Teratology Flashcards
What is meant by “teratology” or “dysmorphology”?
- it is defined as the study of congenital malformations (birth defects)
- these are abnormalities that occur during development that lead to specific phenotypic presentations
What are the 4 different types of congenital malformations?
What do they all have in common?
- structural
- metabolic
- functional
- behavioural
- they are all caused by a substance crossing the placenta
How common are major and minor congenital malformations?
- major structural anomalies affect 3% of live-born infants
- minor anomalies affect 15% of live-born infants
- these may not directly affect the health of the child, but act as a clue to investigate underlying major abnormalities
congenital malformations account for 25% of infant deaths
What are the 3 categories of causes of congenital malformations?
- they can be caused by environmental factors (15%)
- they can be caused by genetic factors (30%)
- or they can be caused by interaction of the environment with a person’s genetic susceptibility (55%)
- most congenital malformations are multifactorial, and for most of these, the details of their origin are unknown
Why is it important to recognise minor abnormalities in children?
- minor structural abnormalities themselves are not detrimental to the health of the child
- minor abnormalities can be associated with major abnormalities, so act as a clue to investigate more serious underlying defects
- the likelihood of having a major abnormality increases with the number of minor abnormalities that an individual has
- e.g. ear anomalies are present in nearly all children with syndromic malformations
How can the developmental time period be split into 3 unequal parts based on fertilisation age?
Early development stage:
- this is the period from week 0 - 3
- it involves rapid cell division (cleavage) to form the morula, followed by the blastocyst
Embryonic period:
- this describes the time period from week 3-8
- it is also called the organogenesis period as it is the time during which body systems are being developed
Foetal period:
- this describes the time period from week 8-38
- there is maturation of structures that have formed during the organogenesis period
During which period of development is the foetus most susceptible to teratogens and why?
What happens if it is exposed to a teratogen before this period?
- the foetus is most susceptible to teratogens during the embryonic period (weeks 3-8)
- a congenital malformation is most likely to occur during this period as this is when organs and body systems are developing
- a congenital malformation can occur outside of this period, but the risk is much lower
- the foetus is also susceptible to teratogens during gastrulation period (weeks 0-3), but is more likely to spontaneously abort
What 5 types of anomaly fall under the term “congenital malformation”?
- malformations
- disruptions
- deformations
- syndromes
- associations
What is meant by a malformation and when do they occur?
- malformations occur during the formation of structures (e.g. organogenesis)
- disturbed formation of a structure results in its complete or partial absence or an abnormal configuration
- can be caused by environmental and/or genetic factors acting together or independently
- e.g. complete/partial absence of a limb, ASD, VSD
What is meant by a disruption?
- a disruption results in a morphological alteration of already formed structures due to a destructive process
- e.g. amniotic bands causing limb defects or vascular accidents leading to transverse limb defects
What is meant by a deformation?
- deformations result from mechanical forces that mold a part of the foetus over a prolonged period
- e.g. clubfeet
- they often involve the musculoskeletal system and are potentially reversible postnatally
What is meant by a syndrome?
- a group of anomalies that are occurring together and have a specific common cause
- e.g. Down’s syndrome, foetal alcohol syndrome
- this term implies that a diagnosis has been made and the risk of recurrence is known
What is meant by an association?
- the nonrandom appearance of 2 or more anomalies that occur together more frequently than by chance alone, but the cause has not been determined
- e.g. VACTERL association
What happens in amniotic band syndrome?
What type of congenital malformation is this?
- it is a disruption as it involves disturbance to a structure that has already started to form and develop normally
- it is not a syndrome - a syndrome involves a group of phenotypic presentations occurring together and involving different systems
- this only involves the limbs
- fibrous bands of the amniotic sac become tangled around the developing foetus
- this presents a serious risk if they wrap around the head or umbilical cord
What type of congenital malformation is produced from oligohydraminos and why?
