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Suspected fetal anomalies

may benefit from antenatal treatment, others may require early

intervention following delivery.
The outcome and prognosis for the fetus or the neonate depends on the presence of other associated structural abnormalities, underlying chromosomal or genetic abnormalities, the
interventions and treatment options available for the structural
abnormality and the short and long-term handicap incurred to
the child as a result of the abnormality. The presence of underlying chromosomal or genetic abnormalities is associated with an
increased incidence of learning difficulties and multiple structural abnormalities, which may or may not be detected before the
birth and may confer significant disability and a limited life expectancy. Isolated structural abnormalities usually have a better
The assessment of fetal structural abnormalities should also
include a detailed maternal medical history, including enquiry
about drug use during the pregnancy, both prescribed and illicit,
and family history. Medical conditions such as diabetes and
medications such as anti-epileptics are associated with an
increased incidence of structural malformations. If an underlying
maternal medical condition such as poorly controlled diabetes is
revealed for the first time during assessment of fetal structural
abnormalities, then it becomes important to manage the
maternal medical condition to prevent any other adverse
outcome for the mother as well as the fetus. Detailed family
history can sometimes point towards a genetic aetiology, which
may have implications for the mother, the unborn child, and
other family members.
In addition to detailed history, further investigations may be
needed to give more information regarding the extent and
prognosis of the condition. These investigations may be in the
form of other imaging modalities e.g. magnetic resonance imaging (MRI) scan in case of fetal brain abnormalities, or may
involve inquisition of the fetal genotype, either invasively using
CVS or amniocentesis, or non-invasively using free fetal DNA
studies of maternal blood.

Amita Mahendru
Victoria De Giorgio-Miller
Alec McEwan

Assessment of the unborn patient following the initial detection of a fetal
structural anomaly involves further detailed ultrasound scanning, usually
followed by other investigations to ascertain the extent of the abnormality, and to attempt to identify an underlying cause. Although many
congenital fetal anomalies are sporadic, some are associated with
maternal infections or medical disorders, such as diabetes, and others
are caused by underlying pathological genetic variants. As the understanding of the human genome advances, the proportion of idiopathic
congenital anomalies will decline. The new molecular technologies of
array hybridization and non-invasive prenatal diagnosis will move the
specialty of prenatal diagnosis into a new era in the very near future.
However, there will always be a place for careful history taking, as one
of the cases below illustrates.
Diagnosis of maternal disease following clinical assessment of fetal
anomalies allows maternal treatment in order to prevent progression of
disease, prevent further fetal consequences and may even have implications for the family and other siblings. Similarly, the diagnosis of genetic
disorders allows for focused earlier testing in future pregnancies, and may
also have wider implications for the family.
This journal has published a number of articles previously which use
case histories to illustrate the principles of prenatal diagnosis and management. This article adds three further cases. The details of the anomalies are less important than the processes by which the final diagnoses
were reached.

Keywords bladder exstrophy; fetal limb abnormalities; free fetal DNA;

maternal diabetes; Okihiro syndrome; sacral agenesis


Case 1: Diagnosis of maternal type 1 diabetes following

diagnosis of fetal structural abnormality at 26 weeks gestation

Once a fetal structural abnormality is detected antenatally,

detailed assessment is undertaken by fetal medicine specialists to
confirm the diagnosis, determine its extent, identify the presence
of other structural abnormalities and counsel regarding the implications for the fetus, the pregnancy and the neonate. Antenatal
diagnosis enables the couple to exercise informed choice. Some
abnormalities may be serious and the couple may be offered the
option of termination of pregnancy. Whereas some abnormalities

An 18-year-old woman in her first pregnancy, thought to be fit

and well, was referred to a fetal medicine unit for further
assessment at 26 weeks gestation following detection of fetal
talipes on her detailed scan a number of weeks earlier. She had
previously declined Down syndrome screening. A scan by the
fetal medicine team showed that both femurs were below the 3rd
centile with normal abdominal and head circumference measurements, and normal amniotic fluid index. Additional structural abnormalities were identified on the scan including the
failure of ossification in the lower spine, consistent with sacral
agenesis (see Figures 1 and 2), persistent dorsiflexion and
abnormal appearance of the left foot (Figure 3), a ventricular
septal defect (VSD) with possible overriding of aorta, and a single
umbilical artery.
A fetal MRI was performed to assess the fetal spine and spinal
cord and this confirmed sacral agenesis with the spinal cord
ending at a higher level than normal with a blunted appearance.
Normal intracranial anatomy was noted (Figure 4). Fetal echocardiography by a paediatric cardiologist confirmed the presence

