Oligohydramnios

Oligohydramnios causes fetal deformation and is well
recognised in fetal renal agenesis (Potter sequence). The
absence of urine production by the fetus results in severe
oligohydramnios, which in turn causes fetal deformation and
pulmonary hypoplasia. Oligohydramnios caused by chronic
leakage of liquor has a similar effect.
A normal fetus may be constrained by uterine
abnormalities, breech presentation or multiple pregnancy. The
prognosis is generally excellent, and the risk of recurrence is
low except in cases of structural uterine abnormality.

Dysplasia

Dysplasia refers to abnormal cellular organisation or function
within a specific organ or tissue type. Most dysplasias are caused
by single gene defects, and include conditions such as skeletal
dysplasias and storage disorders from inborn errors of
metabolism. Unlike the other mechanisms causing birth
defects, dysplasias may have a progressive effect and can lead to
continued deterioration of function.

Classification of birth defects

Single system defects
Single system defects constitute the largest group of birth
defects, affecting a single organ system or local region of the
body. The commonest of these include cleft lip and palate, club
foot, pyloric stenosis, congenital dislocation of the hip and
congenital heart defects. Each of these defects can also occur
frequently as a component of a more generalised multiple
abnormality disorder. Congenital heart defects, for example,
are associated with many chromosomal disorders and
malformation syndromes. When these defects occur as isolated
abnormalities, the recurrence risk is usually low.

Multiple malformation syndromes

When a combination of congenital abnormalities occurs
together repeatedly in a consistent pattern due to a single
underlying cause, the term “syndrome” is used. The literal
translation of this Greek term is “running together”.
Identification of a birth defect syndrome allows comparison of
cases to define the clinical spectrum of the disorder and aids
research into aetiology and pathogenesis.

Sequences

The term sequence implies that a series of events occurs after a
single initiating abnormality, which may be a malformation,
a deformation or a disruption. The features of Potter sequence
are classed as a malformation sequence because the initial
abnormality is renal agenesis, which gives rise to
oligohydramnios and secondary deformation and pulmonary
hypoplasia. Other examples are the holoprosencephaly
sequence and the sirenomelia sequence. In holoprosencephaly
the primary developmental defect is in the forebrain, leading
to microcephaly, absent olfactory and optic nerves, and midline
defects in facial development, including hypotelorism or
cyclopia, midline cleft lip and abnormal development of the
nose. In sirenomelia the primary defect affects the caudal axis
of the fetus, from which the lower limbs, bladder, genitalia,
kidneys, hindgut and sacrum develop. Abnormalities of all
these structures occur in the sirenomelia sequence.

renal aplasia

Murcs association is the name given to the non-random
occurrence of Mullerian duct aplasia, renal aplasia and
cervicothoracic somite dysplasia. In the Charge association the
related abnormalities include colobomas of the eye, heart
defects, choanal atresia, mental retardation, growth
retardation and ear anomalies.

Complexes

The term developmental field complex has been used to
describe abnormalities that occur in adjacent or related
structures from defects that affect a particular geographical
part of the developing embryo. The underlying aetiology may
represent a vascular event, resulting in the defects such as those
seen in hemifacial microsomia (Goldenhar syndrome), Poland
anomaly and some cases of Möbius syndrome.

Identification of syndromes

Recognition of multiple malformation syndromes is important
to answer the questions that parents of all babies with
congenital malformations ask, namely:
What is it?
Why did it happen?
What does it mean for the child’s future?
Will it happen again?
Parents often experience feelings of guilt after the birth of an
abnormal child, and time spent discussing what is known about
the aetiology of the abnormalities may help to alleviate some of
their fears. They also need an explanation of what to expect in
terms of treatment, anticipated complications and long term
outlook. Accurate assessment of the risk of recurrence cannot be
made without a diagnosis, and the availability of prenatal
diagnosis in subsequent pregnancies will depend on whether
there is an associated chromosomal abnormality, a structural
defect amenable to detection by ultrasonography, or an
identifiable biochemical or molecular abnormality.

assessment of infants

The assessment of infants and children with malformations
requires documentation of a detailed history and a physical
examination. Parental age and family history may provide clues
about the aetiology. Any abnormalities during the pregnancy,
including possible exposure to teratogens, should be recorded,
as well as the mode of delivery and the occurrence of any
perinatal problems. The subsequent general health, growth,
developmental progress and behaviour of the child must also
be assessed. Examination of the child should include a search
for both major and minor anomalies with documentation of
the abnormalities present and accurate clinical measurements
and photographic records whenever possible. Investigations
required may include chromosomal analysis and molecular,
biochemical or radiological studies.

A chromosomal or mendelian aetiology

A chromosomal or mendelian aetiology has been identified
for many multiple congenital malformation syndromes
enabling appropriate recurrence risks to be given. When the
aetiology of a recognised multiple malformation syndrome is
not known, empirical figures for the risk of recurrence derived
from family studies can be used, and these are usually fairly
low. The genetic abnormality underlying de Lange syndrome,
for example, is not yet known, but recurrence risk is very low.
Consanguineous marriages may give rise to autosomal recessive
syndromes unique to a particular family. In this situation, the
recurrence risk for an undiagnosed multiple malformation
syndrome is likely to be high. In any family with more than one
child affected, it is appropriate to explain the 1 in 4 risk of
recurrence associated with autosomal recessive inheritance,
although some cases may be due to a cryptic familial
chromosomal rearrangement.

genes

The molecular basis of an increasing number of birth
defect syndromes is being defined, as genes involved in various
processes instrumental in programming early embryonic
development are identified. Mutations in the family of
fibroblast growth factor receptor genes have been found in
some skeletal dysplasias (achondroplasia, hypochondroplasia
and thanatophoric dysplasia), as well as in a number of
craniosynostosis syndromes. Other examples include mutations
in the HOXD13 gene in synpolydactyly, in the PAX3 gene in
Waardenberg syndrome type I, in the PAX6 gene in aniridia
type II, and in the SOX9 gene in campomelic dysplasia.