- oligohydraminos is the failure to form enough amniotic fluid
- it can happen for many reasons, including problems with the development of the kidneys
- it is associated with clubfoot and a slanted cranium as growth of the foetus is restricted due to lack of amniotic fluid
- this is an example of a deformation as there is a physical force acting on the foetus (lack of space in amniotic sac)
What is meant by the principles of teratology?
- how easily a given agent can cause a congenital defect depends on a number of factors
- the factors determining the capacity of an agent to produce birth defects are the principles of teratology
- they influence the teratogen’s ability to cross the placenta and cause a malformation
What are the 5 principles of teratology?
- genetics
- timing
- dose and duration
- mechanism of action
- manifestation of the abnormality that has been caused
How do genetics act as a principle of teratology?
- susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this genetic composition interacts with the environment
- the maternal genome is also important with respect to:
- drug metabolism
- resistance to infection
- other biochemical / mechanical processes affecting the foetus
the ability of the placenta to filter out teratogens has a genetic influence
What is meant by timing as a principle of teratology?
- the timing of exposure describes the point in development at which the foetus is exposed to the teratogen
- the foetus is most susceptible to teratogens during the embryonic period (weeks 3-8)
- some teratogens can affect the foetus outside of the organogenesis period - no stage of development is completely safe
- each organ system may have 1 or more stages of susceptibility
- e.g. cleft palate can occur at the blastocyst stage (day 6) or when the palatal shelves are forming (week 7) amongst others
What is meant by dose and duration as a principle of teratology?
- this describes the quantity of teratogen** that the foetus is exposed to and the **duration of time that this exposure lasts for
- the CNS develops for a long period of time, so these structures are susceptible to teratogens for the longest period of time
- this is why the CNS (incl. eyes) are often involved in congenital malformations)
What is meant by mechanism of action as a principle of teratology?
- teratogens act in specific ways on developing cells and tissues to initiate abnormal embryogenesis
- this is often by switching genes on or off or by inducing / inhibiting enzymes
- pathogenesis may involve cell death, decreased/increased cell proliferation or other cellular phenomena
What is meant by manifestation of the abnormality that has been caused as a principle of teratology?
- this describes the effect of the teratogen
- manifestations of abnormal development are:
- death
- malformation
- growth retardation
- functional disorders
What are the 8 major classes of teratogens?
- infectious agents
- heavy metals
- radiation
- drugs
- pyrexia / hyperthermia
- hormones
- maternal illness / disease
- maternal & paternal advanced age
- heavy metals and radiation are grouped together as physical teratogens
What are the 5 major viruses that can cross the placenta and what birth defects are they associated with?
Rubella:
- causes congenital rubella syndrome that leads to deafness, cataracts and heart defects
Cytomegalovirus:
- often the mother has no symptoms, but can cause serious illness of the foetus at birth and can be fatal
- some infants are asymptomatic at birth but develop abnormalities later in life:
- hearing loss
- visual impairment
- cerebral calcifications (calcium deposits within neural tissue)
- intellectual disability
Herpes simplex:
- usually infection is transmitted during delivery, causing severe illness and death
- infection during pregnancy can cause microcephaly and microphthalmia
Varicella:
- associated with:
- scarring of the skin
- limb hypoplasia
- intellectual impairment
- defects of the eyes and CNS
Toxoplasmosis:
- associated with hydrocephalus and cerebral calcifications
What steps should a pregnant woman take to avoid toxoplasmosis infection?
- they are advised to avoid undercooked meat and cat litter as these carry the parasite Toxoplasmosis gondii
- this can only harm the baby if it is contracted during pregnancy
- if the woman is already infected with the parasite prior to becoming pregnant, this should not cause any problems
What is the importance of hyperthermia/pyrexia as a teratogen and what steps should be taken to avoid this?
- heat can affect formation of the neural tube and can result in the formation of neural tube defects
- pregnant women are advised to avoid hot tubs and saunas
- pyrexia is an increased temperature that results from the pregnant woman fighting an infection, and this can also affect neurulation
What are the 7 main drugs that are known to cross the placenta and cause birth defects?
