DOHAD Flashcards
What is a birth defect defined as?
Structural or functional anomaly which is present at conception or occurs before the end of pregnancy and is either diagnosed in pregnancy or before 6 years of age.
What structural developmental anomalies can affect young foetuses?
Spina bifida
Congenital cardiac defects
Congenital dislocation of the hips
What functional developmental anomalies can affect young foetuses?
Cystic fibrosis
Haemophilia
What is the incidence of developmental anomalies in WA?
5% (1:20)
What is the job of the WARDA?
WARDA is the Western Australian Register for Developmental Anomalies. They collect data on developmental anomalies and cerebral palsy in WA.
WARDA collects data to guide research and investigation into causes, prevention, and management of developmental anomalies.
Notifications to WARDA are mandatory since 2011.
Each individual defect is coded according to the 5-digit British paediatric association ICD-9 system.
What are birth defects associated with?
Major cause of death.
Birth defect is present in 12.4% of still births and 28.9% of neonatal deaths.
Who are birth defects more common in?
Males and multiple pregnancies.
What are WARDAs diagnostic categories of birth defects? Which is most common?
Most common are musculoskeletal defects (in 2014)
Nervous system defects (4.2/1000 births annually)
Urogenital defects
Congenital abnormalities of the eye, ear, face, and neck
Congenital anomalies of the inegument
Cardiovascular defects (common)
Chromosome defects (common)
Respiratory system defects
GI defects
Other
What are the most common nervous system defects?
Neural tube defects (1.2/1000 births):
Anencephaly
Spina bifida
Encephalocele
Other nervous system defects:
Microcephaly (10 per year)
Congenital hydrocephalus (0.5/1000 births)
Congenital deafness (0.8/1000 births)
How does the neural tube close? What happens if there is a failure in this?
Begins in cervical area and spreads from there in the cranial and caudal directions.
Cranial end closes by day 24 and caudal end by day 26.
If the posterior neuropore does not close spina bifida occurs and if anterior neuropore closure fails to take place anencephaly results.
How are neural tube defects detected early on?
They can be seen via ultrasound.
What are the risk factors for neural tube defects?
Most cases of NTDs are multifactorial in origin
2 - 5% recurrence in subsequent pregnancies
Genetic influences (known genetic syndromes, familial clustering)
Multiple pregnancies
Environmental agents (hyperthermia)
Nutritional deficiencies (folate deficiency in particular)
What is folate important for?
It is a group B vitamin that is necessary for production and maintenance of new cells.
Folate is a coenzyme in one-carbon transfer during methylation cycle which form part of DNA and the neurotransmitters.
Methylation of homocysteine to produce methionine uses 5-MTHF as the methyl donor
What happens in folate deficiency?
Accumulation of homocysteine which results in associated cardiovascular disease risk.
How can folate and neural tube defects be prevented?
MTHFR gene mutation affects 8 - 35% of the population depending on ethnicity.
Reduced folate carrier gene (RFC1)
How does genetic influence folate metabolism?
Several gene polymorphisms affect folate metabolism.
These are associated with reduced folate absorption and therefore increased folate needs
How are folate related issues prevented during pregnancy?
Periconceptional folic acid is administered because it reduces the prevalence of NTD.
How much periconceptional folic acid is given to women daily?
Women with no risk factors for NTDs: 400 - 800 mcg folic acid preconception until 12 weeks gestation.
Women with risk factors: 5 mg folic acid
What alternative to folic acid supplementation has been proposed?
5-methyl-tetrahydrofolate
What risk factor is most commonly associated with chromosomal defects?
Age of the mother
How common is trisomy 21?
3.2/1000 in WA (100/year)
It accounts for 50% of chromosomal abnormalities.
What causes trisomy 21?
Non-disjunction (95% of cases)
Unbalanced translocation (4%)
Mosaicism (1%)
What are the phenotypic features of trisomy 21?
