Birth Defects Flashcards
Birth defects - Statistics
Birth defects are the leading cause of death outside of prematurity in the first year of life
5-7% overall prevalence
2% of infants are born with potentially life-threatening defects
Developmental fields
Tissues sharing gene expression - i.e. hedgehog signaling pathways
Tissues related to each other through location - i.e. branchial arches
Tissues sharing developmental timing - i.e. embryonic inner cell mass
Tissues affected by interacting processes
VACTERL
Birth defects associating with each other more frequently than be accounted for by chance alone
Vertebral anomalies Anal atresia Cardiac anomalies (primarily septal defects) Tracheo-esophageal fistula / atresia Renal anomalies Limb anomalies
Phenocopy
Similar abnormal phenotypes resulting from predominantly genetic or predominantly environmental factors
Ex: Tetrology of Fallot
Tetrology of Fallot - Clinical syndrome
Pulmonary artery stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy
Causes of Tetrology of Fallot
Genetic - deletions on chromosome 22
Environmental - Accutane exposure
Common teratogens (5)
Thalidomide Vitamin A analogues (Accutane) Statins Anticonvulsants Ethyl alcohol
Fetal Alcohol Syndrome - Presentation
Growth retardation
Dysmorphic features
Cognitive deficiencies
Where are particularly high rates of NTDs seen?
Western England and Northern Ireland
Population-based screening exists for which 2 common birth defects?
Down Syndrome
NTDs
Targeted screening exists for which 2 clustered disorders?
Tay Sachs
Cystic Fibrosis
Down Syndrome - Maternal Serum Analytes
Low AFP, uE3, and PAPP-A
high hCG and Inhibin
Cell-free fetal DNA testing
Fetal DNA fragments enter maternal circulation with increasing gestational age; levels are sufficiently high to be used for chromosomal trisomy screening > 9 weeks
At what point can a developing embryo be visualized by US?
6 weeks
Indications for ultrasound
Advanced maternal age (> 35)
Positive aneuploidy screening test
Abnormal ultrasound findings (anatomic, IUGR, amniotic fluid volume)
Known parental chromosomal rearrangements
Previously affected child
Amniocentesis
Performed under ultrasound guidance between 14-20 weeks
0.5% increased risk of fetal loss
Allows access to fetal cells for DNA analysis (FISH, karyotype, etc.) and amniotic fluid (biochemical analysis)
Chorionic villous sampling
Performed under US guidance between 9.5 - 12.5 weeks gestation
Risk of fetal loss is 0.5-1% higher than amniocentesis (1-1.5% absolute risk increase)
Percutaneous umbilical cord blood sampling (PUBS)
Highly invasive - complication rate is 1-2%
Usually reserved for diagnosis of fetal infections / anemia in severely compromised pregnancies
Tay Sachs
AR deficiency of Hexosaminidase A causing accumulation of gangliosides in the CNS; presents with blindness, severe neurologic disease, and death by age 6
Diagnosed in at-risk pregnancies by fetal DNA extraction from amniocentesis or CVS; molecular DNA testing detects 94% of heterozygotes
Thalassemia - Diagnosis
Fetal MCV < 80% with exclusion of iron deficiency anemia
Hb electrophoresis showing elevated HbA2 and HbF confirms B-talassemia
DNA-based testing necessary to detect a-globin deletions in alpha-thalassemia
Sickle Cell Disease - Diagnosis
Fetal MCV < 80% with exclusion of iron deficiency anemia
Confirmed by Hb electrophoresis
Cystic Fibrosis - Approach to diagnosis
Screening is offered to all pregnant women; if woman tests positive, screening is offered to partner; if both test positive, amniocentesis or CVS is done to test for CF gene
Cystic Fibrosis - Diagnostic assay
Pan-ethnic mutation panel using 23 mutant CF alleles with a frequency of > 0.1% in the general population
Cystic Fibrosis - Most common mutation
DF508 - results in loss of phenylalanine
Responsible for 75% of CF disease in non-Ashkenazi whites of European descent; screening solely for this mutation identifies 50% of couples at-risk for CF offspring
Estimation of gestational age and fetal weight
First trimester - Crown-rump length (CRL) estimates gestational age
> 12 weeks:
Bi-parietal diameter
Abdominal circumference
Femur length
Down Syndrome - Genetics
95% due to trisomy 21 due to non-dysfunction in the oocyte during meiosis 1; these cases are related to maternal age
5% due to genetic mosaicism and translocations (14;21)
Down Syndrome - Epidemiology
Most common genetic cause of intellectual disability
US prevalence is 1/800 live births
Only 25% of fetuses survive to term
Fetal nuchal thickness
Measured between 10-14 weeks gestation by US; interpreted as multiples of the median based on crown-rump length
65-85% of Down Syndrome fetuses have increased nuchal thickness
Maternal serum analytes - NTD
Elevated AFP with elevated AChE by amniocentesis
Unconjugated estriol (uE3)
The substrate of estriol production is DHEA-S from the fetal adrenal gland, which is converted by the placenta to estriol, which enters maternal circulation
uE3 is low in Trisomy 21