What needs to be taken into account when considering a mother’s medication?
- thalidomide
- anti-epileptics
- isotretinoin
- anti-psychotics & anxiolytics
- antidepressants (SSRIs)
- warfarin
- ACE inhibitors
- it is important to balance both the health of the mother and foetus when advising about medications
What malformations are associated with thalidomide?
- it was used as an antinauseant and sleeping pill
- it has been linked to amelia and meromelia (complete or partial absence of the extremities)
- it is also associated with:
- NTDs
- orofacial clefts
- intellectual disability & autism
- heart defects
- defects of the urogenital and gastrointestinal systems
What malformations are anti-epileptics associated with?
- congenital heart defects
- cleft palate
- valproic acid increases the risk of ASDs, polydactyly, hypospadius and craniosynostosis and spina bifida (highest risk)
What defects are caused by anti-psychotics and anxiolytics?
- certain defects are suspected but no links are proven:
- limb/skeletal malformations
- CNS defects
- cleft palate
- congenital heart defects
What congenital malformations are linked to SSRIs and why?
- congenital heart defects
- increase in frequency of spontaneous abortions
- they inhibit serotonin signalling, which is important for establishing laterality and for heart development
What defects is isotretinoin associated with?
- congenital heart defects
- severe limb malformations
- this is usually prescribed for acne and chronic dermatoses, but it is highly teratogenic and can produce virtually any type of malformation
What defects is warfarin associated with?
- skeletal abnormalities including:
- nasal hypoplasia
- abnormal epiphyses in the long bones
- limb hypoplasia
What defects are ACE inhibitors associated with?
- growth retardation
- foetal death
- renal dysfunction
- oligohydraminos
What are the proposed mechanisms of action of thalidomide?
When might it still be prescribed?
- inhibition of angiogenesis (formation of vascular structures)
- induction of oxidative stress (within the mitochondria)
- decreased expression of FGF genes
- induction of cell death
- it is no longer prescribed for morning sickness, but is still prescribed to treat leprosy in countries (e.g. Brazil) where the incidence is higher
What are the potential malformations associated with cigarette smoking?
- it has been linked to increased risk of orofacial clefts
- it also contributes to intrauterine growth retardation and premature delivery
How does the amount of alcohol consumed during pregnancy relate to the severity of malformation?
the concentration of alcohol consumed during pregnancy is correlated with the severity of phenotypic presentations at birth
- the more alcohol that is consumed during pregnancy, the more severe birth defects produced
What is the advice given to mothers relating to alcohol consumption?
- if you are pregnant or planning a pregnancy, the safest approach is not to drink alcohol at all to keep the risks to the baby to a minimum
- the risk of harm is likely to be low if a woman has only drunk small amounts before finding out she is pregnant
- women who find out they are pregnant after already drinking during pregnancy should avoid further drinking
What is the difference between foetal alcohol spectrum disorder (FASD) and foetal alcohol syndrome (FAS)?
- alcohol can induce a broad spectrum of defects ranging from intellectual disability to structural abnormalities of the face, heart and brain
- FASD is used to refer to any alcohol-related defects
- FAS is the most severe end of the spectrum and includes structural defects, growth deficiency and intellectual disability
What is the spectrum of malformations associated with FAS?
- growth restriction
- intellectual disability
- behavioural problems
- facial abnormalities
- heart defects
- brain defects (e.g. microcephaly)
What are the facial abnormalities associated with FAS?
- smooth philtrum
- thin upper lip
- flat nasal bridge
- flat midface
- epicanthal folds
- short palpebral fissures
How is alcohol able to act as a teratogen?
- ethanol diffuses through the placenta and enters the foetal compartment to accumulate within the amniotic fluid
- the baby will ingest the amniotic fluid, swallow it and digest it and then release it back into the amniotic sac as well as breathing it in
By what mechanisms is ethanol thought to act as a teratogen?