CNS: intellectual disability (IQ50), alzheimer’s disease, and hypotonia.
Conductive hearing loss
Cardiac defects AVSD
GI: duodenal atresia, imperforate anus
Short stature
Facies: Flat facial profile, macroglossia, epicanthal folds, small ears
Short broad fingers, clinodactyly, single palmar crease
Excessive neck skin
Joint laxity.
How can trisomy 21 be diagnosed prenatally?
Main techniques used are:
Prenatal diagnosis based on maternal age (amniocentesis/CVS)
Combined first trimester screening (80 - 90% detection rate)
Second trimester screening (60 - 70% detection rate)
Non-invasive prenatal testing (99.5% detection rate)
When does combined first trimester screening take place? How is it done?
11.3 - 14 weeks gestation
Ultrasound is taken (nuchal translucency)
Maternal biochemistry: Free betaHCG, PAPP-A
What is the sensitivity of combined first trimester screening?
80 - 90%
How is non-invasive prenatal testing able to be used for detection of disease?
Uses circulating cell free DNA with massively parallel sequencing/SNP array/microarray.
Very effective test with a sensitivity of 99.5% and PPV of 80 - 90%
What can non-invasive prenatal testing be used for?
Foetal gender in X-linked conditions.
Foetal rhesus typing
Chromosomal/genetic screening (trisomy 21, 13, 18)
Sex chromosome aneuploidy
Microdeletion/microduplication syndromes.
Some single gene disorders.
How common is trisomy 18?
1/ 5000 incidence
30 cases per year in WA
What other extra chromosome conditions are there?
Trisomy 18 (Edwards syndrome; dangerous for women during pregnancy)
trisomy 13 (Patau’s syndrome; severe and lethal results in alobar prosencephaly)
Monosomy X (Results in short stature, early loss of ovarian function, webbed neck, lymphedema, cardiac abnormalities, and renal abnormalities)
What kind of defects can be found in the heart?
Commonest is Ventricular Septal Defect (VSD) (50% of cases)
Complex cardiac anomalires are less common but more important in terms of morbidity (TGA, TOF, HLHS)
How common are cardiovascular birth defects and how are they identified?
8 - 9/1000 births
Ultrasound is primary technique for identifying cardiac defects prenatally. Sensitivity varies widely.
What is hypoplastic left heart syndrome?
Whole left ventricle, mitral valve and aorta are underdeveloped resulting in neurodevelopmental delay.
How common is hypoplastic left heart syndrome?
90% of HLHS cases are isolated defects
Incidence is 0.2/1000 live births (8-9 / year in WA)
What is tetralogy of Fallot? How common is it?
Underdeveloped right and left side of the heart.
Occurs in 0.3/1000 live births.
What is transposition of the great arteries? How common is it?
Pulmonary artery and aorta are swapped and go to the wrong place.
Incidence 0.5/1000 live births
How are drugs used differently during pregnancy?
Medicines are subcategorized into B, C and D categories.
Category A drugs have been taken by a large number of pregnant women and women of childbearing age without proven increase in frequency of malformations or other direct/indirect harmful effects on the foetus.
Category B drugs: Taken only by a limited number of pregnant women of childbearing age with no increase in frequency of malformation.
Category B1 drugs: Animal data shows no evidence of increased foetal damage
Category B2 drugs: Animal data show lacking but available data to show no evidence of foetal damage
Category B3: Animal data shows evidence of increased occurence of foetal damage, the significance of which is considered uncertain in humans. (eg mirtazipine)
Category C: Drugs which owing to their pharmacological effects have caused or may be suspected of causing, harmful effects on the human foetus or neonate. These effects may be reversible. (eg metformin, naproxine)
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. (eg ramipril, azathioprine)
Category X: Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used. (eg methotrexate, thalidomide, etc)
However, data is lacking in humans. Animal studies are used for most studies.
Medicines in category D are not absolutely contraindicated in pregnancy