Amita Mahendru MD MRCOG is Subspecialty Trainee in Fetal and Maternal

Medicine at Nottingham University Hospitals NHS Trust, Nottingham,
UK. Conflicts of interest: none declared.
Victoria De Giorgio-Miller MBBS BSc(Hons) DRCOG is a Specialty Trainee at
Nottingham University Hospitals NHS Trust, Nottingham, UK. Conflicts
of interest: none declared.
Alec McEwan BA BM BCh MD MRCOG is a Consultant in Fetal Medicine and
Obstetrics at Nottingham University Hospitals NHS Trust, Nottingham,
UK. Conflicts of interest: none declared.



2014 Elsevier Ltd. All rights reserved.


Absent sacrum
with abruptly
ending spine

Figure 1 Ultrasound image of fetal spine in sacral agenesis.

of a ventricular septal defect with an over-riding narrowed aorta,

and the possibility of sub-aortic stenosis.
She was counselled regarding the potential implications of
these abnormalities for the baby and possible causes for the
multiple structural abnormalities were discussed, including diabetes and chromosomal abnormalities.
The finding of sacral agenesis prompted an oral glucose
tolerance test (GTT) and an HbA1c level. The HbA1c was 85
mmol/mol (normal range: 30e59) and the capillary blood
glucose was 14.2 mmol/litre, with a markedly abnormal oral
glucose tolerance test. Detailed history at this stage also revealed
frequent episodes of glycosuria earlier in the pregnancy and a
family history of diabetes. Her father was diagnosed with type 1
diabetes at the age of 13 years and apparently died at the age of
27 secondary to renal failure. Her paternal grandmother had type
2 diabetes and her cousins sister from her fathers side had
diabetes in pregnancy and was subsequently diagnosed with type
1 diabetes.

Although maternal diabetes was considered to be the most

likely cause, the possible implications of an underlying chromosomal abnormality in the fetus were also discussed, including
the high chance of significant learning difficulties. Amniocentesis
was offered but declined at that stage because of fears of preterm
labour. A late amniocentesis at 34e36 weeks was suggested. She
received specialized counselling from a paediatric surgeon and
cardiologist. The option of termination of pregnancy was discussed in the event of an underlying chromosomal disorder.
The implications of caudal regression syndrome for the child,
including the possibility of problems with gait and walking, and
bladder, bowel and sexual dysfunction were described. The child
would be expected to be of normal intelligence if the chromosome analysis was normal. She was made aware that it is very
difficult to predict the exact extent of problems until further
assessment of the lower limb and bladder function by orthopaedic surgeons and urologists after the birth of the child.
She was started on long and short-acting insulin, and was
taught home blood glucose monitoring. She was monitored on a
regular basis by the fetal medicine team for fetal growth and
wellbeing and by the diabetes team with regards to her glucose
An ultrasound scan at 30 weeks gestation revealed polyhydramnios and a macrosomic fetus with short long bones. She
was a poor attender of hospital appointments and she did not
attend any further appointments after 33 weeks. She delivered a
baby boy weighing 3080 g by ventouse delivery following

Figure 2 Three-dimensional image of spine showing small sacral stump.

Figure 3 Persistent dorsiflexion and abnormal position of the left foot.