- through generation of reactive oxygen species / oxidative stress
- damaging effects on the placenta through vessel vasoconstriction
- this means that not enough nutrients are reaching the foetus - leading to growth restriction and intellectual disability
- mitochondrial damage
- disruption of normal cell-cell adhesion
- epigenetic effects
What is the recommendation for the use of ionising radiation in healthcare?
- all patients, but especially those who are young and of child bearing age, should not be exposed to ionising radiation unless completely necessary
- especially for the abdomen and pelvis
- a pregnancy test is commonly performed on women prior to exposure to ionising radiation even if they state they are not pregnant
- staff must wear lead aprons and protect the thyroid
How does radiation act as a teratogen?
- it kills rapidly proliferating cells
- this allows it to produce virtually any type of birth defect depending upon the dose and stage of development of the foetus
- it also acts as a mutagenic agent and can lead to genetic alterations of germ cells and subsequent malformations
What are the main sources of ionising radiation in health care?
Which has a higher radiating dose?
- X-ray is a source of ionising radiation through:
- plain films
- fluoroscopy
- barium studies
- CT scans have a higher radiating dose than X-ray
- With CT scans, exposure increases with contrast agent
How can androgenic agents (hormones) act as teratogens?
- androgenic agents were used in pregnancy to prevent abortion (progestins)
- they cause masculisation of female genitalia through fusion of the labia and enlargement of the clitoris
How can synthetic oestrogens cause congenital malformations?
- they can lead to female tract malformations and can affect the formation of the uterine tubes
- this can lead to reproductive dysfunction in later life
- also assoiated with congenital malformations of the uterus and upper vagina
- there is also an increased risk of carcinoma of the cervix and vagina in later life
How do environmental oestrogens cause congenital malformations?
- these are thought to be linked to a decreased sperm count and increased incidence of malformations of male genitalia
- an increased amount of soya in a males diet is thought to increase levels of oestrogens
- they also increase incidence of testicular cancer, hypospadias and CNS abnormalities
How is cortisone linked to congenital malformations?
- there is an association between increased levels of cortisone and an increased risk of oro-facial clefts
- women who take corticosteroids during pregnancy may be at a higher risk of having a child with an orofacial cleft
How is maternal diabetes linked to congenital malformations?
- in diabetes, there is an inability to monitor the levels of sugars that are crossing the placenta
- this can lead to a wide variety of defects, including NTDs, caudal dysgenesis** and **heart defects
- it is also linked to a high incidence of stillbirths, neonatal deaths and abnormally large infants
How can the risk of congenital malformations in a pregestational diabetic be lowered?
- glucose levels play a role in formation of congenital malformations, and not insulin
- there is a correlation between the severity and duration of maternal disease and incidence of malformations
- strict control of maternal glucose levels before conception and throughout pregnancy can reduce the occurrence of malformations
How can obesity lead to an increased risk of congenital malformations?
- prepregnancy obesity is associated with a 2x increased risk of a child with an NTD
- this is thought to be due to maternal metabolic disturbances affecting glucose, insulin and other factors crossing the placenta
- obesity is also associated with increased risk of omphalocele and heart defects
What is the major nutritional deficiency associated with congenital malformations?
- folic acid is important in neurulation and deficiency can result in NTDs
What are the potential paternal disease / factors that are linked to increased risk of congenital malformations?
occupational / environmental exposure:
- exposure to heavy metals and cigarette smoke has been linked to:
- low birth weight
- spontaneous abortion
- birth defects (via germ cell mutations)
increasing age:
- both increasing age and younger age are associated with increased chance of birth defects
semen contamination:
- this describes certain factors entering the ejaculate and causing malformations within the sperm themselves
What heavy metals have been seen to act as teratogens?
- lead and mercury are able to cross the placenta and act as teratogens
- lead is associated with increased abortions, growth retardation and neurological disorders
- a diet high in fish (especially tuna) contains a lot of mercury, and whilst the mother may not have any symptoms, the foetus is susceptible to mercury
