Prenatal Screening

• Prenatal screening, diagnosis, and treatment

  Relatively new field within obstetrics, tied to advent and advancement of real-time ultrasound imaging and new genetic testing
• Prenatal genetic diagnoses


  Increasingly available as association between genes, chromosomal aberrations, and phenotypes are discovered
• Screening


  Allows high-risk individuals to be selected out of a low-risk population at risk for a given diagnosis or complication
• Diagnostic tests


  Nearly always more specific than screening, but bear greater risk of complications like pregnancy loss
• Noninvasive prenatal diagnosis


  Recently developed screening tool that may maximize sensitivity and minimize false positives, but is not currently a diagnostic test
• Autosomal dominant (AD) diseases


  • Usually inherited from one parent with the disease via a single gene defect, risk of disease and recurrence is usually 50%
• Autosomal recessive (AR) diseases

  • Require two affected alleles, if both parents are carriers the risk to the child is 25%
• 1. linked disorders


  • Usually carried by the mother who is unaffected (in X-linked recessive) or mildly affected (X-linked dominant), passed only to sons, sons affected 50% of the time, daughters unaffected or mildly affected carriers 50% of the time
• 1. chromosome lyonization


  Causes phenotypic variation, especially in females
• Cystic fibrosis (CF)


  AR disease resulting from abnormality in CFTR gene, causes chronic lung disease, pancreatic insufficiency, median survival close to 40 years
• Sickle cell anemia


  AR disease caused by single point mutation in beta chain of hemoglobin, results in hemolytic anemia, shortened life expectancy, frequent pain crises
• Tay-Sachs disease


  AR disease most common in Ashkenazi Jews, caused by deficiency of hexosaminidase A enzyme, results in progressive neurological degeneration and death by age 4
• Thalassemias


  Hereditary hemolytic anemias caused by mutations reducing synthesis of alpha or beta chains of hemoglobin, leading to imbalance in globin chain synthesis
• Chromosomal abnormalities


  Genetic disorders caused by aneuploidy (extra or missing chromosome(s)), often accompanied by phenotypic differences and congenital anomalies
• First-trimester screening


  Includes nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), and beta-hCG
• Second-trimester screening (quadruple screen)


  Includes MSAFP, estriol, beta-hCG, and inhibin
• Noninvasive prenatal diagnosis


  Examines cell-free fetal DNA in maternal serum, highly sensitive and specific in high-risk women but has limitations
• Prenatal screening options


  • First-trimester screening at 11 to 14 weeks
  • Second-trimester screening
  • Sequential screening (combination of first and second trimester)
• Components of first-trimester screening

  • Nuchal translucency
  • Pregnancy-associated plasma protein A (PAPP-A)
  • B-hCG
• Components of second-trimester screening (quadruple or quad screen)

  • MSAFP
  • Estriol
  • B-hCG
  • Inhibin
• Noninvasive prenatal diagnosis


  Examining cell-free fetal DNA in maternal serum
• Noninvasive prenatal diagnosis tests are highly sensitive and specific in women at high risk for having a fetus with aneuploidy, but have limitations (e.g., not applicable in twins, chromosomal mosaicism, etc.) and do not currently assess all chromosomes as one can do with a karyotype
• Most chromosomal aneuploidies result in early miscarriage, but some infants are occasionally born with them and can survive for up to 1 year
• Triploidy (three sets of chromosomes) usually results in miscarriage or gestational trophoblastic disease
• Down syndrome


  Caused by trisomy 21 (an extra chromosome 21)
• Down syndrome


  • Higher rates of miscarriage and stillbirth
  • Short stature, classic facies, developmental delay, mental retardation (IQ 40-90)
  • Associated anomalies include cardiac defects, duodenal atresia/stenosis, short limbs
• Screening tests for Down syndrome

  • First-trimester screen (nuchal translucency, PAPP-A, hCG)
  • Quad screen (MSAFP, hCG, estriol, inhibin A)
• Sensitivity of quad screen alone for Down syndrome

  Just over 80%
• Noninvasive prenatal diagnostic tests for trisomy 21 have shown sensitivity and specificity both in the 98-99% range or better
• Trisomy 18 (Edward syndrome)


  Another common trisomy that can be screened for using first and second trimester screening, with a sensitivity approaching 90% in women who choose sequential screening
• Trisomy 18


  • Lethal aneuploidy, nearly all neonates die in the first 2 years of life
  • Associated with multiple congenital anomalies typically seen on ultrasound (in ~95% of cases)
  • Classically associated with clenched fists, overlapping digits, rocker bottom feet, cardiac defects, omphalocele, congenital diaphragmatic hernia, neural tube defects, choroid plexus cysts
• Noninvasive prenatal diagnostic tests for trisomy 18 have shown sensitivity greater than 97% at a much lower screen positive rate (0.3%) in high-risk populations
• Trisomy 13 (Patau syndrome)


  • Similar findings to trisomy 18, 85% of newborns do not live past 1 year
  • Commonly associated anomalies include holoprosencephaly, cleft lip/palate, cystic hygroma, single nostril/absent nose, omphalocele, cardiac anomalies, limb anomalies
• Serum analytes of first trimester and quad screen are variable in trisomy 13 pregnancies, making it a poor screening test
• Trisomy 13 fetuses would rarely not have anomalies visible on ultrasound
• Noninvasive prenatal diagnostic tests are being augmented to identify trisomy 13 as well
• Turner syndrome (45,X)


  Phenotypically female, short stature, primary amenorrhea, sexual infantilism, webbed neck, low-set ears, low posterior hairline, epicanthal folds, wide carrying angle of the arms, shield-like chest, wide-set nipples, short fourth metacarpal, renal anomalies, lymphedema, cardiovascular anomalies
• No screening test currently available for Turner syndrome
• Klinefelter syndrome (47,XXY)


  • Testicular development initially normal, but germ cells die in meiosis leading to small, firm testes and hyalinization of seminiferous tubules
  • Also associated with infertility, gynecomastia, mental retardation, elevated gonadotropin levels
• No screening test currently available for Klinefelter syndrome