2014 Elsevier Ltd. All rights reserved.


Abrupt ending of
the spinal cord

Figure 4 MRI image of the spinal cord ending at a higher level.

spontaneous labour at 37 weeks and 1 day. The baby was born

with normal Apgars of 10 at 5 and 10 at 10 min. His feet were
abnormal with dorsiflexion at the ankle due to lack of planter
flexion from the calf musculature. Abdominopelvic X-ray on the
1st day of life showed absent sacrum and coccyx, with segmentation abnormalities of the upper spine and bilateral hip dislocation (Figure 5). Echocardiography revealed small VSD with
normal aorta and no evidence of coarctation. Renal ultrasound
scan was normal. The baby was discharged and follow up was
arranged with the orthopaedic and spina bifida team for the hip
dislocation and the foot abnormalities. Splinting was initiated for
correction of the lower limb abnormalities. He was followed up
by the paediatric cardiologists and had a normal echocardiography at 6 months of age, with spontaneous closure of the VSD. He
suffers from neuropathic bladder and urinary continence problems and is also being followed up by the paediatric nephrology

Sacral agenesis is characterized by abnormal development of

the lower portion of the caudal spine. Caudal regression syndrome or sacral agenesis syndrome occurs in approximately 1 in
25,000 live births and is characterized by a series of congenital
abnormalities including absence of a variable portion of the
lumbar and sacral vertebrae and corresponding segments of the
spinal cord. It may be associated with genitourinary, gastrointestinal and cardiac abnormalities similar to the VACTERL association (Vertebral abnormalities, anal atresia, cardiac
abnormalities, oesophageal atresia, renal agenesis and limb abnormalities) and is also usually found with a single umbilical
It arises as a result of abnormal primitive streak migration or
differentiation, perhaps before the 7th week of gestation during
embryogenesis. Due to the proximity and interdependency of the
developing caudal nervous, spinal, hindgut and mesonephric
elements, other associated structural abnormalities are common.

Hypoplastic S1

Figure 5 Skeletal X-ray of the newborn showing absence of the sacrum, coccyx and hypoplastic S1.



2014 Elsevier Ltd. All rights reserved.



Figure 6 Sagittal view showing bladder bulge with cord insertion above it.

this condition. The neonate would require multiple major surgical reconstructions to correct the abnormalities of the urinary
system and genitalia over the first few years of the childs life.
These may have implications for continence, renal function and
genital appearance and function, particularly for a male child.
An amniocentesis was offered, but declined because of fears
of disrupting the pregnancy. The karyotype is normal in the vast
majority of cases of bladder exstrophy. However, the future
parents were very keen to learn the gender of the fetus before the
birth. Maternal blood was taken for free fetal DNA (ffDNA)
testing for fetal sex determination and this showed a male fetus.
They opted to continue with the pregnancy.
She had serial scans by the fetal medicine team which documented normal growth of the fetus and normal appearances of
the fetal kidneys. No other obvious fetal abnormalities were
detected on the scan. Labour was induced at 39 weeks and a
male infant of 3200 g was delivered by normal vaginal delivery.
He had bilateral inguinal hernias at birth and required bilateral
inguinal herniotomies. The surgery for bladder exstrophy is
performed in only two centres in UK (Manchester and Great
Ormond Street) who had been made aware of this baby well in
advance of the birth. Indeed, the family had been seen at Great
Ormond Street during the third trimester and received orientation
to the paediatric unit, and further sources of information.

The majority of cases are sporadic. However, the incidence is

higher in maternal diabetes with approximately 1 in 350 babies
born to women with pre-existing diabetes having some degree of
this disorder with an odds ratio of 26 when compared with nondiabetic pregnancies. It can also occur secondary to rare genetic
causes or vascular disruption. The survival and prognosis depends on the extent of the lesions, other associated abnormalities
and the underlying cause. Therefore, the aim of prenatal diagnosis is to obtain information regarding the extent of caudal
dysgenesis, detect the presence of other structural abnormalities,
and establish the cause if possible.
Pre-existing diabetes is the most common maternal medical
cause of fetal abnormalities, but there are others. Maternal
hyperglycaemia at the time of fetal organogenesis increases the
incidence of structural malformations three to four-fold,
including anencephaly and encephalocele, several subgroups of
congenital heart defects, omphalocele and bilateral renal agenesis. Strict control of maternal metabolism in the peri-conception
period and throughout gestation reduces the occurrence of the
population increased. Poorly controlled maternal phenylketonuria exposes the fetus to elevated levels of amnio acids,
increasing the incidence of microcephaly or cardiac defects.

