fetal hydrops).
37 The last case of a late diagnosed lethal condition (trisomy 18) had spina bifida as the main sonographic diagnosis; spina bifida is usually diagnosed in the second trimester, but it remained undiagnosed because the mother had an incorrect appointment for the second trimester ultrasound examination, later than advised by the national protocol.
On the other side, not all the moderate anomalies are diagnosed late in pregnancy; in fact, 69 out of 88 were diagnosed between 15 and 22 weeks’ gestation, when TOP is still an option for the women. The fear of a negative evolution of the condition, or the expectation of the ‘’perfect baby’’, can lead to TOP even when the diagnosed fetal anomalies are not expected to change significantly the future quality of life. In fact, the Italian law allows TOP if the prenatal diagnosis affects the psychological well-being of the mother-to-be, independently of the severity of the anomaly. However, only 7 patients receiving the diagnosis of a moderate fetal anomaly chose to terminate their pregnancy, whereas the majority continued the pregnancy and delivered at term. On the contrary, TOP was requested by the majority of patients with a lethal (72.5%) and severe (52.0%) fetal anomaly. Therefore, the information regarding the expected outcome of a fetal structural anomaly is very important for the couple in the decision process towards terminating or not the pregnancy, and it may depend also of the gestational age at diagnosis.
Sometimes, a late diagnosis means a better outcome for the fetus, such as in case of diaphragmatic hernia. Its impact on the development of the lungs is lower if the herniation of abdominal organs occurs at a more advanced gestational age. Instead, if the herniation occurs early in pregnancy, this anomaly is often lethal, because of the lung hypoplasia that it causes (Gallot et al., 2007). The information to the couple must also include an estimation of the probability of IUFD, which is high for lethal anomalies and intermediate for severe anomalies.
38 In conclusion, the accuracy of sonography in the diagnosis of fetal structural anomalies at different gestational ages may depend on a variety of factors: besides the resolution of the equipment used and the ability of the sonographic operators, the natural history of the specific anomaly and the organization of the sonographic network play an important and often unrecognized role.
39
BIBLIOGRAPHY
Akgun H, Basbug M, Ozgun MT, Ozturk F, Okten T. Correlation between
prenatal ultrasound and fetal autopsy findings on urinary system anomalies terminated in the second trimester. Prenat Diagn 2014; 34:285–290.
Bakketeig LS, Eik-Nes SH, Jacobsen G, et al. Randomized controlled trial
of ultrasonographic screening in pregnancy. Lancet 1984; 2: 207–211.
Benacerraf, B. The use of obstetrical ultrasound in the obese gravida. Semin Perinatol 2013; 37: 345-7.
Bennet MJ, Little G, Dewhurst J, Chamberlain G. Predictive value of
ultrasound measurement in early pregnancy: a randomised controlled trial.
Br J Obstet Gynecol 1982; 89: 338–341.
Blaas H-GK. Detection of structural abnormalities in the first trimester
using ultrasound. Best Pract Res Clin Obstet Gynaecol 2014; 28:341-53.
Bonnet D, Coltri A, Butera G, Fermont L, Le Bidios J, Kachaner J Detection
of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality Circulation 1999; 99:916–8.
Brent RL, Jensh RP, Beckman DA. Medical sonography: reproductive
effects and risks. Teratology 1991; 44:123 – 46.
Bricker, L., N. Medley, and J. J. Pratt. Routine ultrasound in late pregnancy
(after 24 weeks' gestation) Cochrane Database Syst Rev 2015; Cd001451.
Bromley B, Nadel AS, Pauker S, Estroff JA, Benacerraf BR. Closure of the
cerebellar vermis: evaluation with second trimester US. Radiology 1994;
193: 761–763.
Cardoza JD, Goldstein RB, Filly RA. Exclusion of fetal ventriculomegaly
with a single measurement: the width of the lateral ventricular atrium.
Radiology 1988; 169: 711–714
Cavoretto P, Molina F, Poggi S, Davenport M, Nicolaides KH. Prenatal
diagnosis and outcome of echogenic fetal lung lesions. Ultrasound Obstet
40 D’ Addario V, Rossi AC, Pinto V, Pintucci A, Di Cagno L. Comparison of
six sonographic signs in the prenatal diagnosis of spina bifida. J Perinat
Med 2008; 36: 330–4.
Dane, B., C. Dane, D. Sivri, M. Kiray, A. Cetin, and M. Yayla. Ultrasound
screening for fetal major abnormalities at 11-14 weeks Acta Obstet
Gynecol Scand. 2007; 86: 666-70.
Dashe JS, McIntire D, Twickler DM. Maternal obesity limits the ultrasound
evaluation of fetal anatomy. J Ultrasound Med. 2009; 28:1025–1030.
Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by
pulsed ultrasound. Lancet 1958; 1: 1188–1195.
Eik-Nes SH. An overview of routine versus selective use of ultrasound. Ultrasound in Obstetrics and Gynaecology Vol 1, Chervenak FA, Isaacson GC, Campbell S (eds). Little, Brown &Co: Boston 1993; 229–238.
Eik-Nes, S. H. The 18-week fetal examination and detection of anomalies. Prenat Diagn, 2010; 30: 624-30.
European Concerted Action on Congenital Anomalies and Twins.
Subgroups of Congenital Anomalies, Version 2014, website data.
Filly RA, Cardoza JD, Goldstein RB, Barkovich AJ. Detection of fetal
central nervous system anomalies: a practical level of effort for a routine sonogram. Radiology 1989; 172: 403–408.
Franklin O, Burch M, Manning N, Sleeman K, Gould S, Archer N. Prenatal
diagnosis of coarctation of the aorta improves survival and reduces morbidity. Heart 2002; 87: 67–9.
Gallot, D., C. Boda, S. Ughetto, I. Perthus, E. Robert-Gnansia, C. Francannet, H. Laurichesse-Delmas, J. Jani, K. Coste, J. Deprest, A. Labbe, V. Sapin, and D. Lemery. Prenatal detection and outcome of congenital
diaphragmatic hernia: a French registry-based study Ultrasound Obstet
Gynecol 2007; 29: 276-83.
Garne E, Loane M, Dolk H,et al. Prenatal diagnosis of severe structural
congenital malformations in Europe. Ultrasound Obstet Gynecol 2005;