Numerous malformation syndrome

Numerous malformation syndromes have been identified,
and many are extremely rare. Published case reports and
specialised texts often have to be reviewed before a diagnosis
can be reached. Computer programs are available to assist in
differential diagnosis, but despite this, malformation syndromes
in a considerable proportion of children remain undiagnosed.

Stillbirths

Detailed examination and investigation of malformed fetuses
and stillbirths is essential if parents are to be accurately
counselled about the cause of the problem, the risk of
recurrence, and the availability of prenatal tests in future
pregnancies. As with liveborn infants, careful documentation of
the abnormalities is required with detailed photographic
records. Cardiac blood samples and skin or cord biopsy
specimens should be taken for chromosomal analysis and
bacteriological and virological investigations performed. Other
investigations, including full skeletal x ray examination and
tissue sampling for biochemical studies and DNA extraction,
may be necessary. Autopsy will determine the presence of
associated internal abnormalities, which may permit diagnosis.

Environmental teratogens

Drugs
Identification of drugs that cause fetal malformations is
important as they constitute a potentially preventable cause of
abnormality. Although fairly few drugs are proved teratogens in
humans, and some drugs are known to be safe, the accepted
policy is to avoid all drugs if possible during pregnancy.
Thalidomide has been the most dramatic teratogen identified,
and an estimated 10 000 babies worldwide were damaged by
this drug in the early 1960s before its withdrawal.

Alcohol is currently the most common teratogen

Alcohol is currently the most common teratogen, and
studies suggest that between 1 in 300 and 1 in a 1000 infants
are affected. In the newborn period, exposed infants may have
tremulousness due to withdrawal, and birth defects such as
microcephaly, congenital heart defects and cleft palate. There
is often a characteristic facial appearance with short palpebral
fissures, a smooth philtrum and a thin upper lip. Children with
the fetal alcohol syndrome exhibit prenatal and postnatal
growth deficiency, developmental delay with subsequent
learning disability, and behavioural problems.

Treatment of epilepsy

Treatment of epilepsy during pregnancy presents a
particular problem, as 1% of pregnant women have a
seizure disorder and all anticonvulsants are potentially
teratogenic. There is a two to three-fold increase in the
incidence of congenital abnormalities in infants of mothers
treated with anticonvulsants during pregnancy. Recognisable
syndromes, often associated with learning disability, occur in a
proportion of pregnancies exposed to phenytoin and sodium
valproate. An increased risk of neural tube defect has been
documented with sodium valproate and carbamazepine
therapy, and periconceptional supplementation with folic acid
is advised. Anticonvulsant therapy during pregnancy may be
essential to prevent the risks of grand mal seizures or status
epilepticus. Whenever possible monotherapy using the lowest
effective therapeutic dose should be employed.

Maternal disorders

Several maternal disorders have been identified in which the
risk of fetal malformations is increased, including diabetes and
phenylketonuria. The risk of congenital malformations in the
pregnancies of diabetic women is two to three times higher
than that in the general population but may be lowered by
good diabetic control before conception and during the early
part of pregnancy. In phenylketonuria the children of an
affected woman will be healthy heterozygotes in relation to the
abnormal gene, but if the mother is not returned to a carefully
controlled diet before pregnancy the high maternal serum
concentration of phenylalanine causes microcephaly in the
developing fetus.

Intrauterine infection

Various intrauterine infections are known to cause congenital
malformations in the fetus. Maternal infection early in
gestation may cause structural abnormalities of the central
nervous system, resulting in neurological abnormalities, visual
impairment and deafness, in addition to other malformations,
such as congenital heart disease. When maternal infection
occurs in late pregnancy the risk that the infective agent will
cross the placenta is higher, and the newborn infant may
present with signs of active infection, including hepatitis,
thrombocytopenia, haemolytic anaemia and pneumonitis.

Rubella embryopathy

Rubella embryopathy is well recognised, and the aim of
vaccination programmes against rubella-virus during childhood
is to reduce the number of non-immune girls reaching
childbearing age. The presence of rubella-specific IgM in fetal
or neonatal blood samples identifies babies infected in utero.
Cytomegalovirus is a common infection and 5–6% of pregnant
women may become infected. Only 3% of newborn infants,
however, have evidence of cytomegalovirus infection, and no
more than 5% of these develop subsequent problems. Infection
with cytomegalovirus does not always confer natural immunity,
and occasionally more than one sibling has been affected by
intrauterine infection. Unlike for rubella, vaccines against
cytomegalovirus or toxoplasma are not available, and although
active maternal toxoplasmosis can be treated with drugs such as
pyrimethamine, this carries the risk of teratogenesis.

Herpes simplex infection

Herpes simplex infection in the newborn infant is generally
acquired at the time of birth, but infection early in pregnancy is
probably associated with an increased risk of abortion, late fetal
death, prematurity and structural abnormalities of the central
nervous system. Maternal varicella infection may also affect the
fetus, causing abnormalities of the central nervous system and
cutaneous scars. The risk of a fetus being affected by varicella
infection is not known but is probably less than 10%, with a
critical period during the third and fourth months of
pregnancy. Affected infants seem to have a high perinatal
mortality rate.