Case 2: Use of free fetal DNA to determine fetal gender in a case

of bladder exstrophy
A 21-year-old woman was referred from ultrasound due to nonvisualization of the fetal bladder but with normal liquor volumes
at repeat scans at 20 and 23 weeks. She had one previous normal
pregnancy. Scan by the fetal medicine team showed the bulge of
the bladder exstrophy on the lower abdominal wall below the
cord insertion (Figure 6) with the fetal thighs in a position of
constant abduction (Figure 7). The bladder bulge was better
visualized on 3-D scan (Figure 8). However, it was difficult to
ascertain fetal gender from the scan. There were no other
obvious fetal structural abnormalities. Of particular note there
was no omphalocele, and the fetal spine and kidneys appeared
normal. A provisional diagnosis of bladder exstrophy was made.
The implications of this diagnosis were explained by a paediatric urologist with experience in looking after children with


Figure 7 Fetal legs in persistent abducted position.


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Bladder bulge

Figure 8 Three-dimensional view of the bladder bulge.

Case 3: Diagnosis of an autosomal dominant genetic condition

following detection of fetal upper limb abnormalities

Bladder exstrophy (BE), diagnosed antenatally by absence

of bladder, low insertion of umbilical cord and bony pelvis
abnormality, is a rare fetal structural abnormality with a reported incidence of 1/40,000 live births. Approximately 14e18
babies with BE are born each year in the UK. Antenatal diagnosis is possible but is not always accurate in terms of differentiation between bladder exstrophy and/or associated
cloacal exstrophy. The combination of omphalocele, neural
tube defect and bladder exstrophy (OEIS) must be differentiated from bladder and cloacal exstrophy. There is significant
long-term morbidity in these conditions and extensive reconstruction surgery is usually required to achieve satisfactory
urinary and reproductive outcome. The prognosis is better for
isolated bladder exstrophy, but it is nevertheless a complex
problem. Functional outcome is similar in relation to gender
but the sexual outcome is poorer in boys than in girls and
therefore, for some parents knowing the gender of their baby
is relevant to making a decision about continuation of the
pregnancy. In this condition, ultrasound diagnosis of
gender may not be possible and before the availability of cell
free fetal DNA (cffDNA), fetal gender was ascertained by
amniocentesis. With the help of cffDNA it is now possible to
diagnose fetal sex from maternal blood with a sensitivity of
96.6% and specificity of 98.9%. These vary very little with the
trimester of testing.
Determination of the fetal gender by the non-invasive technique of cffDNA is also useful in X-linked recessive diseases such
as haemophilia and Duchennes muscle dystrophy, maternal
medical conditions such as congenital adrenal hyperplasia or in
further investigation of skeletal dysplasias such as campomelic
dysplasia. In addition, cffDNA has revolutionized management
of Rh-D disease, prenatal testing in various single gene disorders
and is now being used in the non-invasive screening and diagnosis of various chromosomal abnormalities including Down
syndrome screening. Research groups have shown that the entire
fetal genome is accessible using cffDNA and it is likely that the
majority of genetic problems in the future will be diagnosed noninvasively.


A 34-year-old woman was referred to fetal medicine following

the detection of bilateral upper limb abnormalities at her 20 week
detailed scan in her fourth pregnancy having had an uneventful
pregnancy and two miscarriages before. The fetus had radial
aplasia in the right forearm with abnormal flexion of the hand
and an absent forearm on the left side with the hand attached
directly to the elbow (Figure 9). The mother was born with
talipes that required multiple surgeries for correction and had a
history of a right-sided stroke outside of pregnancy for which she
was on daily aspirin 75 mg and enoxaparin during this pregnancy. They were a non-consanguineous couple.
A further ultrasound scan by the fetal medicine specialist
confirmed bilateral radial aplasia and absent ulna on the left.
Both hands were visible but abnormally flexed and rotated at the

Figure 9 Left sided upper limb with humerus, absent radius and ulna and
hand attached to the humerus.


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wrist. Reliable visualization of the thumbs was not possible.

