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Goal
Provide informed reproductive choice and optimal medical care It is achieved by: (i) Assessment of risk, (ii)Transfer of information to the patient, (iii)Guidance and Assistance with the testing process
Prenatal Diagnosis
Why screen? Who to screen? How to screen? When to screen? When and how to do invasive testing What is the societal impact?
Down Syndrome
80% of invasive diagnosis are in women of Advanced Maternal Age ( i.e. > 35 years) but 70% of T-21 occurs in women < 35 years In India women are delaying childbirth in middle to high class society. 7.5% AMA in USA, 15% in Switzerland and Britain
Sensitivity approaches : 100% Specificity approaches : 100% Low false positives High likely hood ratios Minimal invasive diagnosis / high abnormal rate
Sensitivity
: the % of affected with the feature Specificity : the % of normal who are normal False positive : the % of tests with a normal outcome False negative : the % of tests with an abnormal outcome
Likelihood ratio
Sensitivity / False positive rate : - comparison of positive test in affected individuals to positive tests in normal individuals
Risk factors ( i.e. age, ethnic gp, history, etc) Morphology : ultrasound Analytes : PAPP-A, hcG, AFP, inhibin, estriol Combinations Fetal cells
Either deferred to 2nd Trimester or CVS based on maternal age / history 1st Trimester amniocentesis abandoned as unsafe
U/S measurement of nuchal lucency + nasal bone Maternal Analyte screen (PAPP-A1, free beta-hcG, inhibin) Age specific anatomic survey Invasive testing based on specific risk profile
Estimates for the rate of Spontaneous Loss in Fetuses with Various Chromosomal Defects
Estimated Loss Rate Chromosomal Defects Trisomy 21 From 12 wks to 40 wks 32% From 16 wks to 40 wks 20%
Trisomy 18
Trisomy 13 47, XXX or XXY or XYY Triploidy
85%
80% ~5% >99%
75%
70%
50%
~3% >99%
The higher the NT, the higher the risk for trisomies The higher the maternal serum hCG , the higher the risk for Trisomy 21 The lower the maternal serum PAPP-A, the higher is the risk for Trisomy 21
Nuchal Translucency
Prediction of Trisomy 21
Detection Rate
Maternal Age
Maternal serum free hCG
11
10
31%
28%
28
15
78%
42%
28
32
78%
86%
Comparison of detection rates for Trisomy 21, for a false positive rate of 5%, by maternal age, maternal serum free hCG, fetal NT and by a combination of parameters, in a prospective study, involving 5,434 pregnancies
Successful # of T-21
Sensitivity Specificity
29
41% 100%
*Cicero et al Ultrasound Obstet Gynecol 22:31-5, 2003 **Virtzilieos et al Obstet Gynecol, 101:905-8, 2003
Cardiac defects, Diaphragmatic hernia, Skeletal Dysplasias Risk increases with increasing NT 65% of fetal cardiac defects have NT >95th percentile and 40% greater than 99th percentile Fetal echocardiogram recommended for NT >99th percentile
Current Status
Test accuracy parameters vary by operator experience and adherence to protocol 85% detection of T-21 is normal Analyte assay access more wide spread Automated rapid (office) analyte assay and computer derived risk analysis available The test is becoming routine
Total Fetal Loss Rate in Four Randomized Studies Comparing First trimester Chorionic Villus Sampling with Second Trimester Amniocentesis
Study Canadian Danish Finnish European CVS 7.6% 6.3% 6.3% 14% Amniocentesis 7.1% 7.0% 6.4% 9.0%
1 in 100 procedures
U/S characteristics of specific aneuploidies Maternal serum analyte profile (AFP, hCG, Estriol, inhibin A) Maternal age (Age of Ova Provider) Genetic History
Low AFP and Aneuploidy first described by Merkatz et al (AJOB / GYN 148:886, 1984) 2nd Trimester analyte screening (triple or quad screening) now routine and recommended Specific analyte pattern for specific karyotypic and non-karyotypic abnormalities
Obtain sample 15 20 weeks If Down Syndrome Risk > 1 / 190: Do USG for dating If Dates incorrect (9 or more days different from LMP): Recalculate risk based on BPD or repeat Test after 15 weeks If Dates are correct (within 8 days of LMP): Offer amniocentesis or other invasive procedure for fetal Karyotype
Sensitivity varies with age: from 67% (<35 yrs) to 87% (>35 yrs) Adding inhibin A (quad Screen) increases sensitivity to 70% in age <35 years Urine Analyte measures: Hyperglycosylate hCG, urine beta-core hCG are promising but not yet clinically useful
Increased AFP
Anomaly All open Neural Tube Defects All open peritoneal Defects All exudative anomalies Some renal Diseases (nephrosis) Twins Fetal Death U/S Diagnosis 100% 100% >50% 50% 100% 100%
Unexplained high AFP associated with at least a 10X increase in placental disease and fetal consequence Unexplained high hCG associated with modest increase in placental disease Unexplained low serum estriol associated with placental sulfatase deficiency (5% MR), Smith-Hemli-Opitz Syndrome, Congenital Adrenal Hypoplasia, Adrenocorticotrophic Deficiency, Hypothalamic defect, Anencephaly
Echogenic Bowel Mild Hydronephrosis Short Femur / Humerus Sandal Toe Clinodactyly
Ultrasound Criteria and Likelihood Ratios Assigned for Detection of Trisomy 21 U/S Findings Criteria Likelihood ratio
25
Structural Defect
Cardiac defect, cystic hygroma with or without hydrops, cerebral ventricular dilatation >5mm AP
18.6
Present or Absent
>3mm AP None of the Above
2
1.6 0.4
Snijders RJM, Nicolaides KH Ultrasound markers for fetal chromosomal defects. 1996; Parthenon Publishing, London
Trisomy 18
Strawberry Skull Choroid plexus Cysts Absent Corpus Callosum Large Cysterna Magna Facial cleft Micrognathia Heart defects (VSD) Diaphragmatic hernia
Esophageal Atresia Omphalocele Renal defects Myelomeningocele IUGR Radial aplasia Overlapping fingers Talipes / Rocker bottom feet
Percentage
46% 39%
Cardiac Abnormalities
CNS abnormalities Diaphragmatic hernia Ventral wall defect Facial Abnormality
31%
29% 13% 10% 7%
90%
Trisomy 13
Holoprosencephaly Facial Clefts Microcephaly Cardiac Defects Echogenic kidneys Post Axial polydactyly (USG identifies nearly 100% of the above anomalies)
75% cases end in fetal death Cystic Hygroma Non-Immune Hydrops Cardiac Anomalies Non-lethal type has no markers (Normal intellect with short stature + infertility)
Third Trimester
All anomalies discussed in 2nd trimester when missed Some Fetal Anomalies progressively worsens with gestational age: (i) Ebsteins Anomaly (ii) Chylothorax (iii) PUJ Obstruction Upper GI obstruction: (i)Esophageal Atresia (ii) Cong Diaphragmatic hernia (iii) Impaired Fetal Swallowing from Neurological causes