DOHAD

Question 1

What is a birth defect defined as?

Answer 1

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.

Question 2

What structural developmental anomalies can affect young foetuses?

Answer 2

Spina bifida

Congenital cardiac defects

Congenital dislocation of the hips

Question 3

What functional developmental anomalies can affect young foetuses?

Answer 3

Cystic fibrosis

Haemophilia

Question 4

What is the incidence of developmental anomalies in WA?

Answer 4

5% (1:20)

Question 5

What is the job of the WARDA?

Answer 5

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.

Question 6

What are birth defects associated with?

Answer 6

Major cause of death.

Birth defect is present in 12.4% of still births and 28.9% of neonatal deaths.

Question 7

Who are birth defects more common in?

Answer 7

Males and multiple pregnancies.

Question 8

What are WARDAs diagnostic categories of birth defects? Which is most common?

Answer 8

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

Question 9

What are the most common nervous system defects?

Answer 9

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)

Question 10

How does the neural tube close? What happens if there is a failure in this?

Answer 10

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.

Question 11

How are neural tube defects detected early on?

Answer 11

They can be seen via ultrasound.

Question 12

What are the risk factors for neural tube defects?

Answer 12

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)

Question 13

What is folate important for?

Answer 13

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

Question 14

What happens in folate deficiency?

Answer 14

Accumulation of homocysteine which results in associated cardiovascular disease risk.

Question 15

How can folate and neural tube defects be prevented?

Answer 15

MTHFR gene mutation affects 8 - 35% of the population depending on ethnicity.

Reduced folate carrier gene (RFC1)

Question 16

How does genetic influence folate metabolism?

Answer 16

Several gene polymorphisms affect folate metabolism.

These are associated with reduced folate absorption and therefore increased folate needs

Question 17

How are folate related issues prevented during pregnancy?

Answer 17

Periconceptional folic acid is administered because it reduces the prevalence of NTD.

Question 18

How much periconceptional folic acid is given to women daily?

Answer 18

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

Question 19

What alternative to folic acid supplementation has been proposed?

Answer 19

5-methyl-tetrahydrofolate

Question 20

What risk factor is most commonly associated with chromosomal defects?

Answer 20

Age of the mother

Question 21

How common is trisomy 21?

Answer 21

3.2/1000 in WA (100/year)

It accounts for 50% of chromosomal abnormalities.

Question 22

What causes trisomy 21?

Answer 22

Non-disjunction (95% of cases)

Unbalanced translocation (4%)

Mosaicism (1%)

Question 23

What are the phenotypic features of trisomy 21?

Answer 23

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.

Question 24

How can trisomy 21 be diagnosed prenatally?

Answer 24

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)

Question 25

When does combined first trimester screening take place? How is it done?

Answer 25

11.3 - 14 weeks gestation

Ultrasound is taken (nuchal translucency)

Maternal biochemistry: Free betaHCG, PAPP-A

Question 26

What is the sensitivity of combined first trimester screening?

Answer 26

80 - 90%

Question 27

How is non-invasive prenatal testing able to be used for detection of disease?

Answer 27

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%

Question 28

What can non-invasive prenatal testing be used for?

Answer 28

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.

Question 29

How common is trisomy 18?

Answer 29

1/ 5000 incidence

30 cases per year in WA

Question 30

What other extra chromosome conditions are there?

Answer 30

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)

Question 31

What kind of defects can be found in the heart?

Answer 31

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)

Question 32

How common are cardiovascular birth defects and how are they identified?

Answer 32

8 - 9/1000 births

Ultrasound is primary technique for identifying cardiac defects prenatally. Sensitivity varies widely.

Question 33

What is hypoplastic left heart syndrome?

Answer 33

Whole left ventricle, mitral valve and aorta are underdeveloped resulting in neurodevelopmental delay.

Question 34

How common is hypoplastic left heart syndrome?

Answer 34

90% of HLHS cases are isolated defects

Incidence is 0.2/1000 live births (8-9 / year in WA)

Question 35

What is tetralogy of Fallot? How common is it?

Answer 35

Underdeveloped right and left side of the heart.

Occurs in 0.3/1000 live births.

Question 36

What is transposition of the great arteries? How common is it?

Answer 36

Pulmonary artery and aorta are swapped and go to the wrong place.

Incidence 0.5/1000 live births

Question 37

How are drugs used differently during pregnancy?

Answer 37

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