There were no other obvious structural abnormalities on the
The fetal medicine consultant noticed that the male partner
had somewhat unusual hands and enquired further. It transpired
that he was born with complex congenital heart disease, more
specifically truncus arteriosus type 1 associated with a very large
ventricular septal defect for which he underwent several successful cardiac surgeries. He was also born with a hypoplastic
right thumb and a finger-like left thumb. The link between these
anomalies had never been made before but a referral to the
clinical geneticists was suggested in view of the association between upper limb abnormalities and cardiac problems. The
woman had been counselled regarding the possibility of amniocentesis to rule out chromosomal abnormalities and opted to
have this performed whilst waiting to see the geneticists. She was
advised to omit a dose of aspirin and enoxaparin on the day of
the procedure. Fetal echocardiography was normal.
Information was given regarding support groups such as
REACH (the association of children with upper limb deficiency)
and the option of termination of pregnancy was also discussed.
The initial result from amniocentesis showed no evidence of
trisomy 13, 18 or 21 and no evidence of a 22q11.2 microdeletion.
Clinical examination by the genetics team revealed that the
partner had bilateral Duane anomaly (abnormal eye movements)
and bilateral hypoplastic thenar eminences with likely absent
radii on both sides in addition to the cardiac abnormalities for
which he had the surgeries. This was suggestive of Duane-radial
ray syndrome characterized by abnormal eye movement (Duane
anomaly or Duane syndrome) and abnormalities of bones in the
arms and hands. This abnormality results from the improper
development of certain nerves that control eye movement. Bone
abnormalities in the hands include malformed or absent thumbs,
an extra thumb, or a long thumb that looks like a finger. Partial
or complete absence of bones in the forearm is also common.
Together, these hand and arm abnormalities are known as radial
ray malformations.
The likely differential diagnosis of HolteOram syndrome and
Okihiro syndrome were discussed and a blood sample was taken
from the husband to test for gene mutations specific for Holt
eOram syndrome and Okihiro syndrome. The couple were
committed to the pregnancy but wanted to pursue tests to
establish the diagnosis. They were referred to see the hand surgeon to further discuss management of the babys limb
Upper limb abnormalities are very commonly associated with
genetic syndromes. HolteOram syndrome is caused by mutations in the TBX5 gene. This gene provides instructions for
making a protein that plays a role in the development of the
heart, in particular for the process that divides the developing
heart into four chambers and in the development of bones in the
arm and hand and upper limbs before birth. The syndrome is
characterized by skeletal abnormalities of the hands and arms
(upper limbs) and life-threatening cardiac abnormalities such as
an atrial or ventricular septal defect. It has an autosomal dominant inheritance and the affected child of a parent with Holt
eOram syndrome has a 1 in 3 risk of being born with severe
upper limb anomaly and 1 in 22 risk of being born with


The features of HolteOram syndrome are similar to those of a

condition called Duane-radial ray syndrome or Okihiro syndrome, which is caused by a mutation in one copy of SALL4
gene. Okihiro syndrome is characterized by upper limb abnormalities, ocular abnormalities and in some cases renal anomalies
or anal anomalies. It is not usually associated with complex
congenital heart disease or ulnar abnormalities.
The results of the genetic tests confirmed that the father was
affected with Okihiro syndrome rather than HolteOram syndrome. The genetic testing on the amniocyte DNA confirmed that
the baby had inherited mutation in SALL4 gene and therefore
was affected with Okihiro syndrome. Her subsequent scan at 28
weeks did not show any other additional fetal anomaly and she
had an uneventful pregnancy and had a normal delivery.
Neonatal examination showed presence of birthmarks on the
eyelids but the eyes were otherwise normal. The baby had a
humerus and clavicle on both sides with absent radii in both
arms and short forearm on the left side, 3 digits in the left hand, 4
digits in the right hand and no thenar eminence. Echocardiography showed patent ductus arteriosus (PDA) and an atrial septal
defect, both of which were managed conservatively and the baby
was subsequently discharged from cardiac follow up. The renal
ultrasound scan was normal and the baby is thriving well and
having occupational therapy for the upper limbs.
This case illustrates the importance of detailed family history,
three-generation family tree, involvement of clinical genetics and
a general examination of the couple in cases of multiple fetal
structural abnormalities, especially cardiac, upper limb and renal
abnormalities. This may lead to the diagnosis of a specific genetic
syndrome, which will have subsequent implications for the
current and future pregnancies. Some of these genetic syndromes
may have significant implications for the family and other siblings. Moreover, non-invasive prenatal diagnosis using ffDNA
may be available for some of these syndromes for the couples
future pregnancies. As array hybridization techniques become
routine for prenatal samples, genetic disorders such as Okihiro
syndrome are likely to be diagnosed much more frequently
before birth, even in the absence of parental clues.
Another example of a parental genetic condition, which may
also be diagnosed for the first time during pregnancy following
prenatal detection of fetal structural anomalies, is mild maternal
myotonic dystrophy. An affected fetus may present with talipes
or positional limb abnormalities and polyhydramnios in late
mid/early third trimester. Maternal grip myotonia might be elicited with a delay of several seconds in the relaxation of the
muscles of the hand when a handshake is performed. There is
likely to be a family history of this condition. Myotonic dystrophy
is the most common heritable neuromuscular disorder, with a
prevalence of 1 in 8000. It is associated with a poor prognosis for
the affected fetus/neonate (neonatal mortality of 20%) and those
that survive have significant learning disability. It is an autosomal dominant condition caused by a triplet repeat expansion
(CTG) in the non-coding region of the myotonin gene at 19q13.3.
Affected individuals have an increased number of repeats from
50 to thousands (normal is 4e37) and the severity is related to
the number of repeats. The disease is variable in expression and
an increase in the size of the repeat expansion may occur during
parent to child transmission with extreme amplification with
maternal transmission. Therefore, prenatal diagnosis not only


2014 Elsevier Ltd. All rights reserved.


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involves implications for the index pregnancy but also for other
siblings and future pregnancies.

There is an increased incidence of fetal structural abnormalities
in women with medical conditions such as poorly controlled
diabetes. Maternal diabetes may be diagnosed for the first time
during pregnancy on assessment of a fetal structural anomaly
and management would help to avoid further adverse maternal
or fetal outcomes. Apparently spontaneous fetal abnormalities
may have a genetic aetiology, and careful history and family
examination may give vital clues.
The management of many major fetal anomalies involves
additional investigations such as three-dimensional scan, invasive and non-invasive genetic diagnosis and other imaging modalities such as magnetic resonance imaging for fetal nervous
system and pulmonary assessment.
In counselling the couples with multiple or complex fetal
anomalies regarding prognosis for the pregnancy, multidisciplinary input from various teams such as neurosurgeons, paediatric surgeons, plastic surgeons, orthopaedic surgeons,
urologists, clinical genetics and paediatric radiologists is often
required. It is important therefore, that following initial detection
of the anomaly or anomalies the couple are given opportunities
to discuss and decide on the various management options
available to them.

Practice points

Firth H, Hurst J. Oxford desk reference clinical genetics. Oxford university
Press, 2012; 388e9.
Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in
pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol
Teratol 2012; 94: 134e40.
Goyal A, Fishwick J, Hurrell R, Cervellione RM, Dickson AP. Antenatal
diagnosis of bladder/cloacal exstrophy: challenges and possible solutions. J Pediatr Urol 2012; 8: 140e4.
Sadler TW. Langmans medical embryology. 11th edn. Philadelphia Pa:
Lippincott Williams and Wilkins, 2010. 61e63 and 119.



There will always be a place for careful history taking in the

clinical assessment of fetal anomalies as it may allow diagnosis of
maternal medical disease.
Diagnosis of maternal disease following clinical assessment of
fetal anomalies allows maternal treatment in order to prevent
progression of disease, prevent further fetal consequences and
may even have implications for the family and other siblings.
Determination of fetal gender by the non-invasive technique of
cffDNA is useful in counselling in case of structural abnormalities
such as bladder exstrophy, in X-linked recessive diseases such as
haemophilia and Duchennes muscle dystrophy, maternal medical
conditions such as congenital adrenal hyperplasia or in further
investigation of skeletal dysplasias such as campomelic
Detailed family history and careful examination may reveal underlying genetic disorders in case of fetal upper limb
The diagnosis of genetic disorders allows for focused earlier
prenatal testing in future pregnancies by invasive or newer noninvasive techniques such as free fetal DNA, and may also have
wider implications for the family.

2014 Elsevier Ltd. All rights reserved.